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Volume 8 · Number 2 · March 2009

NephSAP

Nephrology Self-Assessment Program

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Fluid, Electrolytes, and Acid-Base Disturbances

Co-Editors: Biff F. Palmer, MD, and Richard H. Sterns, MD

Editor-in-Chief: Stanley Goldfarb, MD Deputy Editor: Jeffrey S. Berns, MD

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NephSAP

EDITOR-IN-CHIEF

Stanley Goldfarb, MD

University of Pennsylvania Medical School Philadelphia, PA

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Preface

NephSAP® is one of the three major publications of the American Society of Nephrology (ASN). Its primary goals are self-assessment, education, and the provision of Continuing Medical Education (CME) credits and Maintenance of Certification (MOC) credits for individuals certified by the American Board of Internal Medicine. Members of the ASN automatically receive NephSAP with their monthly issue of The Journal of the American Society of Nephrology (JASN). EDUCATION: Medical and Nephrologic information continually accrues at a rapid pace. Bombarded from all sides with demands on their time, busy practitioners, academicians, and trainees at all levels are increasingly challenged to review and understand all this new material. Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specific area of clinical nephrology, hypertension, dialysis, and transplantation, and consists of an Editorial, a Syllabus, a Commentary on the Syllabus, and self-assessment questions. Over the course of 24 months, all clinically relevant and key elements of nephrology will be reviewed and updated. The authors of each issue digest, assimilate, and interpret key publications from the previous issues of other years and integrate this new material with the body of existing information. SELF-ASSESSMENT: Twenty-five single-best-answer questions will follow the 50 to 75 pages of Syllabus text. The examination is available online with immediate feedback. Those answering 75% correctly will receive CME credit, and receive the answers to all the questions along with brief discussions and an updated bibliography. To help answer the questions, readers may go to the ASN web site, where relevant material from UpToDate in nephrology will be posted. Thus, members will find a new area reviewed every 2 months, and they will be able to test their understanding with our quiz. This format will help readers stay abreast of developing areas of clinical nephrology, hypertension, dialysis, and transplantation, and the review and update will support those taking certification and recertification examinations. CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well as hospitals are demanding documentation of requisite CME credits for licensure and for staff appointments. A maximum of 36 credits annually can be obtained by successfully completing the NephSAP examination. In addition, individuals certified by the American Board of Internal Medicine may obtain credits towards Maintenance of Certification (MOC) by successfully completing the self-assessment portion of NephSAP. BOARD CERTIFICATION AND INSERVICE EXAMINATION PREPARATION: Each issue will also contain 5 questions and answers examining core topics in the particular discipline reviewed in the Syllabus. These questions are designed to provide trainees with challenging questions to test their knowledge of key areas of nephrology. This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper), effective with July 2002, Vol. 1, No. 1.

DEPUTY EDITOR

Jeffrey S. Berns, MD

University of Pennsylvania Medical School Philadelphia, PA

MANAGING EDITOR

Gisela Deuter, BSN, MSA

Washington, DC

ASSOCIATE EDITORS

Rajiv Agarwal, MD

Indiana University School of Medicine Indianapolis, IN

David J. Cohen, MD

Columbia University New York, NY

Steven Fishbane, MD

Stony Brook School of Medicine Minneola, NY

Richard J. Glassock, MD

Professor Emeritus, The David Geffen School of Medicine at the University of California Los Angeles, CA

Kevin J. Martin, MBBCh

St. Louis University School of Medicine St. Louis, MO

Rajnish Mehrotra, MD

Harbor UCLA Research and Education Institute Torrance, CA

Patrick T. Murray, MD

University College Dublin Dublin, Ireland

Patrick H. Nachman, MD

University of North Carolina Chapel Hill, NC

Paul M. Palevsky, MD

University of Pittsburgh School of Medicine Pittsburgh, PA

Biff F. Palmer, MD

University of Texas Southwestern Medical Center Dallas, TX

Richard H. Sterns, MD

University of Rochester School of Medicine and Dentistry Rochester, NY

Stephen C. Textor, MD

Mayo Clinic Rochester, MN

FOUNDING EDITORS

Richard J. Glassock, MD, MACP Editor-in-Chief Emeritus Robert G. Narins, MD, MACP

Raymond R. Townsend, MD

University of Pennsylvania Medical School Philadelphia, PA

John P. Vella, MD

Maine Medical Center Portland, ME

NephSAP® (Print: 1536-836X; Online: 1934-3175) ©2009 by The American Society of Nephrology

NephSAP

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Volume 8, Number 2, March 2009

Fluid, Electrolytes, and Acid-Base Disturbances

Editorial

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SGK1 in the Regulation of Renal Function and in the Pathogenesis of Salt-Sensitive Hypertension--Florian Lang, MD, Ferruh Artunc, MD, Teresa F. Ackermann, Daniela S. Kempe, MD, Krishna M. Boini, PhD, and Volker Vallon, MD

Commentary

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Fluid, Electrolyte, and Acid-Base Disorders--Tomas Berl, MD

Syllabus

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Fluid, Electrolyte, and Acid-Base Disturbances--Biff F. Palmer, MD and Richard H. Sterns, MD Potassium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70 New Physiologic Concepts . . . . . . . . . . . . . . . . . . . . . . . . .70 Hypokalemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73 Approach to the Patient with Hypokalemia . . . . . . . . . . . .73 Cellular Redistribution . . . . . . . . . . . . . . . . . . . . . . . . . . . .73 Extrarenal K Loss from the Body . . . . . . . . . . . . . . . . . .76 Renal K Wasting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77 Primary Increase in Mineralocorticoid Activity . . . . . . .78 Increased Renin, Increased Aldosterone . . . . . . . . . . . . .78 Suppressed Renin, Increased Aldosterone . . . . . . . . . . . .78 Suppressed Renin and Aldosterone . . . . . . . . . . . . . . . . .79 Primary Increase in Distal Na Delivery . . . . . . . . . . . . . .82 Complications and Treatment of Hypokalemia . . . . . . . . .84

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Volume 8, Number 2, March 2009

Hyperkalemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88 Pseudohyperkalemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .89 Clinical Manifestation of Hyperkalemia . . . . . . . . . . . . . . .89 Excessive K Loads: Exogenous or Endogenous . . . . . . .90 Cell Shift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92 Decreased Renal Excretion of K . . . . . . . . . . . . . . . . . . .93

Primary Decrease in Mineralocorticoid Levels or Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .93 Primary Decrease in Distal Delivery (Acute and Chronic Renal Failure) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .94 Distal Tubular Defects . . . . . . . . . . . . . . . . . . . . . . . . . . .94 Acid Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98 Metabolic Alkalosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98 Exogenous Addition of Base . . . . . . . . . . . . . . . . . . . . . .99 Gastrointestinal Acid Loss . . . . . . . . . . . . . . . . . . . . . . . .99 Renal Acid Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100 Primary Increase in Distal Na Delivery . . . . . . . . . . . . .100 Acetazolamide in Metabolic Alkalosis Treatment . . . . . .102 Metabolic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103 New Physiologic Insights . . . . . . . . . . . . . . . . . . . . . . . . .103 Clinical Approach to Metabolic Acidosis . . . . . . . . . . . . . .105 Lactic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .106 Diabetic Ketoacidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . .107 Starvation Ketosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109 Alcoholic Ketoacidosis . . . . . . . . . . . . . . . . . . . . . . . . . . .109 Ethylene Glycol and Methanol Poisoning . . . . . . . . . . . .109 Pyroglutamic Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . .110 Normal (Hyperchloremic) Anion Gap Acidosis . . . . . . . .110

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Extrarenal Causes of Normal (Hyperchloremic) Anion Gap Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110 Renal Causes of Normal (Hyperchloremic) Anion Gap Acidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .110 Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .114 Isotonic and Hypertonic Hyponatremia . . . . . . . . . . . . . .114 Pseudohyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . .115 Solute-Induced Nonhypotonic Hyponatremia . . . . . . . . . .116 Hypotonic Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . .117 Brain Responses to Hyponatremia . . . . . . . . . . . . . . . . . .117 Brain Responses to Correction of Hyponatremia: Osmotic Demyelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119 Acute Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .121 Exercise-Associated Hyponatremia . . . . . . . . . . . . . . . . . .122 Self-Induced Water Intoxication in Psychosis . . . . . . . . .124 Postoperative Hyponatremia . . . . . . . . . . . . . . . . . . . . . . .125 Chronic Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 Differential Diagnosis of Chronic Hyponatremia . . . . . .127 SIAD versus Cerebral Salt Wasting . . . . . . . . . . . . . . . . .128 Symptoms of Chronic Hyponatremia . . . . . . . . . . . . . . . .129 Beer Potomania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130 Drug-Induced Hyponatremia . . . . . . . . . . . . . . . . . . . . . . .131 Tumor-Associated Hyponatremia . . . . . . . . . . . . . . . . . . .132 Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .132 Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . .133 Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134 Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . .134 Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134

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Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .135 Treatment Options for Hypotonic Hyponatremia . . . . . . .136 Treatment Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .136 Water Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .137 Hypertonic Saline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .137 Vasopressin Receptor Antagonists . . . . . . . . . . . . . . . . .138 Desmopressin for Overcorrection. . . . . . . . . . . . . . . . . .139 Hypernatremia and Diabetes Insipidus . . . . . . . . . . . . . . . . .142 Basic Mechanisms of Osmoregulation . . . . . . . . . . . . . . .142 Age-Related Hypodipsia . . . . . . . . . . . . . . . . . . . . . . . . . .144 Renal Concentrating Mechanism . . . . . . . . . . . . . . . . . . .144 Hypernatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .145 Therapeutic Hypernatremia . . . . . . . . . . . . . . . . . . . . . . . .146 Diabetes Insipidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Central DI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Adipsic DI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .148 Acquired Nephrogenic DI . . . . . . . . . . . . . . . . . . . . . . . . .149 Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .149 Hypercalcemia and Hypercalciuria . . . . . . . . . . . . . . . .150 Congenital Nephrogenic DI . . . . . . . . . . . . . . . . . . . . . .150 Nocturnal Enuresis and Nocturnal Polyuria . . . . . . . . .151

CME Self-Assessment Questions . . . . . . . . . . . . . . . . . . . . . 154

Questions Linked to UpToDate in Green

Core Knowledge Questions. . . . . . . . . . . . . . . . . . . . . . . . . . 164 Upcoming Issues

Acute Kidney Injury and Critical Care Nephrology-- Paul M. Palevsky, MD, and Patrick T. Murray, MD . . . . . . . .May 2009

NephSAP

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Volume 8, Number 2, March 2009

Interventional Nephrology--

Arif Asif, MD, and Anil Agarwal, MD

. . . . . . . . . . . . . . . . . .July 2009 . . . . .September 2009

Chronic Kidney Disease and Progression--

Jeffrey S. Berns, MD, and Steven Fishbane, MD .

Transplantation--

John P. Vella, MD, and David J. Cohen, MD.

. . . . . . .November 2009

Primary Care for the Nephrologist-- Denise M. Dupras, MD, PhD . . . . . . . . . . . . . . . . . . . . .January 2010

NephSAP

Commercial Support:

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Volume 8, Number 2, March 2009

Disclosure of Unapproved or Off-Label Usage:

This educational activity may contain discussion of published and/or investigational uses of agents that are not currently labeled for use by the US Food and Drug Administration (FDA). The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigation uses. The American Society of Nephrology does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.

There is no commercial support for this issue.

Nephrology Self-Assessment Program - Vol 8, No 2, March 2009

Editorial

SGK1 in the Regulation of Renal Function and in the Pathogenesis of Salt-Sensitive Hypertension

Florian Lang, MD* Ferruh Artunc, MD Teresa F. Ackermann,* Daniela S. Kempe, MD* Krishna M. Boini, PhD* and Volker Vallon, MD Departments of *Physiology and Nephrology, University of Tubingen, Tubingen, Germany; ¨ ¨ and Departments of Medicine and Pharmacology, University of California, San Diego, and Veterans Affairs San Diego Healthcare System, San Diego, California

In the past several years, new information has emerged on the complex regulatory network that governs renal control of electrolyte and water balance. In addition to the molecular and atomic specificity of various channel proteins, signaling pathways have emerged centering on enzymatic mechanisms of protein phosphorylation well beyond the familiar G-protein cAMP system. The following brief review highlights some recent literature that is beginning to form the view that one particular enzyme system, the serum- and glucocorticoid-inducible kinase 1 (SGK1), is a central regulator of a myriad of renal functions and electrolyte balance. It may play a central role in the hypertension associated with the metabolic syndrome through its key role in regulating the sodium retention associated with high insulin levels. SGK1 serves a wide variety of functions, including stimulation of renal ion channels, carriers, and the Na / K -ATPase, and is emerging as an important factor in the regulation of renal Na retention and K elimination. In addition, it has been shown in a variety of animal models to regulate mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of the Na /H exchanger and nutrient transport, insulin-dependent salt sensitivity of BP, salt sensitivity of peripheral glucose uptake, and renal and cardiac fibrosis attributed to mineralocorticoid hormones and salt excess. A common SGK1 gene variant (3 to 5% prevalence in Caucasian individuals, 10% in African individuals) is associated with obesity, hypertension, and development of diabetes. Owing to space limitation, this editorial cannot cite the many excellent original articles contributing to our current knowledge. Instead, the reader is encouraged to collect pertinent references from previous reviews (1,2).

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SGK1 was originally cloned as an immediate early gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells (3). The human isoform was discovered as a cell volume­ regulated gene, which is upregulated by cell shrinkage (for review, see reference [1]). SGK1 expression is ubiquitous but may vary profoundly among different cells. Within cells, SGK1 may be localized in nuclei, cytosol, or mitochondrial membranes (3).

Regulation of SGK1 Transcription and Activity

SGK1 transcription is affected by a wide variety of hormones, cytokines, medications, and clinical conditions such as glucocorticoids, mineralocorticoids, 1,25dihydroxyvitamin D3 [1,25(OH)2D3], TGF- , IL-6, endothelin, peroxisome proliferator­activated receptor (PPAR- ) agonists, hyperglycemia, metabolic acidosis, ischemia, heat shock, and oxidative stress (1,4 ­ 6). SGK1 transcription is inhibited by nucleotides, heparin, and mutations in the MECP2 gene (1,7). Signaling involved in stimulation of SGK1 transcription includes increase of cytosolic Ca2 concentration, protein kinase C and other kinases, cAMP, nitric oxide, and other factors (1,8). The rat SGK1 gene promoter contains several transcription factor­ binding sites, including the glucocorticoid, mineralocorticoid, progesterone, and vitamin D receptors, PPAR- , and others. SGK1 is activated by phosphorylation through a signaling cascade involving phosphatidylinositol-3-kinase, the 3-phosphoinositide­ dependent kinase PDK1, and mammalian target of rapamycin in a cascade and is activated by insulin, IGF-1, and other growth factors and hormones (1) (Figure 1).

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Figure 1. Renal transport systems regulated by SGK1. Transport systems in proximal tubule, thick ascending limb, early distal tubule, and collecting duct, which have been shown either in Xenopus oocytes or in vivo to be regulated by SGK1. Note that SGK1 may be expressed in proximal tubules and thick ascending limbs only under distinct physiologic or pathophysiologic conditions, such as hyperglycemia. Only under those conditions may SGK1 contribute to transport regulation in those nephron segments.

SGK1-Dependent Transport Regulation

As listed in Table 1, SGK1 regulates a wide variety of transport systems. The first channel shown to be regulated by SGK1 was the renal epithelial Na channel (ENAC). Mechanisms implicated in SGK1-dependent regulation of ENaC include (1) direct phosphorylation of ENaC protein (1); (2) phosphorylation of the ubiquitin ligase Nedd4-2, which otherwise ubiquitinates ENaC and thus prepares the channel protein for degradation; SGK1dependent phosphorylation fosters binding of Nedd4-2 to 14-3-3, thereby impeding the interaction of Nedd4-2 with ENaC; (3) phosphorylation of WNK4, a kinase that inhibits ENaC activity (9); (4) inhibition of inducible nitric oxide synthase, thereby blunting the inhibitory effect of nitric oxide on ENaC activity; and (5) stimulation of ENaC transcription (10). The stimulation of ENaC activity by mineralocorticoids is only partially dependent on the presence of SGK1, whereas the stim-

ulation of ENaC by antidiuretic hormone or insulin fully depends on SGK1. The sum of these effects results in increased ENaC at the cell surface and an increase in sodium transport. SGK1 affects the activity of a host of renal transporters; it increases the activity of the Na /K -ATPase, an effect at least partially due to enhanced Na /K ATPase abundance in the cell membrane, enhances abundance in the plasma membrane of the epithelial Ca2 channel TRPV5, and stimulates a variety of K channels (Table 1), including the renal outer medullary K channel ROMK1 (1). SGK1 activates ROMK1 activity by increasing the channel protein abundance in the plasma membrane, and by direct phosphorylation of the channel protein. SGK1 also stimulates a variety of Cl channels (Table 1) including the Cl channel complex ClC-Ka,b/barttin (1,11), the Na /H exchanger NHE3 (12), the Na ,K ,2Cl co-transporter NKCC2, and pre-

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Table 1. Channels, carriers, and pumps known to be regulated by SGK1

Ion channels ENaC ROMK1 TRPV5 ClC-Ka/barrtin ClC2 CFTR SCN5A KCNE1/KCNQ1 KCNQ4 Kv1.3, Kv1.5, and Kv4.3 4F2/LAT GluR6 Carriers and pumps NHE3 NKCC2 NCC SGLT1 GLUT1 and GLUT4 ASCT2 SN1 EAAT1, EAAT2, EAAT3, EAAT4, EAAT5 SMIT NaDC-1 CreaT NaPiIIb Na /K -ATPase Epithelial Na channel Renal outer medullary K channel Renal epithelial Ca2 channel Renal (and stria vascularis) epithelial Cl channel Ubiquitous Cl channel Cystic fibrosis transmembrane conductance regulator Cardiac voltage-gated Na channel Cardiac and epithelial K channels Inner ear K channels Voltage-gated K channels Cation channels created by oxidation of the amino acid transporter complex 4F2/LAT Glutamate receptors (cation channel) Na /H exchanger Na ,K ,2Cl co-transporter Na ,Cl co-transporter Na -coupled glucose co-transporter Facilitative glucose transporters Amino acid transporter Glutamine transporter Glutamate transporters Na , myoinosital cotransporter Na ,dicarboxylate co-transporter Creatine transporter Na -coupled phosphate carrier in intestine Na /K pump

sumably the Na ,Cl co-transporter NCC (13). SGK1 also stimulates several glucose transporters, including the Na -glucose co-transporter SGLT1 and the facilitative glucose transporters GLUT1 and GLUT4 (14), and upregulates a variety of amino acid transporters, the Na ,dicarboxylate co-transporter NaDC-1, and others (1,15­17). As is shown next, defects in the function of SGK1 induced by genetic manipulation produce important defects in sodium conservation when animals are placed on a sodium-restricted diet. Conversely, the SGK1 gene variant noted already may be associated with excess rates of sodium transport and other cellular events leading to pathogenetic disturbances in BP control and glucose metabolism.

SGK1-Dependent Regulation of Salt Appetite and Renal Electrolyte Excretion

Effects on Renal Sodium Regulation

Renal tubular SGK1 expression is most abundant in kidney medulla and distal nephron but may extend to glomeruli, proximal tubules, and thick ascending limb

(1). As indicated already, SGK1 stimulates a variety of renal epithelial ion channels, carriers, and Na /K -ATPase. Thus, SGK1 participates in the regulation of renal Na excretion by aldosterone, insulin, and IGF-1 (1). In addition to the widely known renal transport effects of mineralocorticoids, salt appetite is stimulated by mineralocorticoids, an effect largely dependent on the presence of SGK1 (1). An increase of salt intake typically seen after mineralocorticoid hormone administration is blunted in SGK1-deficient mice (sgk1 / ) as compared with their wild-type littermates (sgk1 / ). sgk1 / mice suffer from subtle impairment of renal salt retention (1,13). Under normal salt intake, arterial BP and salt excretion are similar in sgk1 / and sgk1 / mice, but plasma aldosterone concentrations are significantly higher in sgk1 / mice, pointing to volume depletion in those mice (1). After NaCl-deficient diet, sgk1 / mice waste sodium compared with normal mice despite more profound increase of plasma aldosterone concentration, decrease of arterial BP, decrease of GFR, and enhanced proximal tubular Na reabsorption.

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According to a recent study, the salt loss of sgk1 / mice may at least in part be the result of decreased expression of the Na ,Cl co-transporter protein, whereas, presumably as a result of hyperaldosteronism, under salt-depleted diet, ENaC activity was even enhanced in sgk1 / mice (13). Clearly, upregulation of ENaC by aldosterone does not require the participation of SGK1, and the hypertensive effect of acute hyperaldosteronism is similar in sgk1 / and sgk1 / mice. Conversely, SGK1 deficiency virtually abrogates the antinatriuretic effect of insulin and antidiuretic hormone (i.e., renal Na excretion is lowered after insulin infusion in sgk1 / mice but not sgk1 / mice [1]).

Putative Role of SGK1 in Metabolic Syndrome

Hypertension, obesity, insulin resistance, and type 2 diabetes are typical characteristics of metabolic syndrome, and there has been speculation that excess SGK1 may contribute to development of some features of this syndrome. The influence of SGK1 on salt intake and elimination render the SGK1 gene a candidate for the development of hypertension. A distinct SGK1 gene variant (combined polymorphisms in intron 6 [I6CC] and in exon 8 [E8CC/CT]) is indeed associated with moderately elevated BP (1). The SGK1 gene variant affects 3 to 5% of a Caucasian population and approximately 10% of an AfricanAmerican population (20). Individuals who carry this gene variant are particularly prone to develop hypertension during hyperinsulinemia. Thus, SGK1 may be important or even necessary for the hypertension that is caused by hyperinsulinemia. In support of this theory is the observation that induction of hyperinsulinemia sensitized BP to high-salt intake in sgk1 / but not in sgk1 / mice (1). Carriers of the I6CC/E8CC/CT SGK1 gene variant further suffer from enhanced body mass index (for review, see reference [1]). The gene variant thus predisposes to obesity in addition to its effect on BP control. The obesity is possibly due to stimulation of SGK1-dependent intestinal SGLT1 activity leading to accelerated intestinal glucose absorption and enhanced glucose deposition in peripheral tissues by stimulation of the glucose transport protein, GLUT1. Presumably as a result of enhanced prevalence of obesity, carriers of the I6CC/E8CC/CT SGK1 gene variant are more prone to develop type 2 diabetes compared with individuals without the gene variant (20). Although additional experimental effort is needed to define the putative role of SGK1 in the development of metabolic syndrome, interestingly, in experiments in genetically manipulated mice, the metabolic syndrome of offspring after dietary stress (low-protein diet) of the mother, a result of so-called fetal programming, seems to be dependent on maternal SGK1 (21). Some patients who have ESRD and have arterial hypertension express a Nedd4-2 variant (P355LNedd4-2) with enhanced sensitivity to phosphorylation by SGK1. This genetic variant would result in increased ENaC activity and thus be prone to salt-sensitive hypertension. This observation further underlines the role of SGK1 in the development of hypertension.

Effects on Renal Potassium Regulation

Deficiency of SGK1 activity leads to impaired excretion of K . The sgk1 / mice fail to rapidly excrete an acute K load, and during a chronic K load, plasma K concentration increases more sharply in sgk1 / mice than in sgk1 / mice (reviewed in reference [1]) despite increased basal plasma aldosterone levels, which should favor K elimination. SGK1 further participates in the stimulation of cellular K uptake by insulin. Accordingly, the hypokalemic response to administration of insulin and glucose is significantly blunted in sgk1 / mice (18). Despite the ability of SGK1 to stimulate the TRPV5 Ca2 channel and despite decreased TRPV5 expression in sgk1 / mice, renal Ca2 excretion is rather decreased in sgk1 / mice (for review, see reference [1]). The salt depletion of sgk1 / mice upregulates renal tubular Na and presumably Ca2 reabsorption in proximal renal tubules and possibly thick ascending limbs. Under normal conditions, SGK1 is not expressed in proximal renal tubules and thus does not participate in the regulation of proximal renal tubular transport; however, hyperglycemia may stimulate SGK1 expression throughout the kidney, including proximal renal tubules, raising the possibility that, in diabetes, SGK1 may stimulate renal tubular nutrient transport by upregulation of the respective carriers (e.g., SGLT1, EAAT3) and by enhancing the driving force through stimulation of the apical K channel and the basolateral Na /K -ATPase. SGK1-dependent renal salt retention could also contribute to the development of edema after administration of PPAR- agonists, in nephrotic syndrome, and during ascites formation (1,19).

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SGK1-Sensitive Renal Fibrosis and Proteinuria

Beyond its effect on renal tubular transport and BP, SGK1 has been implicated in renal and extrarenal fibrosing disease, such as diabetic nephropathy, glomerulonephritis, liver cirrhosis, and cardiac fibrosis (1,22,23). SGK1 may be particularly important in diabetic nephropathy, because it is upregulated by excessive glucose concentrations and mediates the upregulation of connective tissue growth factor (1). SGK1 is also expressed in podocytes and upregulated in those cells by aldosterone and oxidative stress (6,24). Experimental studies have shown that proteinuria during mineralocorticoid and salt excess is significantly more pronounced in sgk1 / mice than in sgk1 / mice (25).

10.

11.

12.

13.

14.

Conclusions

This brief review highlights how genetic techniques that allow studying targeted gene expression in experimental animals can provide important insights into the role of renal transport systems in the pathogenesis of disorders of wide clinical impact. Further studies of the SGK1 system hold promise for providing important insights into disease pathogenesis, and one may anticipate development of therapeutic agents that target this important regulatory system. References

1. Lang F, Bohmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V: (Patho)physiological significance of the serum- and glucocorticoidinducible kinase isoforms. Physiol Rev 86: 1151­1178, 2006 2. Verrey F, Fakitsas P, Adam G, Staub O: Early transcriptional control of ENaC (de)ubiquitylation by aldosterone. Kidney Int 73: 691­ 696, 2008 3. Firestone GL, Giampaolo JR, O'Keeffe BA: Stimulus-dependent regulation of the serum and glucocorticoid inducible protein kinase (Sgk) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 13: 1­12, 2003 4. Chang CT, Wu MS, Tian YC, Chen KH, Yu CC, Liao CH, Hung CC, Yang CW: Enhancement of epithelial sodium channel expression in renal cortical collecting ducts cells by advanced glycation end products. Nephrol Dial Transplant 22: 722­731, 2007 5. Kim MJ, Chae JS, Kim KJ, Hwang SG, Yoon KW, Kim EK, Yun HJ, Cho JH, Kim J, Kim BW, Kim HC, Kang SS, Lang F, Cho SG, Choi EJ: Negative regulation of SEK1 signaling by serum- and glucocorticoid-inducible protein kinase 1. EMBO J 26: 3075­3085, 2007 6. Shibata S, Nagase M, Yoshida S, Kawachi H, Fujita T: Podocyte as the target for aldosterone: Roles of oxidative stress and Sgk1. Hypertension 49: 355­364, 2007 7. Li L, Wingo CS, Xia SL: Downregulation of SGK1 by nucleotides in renal tubular epithelial cells. Am J Physiol Renal Physiol 293: F1751­F1757, 2007 8. Poulin H, Filion C, Ladanyi M, Labelle Y: Serum- and glucocorticoidregulated kinase 1 (SGK1) induction by the EWS/NOR1(NR4A3) fusion protein. Biochem Biophys Res Commun 346: 306 ­313, 2006 9. Ring AM, Leng Q, Rinehart J, Wilson FH, Kahle KT, Hebert SC, Lifton RP: An SGK1 site in WNK4 regulates Na channel and K

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

channel activity and has implications for aldosterone signaling and K homeostasis. Proc Natl Acad Sci U S A 104: 4025­ 4029, 2007 Zhang W, Xia X, Reisenauer MR, Rieg T, Lang F, Kuhl D, Vallon V, Kone BC: Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na channel alpha. J Clin Invest 117: 773­783, 2007 Bergler T, Stoelcker B, Jeblick R, Reinhold SW, Wolf K, Riegger GA, Kramer BK: High osmolality induces the kidney-specific chloride channel CLC-K1 by a serum and glucocorticoid-inducible kinase 1 MAPK pathway. Kidney Int 74: 1170 ­1177, 2008 Wang D, Zhang H, Lang F, Yun CC: Acute activation of NHE3 by dexamethasone correlates with activation of SGK1 and requires a functional glucocorticoid receptor. Am J Physiol Cell Physiol 292: C396 ­C404, 2007 Fejes-Toth G, Frindt G, Naray-Fejes-Toth A, Palmer LG: Epithelial Na channel activation and processing in mice lacking SGK1. Am J Physiol Renal Physiol 294: F1298 ­F1305, 2008 Jeyaraj S, Boehmer C, Lang F, Palmada M: Role of SGK1 kinase in regulating glucose transport via glucose transporter GLUT4. Biochem Biophys Res Commun 356: 629 ­ 635, 2007 Shojaiefard M, Strutz-Seebohm N, Tavare JM, Seebohm G, Lang F: Regulation of the Na( ), glucose cotransporter by PIKfyve and the serum and glucocorticoid inducible kinase SGK1. Biochem Biophys Res Commun 359: 843­ 847, 2007 Strutz-Seebohm N, Shojaiefard M, Christie D, Tavare J, Seebohm G, Lang F: PIKfyve in the SGK1 mediated regulation of the creatine transporter SLC6A8. Cell Physiol Biochem 20: 729 ­734, 2007 Klaus F, Palmada M, Lindner R, Laufer J, Jeyaraj S, Lang F, Boehmer C: Up-regulation of hypertonicity-activated myo-inositol transporter SMIT1 by the cell volume-sensitive protein kinase SGK1. J Physiol 586: 1539 ­1547, 2008 Boini KM, Graf D, Kuhl D, Haussinger D, Lang F: SGK1 dependence of insulin induced hypokalemia. Pflugers Arch July 30, 2008 [epub ahead of print] Artunc F, Nasir O, Amann K, Boini KM, Haering HU, Risler T, Lang F: Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome. Am J Physiol Renal Physiol 295: F1624 ­F1634, 2008 Schwab M, Lupescu A, Mota M, Mota E, Frey A, Simon P, Mertens PR, Floege J, Luft F, Asante-Poku S, Schaeffeler E, Lang F: Association of SGK1 gene polymorphisms with type 2 diabetes. Cell Physiol Biochem 21: 151­160, 2008 Rexhepaj R, Boini KM, Huang DY, Amann K, Artunc F, Wang K, Brosens JJ, Kuhl D, Lang F: Role of maternal glucocorticoid inducible kinase SGK1 in fetal programming of blood pressure in response to prenatal diet. Am J Physiol Regul Integr Comp Physiol 294: R2008 ­R2013, 2008 Nishimura H, Ito Y, Mizuno M, Tanaka A, Morita Y, Maruyama S, Yuzawa Y, Matsuo S: Mineralocorticoid receptor blockade ameliorates peritoneal fibrosis in new rat peritonitis model. Am J Physiol Renal Physiol 294: F1084 ­F1093, 2008 Terada Y, Kuwana H, Kobayashi T, Okado T, Suzuki N, Yoshimoto T, Hirata Y, Sasaki S: Aldosterone-stimulated SGK1 activity mediates profibrotic signaling in the mesangium. J Am Soc Nephrol 19: 298­309, 2008 Nagase M, Yoshida S, Shibata S, Nagase T, Gotoda T, Ando K, Fujita T: Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: Possible contribution of fat-derived factors. J Am Soc Nephrol 17: 3438 ­3446, 2006 Artunc F, Amann K, Nasir O, Friedrich B, Sandulache D, Jahovic N, Risler T, Vallon V, Wulff P, Kuhl D, Lang F: Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1. J Mol Med 84: 737­746, 2006

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Commentary

Fluid, Electrolyte, and Acid-Base Disorders

Tomas Berl, MD Department of Medicine, University of Colorado Denver, Division of Renal Diseases and Hypertension, Aurora, Colorado

The authors of this issue of NephSAP, Drs. Sterns and Palmer, undertook a thorough review and update of the developments in the area of electrolytes and acid-base disorders. More than any other aspect of our specialty, the one reviewed in this issue is almost entirely devoid of prospective, controlled trials. The authors therefore had to rely primarily on small observational studies and illustrative case reports. Nonetheless, they are to be commended for the clarity of the presentation reflecting their well-established credentials as outstanding teachers who can put forth complex concepts and make them readily understandable. This issue contains a particularly lucid description of the cellular mechanisms by which the WNK4 kinase allows for the dissociation of the effects of aldosterone to retain sodium and excrete potassium (K). The text and Figure 1 clearly depict how this kinase modulates the activity of the Na-Cl co-transporter to enhance sodium retention and independently controls SGK1 phosphorylation of WNK4 to promote K excretion. Equally provocative is the discussion on the kidney-specific short WNK1 and how its relation to a longer WNK1 is modulated by K intake and can affect K excretion, lead to sodium retention, and potentially have a role in sodium-sensitive hypertension, making these kinases attractive targets for new antihypertensive drugs.

Dyskalemic Disorders

Hypokalemia

The discussion on the approach to the patient with hypokalemia is worthy of any textbook. Of particular value is the interpretation of urinary K and the limitations of the transtubular K gradient (TTKG) in the diagnosis of disorders of plasma K concentration, emphasizing that its most valuable role may be in the

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discrimination between aldosterone deficiency and aldosterone resistance; an increment in TTKG after the administration of a mineralocorticoid supports a diagnosis of aldosterone deficiency. Although most of the clinical settings associated with redistribution of K into cells are well known to most clinicians, the author weaves in some less recognized causes, such as hydrofluoric acid dermal injury, hydroxycloroquine overdose, and use of pegylated interferon in a thyrotoxic patient. In this regard, the erudite discussion on periodic paralysis, both genetic and acquired, is worthy of mention. A reference to adrenergic agents, that in their long-acting form can cause substantial decrements in serum K, is surprisingly absent from what is otherwise a very comprehensive review of translocational hypokalemias. Several other aspects of the update on hypokalemic disorders are also noteworthy. One refers to the emerging concept that there may be gastrointestinal sensors and factors that control the renal excretion of not only K but also sodium and phosphate. As it relates to K, the nature of the factor has not been determined but does not seem to be insulin. The other noteworthy discussion revolves around the increasing understanding of the biology of the epithelial sodium channel, which is central not only to K homeostasis but also to the renal control of sodium excretion and thereby of BP. Modulation of channel activity by ubquitination and phosphorylation mediated by extracellular signal­regulated kinase are just two examples of biochemical events that can increase or decrease channel activity, respectively. On a more clinically relevant note, the discussion on diuretic induced K losses and the influence of sodium intake is particularly pertinent, emphasizing the importance of moderate sodium intake, because both very high and very low intakes of sodium can enhance renal losses of K

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by different mechanisms. It is important also to point out studies that link the hypokalemia that is associated with thiazide administration to glucose intolerance and an increase in blood sugar. This is most likely mediated by a mechanism that involves a failure to secrete insulin normally under kaliopenic conditions, rather than peripheral insulin resistance.

Hyperkalemia

In this section of the syllabus, after highlighting the insensitivity of the electrocardiogram as a prognosticator of hyperkalemic arrhythmias and cardiac arrest, the author has amassed a fascinating group of case reports, many unusual and rare, but nonetheless interesting that can lead to hyperkalemia by excessive exogenous or endogenous loads of K even in the background of normal renal function. Such a comment also applies to causes for cell shifts of K out of cells. Of greater clinical relevance is the increasing incidence of hyperkalemia associated with attempts to inhibit more fully the renin-angiotensin-aldosterone system (RAAS) by a variety of combination treatments. Although the syllabus does make reference to this problem, it is in my view underemphasized. Numerous studies have now reported an increased risk for hyperkalemia with combination RAAS inhibiting or blocking regimens, even at a time when their cardiovascular and renal protective effects are being increasingly questioned (see results of the ONTARGET trial). Finally, this section has an elegant discussion of the mechanism of distal tubular defects that lead to hyperkalemia such as the role of mutations in the aforementioned WNK4 in the pathogenesis of pseudohypoaldosteronism type II, also designated as Gordon's syndrome, which is characterized by hypertension and hyperkalemic metabolic acidosis. By enhancing clathrin-dependent endocytosis of the ROMK channel, patients with these mutations have decreased cell surface expression of this channel that is vital for K secretion.

ple, congenital chloride diarrhea seems to be a consequence of a mutation in the solute carrier family 26 member 3 gene (SCLC26A3) affecting the function of the colonic Cl /HCO3 exchangers. Similar defects occur in other syndromes and may contribute to the metabolic alkalosis that is seen in infants with cystic fibrosis. As regards inherited disorders that lead to metabolic alkalosis, the use of a thiazide test to distinguish Bartter syndrome from Gitelman syndrome is of interest. Because the latter group is afflicted by a mutation of the thiazide-sensitive Na-Cl co-transporter, they do not increase their fractional excretion of chloride with this diuretic, whereas those with Bartter (as well as pseudo-Bartter) syndrome do.

Metabolic Acidosis

The authors present a lucid description of the mechanisms involved in tubular H secretion and its control. It must be noted, however, that any role of angiotensin II on the renal handling of ammonia must be viewed as preliminary and of questionable clinical significance, because there is no clinical evidence that inhibition of angiotensin II action results in acid-base derangements, an effect that would have been observed given the widespread use of such drugs. The section on the clinical approach to metabolic acidosis is equally erudite. Besides alluding to the common clinical settings, the section is punctuated by a hefty number of case reports of unusual causes of metabolic acidosis brought about by various drug ingestions. Among these, the different alcohols play a prominent role. In their discussion of ethanol versus fomepizole in the treatment of certain alcohol ingestions, the latter is described as the treatment of choice. Although it clearly has many advantages over ethanol, the cost exceeds 5000 USD for a 48-h treatment and is not available in all settings, a more comprehensive discussion of the relative merits of each treatment modality might be useful in future NephSAP editions. The renal tubular acidoses are clearly described. Of particular note is the description of an alternative test to diagnose the distal variety of this disorder. Few, if any, nephrologists have ever used the classical NH4Cl loading test to ascertain that the patient cannot normally acidify the urine. An alternative test involving the simultaneous administration of fludrocortisone and furosemide seems to be well tolerated, is simpler, and provides the same degree of diagnostic accuracy.

Acid-Base Disorders

Metabolic Alkalosis

The most novel aspect of this section of the syllabus relates to the recognition that alteration in the transepithelial transport of chloride and bicarbonate, which are critical to the function of many epithelia, can culminate in metabolic alkalosis. Thus, for exam-

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Dysnatremic Disorders

Hypornatremia

As the most common electrolyte disorder in clinical medicine, the update on hypernatremia is of particular importance. The opening section on pseudohyponatremia includes the formula recently derived by Nguyen and his collaborators from studies performed in their laboratory involving the addition of lipids and proteins to plasma. This formula is likely to be the best yet to arrive at a correction for water content when these large molecules take up a large volume of the measured samples. The adaptive responses of the brain to changes in tonicity have been the subject of great interest. There are significant intraindividual variations in the adaptive response to decrements in tonicity and the degree of brain edema that follows the onset of hyponatremia. The observation that the levels of expression of aquaporin 4 can determine the degree of brain swelling raises the possibility that variability in the expression of this water channel could underlie the observed differences. Likewise, because the adaptation also involves the release of organic osmolytes, variation in G protein­ coupled receptors involved in their release provide another potential source for the variability. Furthermore, the pathogenesis of the osmotic demyelination remains poorly understood. Recent studies pointing to a downregulation of neutral amino acid transporters SNAT2 during hypotonicity, particularly in oligodendrocytes (the cells most affected by this pathologic process), by delaying the reaccumulation of osmolytes during the correction phase may shed some light on the pathogenesis of this often devastating complication of treatment. The authors correctly allude to the protective effects of urea and for completeness refer to a case that was reported in a dialysis patient. This is a very rare occurrence considering the large number of such patients who undergo correction of hyponatremia on an ongoing basis in this setting. In view of the increasing interest in exerciseinduced hyponatremia, the syllabus deals extensively with this subject, summarizing studies that examined the endocrine responses to exercise and attempts to monitor sodium and water balances, including the contributions of sweat. What emerges is that nonosmotic vasopressin secretion is a mediator of the process and that weight gain, reflecting excessive water intake, underlies much of the problem. It is pertinent to

emphasize the conclusions of the consensus conference pointing to the importance of administering 100 ml of 3% NaCl as the initial treatment for individuals who present with cerebral symptoms in this setting. The very comprehensive and thoughtful update on hyponatremia also brings into focus several other important issues. The first of these is the difficulty encountered in differentiating euvolemic from hypovolemic hyponatremia. None of the tools available-- the spot urinary sodium concentration, the fractional excretion of sodium, the fractional excretion of urea, the fractional excretion of uric acid, or the response to isotonic saline-- either alone or in combination, can reliably discriminate these entities. Along the same lines, it is equally challenging to establish that patients designated as having cerebral salt wasting truly have this entity. The other emerging view is the recognition that hyponatremia may not be entirely asymptomatic even when it seems to be so. Given the cellular adaptive mechanisms that come into play with chronic hyponatremia, this is perhaps not surprising. A recently described gait disturbance has been complemented by the increase risk for fractures in this population. This section also reviews recent publications on the emergence of vasopressin antagonists in the treatment of hyponatremic disorders in both euvolemic and hypervolemic conditions. Although at this time only one intravenous form of the drug is available (conivaptan), the release of oral agents is under active discussion with the Food and Drug Administration. Finally, the increasingly accepted view that DDAVP can and should be used for overcorrection of hyponatremia to prevent a demyelinating syndrome is clearly worthy of the reader's careful attention.

Hypernatremia and Diabetes Insipidus

The introduction to this section of the syllabus has a detailed summary on osmoregulation and the cellular mechanisms involved in the perception of changes in tonicity. Of interest is the recent description of the importance of transient receptor potential vanilloid channels in the response of osmoreceptor neurons to changes in tonicity, as studied in knockout mice deficient in transient receptor potential vanilloid 1 channels (elegantly illustrated in Figure 3). It has been known for some time that the elderly are prone to developing hypernatremia, partially because they have hypodypsia. Positron emission tomography scanning has been performed in elderly and

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younger patients given hypertonic solutions to observe whether there are alterations in regional blood flow. No difference in patterns was unveiled, but the authors of the study concluded that the defect lay not in the perception of thirst but in the satiation of thirst. The central role of the vasopressin-dependent water channel aquaporin 2 continues to evolve because it is clearly involved in the most important cause of acquired nephrogenic diabetes insipidus, namely, lithium use. It seems that the water channel also fails to reach the luminal membrane of the collecting duct in hypercalciuria, another setting in which maximal urinary concentrating ability is impaired. Finally, of note

is the attempt to bypass vasopressin receptor signaling to treat congenital forms of diabetes insipidus by a number of maneuvers, including the use of chaperones that will target the protein to the membrane (in the form of vasopressin agonists), the use of cGMPgenerating compounds such as sildenafil, and even statins to decrease endocytosis of water channels and allow them to remain in the membrane. The greater understanding of the mechanisms that are involved in the control of water excretion on the cellular level and their derangements in pathologic states should in time lead to better targeted treatments of water-losing disorders.

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Syllabus

Fluid, Electrolyte, and Acid-Base Disturbances

Biff F. Palmer, MD* and Richard H. Sterns, MD *Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and University of Rochester School of Medicine and Dentistry, Rochester, New York

Learning Objectives:

1. To understand recent scientific advances in our understanding of the pathophysiology of disorders of potassium, acid base, sodium, and water balance 2. To understand how pathophysiology can be applied to the bedside 3. To understand how recent clinical trials related to fluid, electrolyte, and acid-base disorders can be applied to clinical decision making

Potassium

New Physiologic Concepts

Aldosterone plays and an important role in determining the final composition of the urine through effects in the distal nephron. Aldosterone stimulates electrogenic Na reabsorption through the epithelial Na channel (ENaC), creating a lumen-negative potential. This luminal electronegativity serves as a driving force for Cl reabsorption through the paracellular pathway and secretion of potassium (K ) and hydrogen (H ) into the lumen (reviewed in reference 1). Two physiologic stimuli for aldosterone secretion are extracellular fluid volume depletion and hyperkalemia. In the setting of volume depletion, aldosterone release is mediated by a direct stimulatory effect of angiotensin II on cells in the zona glomerulosa of the adrenal gland. In this setting, aldosterone contributes to salt retention and restoration of extracellular fluid volume without the development of hypokalemia. In the setting of hyperkalemia, aldosterone release occurs through a direct effect of K on the zona glomerulosa. The increase in aldosterone stimulates renal K excretion, restoring the serum K concentration to normal but does so without concomitant renal salt retention.

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The ability of the kidney to provide an appropriate response to two different physiologic perturbations (salt retention without K secretion in volume depletion and K secretion without salt retention in hyperkalemia) despite the same physiologic stimuli (increased aldosterone) is not immediately apparent. Although flow rates and distal delivery of salt and water may account for part of this ability, recent reviews have suggested a more direct mechanism centered on the WNK4 protein kinase in the distal nephron (2,3). WNK4 is a member of the with-no-lysine [K] (WNK) family of kinases. The name is derived from the atypical placement of the catalytic lysine as compared with other types of kinases. There are four mammalian WNK family members, each of which is encoded by a different gene. Inactivating mutations in WNK4 lead to the development of pseudohypoaldosteronism type II (PHAII; Gordon syndrome). PHAII is an autosomal dominant disorder in which increased renal NaCl reabsorption and impaired renal K secretion lead to hypertension and hyperkalemia. Plasma aldosterone levels are low despite the presence of hyperkalemia, which normally exerts a stimulatory effect on aldosterone release from the adrenal gland. Administration of NaCl worsens the hypertension, but Na given with a nonchloride anion such as sulfate or bicarbonate has a beneficial effect. The hypertension and hyperkalemia are particularly responsive to the administration of thiazide diuretics. Wild-type WNK4 acts to reduce the surface expression of the thiazide-sensitive Na -Cl co-transporter and also stimulates the clathrin-dependent endocytosis of the renal outer medullary K (ROMK) channel in the renal collecting duct. The inactivating mutation of WNK4 responsible for PHAII leads to increased co-transporter activity and further stimulates

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endocytosis of ROMK. The net effect is increased NaCl reabsorption along with decreased K secretion. Mutated WNK4 also enhances paracellular Cl permeability as a result of increased phosphorylation of claudins, which are tight junction proteins involved in regulating paracellular ion transport. In addition to increasing salt retention, this change in permeability further impairs K secretion because the lumen-negative charge, which normally serves as a driving force for K secretion, is dissipated. Because volume expansion and hyperkalemia resulting from the PHAII-mutated WNK4 protein can be viewed as an exaggerated response of what normally should occur as the kidney responds to a reduction in extracellular fluid volume (salt retention without increased K secretion), it has been proposed that wild-type WNK4 may act as a molecular switch determining the balance between renal NaCl reabsorption and K secretion. In the basal state, nephron function would be characterized by decreased NaCl reabsorption and K secretion. Under conditions of volume depletion, the switch would be altered in a way reminiscent of the PHAII mutant such that NaCl reabsorption is increased but K secretion is further inhibited. WNK4 may assume a third state to account for K secretion without salt retention under conditions in which aldosterone is directly stimulated by elevations in the serum K concentration (4). The WNK4 protein possesses a site that is phosphorylated by the serumand glucocorticoid-dependent protein kinase SGK1. This site is highly conserved and far removed from the region of WNK4 in which PHAII mutations are clustered. In turn, SGK1 is an immediate transcriptional target of the mineralocorticoid receptor. Evidence suggests that SGK1-mediated phosphorylation of WNK4 leads to a loss in the ability of WNK4 to inhibit ROMK, providing increased K secretion capability. In addition, phosphorylation removes the inhibitory effect of the wild-type WNK4 on ENaC (5). Increased electrogenic Na reabsorption with greater luminal electronegativity would provide an additional stimulatory effect for K secretion. The precise signals that are required to allow WNK4 to switch to the form appropriate for the physiologic stimuli that drive aldosterone release are not entirely clear. Under conditions of volume depletion, WNK4 may switch in the direction of the PHAII mutant protein as a result of aldosterone signaling in

the context of other effectors such as angiotensin II, sympathetic nerve activity, and antidiuretic hormone, all of which are increased in this setting. This environment would be distinct from that in which aldosterone is increased solely as a result of a direct stimulatory effect of K in the adrenal gland. Increased aldosterone either alone or along with increased serum K concentration may provide the signals required to allow SGK1-mediated phosphorylation to dominate (Figure 1). In the previous fluid and electrolyte edition of NephSAP, a discussion was provided about the role of WNK proteins in modulating K secretion in response to changes in dietary K intake (6). This area was discussed further in two recent reviews with particular emphasis placed on the potential role of WNK1 in the pathogenesis of salt-sensitive hypertension (7,8). This area is briefly summarized as follows. WNK1 is ubiquitously expressed throughout the body in multiple spliced forms. By contrast, a shorter WNK1 transcript lacking the amino terminal 1 through 437 amino acids of the long transcript is highly expressed in the kidney but not in other tissues and is referred to as kidney-specific WNK1 (KS-WNK1). Changes in the ratio of KS-WNK1 and long WNK1 in response to dietary K play an important role in the physiologic regulation of renal K excretion. Long WNK1 inhibits ROMK by stimulating its endocytosis, whereas KS-WNK1 functions as a physiologic antagonist to the actions of long WNK1. Under condition of dietary K restriction, the relative abundance of long WNK1 to KS-WNK1 is increased. These changes lead to decreased abundance of ROMK in the renal cortical collecting duct, which is an adaptive response important for renal K conservation. Conversely, dietary K loading increases the abundance of KS-WNK1 relative to long WNK1. This change is accompanied by upregulation of ROMK, which again is an appropriate response to facilitate K secretion in the setting of a high-K diet. The changes in KS-WNK1 and long WNK1 that occur in response to dietary K intake also have effects on renal Na handling that may be of importance in the observed reciprocal relationship between dietary K intake and hypertension. Long WNK1 has been shown to stimulate ENaC activity through activation of SGK1. SGK1 inactivates the ubiquitin-protein ligase Nedd4-2 through phosphorylation, resulting in less retrieval of ENaC from the apical membrane.

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WNK4 BASAL STATE ECF volume

Aldosterone in setting of neurohumoral activation ( All, ADH, Catecholamines)

Serum K+ Norml ECF Volume

Aldosterone in isolation

PHAII like WNK4

Na -Cl cotransporter, ROMK

+ ­

SGK1-Mediated Phosphorylation of WNK4

ENaC, ROMK

Salt retention without K+ wasting

K+ Secretion without salt retention

Figure 1. The WNK4 protein may play an important role in ensuring the transport function of the distal nephron is appropriate to conditions in which aldosterone is increased as a result of volume depletion as compared with conditions in which aldosterone is increased solely as a result of hyperkalemia. With volume depletion, increased circulating levels of aldosterone occur in the setting of increased levels of other neurohumoral effectors. In this environment, the WNK4 protein is altered in a way reminiscent of the PHAII mutant protein. As a result, NaCl reabsorption is enhanced in the absence of K secretion. By contrast, K can directly stimulate aldosterone release at the level of the adrenal gland such that higher levels occur in isolation. In this setting, the WNK4 protein is altered in such a way that K secretion can be enhanced in the absence of salt retention. AII, angiotensin II; ADH, antidiuretic hormone (see references [2­5] for excellent discussions regarding these concepts).

Increased activity of long WNK1 also releases the inhibitory affect of WNK4 on Na reabsorption mediated by the NaCl co-transporter. These effects suggest that the decrease in K secretion under conditions of K deficiency will occur at the expense of increased Na retention. The simultaneous conservation of K and Na during dietary K deficiency is evolutionarily advantageous for early humans, who had limited access to Na and for whom dietary K and Na deficiency likely occurred together (9); however, such an effect is potentially deleterious if present in the setting of plentiful Na intake. In this regard, throughout the evolutionary course, there has been a 50-fold increase in the ratio of dietary intake of Na versus K . The ratio of dietary Na to K intake was approximately 1:16 for Paleolithic humans and is approximately 3:1 for present-day North Americans. The effect of an increased ratio of WNK1 to KS-WNK1 in the kidney from a high-Na /low-K diet could be central to the pathogenesis of salt-sensitive hypertension. The precise role of WNK proteins in regulating fluid homeostasis through the coordination of ion transport in the distal nephron is an area that continues to be actively pursued. This area is of particular

interest because WNK proteins and the pathways that they influence are also potential targets for the development of novel antihypertensive drugs (10). References

1. Giebisch G, Krapf R, Wagner C: Renal and extrarenal regulation of potassium. Kidney Int 72: 397­ 410, 2007 2. Kahle K, Ring A, Lifton R: Molecular physiology of the WNK Kinases. Annu Rev Physiol 70: 329 ­355, 2008 3. Kahle K, Rinehart J, Giebisch G, Gamba G, Hebert S, Lifton R: A novel protein kinase signaling pathway essential for blood pressure regulation in humans. Trends Endocrinol Metab 19: 91­95, 2008 4. Ring A, Cheng S, Leng Q, Kahle K, Rinehart J, Lalioti M, Volkman H, Wilson F, Hebert S, Lifton R: WNK4 regulates activity of the epithelial Na channel in vitro and in vivo. Proc Natl Acad Sci U S A 104: 4020 ­ 4024, 2007 5. Ring A, Leng Q, Rinehart J, Wilson F, Kahle K, Hebert S, Lifton R: An SGK1 site in WNK4 regulates Na channel and K channel activity and has implications for aldosterone signaling and K homeostasis. Proc Natl Acad Sci U S A 104: 4025­ 4029, 2007 6. Sterns R, Palmer BF: Fluid and electrolyte and acid-base disturbances. NephSAP 6: 210 ­272, 2007 7. Huang C, Kuo E, Toto R: WNK kinases and essential hypertension. Curr Opin Nephrol Hypertens 17: 1062­ 4821, 2008 8. Huang C, Kuo E: Mechanisms of disease: WNK-ing at the mechanism of salt-sensitive hypertension. Nat Clin Pract Nephrol 3: 623­ 630, 2007 9. Eaton S: The ancestral human diets: What was it and should it be a paradigm for contemporary nutrition? Proc Nutr Soc 65: 1­ 6, 2006 10. San-Cristobal P, de los Heros P, Ponce-Coria J, Moreno E, Gamba G: WNK kinases, renal ion transport and hypertension. Am J Nephrol 28: 860 ­ 870, 2008

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Hypokalemia

Approach to the Patient with Hypokalemia

Hypokalemia is frequently encountered in clinical practice. Transient causes of hypokalemia are due to cell shift, whereas sustained hypokalemia is due either to inadequate intake or to excessive potassium (K ) loss. Hypokalemia resulting from excessive K loss can be due to renal or extrarenal losses. The clinical history, physical examination with particular emphasis on determination of volume status, and determination of the acid­ base status will allow the cause of hypokalemia to be readily determined in most cases. A variety of urine studies are frequently used to aid in the determination of hypokalemia with the idea that findings indicative of renal K conservation support either cell shift or an extrarenal cause of hypokalemia; urine K wasting confirms a renal source. Renal K handling can be assessed with a 24-h urine collection or a spot urine test determining the K / creatinine ratio. A 24-h urinary K of 15 mEq or a K (mmol)/creatinine (mmol) ratio 1 suggests an extrarenal cause of hypokalemia. A random urine K is oftentimes used as an initial test to discriminate renal from extrarenal K losses but is limited by the influence of renal water handling on urine K concentration. Determining the transtubular K gradient (TTKG) remains a popular tool among some clinicians to assess renal K handling: TTKG [K urine/(Uosmolality/Sosmolality)]/K serum Determining the tubular fluid K concentration at the end of the collecting duct is the ideal measure of aldosterone activity because most K secretion takes place in the collecting duct. Thereafter, the K concentration in the urine progressively rises as a result of water reabsorption. The TTKG is intended to estimate the tubular fluid K concentration at the end of the cortical collecting duct by accounting for water reabsorption that takes place distal to where K secretion has ceased. It is worthwhile considering some of the assumptions made in calculating the TTKG as reviewed in a recent clinical commentary (1). First, the calculation assumes that there is no significant solute transport and only water reabsorption as fluid enters the medullary collecting duct. Any Na or urea reabsorption in this segment would tend to lower urine osmolality and cause the TTKG to overestimate the gradient for

K secretion in the upstream collecting duct. Second, conditions should be optimal for K secretion at the time the TTKG is measured. In this regard, urine Na should be no less than 25 mEq/L to ensure that Na delivery to the collecting duct is not rate limiting in K secretion. In addition, urine osmolality should be equal to--and ideally greater than--the plasma. A higher urine osmolality reflects increased vasopressin, which is known to exert a stimulatory effect on K secretion in the collecting duct. During the workup of a patient with hypokalemia, one can argue whether the TTKG offers any additional insight compared with a spot urine K test and clinical assessment. The TTKG may be most helpful in the evaluation of hyperkalemia when one is attempting to discriminate between low aldosterone levels and aldosterone resistance. The best way to use the test is to compare a basal measurement with one obtained within 4 h after administration of a physiologic dosage (0.05 mg) of 9- -fludrocortisone. An increase in the TTKG to 6 within this time frame suggests aldosterone deficiency. Administration of a pharmacologic dosage (0.2 mg) may elicit an increase in the TTKG during 24 h in the setting of aldosterone resistance.

The TTKG may be most useful in the evaluation of hyperkalemia when one is attempting to discriminate between low aldosterone levels and aldosterone resistance. An increase in the TTKG to >6 after the administration of fludrocortisones suggests aldosterone deficiency as the cause of the increased serum K concentration.

Cellular Redistribution

The regulation of K distribution between the intracellular and extracellular space is referred to as internal K balance. Although the kidney is ultimately responsible for maintenance of total body K , factors that modulate internal balance are important in the disposal of acute K loads. Cell shifts are extremely important, in that only 2% of total body K is located in the extracellular fluid. A large K meal could potentially double extracellular K levels were it not for the rapid shift of the K load into cells. The kidney

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cannot excrete K rapidly enough in this setting to prevent life-threatening hyperkalemia. Thus, it is important that this excess K be rapidly shifted and stored in cells until the kidney has successfully excreted the K load. The major regulators of K shift into cells are insulin and catecholamines with a lesser effect mediated by metabolic and respiratory alkalosis. The various physiologic effects of insulin, including glucose and K regulation, are mediated through the binding to cell surface receptors. This binding stimulates glucose uptake in insulin-responsive tissues through the insertion of the glucose transporter protein GLUT 4. K uptake is stimulated as a result of increased activity of the Na -K -ATPase. Metabolic studies in a patient with leprechaunism demonstrated that the effects of insulin on glucose and K disposal can be separated from one another (2). Leprechaunism is an extreme form of insulin resistance related to mutations in the insulin receptor. Patients present with a lack of subcutaneous fat, decreased muscle mass, and an inability to regulate blood glucose levels properly. Metabolic studies were performed in a patient with two naturally occurring mutant alleles of the receptor that markedly impaired posttranslational processing and intracellular transport of the receptor to the cell surface. Using a glucose clamp technique, the patient was found to have virtually no anabolic effects of insulin on measures of carbohydrate, lipid, and protein metabolism. By contrast, the effect of insulin to stimulate cellular K uptake was intact. The mechanism behind this disassociation is not known but may be due to differences in the folding and surface expression in various insulin target tissues. The release of insulin can be responsible for significant drops in extracellular K concentration as well as drops in other ions when glucose is given to patients with significant malnutrition. Some of the earliest reports of the refeeding syndrome were of starved prisoners of war who developed fatal cardiovascular complications in association with the administration of nutritional therapy. A similar complication has been seen in patients who had anorexia nervosa and were administered aggressive nutritional therapy. A more modern-day occurrence of the syndrome is seen in malnourished patients with cancer. Such patients are frequently malnourished as a result of direct effects of the tumor as well as adverse effects of chemotherapy, such as nausea, vomiting, and mucositis (3).

The administration of a carbohydrate load to malnourished patients can unmask total-body deficits of K , phosphate, and Mg2 as a result of insulinmediated shifts into the intracellular compartment (4,5). Depletion of extracellular K and Mg2 can alter cell membrane function in such a way that patients are predisposed to arrhythmias. Depletion of phosphate can lead to severe muscle weakness (potentially respiratory failure), rhabdomyolysis, and hemolysis. Hypophosphatemia-induced depletion of red blood cell 2,3-DPG can lead to a shift in the O2 disassociation curve, predisposing patients to the development of tissue hypoxemia and potentially lactic acidosis.

The administration of a carbohydrate load can unmask total-body deficits of K , phosphate, and Mg2 as a result of insulinmediated shifts into the intracellular compartment. A similar pathophysiology can develop in individuals with long-term alcoholism. Upon admission to the hospital, such patients often have relatively normal serum chemistry values. Treatment with glucose-containing maintenance fluids and development of respiratory alkalosis as a result of alcohol withdrawal can cause precipitous drops in extracellular K , Mg2 , and phosphate as a result of the presence of total-body deficits. For patients with alcoholic ketoacidosis, glucose administration is an effective way to terminate the ketogenic state in the liver and to correct the acidemia. The additional administration of bicarbonate-containing solutions can cause rapid serum alkalinization and be complicated by life-threatening arrhythmias such as ventricular tachycardia (6). Hydrofluoric acid is an inorganic acid used in the chemical- and oil-refining industry as well as ceramic and graphite production, frosting of glass, and electropolishing of certain metals. Dermal exposure of this agent has primarily been reported to cause hypocalcemia and hypomagnesemia but on occasion has been implicated in the development of hypokalemia (7­10). These cases have been observed in the setting of extensive dermal chemical burns. Depletion of these ions is thought to be a result of binding to the fluoride anion. The degree of hypocalcemia and hypomag-

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nesemia can be severe and result in prolongation of the QT interval and recurrent ventricular tachycardia. One of the features of hydroxychloroquine and chloroquine overdose is the development of hypokalemia because of a cell shift (11). This intracellular shift of K is exacerbated in patients who have hypotension and require pressor support with adrenergic agents. Because total body K is normal in this situation, caution should be used in administering K to avoid rebound hyperkalemia as the clinical condition of the patient improves. Hypokalemic periodic paralysis is a rare disorder that is characterized by muscle weakness or paralysis as a result of the sudden movement of K into cells. Measurement of the TTKG at the time of the attacks typically shows values of 1 (12). The attacks are precipitated by rest after exercise, stress, intake of meals that contain large amounts of carbohydrates, and events accompanied by increased release of catecholamines or insulin. This disorder may be familial or acquired. The acquired form of hypokalemic periodic paralysis typically develops in association with thyrotoxicosis. Thyrotoxic periodic paralysis is more commonly seen in Asian individuals but has also been reported with higher frequency in American Indian and Hispanic individuals (13). A series of 40 Turkish patients with the disorder has now been described (14). The clinical characteristics of these patients were similar to other at-risk populations. Although the incidence of thyrotoxicosis is more common in women, there is a male-to-female predominance that ranges from 17:1 to 70:1 for those who develop hypokalemic periodic paralysis. The typical patient is a young adult man who is between ages 20 and 40 and presents with weakness most commonly between the hours of 9:00 p.m. and 9:00 a.m. in the summer months. The attacks are precipitated by conditions characterized by increased release of catecholamines or insulin such as stress, intake of meals that contain large amounts of carbohydrates, and exercise. With regard to exercise, the timing of attacks is typically in the initial rest period after exertion. Oftentimes, the attacks are heralded by muscle cramps and aches, and many patients learn to avoid paralytic episodes by exercising the involved muscles. Hypophosphatemia and hypomagnesemia are also common during acute attacks and, like K , are the result of shifts into the intracellular compartment.

Excess thyroid hormone may predispose to paralytic episodes by increasing Na /K -ATPase activity. The activity of this pump is likely to be increased further by catecholamines, which are typically increased in this setting. The underlying cause of thyrotoxicosis is most commonly Graves disease but can also be a solitary thyroid adenoma (Plummer disease) (15), a thyroid-stimulating hormone-secreting pituitary adenoma, or abuse of exogenous thyroid hormone. Iodine-induced thyrotoxicosis (Jod-Basedow syndrome) and associated hypokalemic periodic paralysis has been reported after the administration of iodine-containing radiocontrast agents, amiodarone, and iodine-containing herbal supplements. A known complication of IFN- therapy is the development of thyroid abnormalities. Two reports described the onset of thyrotoxic periodic paralysis in patients who received IFN- therapy for hepatitis C and hepatitis B (16,17). The acute attacks of hypokalemic periodic paralysis are best treated with intravenous KCl and propranolol. It is important to administer KCl in non­ dextrose-containing solutions because glucose will stimulate insulin release, potentially exacerbating the movement of K into cells. To minimize the likelihood of rebound hyperkalemia, K should be given at dosages of 10 mmol/h. Propranolol (a nonspecific adrenergic blocker) blocks the effects of catecholamines and inhibits the peripheral conversion of T4 to T3. The definitive treatment is to remove the underlying cause of thyrotoxicosis. Mutations in the genes implicated in the familial form of the disease discussed next are not found in patients with thyrotoxic hypokalemic periodic paralysis (18). In fact, periodic paralysis does not recur once the patient is euthyroid. Nevertheless, in a population of Thai patients, single-nucleotide polymorphisms at intron 3 of the -aminobutyric acid receptor 3 subunit were found to be associated with hypokalemic periodic paralysis (19). How this single-nucleotide polymorphism might relate to the pathogenesis of the disorder is not clear. The familial form of hypokalemic periodic paralysis is inherited as an autosomal dominant disorder and has similar clinical features as the acquired form. Notable differences include a younger age at presentation (usually 20 yr), an equal male/female distribution, and longer duration of attack; it is mostly seen in Caucasian individuals. A slowly progressive perma-

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nent proximal weakness can develop in some patients (20). The familial disorder is most commonly a result of mutations in the muscle calcium channel -1 subunit gene (CACNA1S) on chromosome 1q3132 (21,22). The -1 subunit of the calcium channel serves as the pore for movement of calcium into the T tubule of muscle sarcoplasmic reticulum and also contains the dihydropyridine-binding site. Mutations of this subunit reduce the calcium current into the T tubule. The precise mechanism by which impaired function of the calcium channel dihydropyridine receptor causes the influx of K into muscle cells is not clear. A smaller number of cases have been localized to mutations in the skeletal muscle sodium channel SCN4A and the R83H mutation in the K channel subunit gene KCNE3. A presumed variant of hypokalemic paralysis with a normal K has been described in a mother and son who both manifested symptoms of sensory overload (23). In addition to leg cramps, the mother experienced a sensation of auditory and visual overload. She complained of difficulty in filtering out extraneous conversation and background noise. She also had a feeling of visual impingement for which she would purposely ignore peripheral vision. These symptoms were typically worse after consuming large amounts of carbohydrates as well as after exercise and would be ameliorated by exogenous K . She also was noted to be resistant to the anesthetic effects of lidocaine. The son presented with occasional foot cramps, fatigue, and irritability reminiscent of an attentiondeficit disorder. As in the mother, these findings were typically worse after carbohydrate intake and exercise. He similarly was resistant to the effects of lidocaine anesthesia. On the basis of the favorable experience in the mother, the son was also treated with exogenous K supplements with marked improvement in symptoms.

Extrarenal K Loss from the Body

Gastrointestinal loss is a common cause of hypokalemia and is generally due to diarrhea. Secretory diarrhea is generally believed to be caused by one of two processes that can occur either alone or together. First, inhibition of active intestinal NaCl and NaHCO3 reabsorption may be present, and, second, stimulation of active chloride secretion followed by passive secretion of an equal amount of Na so as to maintain electrochemical balance may take place. In both of

these instances, the stool electrolyte content is similar to plasma with high concentration of NaCl and much lower K concentration. The sodium salts in stool cause an isotonic increase in stool water output such that the fecal content of sodium salts roughly parallels the volume of diarrhea. Despite the low K concentration in fecal fluid, significant total body K losses can occur in the setting of large stool volumes. Vasoactive intestinal peptide (VIP) normally inhibits gastric acid secretion, promotes glycogenolysis and hyperglycemia, and exerts a peripheral vasodilatory effect. A variety of tumors have been found to oversecrete VIP in patients who present with watery diarrhea, hypokalemia, and achlorhydria. Other findings include flushing, weight loss, hypercalcemia, and hyperglycemia. The syndrome most commonly occurs as a complication of pancreatic islet cell tumors but has been reported with bronchogenic carcinoma, medullary thyroid carcinoma, and retroperitoneal histiocytoma. There are now several reports linking pheochromocytoma as a source for VIP hypersecretion (24). Infectious diarrhea can also be a cause of significant hypokalemia. Of note is a recent review concerning alterations in fluid and electrolyte disorders in a variety of tropical diseases, emphasizing those found with malaria and leptospirosis (25). Hypokalemia is particularly common in children with severe malaria and tends to occur within several hours of initiation of therapy. The cause is multifactorial and includes gastrointestinal loss in patients with diarrhea and increased renal excretion as a result of increased delivery of Na in the form of ketoacid salts. Quinine therapy is associated with stimulation of insulin release, which in turn, can cause K to shift into cells. The poor dietary intake characteristic of many rural areas will further exacerbate the tendency for hypokalemia in the setting of tropical infectious diseases. Hypokalemia develops in approximately one third of patients with leptospirosis. Such patients are at risk for both gastrointestinal and renal losses. The outer membrane of the organism has an inhibitory effect on the Na -K -ATPase within the nephron. It has been postulated that this inhibitory effect impairs Na reabsorption proximally and increases distal Na delivery, resulting in kaliuresis (25). In an animal model, leptospirosis leads to downregulation of the sodium/hydrogen exchanger isoform 3 (NHE3) and aquaporin 2, whereas expression of the Na -K -2Cl (NKCCl) co-transporter is increased (26). In the lung,

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the organism decreases expression of ENaC and upregulates expression of NKCCl. Alterations in the function of such transporters caused by the organism could play a role in the development of Weil disease, a severe form of leptospirosis characterized by the acute respiratory distress syndrome and acute renal failure. For patients with acute renal failure, mortality is improved with intensive daily dialysis compared with traditional alternate-day dialysis (27). Abnormalities in K transport have not previously been known to be the primary cause of secretory diarrhea. A previous report described a patient who had colonic pseudo-obstruction (Ogilvie syndrome) and developed a secretory diarrhea that was driven by active K secretion (28). In contrast to the high-Na / low-K concentration typically found in various causes of secretory diarrhea, fecal electrolyte concentration in this patient was reversed. Fecal K concentration ranged from 130 to 170 mEq/L; values for Na concentration varied between 4 and 15 mEq/L. Five additional patients with Ogilvie syndrome have now been described, in which active K secretion (100 to 180 mEq/L) was the primary mechanism for development of diarrhea (29). Surgical diversion of the ureter into an ileal pouch is sometimes used in the treatment of patients with a neurogenic bladder or after cystectomy. The procedure may rarely be associated with the development of hyperchloremic normal gap metabolic acidosis (30,31). The main factors that influence the development and severity of acidosis are the length of time the urine is in contact with the bowel and the total surface area of bowel exposed to urine. Acidosis may occur in part as a result of reabsorption of urinary NH4Cl by the intestine. The ammonia is transported through the portal circulation to the liver, where it is metabolized to urea. This metabolic process consumes equimolar amounts of bicarbonate; therefore, it can result in the development of metabolic acidosis. Metabolic acidosis may also develop because urinary Cl can be exchanged for HCO3 through activation of a Cl /HCO3 exchanger on the intestinal lumen. Hypokalemia is also common with sigmoid loops, although the mechanism is not clear. One possibility is that high concentration of ammonium in the colonic lumen enhances net K secretion by removing any component of K reabsorption as a result of a direct competition effect. This same type of clinical picture was described

in a patient who had uterine cancer and was treated with radiotherapy and later developed an enterovesical fistula (32). The fistula caused diversion of urine from the bladder into the distal ileum, resulting in severe normal gap metabolic acidosis and hypokalemia. A negative urinary anion gap was consistent with an appropriate response of the kidney to the generation of an extrarenal acidosis. A series of articles has provided evidence to support the existence of enteric solute sensors that are capable of responding to Na , K , and phosphate, which can then signal the kidney to alter rapidly ion excretion or reabsorption (33,34). For example, in salt-depleted normal patients, urine Na excretion is greater when a Na load is given orally as compared with the same Na load given intravenously. This difference in Na handling was independent of circulating aldosterone levels. Guanylin and uroguanylin derived from the gut may play a role in modulating this effect.

Receptors within the gastrointestinal tract can signal alterations in renal solute handling in response to changes in dietary Na , K , and phosphate. A similar effect may be present in response to dietary K . The effect of a K load given as a systemic, intraportal, or intragastric infusion on urinary K excretion was studied in rats (35). In the fasting state, plasma K concentration increased to a similar degree with all three maneuvers, as did renal K excretion. By contrast, when studied in rats that were fasted overnight and simultaneously fed a low-K diet, the intragastric infusion caused no change in plasma K ; plasma K increased similarly to the unfed rats with either the systemic or the portal infusion routes. These data are consistent with an enhanced renal response to K infusion when combined with a meal, suggesting the presence of a gut factor that is capable of enhancing the efficiency of renal K excretion.

Renal K Wasting

The circulating levels of aldosterone and distal delivery of Na and water are two important factors in the renal excretion of K . Although increased distal delivery of Na and water and increased aldosterone

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activity each can stimulate renal K secretion, under normal physiologic conditions, these two determinants are inversely related. It is for this reason that K excretion is independent of volume status. For example, under conditions of a contracted extracellular fluid volume, aldosterone levels increase. At the same time, proximal salt and water absorption increase, resulting in decreased distal delivery of Na and water. Renal K excretion remains fairly constant under these conditions because the stimulatory effect of increased aldosterone is counterbalanced by the decreased delivery of filtrate to the distal nephron. A similar situation occurs in the setting of expansion of the extracellular fluid volume. In this setting, distal delivery of filtrate is increased as a result of decreased proximal tubular fluid reabsorption. Under conditions of volume expansion, circulating aldosterone levels are decreased. The effect of the increased delivery of Na and water to stimulate K excretion is opposed by decreased circulating aldosterone levels such that renal K excretion again remains constant. Thus, there is a balanced reciprocal relationship between urinary flow rates and circulating aldosterone levels, which serves to maintain K balance during normal volume regulation. It is only under pathophysiologic conditions that distal Na delivery and aldosterone become coupled. In this setting, renal K wasting will occur. When treating patients who have hypokalemia as a result of renal K wasting, it must be determined whether there is a primary increase in mineralocorticoid activity or a primary increase in distal Na delivery. Primary Increase in Mineralocorticoid Activity. These patients typically have evidence of an expanded extracellular fluid volume and present with hypertension, hypokalemia, and metabolic alkalosis. The differential diagnosis rests on measurement of plasma renin activity and plasma aldosterone levels. Increased Renin, Increased Aldosterone. Reninsecreting tumors fall into this category and have been the subject of a recent review (36). These tumors should be considered in young patients (mean age 27) who present with severe hypertension (mean BP 201/ 130 mmHg) and hypokalemia. On average, the plasma renin activity and aldosterone levels are increased by 12 times and four times the upper limit of normal, respectively. Both magnetic resonance imaging and computed tomography scanning are effective means of detecting the presence of renin-secreting tumors in the kidney. Tumors located peripherally can be success-

fully removed with partial nephrectomy; radical nephrectomy is typically required in deep-seated tumors. Surgical removal of the tumors cures the hypertension in most patients. The tumors are typically vascular and have features characteristic of hemangiopericytomas. These tumors can also secrete fibroblast growth factor 23 and can be responsible for oncogenic osteomalacia. The vascular nature of the tumors can also give rise to a consumptive coagulopathy in which thrombocytopenia is a feature, the Kasabach-Merritt syndrome. At least one report raised the possibility of a Page kidney giving rise to hypokalemia in the setting of hypertension (37). The Page kidney was originally described in an experimental model of hypertension in which canine kidneys were wrapped with cellophane. The human counterpart of this disorder refers to the development of hypertension as a result of some process that extrinsically compresses the kidney, resulting in activation of the renin-angiotensin-aldosterone system. The most common cause of a Page kidney is accumulation of blood around the kidney as a result of trauma, but it can also occur in association with a subcapsular bleed after a native or allograft renal biopsy (38). Complication of extracorporeal shockwave lithotripsy by subcapsular bleeds is also a potential cause of this disorder (37). Suppressed Renin, Increased Aldosterone. Primary hyperaldosteronism as a result of an adrenal adenoma and bilateral adrenal hyperplasia are the two most common disorders to consider in this category. The workup of patients who are suspected of having primary hyperaldosteronism continues to be the subject of reviews to include the most recent NephSAP devoted to hypertension (39 ­ 41). The best screening test is the plasma aldosterone-renin ratio. When plasma aldosterone levels are measured in ng/dl and plasma renin activity (PRA) is measured in ng/ml per h, a value of 20 to 30 reliably excludes primary hyperaldosteronism. To avoid overinflating the ratio and to avoid false-positive tests, the lowest value for PRA should be fixed at 0.5 ng/ml per h. Requiring a plasma aldosterone level of at least 12 to 15 ng/dl will also increase the predictive value of the test. After a positive screening test, confirmatory tests are indicated to document the nonsuppressibility of aldosterone secretion. Saline or oral salt loading, fludrocortisone administration, and acute captopril administration are maneuvers that are used for this purpose. Imaging studies

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and, in some cases, adrenal vein sampling are required to complete the workup (42). Bilateral adrenal hyperplasia (BAH) has now been categorized into at least six different forms (43). These forms are characterized by either micronodular or macronodular hyperplasia. BAH may occur as an isolated finding or part of a systemic disorder and shows variability in the presentation age. Recent findings disclosed abnormalities in cAMP signaling pathways in the majority of BAH cases (44,45). Glucocorticoid-remediable aldosteronism (GRA) is an autosomal dominant disorder that should be suspected in a patient who has hypertension and hypokalemia and similarly affected family members (46). GRA results from the unequal crossover of two genes: The CYP11B1 gene that encodes the enzyme 11 -hydroxylase and the CYP11B2 gene that encodes the enzyme aldosterone synthase (18-hydroxylase). The product of this event creates a chimeric gene in which the adrenocorticotropin hormone (ACTH)-responsive promoter is fused to the aldosterone-synthase coding sequence. As a result, aldosterone-synthase is ectopically expressed in the cortisol-producing zone of the adrenal cortex (zona fasciculata) and is under the control of ACTH. Suppression of aldosterone with exogenous administration of dexamethasone is a useful diagnostic and therapeutic strategy. Measurement of urinary cortisol metabolites can also be useful as a diagnostic tool. Increased urinary excretion of 18hydroxycortisol and 18-oxocortisol is typical for this disease. For unclear reasons, random plasma K levels are frequently normal for patients with GRA. One possibility is that the stimulatory effect on aldosterone release is only intermittent because ACTH is secreted centrally in a diurnal manner with peaks in the early morning and evening. In addition, the normal stimulatory effect of K on aldosterone release is absent in this condition, likely a result of aldosterone release originating in the zona fasciculata rather than the zona glomerulosa. To the extent that dietary K normally stimulates aldosterone release, this insensitivity would further diminish aldosterone secretion. Although plasma K concentration may be normal, the likelihood of developing hypokalemia is increased when patients with GRA are treated with either thiazide or loop diuretics. Suppressed Renin and Aldosterone. Cushing disease refers to an excessive cortisol state, resulting

from pituitary overproduction of ACTH. Cushing syndrome refers to cortisol excess that is either ACTH independent (glucocorticoid-secreting adrenocortical adenomas or carcinomas) or ACTH dependent; however, it arises from a site other than the pituitary. Ectopic secretion of ACTH is most commonly reported in association with tumors such as small cell lung carcinoma, carcinoid tumors, pancreatic islet tumors, and a host of others. A patient who presented with severe muscle weakness in association with hypertension, hypokalemia (K 1.8 mEq/L), and metabolic alkalosis was recently reported (47). The patient was found to have ectopic secretion of ACTH from a previously unreported tumor type, large cell neuroendocrine carcinoma of the lung. As is typical for patients with ectopic secretion of ACTH, this patient did not manifest features of Cushing disease such as buffalo hump and striae because oversecretion of cortisol is typically acute. Rather, the clinical presentation tends to be dominated by hypertension and electrolyte abnormalities. The aldosterone-like effect of excess cortisol is due to the high concentrations that overwhelm the ability of 11- -hydroxysteroid dehydrogenase type II (11 -HSDH) in the principal cells of the collecting duct to convert cortisol into cortisone. The mineralocorticoid receptor is capable of binding aldosterone and cortisol but has no affinity for cortisone. Because cortisol normally circulates in the blood at much higher concentrations than aldosterone, the enzymatic activity of 11 -HSDH is essential in keeping the mineralocorticoid receptor free to interact only with aldosterone. Normal concentrations of cortisol can gain access to the mineralocorticoid receptor under conditions of decreased activity of 11 -HSDH. The syndrome of apparent mineralocorticoid excess is a rare recessive disorder characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed circulating aldosterone levels as a result of an inherited deficiency of the enzyme. Patients with apparent mineralocorticoid excess can be effectively treated with either spironolactone or a sodium channel blocker such as amiloride or triamterene. For patients whose BP remains uncontrolled, recent findings in an animal model of 11 -HSDH deficiency suggested that an adrenergic blocking agent may be useful (48). In an 11 -HSDH type II null mouse, BP was found to be increased in association

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with evidence of impaired renal Na excretion. During a period of several weeks, the mouse began to show evidence of volume contraction. Despite the natriuresis, hypertension was persistent but became mediated by increased adrenergic activity as evidenced by an increase in urinary catecholamines. The mechanism for this change from a volume-dependent to an adrenergically mediated form of hypertension is not clear but was postulated to be a result of either K deficiency or the initial period of Na retention. Decreased activity of 11 -HSDH type II can occur as an acquired disorder as a result of the longterm ingestion of licorice (49). The active component in licorice is glycyrrhetinic acid, which has an inhibitory effect on the enzyme. Plasma K concentrations as low as 1.13 to 1.7 mmol/L have been reported in patients who consumed large amounts of licorice that contained glycyrrhetinic acid, after the discontinuation of smoking (50,51). Glycyrrhetinic acid is found in a variety of flavoring agents, such as "Asam Boi," which is used widely in Malaysia and Singapore as well as in Japanese traditional herbal medications known as Kampo medicines (52). There have been two reported cases for which ingestion of licorice may have inadvertently served a therapeutic purpose. One patient had undiagnosed Addison disease but had been clinically stable as a result of the ingestion of approximately 46 g/d salt in the form of soy sauce combined with large quantities of licorice sticks (53). It was postulated that licoriceinduced inhibition of 11 -HSDH type II potentiated the effect of diminishing adrenal gland secretion of glucocorticoids on the mineralocorticoid receptor, thereby averting full-blown adrenal crisis. Eventually, the amount of cortisol secretion became so minimal that this potentiation effect was no longer sufficient to prevent overt signs of adrenal failure. A second patient had undergone unilateral adrenalectomy and required corticosteroid replacement therapy so as to maintain a normal glucocorticoid state (54). The patient later self-discontinued replacement therapy and presented with findings of hypercalcemia, hypertension, hypernatremia, and hypokalemic metabolic alkalosis. Although hypercalcemia is a feature of acute adrenal insufficiency and readily responded to the administration of hydrocortisone, the other findings were not readily explainable. Acute adrenal insufficiency is normally characterized by hypotension, hyponatremia, hyperkalemia, and a hyperchloremic

metabolic acidosis. It was later discovered the patient had been consuming large quantities of licorice as a laxative. The lack of hemodynamic instability and other electrolyte abnormalities in the setting of adrenal crisis was attributed to presumed inhibition of 11 HSDH type II. In this setting, the effect of residual cortisol secretion from the remaining adrenal gland would be potentiated, thereby averting overt adrenal crisis. Acquired inhibition of 11 -HSDH type II may be of importance in the salt retention that occurs among some patients with cirrhosis of the liver (55). Aldosterone is generally believed to play a major role in the renal salt retention observed in patients with cirrhosis; however, there are many examples of patients who present with ascites and marked total-body sodium excess and have either normal or suppressed aldosterone levels. Bile acids that can accumulate in the setting of chronic liver disease have been shown to inhibit the activity of 11 -HSDH type II. Such an effect would allow cortisol-mediated stimulation of the mineralocorticoid receptor and potentially explain aldosterone-independent salt retention in the distal nephron in liver cirrhosis. Studies of the bile duct ligation and carbon tetrachloride models of chronic liver disease are consistent with a component of cortisol-mediated stimulation of the mineralocorticoid receptor. A recent report described a patient who had sickle cell disease and developed two separate episodes of hypokalemia as a result of renal K wasting in association with sickle cell crisis (56). At baseline, the patient had a normal serum K concentration but had a total bilirubin of approximately 9 mg/dl, presumably as a result of intrahepatic cholestasis, which is typical of patients with this disease. During the two separate episodes of hemolytic crisis, the total bilirubin increased to values between 36 and 42 mg/dl. During these episodes, the serum K concentration decreased to 2.5 and 3.1 mEq/L in association with a high TTKG and low to normal aldosterone levels. It was hypothesized that worsening cholestasis led to greater bile acid inhibition of 11 -HSDH type II in the distal nephron, allowing for cortisol-mediated renal K wasting. Hereditary forms of hypertension to include those with suppressed circulating levels of renin and aldosterone has been the subject of a recent review (57). 11 -Hydroxylase deficiency and 17 -hydroxy-

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lase deficiency are rare autosomal recessive disorders that prevent the production of cortisol. The lack of feedback control results in high ACTH levels, which, in turns, drives the synthesis of mineralocorticoids, giving rise to hypertension and hypokalemic metabolic alkalosis. Glucocorticoid administration provides cortisol replacement and normalizes ACTH, thereby removing the drive for oversecretion of metabolites with mineralocorticoid effects. Na retention and renal K wasting are due to the effects of 11-deoxycortisol and 11-deoxycorticosterone among patients with 11 -hydroxylase deficiency (58). Virilization is typically present in these patients as a result of the overproduction of adrenal androgens. Patients with 17 -hydroxylase deficiency develop hypertension and hypokalemia as a result of accumulation of 11-deoxycorticosterone, corticosterone, and 18-hydroxycorticosterone (59,60). The enzymatic block in these patients leads to lack of sex hormones, resulting in the clinical picture of sexual infantilism in female patients and ambiguous or female external genitalia in male patients. The reabsorption of Na across the apical membrane in the collecting duct occurs through an amiloride-sensitive Na channel formed by the assembly of three subunits: , , and . Liddle syndrome is an inherited form of hypertension and hypokalemic metabolic alkalosis caused by mutations in this channel. These mutations either delete or alter residues in the C-terminal PY motif of the and subunits. Novel mutations in these subunits continue to be described (61). The PY motif of the , , and subunits is the binding site for the WW domain of a cytoplasmic protein called Nedd4-2. The binding of Nedd4-2 to the PY motif on each of the three subunits leads to ubiquination of the epithelial sodium channel, tagging it for eventual endocytosis and degradation. Interference in this binding leads to an inability to retrieve the channel from the membrane and results in increased channel density. The resultant increase in channel density gives rise to the clinical characteristics, suggesting constitutive activation of the epithelial sodium channel. The details of the Nedd4-2­induced ubiquination process, and channel removal from the membrane continues to be explored and has offered insight to other factors that are capable of influencing ENaC activity (62,63). One such factor that has been shown

to be capable of modulating Na transport through ENaC is epidermal growth factor (EGF). EGF leads to intracellular events through activation of extracellular signal­regulated kinases. Studies show that EGF decreases ENaC activity in association with extracellular signal­regulated kinase­mediated phosphorylation of a specific site on the subunit near the PY motif (64). This phosphorylation reduces Na transport initially by decreasing the open probability of the channel and later through increased channel removal. In collecting duct cells derived from a mouse model of Liddle syndrome caused by a subunit truncating mutation, this inhibitory effect of EGF on ENaC activity is no longer seen. Although renal Na retention leads to volume expansion and suppression of plasma renin and aldosterone, findings in a mouse model of Liddle syndrome also suggested that the activity of ENaC in the colon is increased (65). In this model, the Liddle mutation leads to a gain of function in colonic ENaC such that Na reabsorption from the gastrointestinal tract is increased. This activity could further contribute to the volume expansion observed in these animals. An autosomal dominant form of hypertension and hypokalemia that presents at a young age and characteristically worsens during pregnancy has been described in a single kindred. This disorder results from an activating mutation (S810L) in the mineralocorticoid receptor. Under normal circumstances, the mineralocorticoid receptor is activated by agonists that contain a 21-hydroxyl group such as aldosterone and cortisol. Steroids that lack the 21-hydroxyl group but contain a 17-keto group still bind to the normal receptor but are incapable of activating it. By contrast, these compounds can both bind and activate the mutated receptor. Progesterone (a 17 hydroxyl steroid) activates the mutated receptor, thereby explaining the worsening of hypertension that occurs during pregnancy when, progesterone levels are increased. Spironolactone (a synthetic steroid with a 17 lactone that normally exhibits antagonist activity) activates the mutated receptor and therefore should be avoided because the drug will worsen the clinical manifestations of the disorder. Recent studies detailed the binding characteristics of spironolactone to both the normal and the mutated receptor (66). Blocking ENaC with amiloride or triamterene is a treatment option for this disorder.

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Primary Increase in Distal Na Delivery

The word "primary" refers to conditions whereby distal Na delivery is increased for reasons other than expansion of extracellular fluid volume. In fact, extracellular fluid volume is either normal or decreased, so hypertension is not a feature of these disorders. Impaired Na reabsorption proximal to the collecting duct from genetic causes or administration of diuretics are examples of a primary increase in distal Na delivery. Increased distal Na delivery can also be primary as a result of the effects of a nonreabsorbable anion. One can further categorize these conditions as to the presence of metabolic alkalosis or metabolic acidosis. Active vomiting and nasogastric suction are classic examples in which hypokalemia develops due to the effects of a nonreabsorbable anion. Loss of gastric acid from the body results in the delivery of a HCO3 load to the kidney that exceeds the reabsorptive capacity of the proximal nephron. The subsequent delivery of large amounts of NaHCO3 to the distal nephron, coupled with increased aldosterone, provides the necessary requirements for increased renal K excretion. Recurrent protracted vomiting resulting in intermittent but severe hypokalemia can result in potential long-term nephrotoxicity. A renal biopsy was performed in such a patient with chronic peptic ulcer disease as part of the evaluation of a reduced creatinine clearance (67). The finding of chronic tubulointerstitial disease was attributed to recurrent and unremitting hypokalemia, a condition sometimes referred to as kaliopenic nephropathy. Hyperemesis gravidarum is a syndrome of severe vomiting that typically occurs early in pregnancy. In addition to HCO3 , increased urinary excretion of ketoanions acts as a nonreabsorbable anion, obligating large amounts of Na to the distal nephron. The development of hypokalemia in this condition has been shown to be an independent risk factor for the subsequent need for emergent operative delivery (68). Characteristic urine electrolytes in the setting of increased excretion of a nonreabsorbable anion are increased urine Na and K but a low urinary Cl . One would expect such findings in volume-depleted patients who develop hypokalemia after the administration of ticarcillin and carbenicillin. These antibiotics are excreted as Na salts and act as nonreabsorbable anions. In the setting of increased aldosterone levels, the high distal Na delivery led to increased

renal K excretion. A recent report described the development of severe hypokalemia in association with the administration of flucloxacillin (69). Urine Na and K both were increased as expected, but urinary Cl was also high. Measurement of renin and aldosterone levels was suppressed, suggesting that this patient was not volume depleted. The development of hypokalemia in this patient was likely due to a solute diuresis driven by the large Na load that accompanied the antibiotic as opposed to a nonreabsorbable anion effect, although both mechanisms may have been operative. A discussion of hypokalemia in association with use of loop and thiazide diuretics has been the subject of a recent review (70). In patients who have hypertension and take thiazide diuretics, the serum K concentration falls on average by 0.5 mEq/L. This decline can be as high as 0.9 mEq/L with the longacting agent chlorthalidone. Although loop diuretics are more potent natriuretic agents, they typically result in a milder degree of hypokalemia; the average decline in the serum K concentration is 0.3 mEq/L. This lesser effect may be related to the much shorter halflife of loop diuretics compared with the thiazide diuretics. Although not proved, this smaller decline may also be related to the ability of loop diuretics to inhibit Ca2 absorption in the loop of Henle. The ensuing increase in Ca2 delivery to the lumen of the distal nephron may inhibit Na reabsorption and therefore may diminish distal K secretion. The degree of diuretic-induced hypokalemia is influenced by the amount of dietary salt intake. The administration of a diuretic in conjunction with the ingestion of large amounts of dietary Na (180 to 200 mEq/L) renders a patient particularly vulnerable to the development of hypokalemia. This particular combination would allow for maximal Na and fluid delivery to the distal nephron at the very time aldosterone secretion is stimulated by the initial diuretic-induced Na depletion; however, extreme dietary Na restriction also tends to worsen the degree of hypokalemia associated with the use of diuretics. The basis for this effect is the curvilinear relationship between dietary Na intake and serum renin and aldosterone levels. This relationship is gradual at Na intakes of 80 mEq/L. With Na intakes of 50 mEq/L, however, a steep rise in renin and aldosterone levels results (71,72). At these levels, the kaliuretic effect of aldosterone is the predominate factor in promoting renal

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K excretion. Na intake between these extremes (70 to 100 mEq/L) causes only a slight rise in aldosterone levels, which, when coupled with less delivery of Na to the distal nephron, results in an overall decrease in renal K excretion. Thus, moderate dietary Na intake in patients who have hypertension and are treated with diuretics not only will provide the maximal antihypertensive effect but also may limit the degree of K depletion. The decline in the serum K concentration usually develops within the first 2 wk of therapy and then stabilizes as a new steady state is achieved. Thereafter, the serum K concentration should remain stable. Further declines in the serum K concentration are prevented by several factors that serve to decrease renal K secretion. Increased reabsorption of Na in the proximal nephron as a result of the diureticinduced decreases in extracellular fluid volume serves to dampen Na and fluid delivery to the distal nephron. In addition, a progressive increase in mineralocorticoid activity is prevented because the development of hypokalemia tends to inhibit release of aldosterone from the adrenal gland. Chronic hypokalemia is also associated with a direct cellular effect, leading to decreased distal nephron K excretion. Finally, K reabsorption is stimulated in the collecting duct under conditions of chronic hypokalemia as a result of increased activity of the H -K -ATPase pump. The development of more severe hypokalemia in the setting of long-term diuretic administration suggests some other perturbation in K balance such as an intercurrent illness, leading to extrarenal K loss (diarrhea), a decrease in K intake (vomiting), or a change in diuretic dosage. Liver failure as a result of overdose of paracetamol is commonly associated with acute kidney injury; however, renal injury can also occur in the absence of liver disease. Several recent reports emphasized the development of hypokalemia as a complication of paracetamol overdose. The decline in the serum K concentration can be to values 3.0 mmol/L and typically develops in the first 36 h after ingestion (73). In a retrospective examination of 155 patients with paracetamol overdose, an inverse relationship was found between the serum paracetamol level 4 h after ingestion and the decline in serum K concentration (74). In a prospective study of 41 overdose patients, the degree of kaliuresis as measured by the fractional excretion of K and the TTKG was significantly

correlated with the paracetamol concentration on admission. The mechanism of K wasting in this situation is not known but is presumably due to a direct toxic effect of the drug on the kidney. Quetiapine is an oral antipsychotic drug used in the treatment of schizophrenia and bipolar disorder. Large doses of the drug can precipitate the development of hypokalemia within several hours of administration (75). The rapidity of development suggests a K shift into cell; however, the exact mechanism is not known. Although not well studied, this complication is said to occur more commonly in patients of Asian descent. Cleistanthus collinus is a plant used in suicidal and homicidal poisoning in India. A life-threatening complication of the poisoning is the precipitation of a myasthenic crisis­like syndrome as a result of neuromuscular blockade (76). Hypokalemia has also been described in this setting and attributed to renal K wasting, although the exact mechanism is not known. A variety of fluid and electrolyte disorders to include hypokalemia can occur in association with leukemia and lymphomas either through direct effects of the tumor or as a result of treatment strategies (77). Increased urinary excretion of lysozyme, particularly in the setting of acute monocytic and myelomonocytic leukemia, leads to renal K wasting (78). Both tubular toxicity and a nonreabsorbable anion effect of lysozyme has been suggested to account for this effect. Hypokalemia is particularly common in the bone marrow transplant setting, developing in 80% of cases (79). Administration of diuretics, amphotericin B, and hypomagnesemia are just a few of several potential causes of renal K wasting in this setting. With regard to amphotericin B, patients with proteinuria are less prone to develop renal K wasting (80). This protective effect may be a result of binding of amphotericin B to protein in the tubular lumen, resulting in less available free drug to cause tubular toxicity. Hypomagnesemia is also a widely recognized cause of renal K wasting. A recent review summarized evidence to support an inhibitory effect of intracellular Mg2 on K secretion through ROMK channels in the distal nephron (81). A decrease in intracellular Mg2 in the setting of Mg2 deficiency would release this inhibitory effect, causing increased renal K secretion. This kaliuretic effect is likely to be exacerbated under conditions of increased distal Na delivery and increased aldosterone.

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Intracellular Mg2 acts to inhibit K secretion through ROMK in the distal nephron. Depletion of intracellular Mg2 in the setting of hypomagnesemia may account for the renal K wasting typically present in this setting. Direct infiltration into the kidney occurs in 30 to 40% of lymphoma cases. Renal involvement can lead to bilateral enlargement of the kidney and occasionally acute kidney injury, possibly as a result of increased intrarenal pressures (82). These tumors are typically of B cell origin and can be diagnosed with tissue obtained on renal biopsy. In one patient, diffuse lymphomatous infiltration of the kidneys resulted in tubular dysfunction, causing hypokalemia in association with renal tubular acidosis (83). The patient presented with acute onset flaccid paralysis in the setting of a K of 1.5 mEq/L. Capecitabine is an antineoplastic agent used in the treatment of colorectal carcinoma. In a retrospective study, 20% of patients who were treated with this drug developed hypokalemia (84). The degree of hypokalemia was proportional to urinary K , suggesting that the drug caused renal K wasting. Ondansetron, used in the treatment of nausea and vomiting associated with administration of chemotherapy, has also been implicated in the development of renal K wasting and hypokalemia (85). Hypokalemia is a cardinal feature of type 1 distal renal tubular acidosis (dRTA). The mechanism by which hypokalemia develops is likely to vary according to the underlying defect, as emphasized in a review (86). Systemic acidosis can lead to renal K wasting. Metabolic acidosis is associated with decreased net proximal Na reabsorption. The subsequent increase in distal delivery leads to volume contraction and activation of the renin-angiotensin-aldosterone system. The combination of increased distal Na delivery and aldosterone as discussed previously would cause renal K excretion. K wasting can be the result of leakage into the tubular lumen as a result of an ionophoric effect as seen in the gradient type of dRTA associated with administration of amphotericin B. A genetic or acquired defect in the H -K -ATPase will increase renal K excretion by directly impairing K reabsorption in the distal nephron. The most severe

hypokalemia is seen in patients with mutations in certain subunits of the H -ATPase pump.

Complications and Treatment of Hypokalemia

Hypokalemia can cause a variety of clinical manifestations as a result of alterations in the excitability of neuromuscular tissues. Decrease in extracellular K concentration leads to hyperpolarization of the cell membrane, causing the cell to become less sensitive to exciting stimuli. Clinically, this effect accounts for the association of hypokalemia and muscle weakness. Occasionally, muscle weakness can be severe enough to cause paralysis, as in patients with hypokalemic dRTA secondary to Sjogren syndrome (87,88). Severe mus¨ cle weakness can also occur in the setting of dialysis. One patient who was depleted of total-body K as a result of severe gastroenteritis developed quadriplegia during the course of several hours after a hemodialysis treatment (89). The postdialysis K concentration was 0.98 mmol/L. It is important for clinicians to anticipate which patients are at risk for postdialysis hypokalemia and to adjust the dialysate K accordingly. Under normal circumstances, exercise is associated with movement of intracellular K into the interstitial space in skeletal muscle. The increase in interstitial K can be as high as 10 to 12 mmol with intense exercise. This accumulation of K has been implicated as a factor limiting the excitability and contractile force of muscle accounting for the development of fatigue (90,91). In addition, increases in interstitial K are thought to be an important factor in eliciting rapid vasodilation, allowing for blood flow to increase in exercising muscle (92). Hypokalemia is a cause of rhabdomyolysis. Although the mechanism is likely to be multifactorial, total-body K depletion may blunt the accumulation of K into the interstitial space, thereby limiting blood flow to skeletal muscle and resulting in muscle breakdown. Total-body K depletion from any cause can potentially result in this complication and has been described with vomiting, ingestion of herbal medications that contain licorice, and inherited 11-hydroxyase deficiency (93­95). Hypokalemic nephropathy or kaliopenic nephropathy is a tubulointerstitial disease characterized by polyuria, proteinuria, development of renal cysts, and loss of renal function. Histologically, there is evidence of tubular atrophy, interstitial infiltration of macrophages, and interstitial fibrosis. Mediators of

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renal injury in this setting include local ischemia, complement activation as a result of increased ammoniagenesis, and local effects of angiotensin II and endothelin. Studies of Sprague-Dawley rats that were fed a low-K diet implicated impaired angiogenesis as an additional mechanism of renal injury in this disorder (96). The renal lesion in these animals is characterized by an influx of macrophages likely as a result of increased expression of monocyte chemoattractant peptide 1 and osteopontin. A decrease in capillary density in the interstitium that correlated closely with the development of interstitial fibrosis was noted. There was a significant reduction in the amount of vascular endothelial growth factor and evidence of oxidative stress possibly related to the local accumulation of macrophages. Other studies of the Sprague-Dawley rat examined whether renal injury would differ among rats made hypokalemic by feeding a moderately low-K diet or through the administration of a thiazide diuretic (97). In both groups of rats, there was evidence of decreased endothelial-dependent vasorelaxation that correlated with the degree of hypokalemia; however, despite the same BP and degree of hypokalemia, only thiazide-treated rats developed renal injury. The mechanism is unclear. In addition, thiazides can cause hyperaldosteronism secondary to contraction of extracellular fluid volume. Aldosterone has been implicated in the development of renal injury in other types of experimental models. In addition, renal cysts are highly frequent among patients with various types of primary hyperaldosteronism. Medical or surgical treatment of these disorders effectively halts the progression of cysts, supporting a pathologic role of persistently elevated levels of aldosterone (98). Hypokalemia may play a role in the association between new-onset diabetes and use of thiazide diuretics. In a review of 50 trials in which thiazides were compared with other drugs or placebo, a significant inverse relationship was found between the decrease in K and the increase in glucose level (99). For every 1-mEq/L decrease in K , there was an approximately 10-mg/dl increase in glucose. Further strengthening the argument that hypokalemia plays an important role in the genesis of glucose intolerance is the observation that prevention of hypokalemia with K supplements prevented the development of thiazide-induced glucose intolerance (100). In addition, changes in glucose

levels can be normalized after K repletion in patients who have hypokalemia. The mechanism of thiazide-induced hyperglycemia is thought to be the result of decreased insulin released from the pancreatic cell. ATP-sensitive K channels couple cell metabolism to electrical activity, thereby playing an essential role in the control of insulin secretion (101). The involvement of K in this process at least raises the possibility that K depletion might alter cell insulin release. Impaired insulin release that is reversible with drug discontinuation or K supplements is in contrast to the persistent insulin resistance that is typical of patients with type 2 diabetes. This difference in mechanism of glucose intolerance may help to explain the lack of convincing evidence that thiazide-induced diabetes increases the incidence of morbid or fatal cardiovascular events (102). Central pontine myelinosis (CPM) is a lesion typically ascribed to the rapid correction of hyponatremia but rarely may occur in association with hypokalemia. A patient with a normal serum Na concentration but severe hypokalemia as a result of hyperemesis gravidarum underwent a magnetic resonance imaging scan after presenting with urinary incontinence, weakness, and lower extremity pain (103). A diagnosis of CPM was made on the basis of the findings of hyperintensity within the central pons. During the course of several months, the symptoms resolved, and a repeat scan 4 mo later was normal. Hypokalemia has also been reported to be a risk factor for CPM in patients who present with hyponatremia (104). In the patient with hypokalemia, K can be given orally or intravenously as the KCl salt. KHCO3 or potassium citrate can be given when there is concomitant metabolic acidosis. Oral administration of KCl is safest. KCl can be given in dosages of 100 to 150 mEq/d. Liquid KCl is bitter tasting, and the tablet can be irritating to the gastric mucosa. The microencapsulated or wax-matrix forms of KCl are better tolerated. Intravenous administration of K may be necessary when the patient cannot take oral medications or when the K deficit is large and is resulting in cardiac arrhythmias, respiratory paralysis, or rhabdomyolysis. Intravenous KCl should be given at a maximum rate of 20 mEq/h and maximum concentration of 40 mEq/L. Higher concentrations will result in phlebitis. Replace-

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ment of KCl in dextrose-containing solutions can result in further lowering of the serum K secondary to insulin release; therefore, saline solutions are preferred. On rare occasions, higher concentrations of K may have to be given. In a patient with a serum K of 2.6 mmol/L and an implantable cardiac defibrillator, rapid administration of K successfully led to the termination of recurrent unstable ventricular tachycardia (105). This patient was given a rapid bolus of 20 mEq of KCl solution using a central access, followed by an additional 80 mEq orally and intravenously during the next 2 h. A 12-yr-old boy with a K of 1.2 mEq/L as a result of gastrointestinal losses was given 140 mEq of KCl as a hand-pushed bolus after developing pulseless ventricular tachycardia (106). The bolus administration led to resolution of the arrhythmia. Aggressive K administration of this type requires frequent measurement of serum K and continuous electrocardiographic monitoring to prevent iatrogenic hyperkalemia. In a retrospective look at 140 hospitalized patients with hypokalemia, 16% of patients developed therapy-induced hyperkalemia. Compared with patients who simply corrected to normal, the amount of K given was greater for patients with iatrogenic hyperkalemia (107). References

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50. Mumoli N, Cei M: Licorice-induced hypokalemia. Int J Cardiol 124: e42­ e44, 2008 51. Tancevski I, Eller P, Spiegel M, Kirchmair R, Patsch J: Malicious licorice. Circulation 117: e299, 2008 52. Ohtake N, Kido A, Kubota K, Tsuchiya N, Morita T, Kase Y, Takeda S: A possible involvement of 3-monoglucuronyl-glycyrrhetinic acid, a metabolite of glycyrrhizin (GL), in GL-induced pseudoaldosteronism. Life Sci 80: 1545­1552, 2007 53. Cooper H, Bhattacharya B, Verma V, McCulloch AJ, Smellie W, Heald A: Liquorice and soy sauce, a life-saving concoction in a patient with Addison's disease. Ann Clin Biochem 44: 397­399, 2007 54. Isaia G, Pellissetto C, Ravazzoli M, Tamone C: Acute adrenal crisis and hypercalcemia in a patient assuming high liquorice doses. Minerva Med 99: 91­94, 2008 55. Frey F: Impaired 11 -hydroxysteroid dehydrogenase contributes to renal sodium avidity in cirrhosis: Hypothesis or fact? Hepatology 44: 795­ 801, 2006 56. Jaitly M, Mohan S, Park C, Anderson H, Cheng J, Pogue V: Hypokalemia during sickle cell crises apparently due to intermittent mineralocorticoid excess. Am J Kidney Dis 51: 319 ­325, 2008 57. Vehaskari V: Heritable forms of hypertension. Pediatr Nephrol July 24, 2007 [epub ahead of print] 58. Nimkarn S, New M: Steroid 11beta-hydroxylase deficiency congenital adrenal hyperplasia. Trends Endocrinol Metab 19: 96 ­99, 2008 59. Shoemaker L, Eaton B, Buchino J: A three-year-old with persistent hypokalemia. J Pediatr 151: 696 ­ 699, 2007 60. Benetti-Pinto C, Vale D, Garmes H, Bedone A: 17-Hydroxyprogesterone deficiency as a cause of sexual infantilism and arterial hypertension: Laboratory and molecular diagnosis--A case report. Gynecol Endocrinol 23: 94 ­98, 2007 61. Rossi E, Farnettie E, Debonneville A, Nicoli D, Grasselli C, Regolisti G, Negro A, Perazzoli F, Casali B, Mantero F, Staub O: Liddle's syndrome caused by a novel missense mutation (P617L) of the epithelial sodium channel beta subunit. J Hypertens 26: 921­927, 2008 62. Wiemuth D, Ke Y, Rohlfs M, McDonald F: Epithelial sodium channel (ENaC) is multi-ubiquitinated at the cell surface. Biochem J 405: 147­155, 2007 63. Kabra R, Knight K, Zhou R, Snyder P: Nedd4 ­2 induces endocytosis and degradation of proteolytically cleaved epithelial Na channels. J Biol Chem 283: 6033­ 6039, 2008 64. Falin R, Cotton C: Acute downregulation of ENaC by EGF involved the PY motif and putative ERK phosphorylation site. J Gen Physiol 130: 313­328, 2007 65. Bertog M, Cuffe J, Pradervand S, Hummler E, Hartner A, Porst M, Hilgers K, Rossier B, Korbmacher C: Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome. J Physiol 586: 459 ­ 475, 2008 66. Huyet J, Pinon G, Fay M, Fagart J, Rafestin-Oblin M: Structural basis of spirolactone recognition by the mineralocorticoid receptor. Mol Pharmacol 72: 563­571, 2007 67. Akimoto T, Saito O, Kotoda A, Nishino K, Umino T, Muto S, Kusano E: A case of recurrent renal failure associated with metabolic alkalosis induced by protracted vomiting. Clin Exp Nephrol 10: 279 ­283, 2006 68. Tan P, Jacob R, Quek K, Omar S: Pregnancy outcome in hyperemesis gravidarum and the effect of laboratory clinical indicators of hyperemesis severity. J Obstet Gynaecol 33: 457­ 464, 2007 69. Hoorn E, Zietse R: Severe hypokalemia caused by flucloxacillin. J Antimicrob Chemother 61: 1396 ­1398, 2008 70. Palmer B, Naderi A: Metabolic complications associated with use of thiazide diuretics. J Am Soc Hypertens 1: 381­392, 2007 71. Van Brummelenp P, Schalekamp M, De Graeff J: Influence of sodium intake on hydrochlorothiazide-induced changes in blood

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pressure, serum electrolytes, renin and aldosterone in essential hypertension. Acta Med Scand 204: 151­157, 1978 Landmann-Suter R, Struyvenberg A: Initial potassium loss and hypokalaemia during chlorthalidone administration in patients with essential hypertension: The influence of dietary sodium restriction. Eur J Clin Invest 8: 155­164, 1978 Godber I, Jarvis S, Maguire D: Hypokalaemia following paracetamol overdoes in two teenage girls. Ann Clin Biochem 44: 403­ 405, 2007 Pakravan N, Bateman D, Goddard J: Effect of acute paracetamol overdose on changes in serum and urine electrolytes. Br J Clin Pharmacol 64: 824 ­ 832, 2007 Lin Y, Chen H, Chang T, Lane H: Hypokalemia following rapid titration of quetiapine treatment. J Clin Psychiatry 69: 165­166, 2008 Damodaram P, Manohar I, Kumar D, Mohan A, Vengamma B: Myasthenic crisis-like syndrome due to cleistanthus collinus poisoning. Indian J Med Sci 62: 62­ 64, 2008 O'Regan S, Carson S, Chesney R, Drummon K: Electrolyte and acid-base disturbances in the management of leukemia. Blood 49: 345­353, 1977 Muggia F, Heinemann H, Farhangi M, Osserman E: Lysozyrmuria and renal tubular dysfunction in monocytic and myelomonocytic leukemia. Am J Med 47: 351­366, 1969 Philibert D, Desmeules S, Filion A, Poirier M, Agharazii M: Incidence and severity of early electrolyte abnormalities following autologous hematopoietic stem cell transplantation. Nephrol Dial Transplant 23: 359 ­363, 2008 Mohan S, Ahmed S, Alimohammadi B, Jaitly M, Cheng J, Pogue V: Proteinuria lowers the risk of amphotericin B-associated hypokalaemia. J Antimicrob Chemother 60: 690 ­ 693, 2007 Huang C, Kuo E: Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol 18: 2649 ­2652, 2007 Tornroth T, Heiro M, Marcussen N, Franssila K: Lymphomas diagnosed by percutaneous kidney biopsy. Am J Kidney Dis 42: 960 ­971, 2003 Jhamb R, Gupta N, Gar S, Kumar S, Gulati S, Michra D, Beniwal P: Diffuse lymphomatous infiltration of kidney presenting as renal tubular acidosis and hypokalemic paralysis: Case report. Croat Med J 48: 860 ­ 863, 2007 Saif M, Fekrazad M, Ledbetter L, Diasio R: Hypokalemia secondary to capecitabine: A hidden toxicity? Ther Clin Risk Manag 3: 177­180, 2007 Turner S, Pinsk M: Ondansetron-associated hypokalemia in a 2-year-old with pre-B-cell ALL. J Pediatr Hematol Oncol 30: 58 ­ 60, 2008 Batlle D, Moorthi K, Schlueter W, Kurtzman N: Distal renal tubular acidosis and the potassium enigma. Semin Nephrol 26: 471­ 478, 2006 [published erratum appears in Semin Nephrol 27: 373, 2007] Comer D, Droogan A, Young I, Maxwell A: Hypokalaemic paralysis precipitated by distal renal tubular acidosis secondary to Sjogren's syndrome. Ann Clin Biochem 45: 221­225, 2008 ¨ Aygen B, Dursun F, Dogukan A, Ozercan I, Celiker H: Hypokalemic quadriparesis associated with renal tubular acidosis in a patient with Sjogren's syndrome. Clin Nephrol 69: 306 ­309, 2008 ¨ Saif I, Halim A, Saif M, Siddiqui U, Rahman M, Azam N: Severe post-dialysis hypokalaemia leading to quadriparesis. J Pak Med Assoc 58: 41­ 43, 2008 Clausen T, Nielsen O: Potassium, Na , K -pumps and fatigue in rat muscle. J Physiol 584: 295­304, 2007 McKenna M, Bangsbo J, Renaud J: Muscle K , Na , and C1 disturbances and Na -K pump inactivation: Implications for fatigue. J Appl Physiol 104: 288 ­295, 2008 Clifford P: Skeletal muscle vasodilatation at the onset of exercise. J Physiol 583: 825­ 833, 2007 Atabek M, Pirgon O, Sert A: Hypokalemic rhabdomyolysis in a

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child with 11-hydroxylase deficiency. J Pediatr Endocrinol Metab 21: 93­96, 2008 Yasue H, Itoh T, Mizuno Y, Harada E: Severe hypokalemia, rhabdomyolysis, muscle paralysis, and respiratory impairment in a hypertensive patient taking herbal medicines containing licorice. Intern Med 46: 575­578, 2007 Possamai L, Waring W: Acute myopathy in a patient with esophageal stricture. Age Ageing 36: 698 ­ 699, 2007 Reungjui S, Roncal C, Sato W, Glushakova O, Croker B, Suga S, Ouyang X, Tunsanga K, Nakagawa T: Hypokalemic nephropathy is associated with impaired angiogenesis. J Am Soc Nephrol 19: 125­134, 2008 Reungjui S, Hu H, Mu W, Roncal C, Croker B, Patel J, Nakagawa T, Srinivas T, Byer K, Simoni J, Wesson D, Sitprija V, Johnson R: Thiazide-induced subtle renal injury not observed in states of equivalent hypokalemia. Kidney Int 72: 1483­1492, 2007 Novello M, Catena C, Nadalini E, Colussi G, Baroselli S, Chiuch A, Lapenna R, Bazzocchi M, Sechi L: Renal cysts and hypokalemia in primary aldosteronism: Results of long-term follow-up after treatment. J Hypertens 25: 1443­1450, 2007 Zillich A, Garg J, Basu S, Bakris G, Carter B: Thiazide diuretics, potassium, and the development of diabetes: A quantitative review. Hypertension 48: 219 ­224, 2006 Alderman M: New onset diabetes during antihypertensive therapy. Am J Hypertens 21: 493­ 499, 2008 Koster J, Remedi M, Masia R, Patton B, Tong A, Nichols C: Expression of ATP-insensitive KATP channels in pancreatic betacells underlies a spectrum of diabetic phenotyes. Diabetes 55: 2957­2964, 2006 Barzilay J, Cutler J, Davis B: Antihypertensive medications and risk of diabetes mellitus. Curr Opin Nephrol Hypertens 16: 256 ­260, 2007 Patel S, Parish D, Patel R, Grimsley E: Resolution of MRI findings in central pontine myelinosis associated with hypokalemia. Am J Med Sci 334: 490 ­ 492, 2007 Heng A, Vacher P, Aublet-Cuvelier B, Garcier J, Sapin V, Deteix P, Souweine B: Centropontine myelinolysis after correction of hyponatremia: Role of associated hypokalemia. Clin Nephrol 67: 345­ 351, 2007 Philips D, Bauch T: Rapid correction of hypokalemia in a patient with an ICD and recurrent ventricular tachycardia. J Emerg Med March 27, 2008 [epub ahead of print] Garcis E, Nakhleh N, Simmons D, Ramsay C: Profound hypokalemia: Unusual presentation and management in a 12-year-old boy. Pediatr Emerg Care 24: 157­160, 2008 Crop M, Hoorn E, Lindemans J, Zietse R: Hypokalaemia and subsequent hyperkalaemia in hospitalized patients. Nephrol Dial Transplant 22: 3471­3477, 2007

Hyperkalemia

The normal adult is in potassium (K ) balance such that dietary intake is matched by K excretion primarily by the kidney, with a lesser contribution by the gastrointestinal tract. K is freely filtered by the glomerulus and then reabsorbed in the proximal tubule and loop of Henle such that only 10% of the filtered load reaches the distal nephron. In this segment, K secretion primarily occurs in the initial collecting duct and the cortical collecting duct. Under most physiologic and pathologic conditions, K delivery to the distal nephron remains small and is fairly constant. By

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contrast, the rate of K secretion by the distal nephron varies and is regulated according to physiologic needs. K secretion in the distal nephron is generally responsible for most urinary K excretion. Two populations of K channels have been identified in the cells of the cortical collecting duct. The ROMK channel is considered the major K -secretory pathway. This channel is characterized by having low conductance and a high probability of being open under physiologic conditions. The maxi-K channel is characterized by a large single-channel conductance and is relatively quiescent in the basal state. This channel is activated by increases in intracellular Ca2 concentration, and stress and is thought to play a major role in flow-stimulated K secretion. This channel is found in both principal cells and intercalated cells but may have a density greater in the latter (1). In contrast to adults, growing infants and children are in a state of positive K balance, which correlates with growth and increasing cell number. In early developmental stages, there is a limited capacity of the distal nephron to secrete K as a result of decreased numbers of apically located K channels. The increase in K secretory capacity with maturation is initially a result of increased expression of ROMK. Several weeks later, there is evidence of flow-mediated K secretion as maxi-K channels begin to be expressed (reviewed in reference2). This temporal sequence in K channel expression helps to explain the transient hyperkalemia typically seen in the perinatal period of infants with type II Bartter syndrome. These patients have a mutation in ROMK that severely limits K secretion in the collecting duct. With time, maxi-K channel expression begins to appear, and hyperkalemia gives way to the typical hypokalemia as a result of increased flow-mediated K secretion. The H -K -ATPase is a pump that couples hydrogen (H ) secretion to K reabsorption in the distal nephron. The activity of this pump is similar in newborns and adults. K reabsorption through the pump along with decreased expression of K -secretory channels contributes to K retention in the neonatal kidney. These features of distal K handling by the developing kidney are a likely explanation for the high incidence of nonoliguric hyperkalemia in preterm infants (3). When therapy is needed in such patients, salbutamol infusion is more effective and safer than use of a rectal cation-exchange resin (4).

In contrast to adults, growing infants and children are in a state of positive K balance, which correlates with growth and increasing cell number. An intact H -K ATPase along with decreased expression of K -secretory channels contributes to K retention in the neonatal kidney.

Pseudohyperkalemia

Pseudohyperkalemia is an in vitro phenomenon that is a result of the mechanical release of K from cells during the phlebotomy procedure or specimen processing. Common causes of pseudohyperkalemia include fist clenching during the phlebotomy procedure, application of tourniquets, and use of small-bore needles (5). Variations in ambient temperature can also influence the laboratory determination of K values. The incidence of pseudohyperkalemia increases during the winter, when samples are likely to be exposed to lower ambient temperatures during transport (6). Higher ambient temperatures decrease the frequency of this complication. A spurious increase in plasma K concentration should be considered when accompanied by a very low plasma Ca2 concentration. In vitro contamination with K-EDTA, a liquid used as an anticoagulant in certain sampling tubes, can cause this problem through Ca2 chelation and simultaneous release of K (7). Pathologic causes of pseudohyperkalemia are mostly seen in the setting of hematologic disorders such as thrombocytosis and pronounced leukocytosis. This disorder was recently described in a patient with myelofibrosis complicated by giant platelets and nucleated red blood cells (8).

The incidence of pseudohyperkalemia increases during the winter, when samples are likely to be exposed to lower ambient temperatures during transport. Higher ambient temperatures decrease the frequency of this complication.

Clinical Manifestation of Hyperkalemia

All of the clinically important manifestations of hyperkalemia occur in excitable tissue. Neuromuscular manifestations include paresthesias and fascicula-

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tions in the arms and legs. As the serum K continues to rise, an ascending paralysis with eventual flaccid quadriplegia supervenes. Classically, trunk, head, and respiratory muscles are spared, but rarely respiratory failure can occur. The depolarizing effect of hyperkalemia on the heart is manifested by changes that are observable in the electrocardiogram (ECG). The progressive changes of hyperkalemia are classically listed as peaking of T waves, ST-segment depression, widening of the PR interval, widening of the QRS interval, loss of the P wave, and development of a sine-wave pattern (9). The appearance of a sine-wave pattern is ominous and is a harbinger of impending ventricular fibrillation and asystole (10,11). Hyperkalemia can also be associated with a number of less common patterns on the ECG. Brugada syndrome is a genetic disease associated with sudden cardiac death as a result of mutations in a cardiac Na channel. ECG changes are characterized by a rightbundle branch block pattern and right precordial STsegment elevations. A similar pattern has been reported in patients with hyperkalemia; however, the hyperkalemic Brugada pattern differs from the genetic disorder in that P waves are often absent, abnormal axis deviation is present, and the QRS complex is wider (12). Hyperkalemia can also give rise to ECG changes that are typical of cardiac ischemia. The tall, narrow, and symmetrical peaked T waves that are typical of hyperkalemia can occasionally be confused with the hyperacute T-wave change associated with a ST-segment elevation myocardial infarction (13); however, in this latter condition, the T waves tend to be more broad based and asymmetric in shape. A pseudoinfarct pattern has also been described, resembling both an anteroseptal and an inferior wall myocardial infarction (14,15). These changes resolve with treatment of the hyperkalemia and in the absence of increased cardiac enzymes. Double counting of the heart rate by ECG interpretation software can also occur as a result of hyperkalemic ECG changes (16). The correlation of ECG changes and serum K concentration depends on the rapidity of the hyperkalemia onset. Generally, with acute onset of hyperkalemia, ECG changes appear at a serum K of 6 to 7 mEq/L; however, with chronic hyperkalemia, the ECG may remain normal up to a concentration of 8 to 9 mEq/L. Despite these generalities, clinical studies

show a poor correlation between serum K concentration and cardiac manifestations. In a retrospective review, only 16 of 90 cases met strict criteria for ECG changes reflective of hyperkalemia (defined as new peaked and symmetric T waves that resolved on follow-up) (17). In 13 of these cases, the cardiologist read the ECG as showing no T-wave changes. Strict ECG changes were noted in only one of 14 hyperkalemic patients who manifested arrhythmias or cardiac arrest, which calls into question the prognostic use of the ECG in this setting. Given the poor sensitivity and specificity of the ECG, the authors stressed that the clinical scenario and serial measurements of K are the preferred tools to guide the treatment of patients with hyperkalemia.

Excessive K Loads: Exogenous or Endogenous

In the presence of normal renal and adrenal function, it is difficult to ingest sufficient K in the diet to produce hyperkalemia. Rather, dietary intake of K as a contributor to hyperkalemia is usually observed in the setting of impaired kidney function. There are examples of unusual dietary habits leading to hyperkalemia. A 51-yr-old man developed ascending symmetric paralysis in association with a serum K of 9.0 mEq/L (18). Upon further investigation, the patient noted daily intake of 2.5 L of orange juice, giving him an estimated K load of 1125 mEq/d for 3 wk. A 15-yr-old woman with anorexia nervosa admitted to a diet that consisted of up to 20 bananas each day and small amounts of mineral water (19). Measurement of the serum K on this diet ranged from 4.7 to 6.1 mEq/L. The large quantity of banana intake also caused increased dopamine levels, which led to changes in behavior consistent with dysthymia. A 55-yr-old woman developed a serum K of 9.6 mmol/L after self-medication of potassium citrate for treatment of dysuria (20). This patient was ingesting 500 ml of the solution each week, which provided a daily K intake of 200 mmol. Hyperkalemia can also occur as an iatrogenic complication in the hospital setting. A 16-d-old infant with newly diagnosed maple syrup urine disease was placed on continuous venovenous hemofiltration to treat markedly elevated levels of leucine, isoleucine, and valine (21). To treat a decrease in serum K , a 10-ml vial containing 20 mEq of KCl was injected into a 5-L bag of replacement fluid. Within 4 min, ventricular premature beats that rapidly deteriorated into

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ventricular fibrillation developed. The serum K concentration was 9.6 mEq/L. The rapid development of hyperkalemia was attributed to injecting the KCl into the dependent portion of the hanging 5-L bag through a port immediately adjacent to the exit port. As a result of poor mixing, the concentrated KCl was immediately delivered into the patient, resulting in life-threatening hyperkalemia. Surgical diversion of the ureter into the sigmoid colon or the terminal ileum can be associated with the development of a normal gap metabolic acidosis, particularly when the exposure of urine to the intestinal mucosa is extensive and prolonged. Patients with ureterosigmoid anastomosis can occasionally develop hypokalemia as a result of colonic secretion of K . By contrast, anastomosis of the ureter to the jejunum can lead to hyperkalemia because this segment of the intestine normally reabsorbs K . This complication arose in a 77-yr-old man who underwent extensive pelvic surgery for treatment of rectal carcinoma (22). Because of the presence of multiple pelvic adhesions, the ureters were inadvertently diverted into a section of the jejunum. Upon institution of enteral feedings that contained a high K content, the patient quickly developed hyperkalemia. Hyperkalemia can also be the result of endogenous K loads. A 37-yr-old woman with stage 4 chronic kidney disease (CKD) at 26 wk gestation noted the onset of abdominal pain and cessation of fetal movement (23). She was admitted to the hospital and found to have a serum K concentration of 6.1 mEq/L that later increased to 7.5 mmol/L, despite intensive medical management. Because of increasing abdominal pain, she was taken to the operating room and found to have a ruptured uterus and dead fetus. The fetus was noted to have peeling skin consistent with intrauterine death that had occurred several days before the surgery. After removal of the fetus, the serum K concentration normalized. The development of hyperkalemia was attributed to a K load delivered into the maternal circulation from the degenerating fetus. Severe hemolysis can produce an endogenous K load sufficient to cause hyperkalemia, particularly in the setting of impaired renal function. A long-term dialysis patient with a prosthetic aortic valve developed severe hemolysis and hyperkalemia after the abrupt onset of atrioventricular nodal reentrant tachycardia (24). The hemolysis and release of K was

attributed to fragmentation of red blood cells by the prosthetic value as a result of the hemodynamic turbulence brought on by the arrhythmia. Hyperkalemia as a result of hemolysis is also a potential complication of tropical diseases such as malaria and leptospirosis (25). In addition to direct effects of the organism, hemolysis can develop from drugs that are used in the treatment of these infections, such as patients who have glucose-6-phosphate dehydrogenase deficiency and are given primaquine. An exogenous K load can be one of several factors contributing to the development of hyperkalemia in the setting of orthotopic liver transplantation. A retrospective observational study identified factors that were associated with development of hyperkalemia at three different time periods surrounding the procedure (26,27). These periods included the 2 h before reperfusion of the allograft, the first 15 min after reperfusion, and a late period of 1 h after reperfusion until the end of the case. At all time periods, there was a direct correlation between the baseline K value and risk for hyperkalemia. In the first time period, red blood cell transfusions added to this risk. In the second time period, hyperkalemia was more likely to occur when the allograft was taken from a cardiac death donor. In the later period, risk factors included decreased urine output, use of venovenous bypass, and longer warm ischemia time. An observational prospective cohort study conducted in Iraq examined the prevalence of hyperkalemia ( 5.5 mmol/L) in patients with penetrating, blunt, or explosive trauma in the 12-h period beginning from the time of emergency department evaluation (28). Exclusion criteria were hyperkalemia and a creatinine level of 1.5 mg/dl at the time of initial evaluation, burn, or crush injury. The period prevalence of hyperkalemia was 29%. Risk factors included a baseline K concentration of 4.0 mmol/L and transfusion of cellor plasma-based products. A subsequent report from the same group found that transfusion of 7 U of packed red blood cells (PRBCs) was independently associated with this risk (29). The risk for transfusion-associated hyperkalemia is related not only to the number of red blood cell transfusions but also to the rapidity in which the units are given. Concomitant conditions such as low cardiac output, metabolic acidosis, hypocalcemia, hyperglycemia, and hypothermia increase this risk (30). Whole blood and PRBCs are stored in anticoag-

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ulant preservative solution and have a shelf-life of approximately 35 d. The duration of storage can be extended to 42 d through the addition of an additive solution that contains varying concentrations of adenine, dextrose, and other substances (31). During storage, K leaks into the supernatant as a result of aging of red blood cell membranes and decreased synthesis of adenosine triphosphate. The magnitude of this leak increases with duration of storage. Irradiation of blood to inactivate T lymphocytes and minimize the risk for graft-versus-host disease enhances K leakage from red cells as a result of subtle membrane injury. Depending on the conditions, the supernatant of stored red blood cell units may contain 60 mEq/L K . When fresh PRBCs are unavailable, the risk for posttransfusion hyperkalemia can be minimized by washing the cells and decreasing the amount of additive solution. These maneuvers are of particular use for neonatal patients who undergo surgery for congenital heart disease and require irradiated blood as a result of the concomitant presence of cell-mediated immunodeficiency disorders (32).

Cell Shift

Tissue damage is one of the most common causes of hyperkalemia resulting from a redistribution of K out of cells. Common clinical examples include rhabdomyolysis, trauma, massive hemolysis, and tumor lysis. The major regulators of K shift into cells are insulin and catecholamines, with a lesser effect mediated by metabolic and respiratory alkalosis. Congenital hyperinsulinism is characterized by the unregulated secretion of insulin from pancreatic cells mostly as a result of mutations in subunits of the pancreatic cell ATP-sensitive K channel (33). A recent report described a neonatal patient who had this disorder and required several weeks of intravenous glucose to avoid hypoglycemia (34). The patient ultimately underwent a pancreatectomy to treat the hyperinsulinemic state. In the immediate postoperative period, the patient developed a serum K concentration of 12.3 mmol/L complicated by ventricular tachycardia. The hyperkalemia was successfully treated with no further recurrence. The authors postulated that weeks of hyperinsulinemia led to sequestration of large quantities of K in the intracellular compartment. After pancreatectomy and the sudden removal of insulin, K was free to exit the cells, resulting in a period of short-lived rebound hyperkalemia.

Another example of rebound hyperkalemia has been reported in association with the infusion of thiopental. This drug is a short-acting barbiturate that sometimes is used in patients who experienced head trauma to control increased intracranial pressure. Infusion of the drug is known to cause hypokalemia as a result of a shift into cells. Three patients who received large amounts of K to maintain normokalemia during thiopental infusion therapy were recently reported (35). In each case, hyperkalemia developed immediately after cessation of the intravenous infusion, consistent with a rebound effect. Hyperkalemia as a result of a shift out of cells is a widely known complication of the paralytic agent succinylcholine. Risk factors for this complication include denervation, prolonged immobilization, chronic infection, and burn injury (36). Under these conditions, acetylcholine receptors become upregulated and widespread throughout the skeletal muscle membrane as opposed to the normal state, whereby they are primarily confined to the neuromuscular junction. As a result, succinylcholine-induced depolarization leads to a magnitude of K efflux sufficient to cause hyperkalemia. Patients who have received previous radiation therapy may also be at risk for this complication (37). Such treatment can lead to chronic thermal injury to skeletal muscle and potentially cause redistribution of acetylcholine receptors similar to what is seen with immobilization and burns. Cell shift is a potential complication of hypertonic states as well. Hyperglycemia leads to water movement from the intracellular to extracellular compartment. This water movement favors K efflux from the cell through the process of solvent drag. In addition, cell shrinkage causes intracellular K concentration to increase, creating a more favorable concentration gradient for K efflux. This same phenomenon has been described in neurosurgical patients who were given large amounts of hypertonic mannitol (38). Intravenous Ig preparations contain sugar additives such as sorbitol, maltose, and sucrose to prevent Ig aggregation. These sugars have been implicated in the development of Ig-induced acute renal failure. Risk factors include preexisting CKD, volume depletion, and advanced age. Renal histology typically shows marked vacuolization of the tubular cells, a lesion referred to as osmotic nephrosis. A less common adverse effect of such therapy is the development of hyponatremia and hyperkalemia. In a manner sim-

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ilar to that of hyperglycemia or administration of mannitol, accumulation of these sugars in the blood will increase tonicity and potentially increase the serum K concentration (39). Rhabdomyolysis can cause severe hyperkalemia as a result of leakage of K from damaged skeletal muscle. Malignant hyperthermia is a rare clinical syndrome manifested by muscle rigidity, tachycardia, increased CO2 production, skin cyanosis and mottling, rhabdomyolysis, and potentially hyperkalemia (40). The onset of the disorder is usually within 1 h of the administration of general anesthesia, with the most common triggers being halothane and succinylcholine. The syndrome is due to a mutation in the gene that encodes the skeletal muscle ryanodine receptor. This receptor is a calcium channel that, when mutated, allows excess amounts of calcium to exit the sarcoplasmic reticulum, resulting in tetany and heat production. Mutational analysis is now available to identify individuals who are at risk for this syndrome. The neuroleptic malignant syndrome is a similar disorder that occurs in association with ingestion of haloperidol and other antipsychotic drugs; however, there is no crossover susceptibility to malignant hyperthermia, and there is no diagnostic test to predict which patients will develop the complication. Cell shift is the cause of the increased serum K concentration in patients with hyperkalemic periodic paralysis (41,42). This disorder is most commonly due to mutations in the sodium channel SCN4A gene. In contrast to familial hypokalemic periodic paralysis, patients with the hyperkalemic form are typically younger ( 10 versus 5 to 20 yr) and have a greater frequency of attacks that tend to be of shorter duration ( 24 versus 24 h). The attacks tend to occur more commonly in the morning, whereas nighttime attacks dominate in the familial hypokalemic form. The attacks can be precipitated by fasting and K administration.

Decreased Renal Excretion of K

Decreased renal excretion of K can be divided into one or more of three abnormalities: Abnormal cortical collecting duct function, a primary decrease in mineralocorticoid levels, and a primary decrease in distal delivery of salt and water. The relevant literature is divided according to these categories. Primary Decrease in Mineralocorticoid Levels or Activity. Decreased mineralocorticoid activity can result from disturbances that originate at any point

along the renin-angiotensin-aldosterone system (RAAS). Such disturbances can be the result of a disease state or be due to effects of various drugs. Diabetes, CKD, and advancing age all are associated with decreased renin and aldosterone levels and have been identified as independent risk factors for the development of hyperkalemia (43). Elderly patients may also have a component of mineralocorticoid resistance, given the lack of increase in transtubular K gradient noted after the administration of fludrocortisone (44). The risk for hyperkalemia is further increased when such patients are treated with drugs that inhibit the RAAS. The development of hyperkalemia after the administration of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is of particular concern because patients who are at highest risk for this complication are oftentimes the same ones who derive the greatest cardiovascular benefit. These drugs are now being used with much greater frequency in the posttransplantation period, when factors such as a reduced GFR and administration of calcineurin inhibitors increase the likelihood of hyperkalemia (45,46). There is a great deal of clinical interest in combining drugs that block the RAAS at different points in an attempt to improve cardiovascular outcome (47,48). The downside of this approach is a greater risk for hyperkalemia, particularly because at-risk patients tend to be the target of such strategies (49,50). Studies designed to assess the frequency with which clinicians monitor patients for the development of hyperkalemia is less than optimal (51). Perhaps more disturbing is the time that it takes for follow-up after receipt of laboratory results to indicate the presence of hyperkalemia (52). Even in the setting of an emergency department, there is often a delay from the time of hyperkalemia discovery until appropriate therapy is instituted (53). The oral contraceptive Yasmin-28 contains the non­testosterone-derived progestin drospirenone, which possesses mineralocorticoid-blocking effects similar to what is seen with spironolactone. The product labeling recommends K monitoring in the first month after prescribing the drug for patients who are receiving K supplements, renin-angiotensin blockers, or nonsteroidal anti-inflammatory drugs (54). Despite this recommendation, there are many instances in which monitoring does not occur or patients are pre-

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scribed the contraceptive in the setting of other drugs that either provide a K load or interfere in renal K secretion (55,56).

The oral contraceptive Yasmin-28 contains the non­testosterone-derived progestin drospirenone that possesses mineralocorticoid-blocking effects similar to what is seen with spironolactone. The serum K should be monitored when this drug is prescribed for patients who receive K supplements, renin-angiotensin blockers, or nonsteroidal anti-inflammatory drugs. Factors that interfere with adrenal mineralocorticoid secretion are in the differential of impaired renal K secretion. Adrenal insufficiency should be considered for patients who present with abdominal pain and hyperkalemia (57). Both unfractionated and low molecular weight heparin can suppress adrenal aldosterone production and can cause hyperkalemia (58). Primary Decrease in Distal Delivery (Acute and Chronic Renal Failure). Acute kidney injury may lead to marked decreases in distal delivery of salt and water, which may secondarily decrease distal K secretion. For this reason, hyperkalemia tends to occur more commonly in oliguric renal failure. Hyperkalemia is much less common in nonoliguric renal failure because distal delivery of salt and water is plentiful. CKD is more complicated than acute renal failure. In addition to the decreased GFR and secondary decrease in distal delivery, there is nephron dropout and a smaller number of collecting ducts to secrete K ; however, this is counterbalanced by an adaptive process in which the remaining nephrons develop an increased ability to excrete K . In a study of normokalemic patients with stage 4 CKD, the fractional excretion of K was 126% compared with 26% in normal control subjects (59). The fractional excretion of Na in the two groups was 2.3 and 15%, respectively. After the intravenous administration of amiloride, the fractional excretion of K decreased by 87% in the patients with CKD compared with 19.5% in control patients. These findings support the idea that patients with CKD are able to maintain a normal serum K concentration through an adaptive increase

in renal K secretion that is largely amiloride sensitive. Two other defenses against hyperkalemia include a more rapid shift of K into cells in response to a K load and a markedly increased rate of K excretion in the colon. Aldosterone continues to play a role in regulating K even in anephric patients through stimulatory effects on colonic secretion. In this regard, fludrocortisone has been used sporadically to control better the plasma K concentration in long-term dialysis patients with hyperkalemia. In a prospective study, fludrocortisone administered at 0.1 mg/d was compared with no treatment in 21 hemodialysis patients with hyperkalemia (60). At the end of 10 mo, the serum K concentration in the two groups was not statistically different; however, there was a decrease in serum K compared with pretreatment values in patients who received the drug. The emergent therapy of hyperkalemia has been the subject of two recent reviews (61,62). Renin-angiotensin system blockers are frequently used to treat hypertension in patients with ESRD. Hyperkalemia is a potential concern with these drugs, even in the functionally anephric patient, to the extent that aldosterone levels fall and colonic K excretion decreases. Indeed, a small number of patients who underwent dialysis and developed hyperkalemia in association with ACEI and ARB therapy have been described. By contrast, this complication did not occur in a prospective crossover study of 69 maintenance hemodialysis patients who were treated with either ACEI or ARB therapy alone or in combination (63). Distal Tubular Defects. Tubulointerstitial renal diseases can affect the distal nephron and lead to hyperkalemia in the presence of only mild decreases in GFR and normal aldosterone levels. Obstructive uropathy should be included in the differential diagnosis of unexplained hyperkalemia (64). For patients who have bladder outlet obstruction and fail to respond to insertion of a Foley catheter, concomitant ureteral obstruction should be considered (65). Trimethoprine-sulfamethoxazole can interfere in renal K secretion in a manner similar to amiloride and triamterene (66). A similar mechanism may account for hyperkalemia after the administration of nafamostat mesylate (67,68). This drug is a synthetic serine protease inhibitor that is used for pancreatitis treatment.

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Pseudohypoaldosteronism type II (PHAII; Gordon syndrome) is an autosomal dominant form of hypertension in which hyperkalemia and metabolic acidosis are key features. Plasma concentrations of aldosterone are low despite the presence of hyperkalemia, which normally exerts a stimulatory effect on aldosterone released from the adrenal gland. Administration of NaCl worsens the hypertension, but Na given with a non-Cl anion such as sulfate or bicarbonate has a beneficial effect. The hypertension and hyperkalemia are particularly responsive to the administration of thiazide diuretics. The protein kinases WNK4 and WNK1 are responsible for this disease. Wild-type WNK4 acts to reduce the surface expression of the thiazide-sensitive Na -Cl co-transporter, likely through a lysosomemediated degradation pathway. The mutant protein (inactivating mutation of WNK4) loses this ability, resulting in increased co-transporter activity accompanied by marked hyperplasia of the distal convoluted tubule. In a mutant WNK4 knockin mouse model of the disease, the apical surface area of the distal convoluted tubule was increased (69). This change was accompanied by increased expression of the Na -Cl cotransporter, providing a histologic basis to account for the clinical findings and suggesting increased NaCl reabsorption in this segment. In an attempt to determine whether humans with PHAII have similar changes in protein expression, immunoblot studies were performed on urine samples to quantify the abundance of the Na -Cl co-transporter (70). A precedent for this approach is the known shedding of apically located tubular proteins into the urine. For example, aquaporin 2 is present in the urine and increases in concentration under conditions in which arginine vasopressin is increased. Using this approach, urinary Na -Cl co-transporter protein was found to be approximately four times higher when measured in eight patients with the disease compared with eight unrelated control patients. Wild-type WNK4 normally stimulates clathrindependent endocytosis of the ROMK channel in the renal collecting duct, leading to decreased cell surface expression. The mutant protein enhances this removal, giving rise to decreased K secretion and hyperkalemia. The process by which both wild-type and mutant WNK4 mediate the endocytosis involves a scaffolding protein known as intersectin (71).

WNK4 has also been shown to affect Cl permeability through the paracellular pathway. The mutated WNK4 protein causes an increase in paracellular Cl permeability by phosphorylating claudins, which are tight junction proteins that are involved in regulating paracellular ion transport. This increase in permeability dissipates the lumen-negative charge that normally is generated by Na reabsorption through the ENaC. The reduction in luminal electronegativity will decrease the driving force for K secretion, providing an additional mechanism by which the mutated protein can cause hyperkalemia. This reduction in luminal electronegativity also contributes to the development of metabolic acidosis as a result of the less favorable electrical gradient for H secretion. In addition, hyperkalemia slows H secretion by limiting buffer availability through its suppressive effect on ammoniagenesis. Mutations in WNK1 can give rise to the manifestations of Gordon syndrome as well. Wild-type WNK1 normally exerts an inhibitory effect on WNK4. Mutations in WNK1 that give rise to PHAII are gain-of-function mutations that augment this inhibitory effect on WNK4 activity. As a result, Na -Cl co-transport activity is increased, and there is increased removal of ROMK from the apical membrane. WNK1 can also cause salt retention by increasing the activity of ENaC through a stimulatory effect on SGK1. In addition, increased activity of WNK1 enhances paracellular Cl permeability in a similar manner as disease-causing mutations in WNK4. This increase in Cl permeability may be related to WNK1-mediated phosphorylation of claudin 4. The observation that hypertension in patients with the WNK1 mutation is less sensitive to the effects of thiazide diuretics suggests that these non­ Na -Cl co-transporter mechanisms of salt retention are quantitatively more important in causing volume expansion in this setting. One additional difference in the clinical manifestations that result from mutations in WNK4 and WNK1 relates to urinary calcium excretion. Increased Na -Cl co-transporter activity is normally associated with hypercalciuria; inhibition of the co-transporter decreases urinary calcium excretion. This latter effect explains the hypocalciuric effect of thiazide diuretics. Patients with the WNK4 mutation have hypercalciuria and show a heightened sensitivity to the

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hypocalciuric effects of thiazide diuretics compared with normal patients. These findings are consistent with constitutive activation of the Na -Cl co-transporter as the major cause of salt retention in patients with the WNK4 mutation. By contrast, hypercalciuria is not a feature in patients with the WNK1 mutation, suggesting that increased ENaC activity and paracellular Cl permeability play a more important role in mediating salt retention in these patients compared with increased Na -Cl co-transporter activity (72). WNK4 has also been shown to have effects on the epithelial Ca2 channel transient receptor potential vanilloid subfamily member 5 (TRPV5). Studies of Xenopus laevis oocytes showed that both wild-type and mutant WNK4 exerted a positive effect on TRPV5-mediated Ca2 uptake (72). Coexpression of the Na -Cl co-transporter inhibits this stimulatory effect in a dosage-dependent manner. These studies suggested that the increased expression of the Na Cl co-transporter in patients with PHAII may lead to hypercalciuria through inhibitory effects on TRPV5. Pseudohypoaldosteronism type I (PHAI) is a disorder characterized by mineralocorticoid resistance that typically presents in newborns. Clinical findings include hyperkalemia, metabolic acidosis, and a tendency toward volume depletion as a result of renal salt wasting. Two modes of inheritance give rise to slightly different characteristics. In the autosomal recessive form of PHAI, the defect has been localized to homozygous mutations in the three subunits of the ENaC. This form of the disease tends to be more severe and requires lifelong therapy with salt to prevent recurrent life-threatening volume depletion. Extrarenal manifestations include frequent respiratory tract infections as a result of the presence of dysfunctional channels in the lung. Cutaneous lesions can also develop as a result of the chronic irritative effect of high salt concentrations in sweat. The autosomal dominant form of PHAI results from mutations in the mineralocorticoid receptor that, in turn, results in mineralocorticoid resistance. The clinical manifestations are limited to the kidney and tend to resolve with time such that therapy with K-binding resins and salt supplementation can eventually be discontinued. The maintenance of normal volume homeostasis and electrolyte values occurs at the expense of a persistent increase in circulating aldosterone levels in adults with the disorder. Al-

though the majority of cases are inherited in an autosomal dominant manner, de novo mutations may be responsible for the disease in approximately one fifth of patients (73). The autosomal dominant and autosomal recessive forms of PHAI are typically diagnosed shortly after birth with the discovery of salt wasting and hyperkalemia. These genetic disorders need to be distinguished from secondary causes of salt wasting and hyperkalemia as can occur in acute pyelonephritis, congenital urinary obstruction, and other renal malformation disorders (74).

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55. Eng P, Seeger J, Loughlin J, Oh K, Walker A: Serum potassium monitoring for users of ethinyl estradiol/drospirenone taking medications predisposing to hyperkalemia: physician compliance and survey of knowledge and attitudes. Contraception 75: 101­107, 2007 56. Schutt B, Kunz M, Blode H: Coadministration of estradiol/drospirenone and indomethacin does not cause hyperkalemia in healthy postmenopausal women: A randomized open-label crossover study. J Clin Pharmacol 47: 774 ­781, 2007 57. Lelubre C, Lheureux P: Epigastric pain as presentation of an addisonian crisis in a patient with Schmidt syndrome. Am J Emerg Med 26: 251.e3­251.e4, 2008 58. Thomas C, Thomas J, Smeeton F, Leatherdale B: Heparin-induced hyperkalemia. Diabetes Res Clin Pract 80: e7­ e8, 2008 59. Yeyati N, Fellet A, Arranz C, Balaszczuk A, Adrogue H: Amiloridesensitive and amiloride-insensitive kaliuresis in advance chronic kidney disease. J Nephrol 21: 93­98, 2008 60. Dong-Min K, Chung J, Yoon S, Kim H: Effect of fludrocortisones acetate on reducing serum potassium levels in patients with end-stage renal disease undergoing haemodialysis. Nephrol Dial Transplant 22: 3273­3276, 2007 61. Sood M, Sood A, Richardson R: Emergency management and commonly encountered outpatient scenarios in patients with hyperkalemia. Mayo Clin Proc 82: 1553­1561, 2007 62. Putcha N, Allon M: Management of hyperkalemia in dialysis patients. Semin Dial 20: 431­ 439, 2007 63. Han S, Won Y, Yi J, Kim H: No impact of hyperkalaemia with renin-angiotensin system blockade in maintenance haemodialysis patients. Nephrol Dial Transplant 22: 1150 ­1155, 2007 64. Mirandi A, Williams T, Holt J, Kassotis J: Hyperkalemia secondary to a postobstructive uropathy manifesting as complete heart block in a hypertensive patient receiving multiple atrioventricular nodal blocking agents. Angiology 59: 121­124, 2008 65. Segal A: A case of acute kidney injury due to complex partial, multifocal ureteral strictures. Nat Clin Pract 4: 102­108, 2008 66. Sanjay S, Annigeri R, Gopalakrishnana R: Refractory hyperkaleamia due to trimethoprim, successfully treated with fludrocortisones. J Assoc Physicians India 55: 74 ­75, 2007 67. Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakama Y, Maruhashi T, Kagawa E, Dai K, Aokage T: Role of medications in symptomatic hyperkalemia. Q J Med 100: 591­596, 2007 68. Kitagawa H, Change J, Fujita T: Hyperkalemia due to nafamostat mesylate. N Engl J Med 332: 687, 1995 69. Yang S, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin S, Moriguchi T, Shibuya H, Kondo Y, Sasaki S: Molecular pathogenesis of pseudohypoaldosteronism type II: Generation and analysis of a Wnk4D561A/ knockin mouse model. Cell Metab 5: 331­344, 2007 70. Mayan H, Attar-Herzberg D, Shaharabany M, Holtzman E, Farfel Z: Increased urinary Na-Cl cotransporter protein in familial hyperkalaemia and hypertension. Nephrol Dial Transplant 23: 492­ 496, 2008 71. He G, Want H, Huang S, Huang C: Intersectin links WNK kinases to endocytosis of ROMK1. J Clin Invest 117: 1078 ­1087, 2007 72. Jiang Y, Ferguson W, Peng J: WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4. Am J Physiol Renal Physiol 292: F545­F554, 2007 73. Pujo L, Fagart J, Gary F, Papadimitriou D, Claes A, Jeunemaite X, Zennaro M: Mineralocorticoid receptor mutations are the principal cause of renal type 1 pseudohypoaldosteronism. Hum Mutat 28: 33­ 40, 2007 74. Belot A, Ranchin B, Fichtner C, Pujo L, Rossier B, Liutkus A, Morlat C, Nicolino M, Zennaro M, Cochat P: Pseudohypoaldosteronisms, report on a 10-patient series. Nephrol Dial Transplant 23: 1636 ­ 1641, 2008

Acid Base

Metabolic Alkalosis

Metabolic alkalosis is a common disorder. In a long-term care facility a plasma HCO3 concentration of 34 mEq/L was found in 12% of bedridden patients (1). The alkalotic state was more likely to be present in people who required nasogastric feeding compared with oral feeding. Although generally considered a benign condition, a high blood pH is associated with pathophysiologic effects that can adversely affect patient outcomes. First, increases in blood pH (alkalemia) cause respiratory depression. This effect is mediated via both central and peripheral chemoreceptors. Second, alkalosis decreases oxygen delivery to the tissues by exerting a vasoconstrictor effect and by impairing hemoglobin's ability to release oxygen. Alkalosis-induced tissue hypoxemia can adversely affect cerebral, coronary, and peripheral circulation. The initial approach for the patient who is suspected of having metabolic alkalosis begins with arterial blood gas analysis to ensure that one is dealing with a primary metabolic alkalosis rather than a compensation for a respiratory acidosis. A primary increase in PCO2 because of respiratory failure will lead to increased kidney HCO3 reabsorption as a compensatory response. In the chronic respiratory acidosis setting, the serum HCO3 concentration increases by 3.5 mEq/L for every 10-mmHg increase in PCO2. An inadequate metabolic response to chronic hypercapnia has been associated with increased mortality (2). The reader is referred to a recent review detailing the approach to fluid and electrolyte and acid-base disorders (3). The two ingredients that are required for metabolic alkalosis pathogenesis are new bicarbonate generation combined with an augmentation in the kidney's capacity to reclaim the filtered bicarbonate. Metabolic alkalosis generation occurs through adding nonvolatile base or removing nonvolatile acid from the blood; however, when the kidneys are functioning normally, metabolic alkalosis causes a marked inhibition of renal HCO3 absorption, which leads to bicarbonaturia and rapid metabolic alkalosis correction. To maintain a metabolic alkalosis, the kidney's capacity to correct the alkalosis must be impaired, or, equivalently, the capacity to reclaim HCO3 must be enhanced. The relevant literature regarding this subject is grouped according to the three ways in which meta-

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bolic alkalosis can be generated: Exogenous addition of base, gastrointestinal acid loss, and renal acid loss. A comprehensive review of this subject has been published (4). Exogenous Addition of Base. In the previous edition of NephSAP, several cases in which metabolic alkalosis developed because of exogenous administration of alkali in reduced renal function were cited. One unusual case was a dialysis patient who developed metabolic alkalosis from an alkali load contained in crack cocaine. Net gain of HCO3 can occur in the setting of massive transfusion as a result of administration of citrate found in packed red blood cells (5). A similar situation can complicate plasmapheresis when citrate containing fresh-frozen plasma is used as a replacement fluid. Self-administration of large quantities of antacids that contain NaHCO3 can occur as a manifestation of pica during pregnancy or for selftreatment of abdominal pain (6,7). Severe metabolic alkalosis will develop when administered in the setting of volume depletion or renal insufficiency. Metabolic alkalosis accompanied by hypercalcemia and renal failure can occur when excessive quantities of antacids that contain calcium are ingested, a condition referred to as "milk-alkali syndrome" (8). A bicarbonate load can be delivered to a newborn transplacentally from the mother. Such a situation was described in a newborn with hypokalemic metabolic alkalosis resulting in respiratory depression (9). Measurement of serum chemistries in the mother at delivery showed similar results. NaCl and KCl administration to the infant through a nasogastric tube corrected the metabolic alkalosis over a 3-d period. The mother was suspected of having an eating disorder, namely bulimia, as an explanation for the metabolic alkalosis. Gastrointestinal Acid Loss. In vomiting or nasogastric suction, gastric acid loss generates a metabolic alkalosis, whereas NaCl loss in the gastric fluid leads to volume contraction (10). While the patient is vomiting, the plasma HCO3 concentration tends to be higher than the threshold for proximal HCO3 reabsorption. The delivery of large HCO3 quantities to the distal nephron leads to renal loss of NaHCO3 (further exacerbating total body Na depletion) and KHCO3 (leading to K depletion). The volume depletion leads to an increase in aldosterone secretion. At this point in time, urinary electrolytes show a urine Cl 15 mEq/L, in the presence of a high urine Na ,

a high urine K , and a urine pH of 7 to 8. When the patient stops vomiting, bicarbonaturia disappears, but a metabolic alkalosis is maintained by the volume contraction and K depletion. At this time, urine Na and Cl both are low. When saline is infused into the patient, bicarbonaturia ensues and the metabolic alkalosis is corrected. Gastric acid loss leading to a metabolic alkalosis can also be a complication of gastrocystoplasty (11). Although not commonly performed, this procedure involves implantation of a gastric patch onto the bladder. The gastric mucosa retains its normal secretory function and, depending on the patch's size, can lead to significant acid loss from the body into the urine. The aciduria can be minimized with administration of a proton pump inhibitor. An increased risk for malignancy in the gastric patch is an additional long-term complication of bladder augmentation procedures of this type (12). The solute carrier 26 family of proteins functions as anion exchangers or Cl channels in the luminal membrane of epithelial cells (reviewed in reference13). Gene mutations that encode these proteins have been associated with well-defined disease states. Congenital chloride diarrhea is an autosomal recessive disorder caused by mutations in the solute carrier family 26 member 3 gene (SCLC26A3). Mutations lead to misfolding and abnormal trafficking of a colonic Cl /HCO3 exchanger (14). Patients present at birth with watery Cl -rich, HCO3 -poor diarrhea and develop metabolic alkalosis. Lifelong NaCl and KCl therapy is required to prevent volume depletion and electrolyte abnormalities. The protein product of the SCLC26A3 gene is also found in the sweat gland and in the male seminal vesicle. Sweat Cl is higher in these patients but not to an extent to cause clinical sequelae. Disturbances in sweat salt transport are minimal because the cystic fibrosis transmembrane conductance regulator is the major protein regulating salt transport in the sweat glands. By contrast, these patients frequently have fertility disturbances. Mutations in the solute carrier family 26 member 4 gene (SCLC26A4) gene have been linked to Pendred syndrome. This disorder is autosomal recessive characterized by thyroid goiter and sensorineural hearing loss. The SCLC26A4 protein is thought to function in both I transport and Cl /HCO3 exchange. Impaired protein function disrupts organification of I in the thyroid and causes aberrant HCO3 secretion in the

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inner ear, leading to acidified endolymph. The pendrin protein is also thought to mediate apical Cl /HCO3 exchange in the intercalated cell of the kidney; however, patients with Pendred syndrome have no renal manifestations in the basal state. A single patient who had Pendred syndrome and developed a profound hypokalemic metabolic alkalosis (K 1.7 mEq/L, HCO3 43.8 mEq/L) after the routine administration of a thiazide diuretic has been described (15). The authors postulated that subtle disturbances in pendrin in the distal nephron may have provoked this excessive response. Metabolic alkalosis and volume depletion can be the initial manifestation of cystic fibrosis in infants and rarely in adults (16 ­18). Decreased HCO3 secretion in the distal nephron is a likely explanation for the development of this complication. There are two functionally distinct subtypes of intercalated cells in the collecting duct. The intercalated cell secretes H by an apical H -ATPase. As mentioned, the intercalated cell secretes HCO3 in exchange for Cl through an apically located Cl /HCO3 exchanger (pendrin). Under conditions of metabolic acidosis, intercalated cells can convert to type (19). An alkaline pH increases both the gene and protein expression of pendrin (20). Patients with cystic fibrosis are at increased risk for volume depletion because of excessive loss of salt in sweat. In this setting, distal Cl delivery is markedly reduced. Because HCO3 secretion by the intercalated cell requires luminal Cl , the HCO3 secretion rate will be reduced, potentially explaining the development of metabolic alkalosis in patients without a vomiting history or diuretic use. Renal Acid Loss. In most cases, the renal generation of bicarbonate involves three features that function synergistically to increase H secretion in the distal nephron and cause renal net acid excretion to exceed metabolic acid production: (1) High distal delivery of Na salts, (2) mineralocorticoid excess, and (3) K deficiency. To augment net acid excretion and thereby generate a metabolic alkalosis through renal mechanisms, Na salt delivery to the distal nephron must occur with sustained or increased mineralocorticoid activity. Aldosterone stimulates electrogenic Na reabsorption in the principal cell of the cortical collecting duct, leading to an increased negative voltage in the tubular lumen. In addition to providing a more favorable driving force for K secretion, this change

in lumen voltage increases the rate of H secretion by the intercalated cell. For every H secreted into the lumen, a new bicarbonate ion is returned to the blood. This coupling of increased distal Na delivery and increased mineralocorticoid activity leading to the renal generation of new bicarbonate is similar to the conditions that give rise to renal K wasting and can be approached similarly.

Primary Increase in Distal Na Delivery

A primary increase in distal Na delivery is defined as increased distal delivery that is not due to expansion of effective arterial blood volume. Effective volume is either normal or low, and BP is not increased. These disorders are best differentiated on clinical grounds and measurement of urinary Na and Cl concentration and/or excretion rates. The majority of new publications regarding these conditions have already been discussed in the Hypokalemia section. Bartter syndrome is a group of complex hereditary disorders characterized by renal salt wasting and hypokalemic metabolic alkalosis resembling the features of chronic loop diuretic therapy. These disorders result from gene defects that lead to decreased NaCl reabsorption in the thick ascending limb of Henle. Genetic defects of the Na -K -2Cl (NKCC2) co-transporter usually present with evidence of severe salt wasting in the prenatal period (21). Typically, late-onset and mild Bartter syndrome is due to defects in the CLCNKB gene coding for the CLC-Kb chloride channel (22). The most recent gene defect described to give rise to Bartter syndrome is a digenic disorder involving both chloride channels (CLC-Kb and CLCKa) that normally reside on the basolateral surface of the thick ascending limb. Similar to patients with the gene defect in the subunit of CLC-K (barttin), these patients show evidence of deafness; however, the inability to insert the channels into the membrane is due to abnormalities in both Cl channels as opposed to defects in the accessory Barttin protein (23). Gitelman syndrome is an inherited disorder with clinical manifestations that mimic the long-term use of a thiazide diuretic. This disease is due to an inactivating mutation in the gene (SLC12A3) for the thiazidesensitive NaCl co-transporter (NCC) in the distal convoluted tubule (24,25). Immunohistochemistry performed on renal biopsy material taken from two adults with Gitelman syndrome were devoid of intact NCC immu-

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nostaining (26). Immunoblot studies of urine taken from patients also showed absent or markedly decreased band signal for the co-transporter (27). The disease is generally benign, with most individuals experiencing either no or minimal symptoms. Paralysis and prolongation of the QT interval with malignant arrhythmias attributed to hypokalemia and hypomagnesemia have rarely been described (28,29). The clinical presentation of adult patients with Bartter and Gitelman syndrome is similar with respect to the findings of hypokalemia, metabolic alkalosis, and normal or low BP. Urinary Ca2 excretion has been one tool used to differentiate the two conditions. Urine Ca2 excretion in Bartter syndrome is increased, whereas hypocalciuria is a typical feature of Gitelman syndrome. One mechanism to explain the hypocalciuria in patients with Gitelman syndrome is increased proximal reabsorption resulting from a contracted extracellular fluid volume. In a recent study of eight patients with Gitelman syndrome, extracellular fluid volume expansion with isotonic saline caused only a small increase in urinary Ca2 excretion despite a large increase in urinary Na excretion (30). This study suggested that increased tubular Ca2 reabsorption in more distal sites is an important component of the hypocalciuria that typically is seen in these patients. Another test that may be useful in distinguishing patients with Bartter and Gitelman is the change in urinary Cl excretion after the administration of a thiazide diuretic. Because patients with Gitelman syndrome have impaired function of the thiazidesensitive NaCl co-transporter, one would predict no change in urinary Cl excretion after administration of the drug. By contrast, patients with Bartter should demonstrate an increase in urinary Cl excretion. This difference should be particularly evident because the distal nephron in patients with Bartter is likely to have undergone hypertrophy because of the long-term delivery of large NaCl quantities that escape reabsorption in the upstream thick limb. Indeed, these predictions were verified in a cohort of patients who had Gitelman or Bartter syndrome and were given 50 mg of hydrochlorothiazide (31). The Cl fractional clearance was increased in the patients with Bartter syndrome, whereas only a blunted response was observed in those with Gitelman syndrome.

Patients Bartter or Gitelman syndrome can be distinguished by examining the change in urinary Cl excretion after the administration of a thiazide diuretic. The Cl fractional clearance will increase in patients with Bartter syndrome, whereas only a blunted response is seen in patients with Gitelman syndrome. Because the recessive loss-of-function mutations that are responsible for Bartter and Gitelman syndromes give rise to salt wasting and normal or low BP, there has been interest in whether heterozygous mutations in these genes might exert a protective effect for hypertension development. Patients who participated in the Framingham Heart Study were screened for variations in two of the genes that are responsible for Bartter syndrome (SLC12A1 encoding NCCT and KCNJ1 encoding ROMK) and the one gene that is responsible for Gitelman syndrome (SLC12A3 encoding NCCT) (32). In more than 3000 individuals screened, 49 were identified as mutation carriers. Eighty percent of the carriers had long-term systolic BP below the cohort's mean. In particular, the longterm systolic BP among the carriers was 6.3 mmHg lower that the mean of the entire cohort. The carriers showed reduced BP from the earliest age measured to the last. It is likely that the protection against development of hypertension in the carriers is related to effects on renal salt handling. Mutations in CLCNKB results in a loss of function in CLC-Kb and can give rise to an adult form of Bartter syndrome. A common polymorphism in the CLC-Kb protein leads to increased Cl transport when expressed in vitro, and this polymorphism is known to be associated with essential hypertension (33). In addition to providing information about the pathogenesis of essential hypertension, examination of these rare genetic diseases has given insight to novel mechanisms of action for therapeutic agents. For example, angiotensin II affects the trafficking of the NCC between the apical membrane and submembrane vesicles in the distal nephron (34,35). The ACEI captopril reduces cell surface expression of the protein, suggesting that the drug also may lower BP by reducing salt absorption in this segment. As previously discussed, inactivating mutations in WNK4 and activating mutations in WNK1 give rise

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to pseudohypoaldosteronism type II in which patients develop hypertension, hyperkalemia, and normal gap metabolic acidosis. There is a great deal of interest in whether variations in the gene mutations and altered signaling pathways present in pseudohypoaldosteronism type II also might be responsible for the more common hypertension found in the general population (34).

Acetazolamide in Metabolic Alkalosis Treatment

In certain patients, it may be difficult to correct the factors that are responsible for maintenance of metabolic alkalosis. This most frequently occurs in patients whose metabolic alkalosis is maintained by decreased effective arterial volume but whose cardiovascular system cannot tolerate NaCl administration. Patients who warrant aggressive metabolic alkalosis treatment include the following: (1) Patients who have chronic lung disease and for whom intubation is imminent or extubation is difficult and metabolic alkalosis must be corrected to improve the drive to respiration; (2) patients with myocardial ischemia with evolving myocardial infarction, patients who are having chest pain after infarction, or patients with unstable angina; and (3) ill patients who have cerebral dysfunction and for whom cerebral hypoperfusion is a possible contributing factor. The most commonly used approach toward correcting alkalosis in these patients is administration of carbonic anhydrase inhibitors such as acetazolamide (36,37). Carbonic anhydrase catalyzes the dehydration of luminal carbonic acid (produced when filtered HCO3 reacts with secreted H ) to water and CO2 and the hydration of cellular CO2 to carbonic acid, allowing the formation of H for secretion into the luminal fluid. The uncatalyzed dehydration of carbonic acid occurs very slowly. By inhibiting the enzyme's activity, carbonic anhydrase inhibitors hinder renal acidification and thereby cause the kidney at least partially to correct the metabolic alkalosis. The magnitude of the bicarbonaturia induced is directly related to the serum HCO3 concentration. As the HCO3 concentration falls, the drug's clinical effectiveness declines in a parallel manner. As a result, only rarely does the plasma HCO3 concentration return to normal. Acetazolamide is frequently used for patients who have chronic respiratory acidosis and develop a metabolic alkalosis. Normally, among patients with chronic respiratory acidosis, the kidney's capacity to

reabsorb bicarbonate increases, resulting in a rise in plasma HCO3 concentration. Use of loop diuretics for such patients, as in the treatment of cor pulmonale, can result in further increases in the serum HCO3 concentration. In this setting, the induction of a metabolic alkalosis can depress ventilation, aggravating both the hypoxemia and hypercapnia. Normally the metabolic alkalosis can be treated by discontinuing the diuretic and administering NaCl. For the patient who is significantly edematous, however, this approach may not be practical; in this circumstance, acetazolamide can be used to inhibit HCO3 reabsorption and thus lower serum HCO3 concentration. A potential problem associated with use of carbonic anhydrase inhibitors in patients with lung disease is a worsening of hypercapnia. Carbonic anhydrase in normally present within red blood cells and is involved in CO2 movement into red cells in peripheral tissues and movement from red cells into the alveoli in the lungs. Thus, carbonic anhydrase inhibition can prevent red cell uptake of CO2 in peripheral tissues and can prevent CO2 release in the lung. The latter can lead to an increase in the PCO2 of the arterial blood, whereas the former leads to an even further increase in PCO2 in peripheral tissues. Generally, patients with normal lungs can respond to this by increasing respiration and preventing the increase in the PCO2 of the arterial blood; however, patients with lung disease may not be able to respond adequately and manifest further increases in arterial and tissue PCO2 . Acetazolamide is also used in the prophylaxis and treatment of acute mountain sickness. The reader is referred to a recent review of this subject (38). Monges disease (chronic mountain sickness) is characterized by excessive erythrocytosis frequently associated with pulmonary hypertension among people who live at high altitude. The daily administration of acetazolamide reduces erythrocytosis and improves the pulmonary circulation in these patients (39). The therapy is well tolerated, and the beneficial effects are sustained over time. References

1. Segal R, Iaina A, Lubart E, leikin I, Leibovitz A: Metabolic alkalosis in skilled nursing patients. Arch Gerontol Geriatr 10: 1016, 2008 2. Uegan I, Oztuna F, Dagli CE, Yildirim H, Bal C: Relationship of metabolic alkalosis, azotemia and morbidity in patients with chronic obstructive pulmonary disease and hypercapnia. Respiration 2008, in press 3. Palmer B: Approach to fluid and electrolyte disorders and acid-base problems. Prim Care 35: 195­213, 2008

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4. Laski M, Sabatini S: Metabolic alkalosis, bedside and bench. Semin Nephrol 26: 404 ­ 421, 2006 5. Nagai Y, Itabashi M, Mizutani M, Ogawa T, Yumura W, Tsuchiya K, Nitta K: A case report of uncompensated alkalosis induced by daily plasmapheresis in a patient with thrombotic thrombocytopenic purpura. Ther Apher Dial 12: 86 ­90, 2007 6. Ajbani K, Chansky M, Baumann B: Homespun remedy, homespun toxicity: Baking soda ingestion for dyspepsia. J Emerg Med December 26, 2007 [epub ahead of print] 7. Gawarammana L, Coburn J, Greene S, Dargan P, Jones A: Severe hypokalaemic metabolic alkalosis following ingestion of gaviscon. Clin Toxicol 45: 176 ­178, 2007 8. Gabriely I, Leu J, Barzel U: Back to basics. N Engl J Med 358: 1952­1956, 2008 9. Schimert P, Bernet-Buettiker V, Rutishauser C, Schams M, Frey B: Transplacental metabolic alkalosis. J Paediatr Child Health 43: 851­ 853, 2007 10. McCauley M, Gunawardane M, Cowan M: Severe metabolic alkalosis due to pyloric obstruction: Case presentation, evaluation, and management. Am J Med Sci 332: 346 ­350, 2006 11. Renaud C: Conventional bicarbonate haemodialysis in postgastrocystoplasty metabolic alkalosis. Singapore Med J 49: e121, 2008 12. Castellan M, Gosalbex R, Perez-Brayfield M, Healey P, McDonald R, Labbie A, Lendvay T: Tumor in bladder reservoir after gastrocystoplasty. J Urol 178: 1771­1774, 2007 13. Dorwart M, Shcheynikov N, Yang D, Muallem S: The solute carrier 26 family of proteins in epithelial ion transport. Physiology (Bethesda) 23: 104 ­114, 2008 14. Dorwart M, Shcheynikov N, Baker J, Forman-Kay J, Muallem S, Thomas P: Congenital chloride-losing diarrhea causing mutation in the STAS domain result in misfolding and mistrafficking of SLC26A3. J Biol Chem 283: 8711­ 8722, 2008 15. Pela I, Bigozzi M, Bianchi B: Profound hypokalemia and hypochloremic metabolic alkalosis during thiazide therapy in a child with Pendred syndrome. Clin Nephrol 69: 450 ­ 453, 2008 16. Augusto J, Sayegh J, Malinge M, Illouz F, Subra J, Ducluzeau P: Severe episodes of extra cellular dehydration: An atypical adult presentation of cystic fibrosis. Clin Nephrol 69: 302­305, 2008 17. Yalcin S, Akca T, Genc O, Celik M, Dogru D, Ozcelik U: Modified oral rehydration therapy in a case with cystic fibrosis. Turk J Pediatr 49: 102­104, 2007 18. Ballestero Y, Hernandez M, Rojo P, Manzanares J, Nebreda V, Carbajosa H, Infante E, Baro M: Hyponatremic dehydration as a presentation of cystic fibrosis. Pediatr Emerg Care 22: 725­727, 2006 19. Al-Awqati Q: Control of terminal differentiation in epithelia. J Am Soc Nephrol 19: 443­ 449, 2008 20. Adler L, Efrati E, Zelikovic I: Molecular mechanisms of epithelial cell-specific expression and regulation of the human anion exchanger (pendrin) gene. Am J Physiol Cell Physiol 294: C1261­C1276, 2008 21. Adachi M, Asakura Y, Sato Y, Tajima T, Nakajima T, Yamamoto T, Fujieda K: Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1. Endocr J 54: 1003­1007, 2007 22. Kramer B, Bergler T, Stoelcker B, Waldegger S: Mechanisms of disease: The kidney-specific chloride channels C1CKA and C1CKB, the barttin subunit, and their clinical relevance. Nat Clin Pract Nephrol 4: 38 ­ 46, 2008 23. Nozu K, Inagaki T, Fu X, Nozu Y, Kaito H, Kanda K, Sekine T, Igarashi T, Nakanishi K, Yoshikawa N, Iijima K, Matuso M: Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. J Med Genet 48: 182­186, 2008 24. Aoi N, Nakayama A, Tahira Y, Haketa A, Yabuki M, Sekiyama Y, Nakane C, Mano H, Kawachi H, Sato N, Soma M, Matsumoto K: Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome. Endocrine 31: 149 ­153, 2007

25. Aoki K, Tajima T, Yabushita Y, Nakamura A, Nezu U, Takahashi M, Kimura M, Terauchi Y: A novel initial codon mutation of the thiazide-sensitive Na-Cl cotransporter gene in a Japanese patient with Gitelman's syndrome. Endocr J 55: 557­560, 2008 26. Jang H, Lee J, Oh Y, Na K, Joo K, Jeon U, Cheong H, Kim J, Han J: From bench to bedside: Diagnosis of Gitelman's syndrome-- Defect of sodium-chloride cotransporter in renal tissue. Kidney Int 70: 813­ 817, 2006 27. Joo K, Lee J, Jang H, Heo N, Jeon U, Oh Y, Lim C, Na K, Kim J, Cheong H, Han J: Reduced urinary excretion of thiazide-sensitive Na-Cl cotransporter in Gitelman syndrome: Preliminary data. Am J Kidney Dis 50: 765­773, 2007 28. Pachulski R, Lopez F, Sharaf R: Gitelman's not-so-benign syndrome. N Engl J Med 353: 850 ­ 851, 2005 29. Akinci B, Celik A, Saygili F, Yesil S: A case of Gitelman's syndrome presenting with extreme hypokalaemia and paralysis. Exp Clin Endocrinol Diabetes June 3, 2008 [epub ahead of print] 30. Cheng C, Shiang J, Hsu Y, Yang S, Lin S: Hypocalciuria in patients with Gitelman syndrome: Role of blood volume. Am J Kidney Dis 49: 693­700, 2007 31. Colussi G, Bettinelli A, Tedeschi S, De Ferrari M, Syren M, Borsa N, Mattiello C, Casari G, Bianchetti M: A thiazide test for the diagnosis of renal tubular hypokalemic disorders. Clin J Am Soc Nephrol 2: 454 ­ 460, 2007 32. Weizhen J, Foo J, O'Roak B, Zhao H, Larson M, Simon D, NewtonCheh C, State M, Levy D, Lifton R: Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet 40: 592­599, 2008 33. Ariceta G, Rodriguez-Soriano J: Inherited renal tubulopathies associated with metabolic alkalosis: Effects on blood pressure. Semin Nephrol 26: 422­ 433, 2006 34. Flatman P: Cotransporters, WNKs, and hypertension: An update. Curr Opin Nephrol Hypertens 17: 186 ­192, 2008 35. Sandberg M, Riquier A, Pihakaski-Maunsbach K, McDonough A, Maunsbach A: ANG II provokes acute trafficking of distal tubule Na -C1 co transporter to apical membrane. Am J Physiol Renal Physiol 293: F662­F669, 2007 36. Moffett B, Moffett T, Dickerson H: Acetazolamide therapy for hypochloremic metabolic alkalosis in pediatric patients with heart disease. Am J Ther 14: 331­335, 2007 37. Caramelo C, Albalate M, Tejedor A, Alcazar R, Baldovi S, Perez A, Marin M: Actuality of the use of acetazolamide as a diuretic: Usefulness in refractory edema and in aldosterone-antagonist-related hyperkalemia. Nefrologia 28: 234 ­238, 2008 38. Leaf D, Goldfarb D: Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol 102: 1313­1322, 2007 39. Richalet J, Rivera M, Maignan M, Privat C, Pham I, Macarlupu J, Petitjean O, Leon-Velarde F: Acetazolamide for Monge's disease: Efficiency and tolerance of a 6 month treatment. Am J Respir Crit Care Med 177: 1370 ­1376, 2008

Metabolic Acidosis

New Physiologic Insights

The kidney's role in regulating acid-base balance includes two components: (1) Reclamation of filtered HCO3 and (2) regeneration of HCO3 consumed by net acid production. In the proximal tubule, approximately two thirds of the filtered HCO3 is reabsorbed via the apical membrane Na -H antiporter NHE-3. A vacuolar apical membrane, H -ATPase, mediates the remaining one third of HCO3 absorption. Both of

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these H transporters generate bicarbonate in the cell, which must exit across the basolateral membrane to affect transepithelial transport. The Na -3HCO3 cotransporter NBCe1-A, encoded by the gene SLC4A4, mediates the majority of proximal tubule basolateral bicarbonate exit. The NBCe1-A protein shows evidence of posttranslational regulation in response to metabolic acidbase disorders. Under conditions of acute metabolic acidosis, the mRNA and protein level of the cotransporter is unchanged, but the co-transporter is recruited into the basolateral membrane (1). By contrast, under conditions of metabolic alkalosis, whereby HCO3 absorption should be inhibited, there is cytoplasmic redistribution. This type of regulation is in contrast to respiratory acid-base disturbances. Under condition of hypercapnia, there is an actual increase in protein abundance as opposed to the same amount of protein being simply redistributed (2). The distal nephron is responsible for reabsorbing the small quantity of filtered HCO3 that escapes the proximal tubule and thick ascending limb. In addition, the distal nephron secretes a quantity of H equal to that generated systemically by metabolism to maintain acid-base balance. Depending on chronic acid-base status, the cortical collecting duct is capable of either H or HCO3 secretion. These functions are mediated by one of two types of intercalated cells: The acidsecreting intercalated cell and the base-secreting intercalated cell. H secretion by the intercalated cell is mediated by one of two transporters: A vacuolar H ATPase and an H -K -ATPase. The activity of the H -K -ATPase increases in K depletion and thus provides a mechanism by which K depletion enhances both collecting duct H secretion and K absorption (3). Intracellular base generated by these transporters exits the basolateral membrane by way of a Cl /HCO3 exchanger. The Cl that enters the cell in exchange for HCO3 exits the cell through a basolateral membrane Cl conductance channel. The HCO3 -secreting intercalated cell is in many respects a mirror image of the intercalated cell. It possesses an H -ATPase on the basolateral membrane, which mediates active H extrusion. Alkali that is generated within the cell then exits on an apical membrane Cl -HCO3 . As mentioned in the Metabolic Alkalosis section, this exchanger is the pendrin protein and is distinct from the basolateral

Cl -HCO3 exchanger present in the intercalated cell. In a model of chronic hypercapnia, expression of pendrin was found to be significantly decreased (2). This is the same model mentioned previously in which hypercapnia led to redistribution of the Na -3HCO3 co-transporter to the basolateral membrane in the proximal tubule. These findings suggest that the renal adaptation to chronic hypercapnia is due not only to enhanced proximal HCO3 absorption but also to deceased distal HCO3 secretion. For the distal nephron to secrete an adequate amount of H , buffer must be available to prevent extreme luminal acidity. Quantitatively, the most important urinary buffer is the NH3/NH4 system. Unlike other buffers, the rate of NH3 production and excretion can be varied according to physiologic needs. Under normal circumstances, excretion of NH4 accounts for more than half of the net acid excreted per day. The proximal tubule is responsible for both ammonia production and luminal secretion. Ammonia is synthesized in the proximal tubule predominantly from glutamine metabolism through enzymatic processes in which phosphoenolpyruvate carboxykinase and phosphate-dependent glutaminase are the ratelimiting steps. This results in production of 2 NH4 and 2 HCO3 ions from each glutamine ion. Ammonia is then preferentially secreted into the lumen. Most of the ammonia that leaves the proximal tubule does not return to the distal tubule. Rather, the thick ascending limb of Henle reabsorbs the majority of luminal ammonia into the renal interstitium, where it becomes available for secretion into the collecting duct in response to H secretion. Although traditionally thought that NH3/NH4 then enters the collecting duct by nonionic diffusion driven by the acid luminal pH, increasing evidence suggests that the nonerythroid glycoproteins RhBg and RhCg may be involved in ammonia secretion (4). The polarized location in major sites of ammonia transport along with the increase in RhCg expression in response to acidosis suggests that these proteins may play an important role in the vectorial transport of ammonia. In addition, redistribution of these proteins into the cell membrane may contribute to the adaptive increase in single-nephron ammonia transport under reduced renal mass conditions (5). In addition to an increased ability to transport ammonia, metabolic acidosis leads to increased am-

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monia production in the proximal tubule. Metabolic acidosis increases the mobilization of glutamine form skeletal muscle and intestinal cells. Glutamine is preferentially taken up by the proximal tubular cell via the Na - and H -dependent glutamine transporter SNAT3. This transporter is a member of the SCL38 gene family of Na -coupled neutral amino acid transporters. SNAT3 expression increases severalfold in metabolic acidosis, and it is preferentially expressed on the cell's basolateral surface, where it is poised for glutamine uptake (6). The increase in plasma glucocorticoids that typically accompanies metabolic acidosis plays a role in this transporter's upregulation (7). Metabolic acidosis also causes increased expression and activity of phosphate-activated glutaminase and glutamate dehydrogenase. Proteomic analysis of rat proximal tubules taken from acidotic rats is consistent with upregulation of these enzymes (8). The primary mechanism for secretion of NH4 into the lumen is transport on the apical Na -H antiporter NHE-3. This transport process is influenced by angiotensin II (9). Metabolic acidosis is known to stimulate the systemic renin-angiotensin system. Angiotensin II either generated systemically or produced locally increases the protein expression of luminal NHE3 and as a result causes increased secretion of NH4 into the tubular lumen. Although this theory is not proved, patients who take inhibitors of the reninangiotensin system might be prone to more overt acid-base problems when faced with an acid load resulting from an inability to augment ammonia secretion through this transporter. Obstructive uropathy is typically associated with metabolic acidosis development and a defect in urinary acidification that frequently persists even after reestablishment of free urinary flow. Alterations in the expression of several proteins involved in acid-base homeostasis may explain these disturbances. In a rat model of bilateral urinary obstruction protein, expression of NHE3 and the Na -3HCO3 co-transporter in the proximal nephron and pendrin in the distal nephron were significantly decreased (10). The H -ATPase expression in the inner medullary collecting duct initially is increased but later falls after obstruction release. The other transporters also remain reduced after obstruction release. The persistent decrease in expression of NHE3, the Na -3HCO3 co-transporter, and H -ATPase after release of urinary obstruction will impair both HCO3 reclamation and regeneration. The

pendrin expression decrease may be a compensatory response to limit HCO3 secretion in metabolic acidosis. References

1. Brandes A, Oehlke O, Schumann A, Heidrich S, Thevenod F, Roussa E: Adaptive redistribution of NBCe1-A and NBCe1-B in rat kidney proximal tubule and striated ducts of salivary glands during acid-base disturbances. Am J Physiol Regul Integr Comp Physiol 293: R2400 ­ R2411, 2007 2. de Seigneux S, Malte H, Dinke H, Frekiaer J, Nielsen S, Frishce S: Renal compensation to chronic hypoxic hypercapnia: Downregulation of pendrin and adaptation of the proximal tubule. Am J Physiol Renal Physiol 292: F1256 ­F1266, 2006 3. Codina J, DuBose T: Molecular regulation and physiology of the H ,K -ATPases in kidney. Semin Nephrol 26: 345­351, 2006 4. Planelles G: Ammonium homeostasis and human Rhesus glycoproteins. Nephron Physiol 105: 11­17, 2007 5. Kim H, Baylis C, Verlander J, Han K, Reungjui S, Harellgton M, Weiner I: Effect of reduced renal mass on renal ammonia transporter family, Rh C glycoprotein and Rh B glycoprotein, expression. Am J Physiol Renal Physiol 293: F1238 ­F1247, 2007 6. Moret C, Dave M, Schulz N, Jiang J, Verrey F, Wagner C: Regulation of renal amino acid transporters during metabolic acidosis. Am J Physiol Renal Physiol 292: F555­F566, 2007 7. Karinch A, Lin C, Meng Q, Pan M, Souba W: Glucocorticoids have a role in renal cortical expression of the SNAT3 glutamine transporter during chronic metabolic acidosis. Am J Physiol Renal Physiol 292: F448 ­F455, 2007 8. Curthoys N, Taylor L, Hoffert J, Knepper M: Proteomic analysis of the adaptive response of rat renal proximal tubules to metabolic acidosis. Am J Physiol Renal Physiol 292: F140 ­F147, 2007 9. Nagami G: Role of angiotensin II in the enhancement of ammonia production and secretion by the proximal tubule in metabolic acidosis. Am J Physiol Renal Physiol 294: F874 ­F880, 2008 10. Wang G, Li C, Kim S, Ring T, Wen J, Djurhuss J, Wang W, Nielsen S, Frokaer J: Ureter obstruction alters expression of renal acid-base transport proteins in rat kidney. Am J Physiol Renal Physiol 295: F497­F506, 2008

Clinical Approach to Metabolic Acidosis

Metabolic acidosis is diagnosed by a low pH, a reduced HCO3 concentration, and respiratory compensation resulting in a decrease in the PCO2. A low HCO3 concentration alone is not diagnostic of metabolic acidosis because it also results from the renal compensation to chronic respiratory alkalosis. Measurement of the arterial pH differentiates between these two possibilities. The pH is low in hyperchloremic metabolic acidosis and high in chronic respiratory alkalosis. A two-part overview of metabolic acidosis with an emphasis on the critically ill patient recently was published (1,2). After confirming the presence of metabolic acidosis, calculation of the serum anion gap is a useful step in determining the differential diagnosis of the disorder. The anion gap is equal to the difference between the plasma concentrations of the

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major cation (Na ) and the major measured anions (Cl HCO3 ). Although calculation of the anion gap is a valuable clinical tool, a recent review highlighted some of the tool's limitations (3). As a result of changes in how serum Na and Cl are measured, the normal value for the anion gap has tended to fall over time. In healthy individuals, the anion gap has typically been reported to range from 11 to 15 mEq/L. These values were based on the use of flame photometry for Na measurement and a colorimetric assay for Cl . As laboratories moved to using ion selective electrodes, the serum Na values have largely remained the same, whereas the serum Cl values have tended to be higher. As a result, the normal value for the anion gap has decreased to as low as 6 mEq/L in some reports. Recognizing this change, some laboratories have actually adjusted the calibration set point for Cl so as to return the normal value for the anion gap back to the 11- to 15-mEq/L range. It is important for the clinician to be aware that the average anion gap and range of normal values will vary among health care facilities. In patients with high anion gap acidosis (e.g., 30 mEq/L), the contributing anion's identity is usually identifiable. The most common anions found in this setting are lactate and ketoacid anions resulting from lactic acidosis and ketoacidosis, respectively. With less pronounced elevations in the gap, the unmeasured anion's identity often is not apparent. Kreb cycle intermediates, amino acids, and uric acid may account for some of the gap in this setting (4). In addition, the anion gap-- even when adjusted for the serum albumin concentration--may be only minimally outside the normal range among patients with documented organic acidosis, suggesting that the test is an insensitive screen for mild to moderate disturbances (5). The review by Kraut and Madias (3) acknowledged that the anion gap will remain an inexpensive and effective means to detect various disorders but emphasized the need to interpret the results in the context of the history, physical examination, and other clinical information.

Lactic Acidosis

One of the most common causes of anion gap metabolic acidosis is lactic acidosis. Under normal circumstances, virtually all tissues in the body metabolize glucose via the glycolytic pathway and generate lactate, with the greater part of lactate production

occurring in brain, erythrocytes, and skeletal muscle. In turn, lactate is extracted predominately by the liver and renal cortex and either is reconverted to glucose or becomes fuel for oxidation for CO2 and H2O. This dynamic relationship between lactate and glucose is termed the Cori cycle. The importance of this cyclical relationship can best be appreciated when one considers that the normal daily production of lactate has been estimated to be 15 to 30 mmol/kg (equivalent to 15 to 30 mmol/kg H per d). Because daily net acid excretion by the kidney is only 1 mmol/kg, the quantitative importance of this pathway in disposing of the H that is produced during glycolysis becomes obvious. Furthermore, it is apparent that only a mild disruption in the equilibrium between lactate production and consumption in the Cori cycle can lead to the rapid development of devastating metabolic acidosis. Type A lactic acidosis is characterized by disorders in which there is underperfusion of tissue or acute hypoxia. Such disorders include patients with cardiopulmonary failure, severe anemia, hemorrhage, hypotension, sepsis, and CO poisoning. In blood samples taken from collapsed Boston Marathon runners, lactate levels were increased in virtually all individuals (6). In almost half of the cases, the lactate level was above what would be considered a critical value ( 31.5 mg/dl, 3.5 mmol/L). Adult patients with salicylate poisoning characteristically present with evidence of an anion gap metabolic acidosis and respiratory alkalosis (7). This same acid-base disturbance may also be a distinctive feature of thiamine deficiency presenting as Wernicke's encephalopathy (8). Significant increases in lactate levels ranging from 5.5 to 7.9 mmol/L were found in three of four such patients with this acid-base pattern. Type B lactic acidosis occurs in patients with a variety of disorders that share the development of lactic acidosis in the absence of overt hypoperfusion or hypoxia. These conditions include congenital defects in glucose or lactate metabolism, diabetes, liver disease, effects of drugs and toxins, and neoplastic diseases. Lactic acidosis is a feature of genetic mitochondrial disease. Chronic oral dichloroacetate therapy is effective in such patients. This drug stimulates the activity of the pyruvate dehydrogenase complex, thereby facilitating aerobic glucose and lactate oxida-

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tion. In an observational study of 36 individuals with disorders such as congenital lactic acidosis resulting from pyruvate dehyrogenase deficiency, defects in various respiratory chain complexes, or MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), both the basal and carbohydrateinduced increases in lactate were blunted with this drug (9). Long-term therapy lowered cerebrospinal fluid lactate levels and improved various measures of peripheral nerve function. Mitochondrial dysfunction leading to lactic acidosis can also be an acquired disorder. Highly active antiretroviral therapy to include didanosine and stavudine can cause fatal lactic acidosis. These drugs cause severe biochemical and ultrastructural damage to mitochondria in multiple tissues to include the liver, kidney, and skeletal and cardiac muscles (10). Preliminary evidence suggests that exogenous supplementation with uridine may be an effective treatment for this complication (11). Mangosteen (Garcinia mangostana) is a tropical fruit from Southeast Asia that is available for US importation. The fruit contains -mangostin, which is a known potent inhibitor of mitochondrial function. Daily ingestion of mangosteen juice was recently implicated in the development of severe lactic acidosis in a 58-yr-old man who used the juice to lose weight (12). Metformin therapy is a widely known cause of lactic acidosis, particularly when administered to patients with decreased renal function. In patients who have diabetes, are treated with renin-angiotensin system blockers, and develop volume depletion or are given a nonsteroidal anti-inflammatory drug or both can quickly develop acute kidney injury, precipitating severe lactic acidosis in the setting of metformin therapy (13,14). Intentional metformin overdose can also cause lactic acidosis (15,16). Continuous renal replacement therapy is useful in this setting because it removes both lactate and metformin and corrects the acidosis without the risk for volume overload. Propofol used for sedation can lead to lactic acidosis particularly in high dosages and for prolonged periods (17). Similarly, sedation with high-dosage lorazepam infusions can lead to propylene glycol toxicity. Accumulation and metabolism of this diluent causes lactic acidosis, increased osmolar gap, and acute kidney injury (18).

Clenbuteral is a long-acting adrenergic agonist that frequently is used in veterinary medicine to treat bronchoconstriction in animals. The drug also has anabolic properties, and body builders have used it illicitly to increase muscle mass. An outbreak of lactic acidosis has recently been reported with use of heroin adulterated with clenbuterol (19). The development of metabolic acidosis is likely similar to that reported in patients who had asthma and were treated with either inhaled or parenteral adrenergic agonists (20,21). Given the popularity of coffee and other caffeinated beverages, it should be mentioned that caffeine toxicity has been reported to cause increases in plasma lactate levels (22). Toxic levels of caffeine cause excessive sympathetic stimulation, leading to increased glycogenolysis and lipolysis and causing accumulation of pyruvate. To the extent that pyruvate fails to be aerobically metabolized, it will be converted to lactate. -Adrenergic blockade is a useful therapy in patients with caffeine overdose. Type B lactic acidosis can also be a complication of certain tumors. A recent review and case report discussed the association of lactic acidosis with hematologic malignancies (23,24).

Diabetic Ketoacidosis

Diabetic ketoacidosis is a metabolic condition characterized by the accumulation of acetoacetic acid and -hydroxybutyric acid. Its development is the result of insulin deficiency and a relative or absolute increase in glucagon concentration. These hormonal changes lead to increased fatty acid mobilization from adipose tissue and, at the same time, alter the oxidative machinery of the liver such that delivered fatty acids are primarily metabolized into keto acids. In addition, peripheral glucose utilization is impaired and the gluconeogenic pathway in the liver is maximally stimulated. The resultant hyperglycemia results in an osmotic diuresis and volume depletion. Ketoacidosis results when the rate of hepatic keto acid generation exceeds peripheral utilization and the blood keto acid concentration increases. The H accumulation in the extracellular fluid combines with and reduces HCO3 concentration, whereas the keto acid anion concentration increases. The reduction in serum HCO3 concentration approximates the increase in anion gap initially. The degree to which the anion gap is elevated will depend on the rapidity,

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severity, and duration of the ketoacidosis as well as the status of the extracellular fluid volume (25). Although an anion gap acidosis is the dominant disturbance in diabetic ketoacidosis, a hyperchloremic normal gap acidosis is often present, depending on the stage of the disease process. In the earliest stages of ketoacidosis, when extracellular volume is near normal, keto acid anions that are produced are rapidly excreted by the kidney as Na and K salts. Excretion of these salts is equivalent to the loss of potential HCO3 . This loss of potential HCO3 in the urine at the same time as the kidney is retaining dietary NaCl results in a hyperchloremic normal gap acidosis. As the ketogenic process becomes more accelerated and volume depletion becomes more severe, a larger proportion of the generated keto acid anions are retained within the body, thereby increasing the anion gap. During treatment, the anion gap metabolic acidosis transforms once again into a hyperchloremic normal gap acidosis. Treatment leads to a termination in keto acid production. As the extracellular fluid volume is restored, there is increased renal excretion of the Na salts of the keto acid anions. The loss of this potential HCO3 combined with the retention of administered NaCl accounts for the emergence of a hyperchloremic normal gap acidosis. In addition, K and Na administered in solutions that contain NaCl and KCl enter into cells in exchange for H . The net effect is infusion of HCl into the extracellular fluid. The reversal of the hyperchloremic acidosis is accomplished over several days as the HCO3 deficit is corrected by the kidney. Confirmation of the presence of keto acids can be achieved with use of nitroprusside tablets or reagent strips; however, this test can be misleading in assessing the severity of ketoacidosis because it detects only the presence of acetone and acetoacetate and does not permit reaction with -hydroxybutyrate. Acetoacetic acid and -hydroxybutyric acid are interconvertible, with the NADH:NAD ratio being the primary determinant as to which moiety predominates. In a high ratio, formation of -hydroxybutyric acid is favored, and the nitroprusside test will become less positive or even negative despite significant ketoacidosis. This situation can occur when ketoacidosis is accompanied by lactic acidosis or in alcoholic ketoacidosis. During treatment, the NADH:NAD ratio tends to decline, favoring the formation of acetoacetic acid. As a result, it is common for the nitroprusside test to register more

strongly positive during the treatment of diabetic ketoacidosis. Readily available assays are now available for the detection of -hydroxybutyrate. In the presence of uncontrolled diabetes, serum -hydroxybutyrate levels 3.0 and 3.8 mmol/L in children and adults, respectively, can be used to diagnose diabetic ketoacidosis (26). When compared with urinary ketone measurements, capillary blood levels of -hydroxybutyrate more strongly correlate with the degree of systemic acidosis and offer a more precise way to monitor patients' response to therapy (27). Diabetic ketoacidosis treatment involves the use of insulin and intravenous fluids to correct volume depletion. Deficiencies in K , Mg2 , and phosphate are common; therefore, these electrolytes are typically added to intravenous solutions, although there is not clear evidence of a benefit of routine administration of phosphate. Alkali therapy is generally not required because insulin administration leads to the metabolic conversion of keto acid anions into HCO3 and allows partial correction of the acidosis. HCO3 therapy may be indicated in patients who present with severe acidemia (pH 7.0). The pros and cons of bicarbonate therapy among patients with severe acidosis is the subject of a recent discussion (28). Tris-hydroxymethyl aminomethane (THAM) is a weak base that is used in the treatment of metabolic and respiratory acidosis. THAM binds H and regenerates HCO3 without releasing CO2. The drug also easily penetrates cells and provides an intracellular buffering effect (29). The drug's protonated form is eliminated in the urine. THAM was given to a hemodynamically unstable 13-yr-old girl who presented with diabetic ketoacidosis and a pH of 6.8 (30). THAM along with conventional therapy produced a rapid improvement in the patient's metabolic profile and hemodynamic condition. There is limited experience with the use of THAM in treatment of metabolic acidoses. One also must be open to the possibility of more than one process in patients who have diabetes and present with severe academia (31,32). A 19-yr-old patient with diabetes presented with ketoacidosis and a pH of 6.7 but had only moderately elevated -hydroxybutyrate levels (31). A drug screen disclosed the presence of ketamine. This drug is consumed intentionally or via spiked drinks and gives rise to dosagedependent effects ranging from relaxation (referred to

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by users as "K-land") to near-death experiences ("Khole"). Drug ingestion can lead to metabolic acidosis, rhabdomyolysis, and seizures.

ulation leads to diminished fatty acid mobilization from adipose tissue as well as decreased hepatic output of keto acids.

Starvation Ketosis

Abstinence from food can lead to a mild anion gap metabolic acidosis secondary to increased production of keto acids. The pathogenesis of this disorder is similar to that of diabetic ketoacidosis in that starvation leads to relative insulin deficiency and glucagon excess. As a result, there is increased mobilization of fatty acids while the liver is set to oxidize fatty acids to keto acids. The serum HCO3 concentration rarely falls to values 18 mmol/L. More fulminant ketoacidosis is aborted by the fact that ketone bodies stimulate the pancreatic islets to release insulin, and lipolysis is held in check. This break in the ketogenic process is notably absent in patients with insulin-dependent diabetes. More severe reduction in serum HCO3 should prompt a search for other conditions (32).

Ethylene Glycol and Methanol Poisoning

Ethylene glycol metabolism by alcohol dehydrogenase generates various acids, including glycolic, oxalic, and formic acids. Ethylene glycol is a component of antifreeze and solvents and is ingested by accident or as a suicide attempt. The initial effects of intoxication are neurologic and begin with acute inebriation similar to that of alcohol but can quickly progress to seizures and coma. When left untreated, cardiopulmonary symptoms such as tachypnea, noncardiogenic pulmonary edema, and cardiovascular collapse may appear. Twenty-four to 48 h after ingestion, patients may develop flank pain and renal failure often accompanied by abundant calcium oxalate crystals in the urine. Renal biopsy shows tubular necrosis and widespread deposition of calcium oxalate crystals within the tubular epithelial cells (36). Methanol also is metabolized by alcohol dehydrogenase and forms formaldehyde, which is then converted to formic acid. Methanol is found in a variety of commercial preparations such as shellac, varnish, and deicing solutions. As with ethylene glycol ingestion, methanol is ingested by accident or as a suicide attempt. Clinically, methanol ingestion is associated with an acute inebriation followed by an asymptomatic period lasting 24 to 36 h. Thereafter, pancreatitis, seizures, blindness, and coma may develop. The blindness is due to direct retinal toxicity of formic acid. Methanol intoxication can lead to the delayed onset of a Parkinson-like syndrome because it may induce hemorrhage in the white matter and putamen. Lactic acidosis also is a feature of methanol and ethylene glycol poisoning and contributes to the elevated anion gap. Together with the appearance of the anion gap, an osmolar gap becomes manifest and is an important clue to ethylene glycol diagnosis and methanol poisoning. In addition to supportive measures, the treatment of ethylene glycol and methanol poisoning is centered on reducing the metabolism of the parent compound and accelerating its removal from the body. Decreasing metabolism of the parent compound is important because the metabolites rather than the parent compound are primarily responsible for the toxic effects. Fomepizole (4-methylpyrazole) is now the agent of choice to inhibit the enzyme alcohol dehy-

Alcoholic Ketoacidosis

Ketoacidosis develops in patients with a history of long-term ethanol abuse, decreased food intake, and often a history of nausea and vomiting. The clinician must consider this condition in young people because alcohol use is on the rise in the adolescent population (33). Alcoholic ketoacidosis is a serious condition that has been associated with sudden cardiac death (34). As with starvation ketosis, a decrease in the insulin to glucagon ratio leads to accelerated fatty acid mobilization and alters the enzymatic machinery of the liver to favor keto acid production; however, several features differentiate this disorder from simple starvation ketosis. First, the presence of alcohol withdrawal combined with volume depletion and starvation markedly increases the circulating catecholamine levels (35). As a result, the peripheral mobilization of fatty acids is much greater than that typically found with starvation alone. This sometimes massive mobilization of fatty acids can lead to marked keto acid production and severe metabolic acidosis. Second, alcohol metabolism leads to NADH accumulation. The increase in the NADH:NAD ratio is reflected by a higher -hydroxybutyrate to acetoacetate ratio. As mentioned, the nitroprusside reaction may be diminished by this redox shift despite the presence of severe ketoacidosis. Treatment of this disorder is centered on administering glucose. Glucose administration leads to the rapid resolution of the acidosis, because insulin release stim-

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drogenase and prevent formation of toxic metabolites. If fomepizole is unavailable, then intravenous ethanol can be used to prevent the formation of toxic metabolites. Ethanol has 10-fold greater affinity for alcohol dehydrogenase than other alcohols. With fomepizole and ethanol therapy, hemodialysis therapy should be used to remove both the parent compound and metabolites. The reader is referred to a recent in-depth review of the diagnosis and management of toxic alcohol ingestions (37).

Pyroglutamic Acidosis

The diagnosis of pyroglutamic acidosis should be considered in patients with unexplained anion gap metabolic acidosis and recent acetaminophen ingestion (38,39). In this setting, glutathione levels are reduced because of the oxidative stress associated with critical illness. In addition, acetaminophen metabolism depletes glutathione. The reduction in glutathione secondarily leads to increased production to pyroglutamic acid. High pyroglutamic acid concentrations are found in the blood and urine, and plasma concentrations parallel the increase in the anion gap.

phritis or high colonic pressures secondarily causing urinary obstruction. The main factors that influence the development and severity of acidosis are the length of time the urine is in contact with the bowel and the total surface area of bowel exposed to urine. Among patients with an ureterosigmoid anastomosis, the acidosis tends to be more common and more severe than in those with an ileal conduit. One patient who presented with quadriparesis and rhabdomyolysis was found to have a pH of 7.05 and a serum K concentration of 1.27 mmol/L (40). Patients who undergo this procedure and develop an acidosis should be examined for the possibility of an ileal loop obstruction, because this would lead to an increase in contact time between the urine and the intestinal surface.

Renal Causes of Normal (Hyperchloremic) Anion Gap Acidosis

Under normal circumstances, approximately 90% of the filtered load of HCO3 is reabsorbed in the proximal tubule. Normally the serum HCO3 concentration is maintained slightly below the threshold at which bicarbonaturia develops. In this manner, when the serum concentration of HCO3 exceeds 26 to 28 mmol/L, the excess HCO3 is excreted in the urine. In proximal renal tubular acidosis (RTA), the threshold for HCO3 reabsorption is lower and results in a self-limited bicarbonaturia. This defect causes a portion of the filtered HCO3 to escape reabsorption in the proximal tubule and to be delivered into the distal nephron. The distal nephron has a low capacity for HCO3 reabsorption, and HCO3 appears in the urine. The net effect is that the serum concentration and filtered load of HCO3 begin to fall. Despite systemic acidemia development, the urine pH is alkaline because of the presence of HCO3 in the urine. Eventually a steady state is reached, at which point all of the filtered HCO3 is reabsorbed. Now the delivery of HCO3 to the distal nephron may be abnormally increased, but it is of a magnitude that can be reabsorbed in the distal nephron. The urine is acidified to a pH of 5.5, and net acid excretion is equal to endogenous acid production but at a lower serum HCO3 concentration. In the steady state, the serum HCO3 concentration in proximal RTA usually is in the range of 16 to 18 mmol/L. One of the characteristic findings in proximal RTA is the presence of hypokalemia. The develop-

Normal (Hyperchloremic) Anion Gap Acidosis

A hyperchloremic normal anion gap metabolic acidosis can be of renal or extrarenal origin. Metabolic acidosis of renal origin is the result of abnormalities in tubular H transport. Metabolic acidosis of extrarenal origin is most commonly caused by gastrointestinal losses of HCO3 . Other causes include the external loss of biliary and pancreatic secretions and ureteral diversion procedures.

Extrarenal Causes of Normal (Hyperchloremic) Anion Gap Acidosis

Surgical diversion of the ureter into an ileal pouch is a procedure often used to treat patients with neurologic bladder abnormalities and urologic tumors. The procedure may rarely be associated with the development of a hyperchloremic normal gap metabolic acidosis. Acidosis may occur in part because of reabsorption of NH4 and Cl from the urinary fluid by the intestine, which then metabolizes the NH4 in the liver to NH3 and H . Urinary Cl may also be reabsorbed in exchange for HCO3 through activation of the Cl / HCO3 exchanger on the intestinal lumen. In some patients, a renal defect in acidification can develop and exacerbate the acidosis. Such a defect may result from tubular damage caused by pyelone-

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ment of hypokalemia is the result of renal K wasting caused by the coupling of increased aldosterone levels and increased distal Na delivery. In the steady state, when virtually all of the filtered HCO3 is reabsorbed in the proximal and distal nephron, renal K wasting is minimal and the degree of hypokalemia tends to be mild. By contrast, treatment of metabolic acidosis with HCO3 improves the acidosis but worsens the degree of hypokalemia. An increase in the filtered concentration of HCO3 above the kidney's reabsorptive threshold will result in an increase in excretion of NaHCO3 and KHCO3. An example of this effect was recently reported in a 39-yr-old man with proximal RTA because of myeloma kidney (41). Basolateral NaHCO3 co-transporter (NBCe1/ SLC4A4) gene mutations give rise to an inherited form of proximal RTA (42). This form of proximal RTA is accompanied by ocular abnormalities such as cataracts, glaucoma, and band keratopathy. Only two families have been described with isolated pure proximal RTA. In one family, nine genes that are known to be involved in proximal acidification were studied, but a molecular basis for the disease could not be identified (43). Topiramate is a drug that initially was approved as an antiepileptic drug and increasingly is used to treat of a number of neurologic and metabolic disorders. The drug exerts an inhibitory effect on renal carbonic anhydrase activity, resulting in a proximal acidification defect similar to that observed with acetazolamide. Use of the drug also is associated with hypocitraturia, hypercalciuria, and elevated urine pH, leading to an increased risk for kidney stone disease (44 ­ 46). Proximal RTA may occur as an isolated defect in acidification alone but is more commonly associated with widespread proximal tubule dysfunction (Fanconi syndrome). In addition to decreased HCO3 reabsorption, patients with Fanconi syndrome have impaired reabsorption of glucose, phosphate, uric acid, amino acids, and low molecular weight proteins. Several inherited and acquired disorders have been associated with the development of Fanconi syndrome and proximal RTA. The most common inherited cause is cystinosis. Adults with Fanconi syndrome most commonly have a dysproteinemic condition such as multiple myeloma. Fanconi syndrome has occurred in association with administration of imatinib mesylate in a patient with chronic myeloid leukemia and in a liver transplant patient who was treated with tacrolimus and lamivudine (47,48). Fanconi syndrome can be a clin-

ical manifestation of the syndrome of tubulointerstitial renal disease and uveitis (TINU syndrome) (49,50). Tenofovir is commonly used as a component in highly active antiretroviral therapy. Its principal renal adverse effects are related to tubular toxicity, giving rise to manifestations such as RTA, Fanconi syndrome, and nephrogenic diabetes insipidus (51). In a study designed to investigate its renal toxicity, rats were fed varying dosages of tenofovir during a several-week period (52). The rats developed phosphaturia, proximal RTA, and a reduced concentrating ability. These renal manifestations were accompanied by downregulation of the sodium-phosphorus co-transporter (NaPi-IIa), NHE3, and aquaporin 2. Because previous studies had shown that normal rats that were given the peroxisome proliferator­activated receptor agonist rosiglitazone led to increased expression of these same transporters, the investigators hypothesized that the nephrotoxicity of tenofovir could be prevented by this drug. Indeed, rosiglitazone reversed tenofovir nephrotoxicity and normalized the altered membrane transporter protein expression. In contrast to patients with proximal RTA, those with distal RTA (dRTA) do not acidify their urine despite severe metabolic acidosis. This disorder results from a reduction in net H secretion in the distal nephron, which gives rise to an impairment in HCO3 regeneration. As a result, these patients are in a state of persistent positive acid balance that requires bone buffers to prevent severe systemic acidemia. The pathophysiologic basis for this defect could be either impaired H secretion (secretory defect) or an abnormally permeable distal tubule, resulting in increased backleak of normally secreted H (gradient defect). The RTA that is seen in the setting of amphotericin B administration is an example of impaired H secretion resulting from a gradient defect. For patients with a secretory defect, the inability to acidify the urine below pH 5.5 results from an abnormality in one or both of the H secretory mechanisms. Some patients may have an isolated defect in the H -K ATPase that impairs H secretion and K reabsorption. The second mechanism of H secretion in the distal nephron is the vacuolar ATPase. This pump couples the energy from hydrolysis of ATP to the active transport of H from the cytoplasm into the tubular lumen (reviewed in reference [53]). Mutations in ATP6V1B1 (B1 subunit) or ATP6V0A4 (a4 subunit) are responsible for the rare autosomal recessive from of dRTA in which sensorineu-

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ral deafness also is present (54). It has been proposed that subtle defects in these subunits could give rise to a normal blood pH and bicarbonate concentration but impair maximal acidification of the urine when challenged with an acid load (55,56). Given the link between reduced urinary acidification and calcium stone formation, such defects could play a role among calcium stone formers in the general population. A dRTA diagnosis should be considered for a patient with hyperchloremic normal gap acidosis, hypokalemia, and an inability to lower the urine pH maximally. A urine pH 5.5 in the setting of systemic acidosis is consistent with a dRTA, as is a positive urinary anion gap. In patients with only minimal disturbances in blood pH and plasma HCO3 concentration, a test of urinary acidification is required. Traditionally, such a test involved oral NH4Cl administration to induce metabolic acidosis and then assess the renal response by serially measuring the urine pH. Many patients poorly tolerate NH4Cl ingestion because of gastric irritation, nausea, and vomiting. An alternative way to test the capacity for distal acidification is to administer furosemide and mineralocorticoid fludrocortisone simultaneously. The combination of both increased distal Na delivery and mineralocorticoid effect will stimulate distal H secretion by both increasing the luminal electronegativity and having a direct stimulatory on H secretion. In a study of 10 patients with known dRTA and 11 control subjects, urinary acidification assessment was compared between NH4Cl loading and simultaneous administration of furosemide and fludrocortisone (57). The control subjects could lower their urine pH to 5.3, whereas all of the patients with dRTA failed to acidify their urine with either test; however, two aspects of the study favored the furosemide/ fludrocortisones protocol. The test was better tolerated and the time to maximal reduction in urine pH was significantly shorter when compared NH4Cl loading. The administration of furosemide and the mineralocorticoid fludrocortisone is an effective way to test the capacity for distal acidification. This approach is better tolerated than NH4Cl ingestion. The systemic acidosis in dRTA tends to be more severe than in patients with a proximal RTA. The

serum HCO3 concentration can reach values as low as 10 mmol/L. Hypokalemia can also be severe; it can lead to musculoskeletal weakness and symptoms of nephrogenic diabetes insipidus in patients with dRTA. Unlike patients with proximal RTA, patients with dRTA frequently manifest nephrolithiasis and nephrocalcinosis. This predisposition to renal calcification results from a number of factors. Urinary Ca2 excretion is high secondary to acidosis-induced bone mineral dissolution. This increase in urinary Ca2 excretion is worsened by the low intraluminal concentration of HCO3 in the distal nephron. Normally, HCO3 acts to increase distal Ca2 absorption. Systemic acidemia lowers the luminal concentration of HCO3 in the distal nephron, with the result that Ca2 absorption is decreased and urinary Ca2 excretion is further augmented (58). The increased Ca2 excretion is more likely to result in urine supersaturation in the presence of an alkaline pH. The high urine pH decreases the solubility of calcium phosphate complexes. Stone formation is further enhanced because of low urinary citrate excretion. Citrate is metabolized to HCO3 , and thus its reabsorption contributes to correction of metabolic acidosis. Unfortunately, urinary citrate serves as the major Ca2 chelator in the urine; therefore, its enhanced reabsorption in acidosis predisposes to nephrolithiasis and nephrocalcinosis. The results of intraoperative renal papillae biopsies obtained during percutaneous nephrolithotomy in five stone-forming patients with dRTA were recently reported (59). The degree of papillary renal disease was more diffuse compared with patients with other forms of renal stone disease. In particular, there was plugging of inner medullary collecting ducts and Bellini ducts with deposits of calcium phosphate. The degree of interstitial fibrosis was marked and diffusely present. By comparison, biopsy material from patients with idiopathic calcium oxalate stones did not show intratubular crystals or interstitial fibrosis. dRTA may be a primary disorder, either idiopathic or inherited, but most commonly occurs in association with a systemic disease, one of the most common causes of which is Sjogren syndrome (60). In ¨ two cases, dRTA developed in association with a wasp sting (61). The inherited form of dRTA because of gene mutations that encode H secretory pumps was discussed already. Mutations in the human SLC4A1 gene encode the erythroid and kidney isoform of anion

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exchanger 1. The erythroid isoform (eAE1) is present in red blood cell membranes and mediates Cl / HCO3 exchange. The kidney isoform (kAE1) is found in the basolateral surface of the intercalated cell and is required for normal urinary acidification. Human SLC4A1 gene mutations are responsible for the development of dRTA and ovalocytosis primarily reported in patients from Southeast Asia and rarely in other ethnic groups (62,63). The disturbance in transport properties of the anion exchanger varies depending on the precise SLC4A1 gene mutations (64). References

1. Morris C, Low J: Metabolic acidosis in the critically ill: Part 1. Classification and pathophysiology. Anaesthesia 63: 294 ­301, 2008 2. Morris C, Low J: Metabolic acidosis in the critically ill: Part 2. Causes and treatment. Anaesthesia 63: 396 ­ 411, 2008 3. Kraut J, Madias N: Serum anion gap: Its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2: 162­174, 2007 4. Moviat M, Terpstra A, Ruitenbeek W, Kliijtmans L, Pickkers P, van der Hoeven J: Contribution of various metabolites to the "unmeasured" anions in critically ill patients with metabolic acidosis. Crit Care Med 36: 752­758, 2008 5. Chawla L, Jagasia D, Abell L, Seneff M, Egan M, Danino N, Nguyen A, Ally M, Kimmel P, Junker C: Anion gap, anion gap corrected for albumin, and base deficit fail to accurately diagnose clinically significant hyperlactatemia in critically ill patients. J Intensive Care Med 23: 122­127, 2008 6. Siegel A, Januzzi J, Sluss P, Lee-Lewandrowski E, Wood M, Shirey T, Lewandrowski K: Cardiac biomarkers, electrolytes, and other analytes in collapsed marathon runners: Implications for the evaluation of runners following competition. Am J Clin Pathol 129: 948 ­ 951, 2008 7. Kent K, Ganetsky M, Cogen J, Bird S: Non-fatal ventricular dysrhythmias associated with severe salicylate toxicity. Clin Toxicol (Phila) 46: 297­299, 2008 8. Donnino M, Miller J, Garcia A, McKee E, Walsh M: Distinctive acid-base pattern in Wernicke's encephalopathy. Ann Emerg Med 50: 722­725, 2007 9. Stacpoole P, Gilbert L, Neiberger R, Carney P, Valenstein E, Theriaque D, Shuster J: Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics 121: e1223­ e1228, 2008 10. Thoden J, Lebrecht D: Highly active antiretroviral HIV therapyassociated fatal lactic acidosis: Quantitative and qualitative mitochondrial DNA lesions with mitochondrial dysfunction in multiple organs. AIDS 22: 1093­1094, 2008 11. Lebrecht D, Deveaud C, Beauvoit B, Bonnet J, Kirschner J, Walker U: Uridine supplementation antagonizes zidovudine-induced mitochondrial myopathy and hyperlactatemia in mice. Arthritis Rheum 58: 318 ­326, 2008 12. Wong L, Klemmer P: Severe lactic acidosis associated with juice of the mangosteen fruit Garcinia mangostana. Am J Kidney Dis 51: 829 ­ 833, 2008 13. Bruijstens L, van Luin M, Buscher-Jungerhans P, Bosch F: Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment. Neth J Med 66: 185­190, 2008 14. Audia P, Feinfeld D, Dubrow A, Winchester J: Metformin-induced lactic acidosis and acute pancreatitis precipitated by diuretic, celecoxib, and candesartan-associated acute kidney dysfunction. Clin Toxicol (Phila) 46: 164 ­166, 2008

15. Dell'aglio D, Perino L, Todino J, Algren D, Morgan B: Metformin overdose with a resultant serum pH of 6.59: Survival without sequelae. J Emerg Med March 14, 2008 [epub ahead of print] 16. Hong Y, O'Boyle C, Chen I, Hsiao C, Kuan J: Metformin-associated lactic acidosis in a pregnant patient. Gynecol Obstet Invest 66: 138 ­141, 2008 17. Fodale V, La Monaca E: Propofol infusion syndrome: An overview of a perplexing disease. Drug Saf 31: 293­303, 2008 18. Zar T, Yusufzai I, Sullivan A, Graeber C: Acute kidney injury, hyperosmolality and metabolic acidosis associated with lorazepam. Nat Clin Pract Nephrol 3: 515­520, 2007 19. Hoffman R, Kirrane B, Marcus S: A descriptive study of an outbreak of clenbuterol-containing heroin. Ann Emerg Med 52: 548 ­553, 2008 20. Creagh-Brown B, Ball J: An under-recognized complication of treatment of acute severe asthma. Am J Emerg Med 26: 514.e1­514.e3, 2008 21. Veenith T, Pearce A: A case of lactic acidosis complicating assessment and management of asthma. Int Arch Med 1: 3, 2008 22. Schmidt A, Karlson-Stiber C: Caffeine poisoning and lactate rise: An overlooked toxic effect? Acta Anaesthesiol Scand 52: 1012­1014, 2008 23. Friedenberg A, Brandoff D, Schiffman F: Type B lactic acidosis as a severe metabolic complication in lymphoma and leukemia: A case series from a single institution and literature review. Medicine (Baltimore) 86: 225­232, 2007 24. Udayakumar N, Rajendiran C, Muthuselvan R: A typical presentation of acute myeloid leukemia. J Cancer Res Ther 2: 82­ 84, 2006 25. Gowrishankar M, Carlotti A, George-Hyslop C, Bohn D, Kamel K, Davids M, Halperin M: Uncovering the basis of a severe degree of acidemia in a patient with diabetic ketoacidosis. QJM 100: 721­735, 2007 26. Sheikh-Ali M, Karon B, Basu A, Kudva Y, Muller L, Xu J, Schwenk W, Miles J: Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 31: 4: 643­ 647, 2008 27. Turan S, Omar A, Bereket A: Comparison of capillary blood ketone measurement by electrochemical method and urinary ketone in treatment of diabetic ketosis and ketoacidosis in children. Acta Diabetol 45: 83­ 85, 2008 28. Sabatini S, Jurtzman N: Bicarbonate therapy in severe metabolic acidosis. J Am Soc Nephrol March 5, 2008 [epub ahead of print] 29. Giunti C, Priouzeau F, Allemand D, Levraut J: Effect of trishydroxymethyl aminomethane on intracellular pH depends on the extracellular non-bicarbonate buffering capacity. Transl Res 150: 350 ­356, 2007 30. Marano M, Iodice F, Stoppa F, Tomasello C, Perrotta D, Cecchetti C, Di Nardo M, Ciampalini P, Pirozzi N: Treatment of severe diabetic acidosis with tris-hydroxymethyl aminomethane in a thirteen-yearold child. Minerva Anestesiol 74: 93­95, 2008 31. Lee P, Campbell L: Diabetic ketoacidosis: The usual villain or a scapegoat? A novel cause of severe metabolic acidosis in type 1 diabetes. Diabetes Care 31: e13, 2008 32. Vermeersch N, Stolte C, Fostier K, Delooz H: An unusual case of hyperglycemia, abdominal pain, and increased anion gap acidosis. J Emerg Med February 13, 2008 [epub ahead of print] 33. Manini A, Hoffman R, Nelson L: Alcoholic ketoacidosis in an 11-year-old boy. Pediatr Emerg Care 24: 170 ­171, 2008 34. Yanagawa Y, Sakamoto T, Okada Y: Six cases of sudden cardiac arrest in alcoholic ketoacidosis. Intern Med 47: 113­117, 2008 35. Bilbault P, Levy J, Vinzio S, Castelain V, Schneider F: Abrupt alcohol withdrawal: Another cause of ketoacidosis often forgotten. Eur J Emerg Med 15: 100 ­101, 2008 36. Pomara C, Fiore C, D'Errico S, Riezzo I, Finshcei V: Calcium oxalate crystals in acute ethylene glycol poisoning: A confocal laser scanning microscope study in a fatal case. Clin Toxicol (Phila) 46: 322­324, 2008

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37. Kraut J, Kurtz I: Toxic alcohol ingestions: Clinical features, diagnosis, and management. Clin J Am Soc Nephrol 3: 208 ­225, 2008 38. Fenves A, Kirkpatrick H, Patel V, Sweetman L, Emmett M: Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): A role for acetaminophen. Clin J Am Soc Nephrol 1: 441­ 447, 2006 39. Brooker G, Jeffery J, Nataraj T, Sair M, Ayling R: High anion gap metabolic acidosis secondary to pyroglutamic aciduria (5-oxoprolinuria): Association with prescription drugs and malnutrition. Ann Clin Biochem 44: 406 ­ 409, 2007 40. Ozmen S, Danis R, Akin D, Gullu N, Ozmen C, Yazanel O: Ureterosigmoidostomy-associated quadriparesis, non-traumatic rhabdomyolysis, and tetany in an adult. Int Urol Nephrol 40: 245­247, 2008 41. Hoorn E, Zietse R: Combined renal tubular acidosis and diabetes insipidus in hematological disease. Nat Clin Pract Nephrol 3: 171­ 175, 2007 42. Dinour D, Chang M, Satoh J, Smith B, Angle N, Knecht A, Serban I, Holtzman E, Romero M: A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects. J Biol Chem 279: 52238 ­52246, 2004 43. Katzir Z, Dinour D, Reznik-Wolf H, Nissenkorn A, Holtzman E: Familial pure proximal renal tubular acidosis­a clinical and genetic study. Nephrol Dial Transplant 23: 1211­1215, 2008 44. Vega D, Maalouf N, Sakhaee K: Increased propensity for calcium phosphate kidney stones with topiramate use. Expert Opin Drug Saf 6: 547­557, 2007 45. Welch B, Graybeal D, Moe O, Maalouf N, Sakhaee K: Biochemical and stone-risk profiles with topiramate treatment. Am J Kidney Dis 48: 555­563, 2006 46. Warner B, LaGrange C, Tucker T, Bensalem-Owen M, Pais V: Induction of progressive profound hypocitraturia with increasing doses of topiramate. Urology 72: 29 ­32, 2008 47. Francois H, Coppo P, Hayman J, Fouqeray B, Mougenot B, Ronco P: Partial Fanconi syndrome induced by imatinib therapy: A novel cause of urinary phosphate loss. Am J Kidney Dis 51: 298 ­301, 2008 48. Bayrakci U, Baskin E, Ozcay F, Handan B, Karakayali H, Haberal M: Renal Fanconi syndrome and myopathy after liver transplantation: Drug-related mitochondrial cytopathy? Pediatr Transplant 12: 109 ­ 112, 2008 49. Koike K, Lida S, Usui M, Matsumoto Y, Fukami K, Ueda S, Tamaki K, Kato S, Okuda S: Adult-onset acute tubulointerstitial nephritis and uveitis with Fanconi syndrome: Case report and review of the literature. Clin Nephrol 64: 255­259, 2007 50. Chow K, Lai F, Szeto C, Chan N, Wong E, Li P: Quiz page March 2008: Fever, anorexia, and renal failure. TINU syndrome. Am J Kidney Dis 51: A39 ­A40, 2008 51. Shepp D, Curtis S, Rooney J: Causes and consequences of hypokalemia in patients on tenofovir disoproxil fumarate. AIDS 21: 1479 ­ 1481, 2007 52. Liborio A, Andrade L, Pereira L, Sanches T, Shimizu M, Seguro A: Rosiglitazone reverses tenofovir-induced nephrotoxicity. Kidney Int 74: 910 ­918, 2008 53. Jefferies K, Cipriano D, Forgac M: Function, structure and regulation of the vacuolar (H )-ATPases. Arch Biochem Biophys 476: 33­ 42, 2008 54. Tasic V, Korneti P, Gucev Z, Hoppe B, Blau N, Cheong H: Atypical presentation of distal renal tubular acidosis in two siblings. Pediatr Nephrol 23: 1177­1181, 2008 55. Wagner C: When proton pumps go sour: Urinary acidification and kidney stones. Kidney Int 73: 1103­1105, 2008 56. Fuster D, Zhang J, Xie X, Moe O: The vacuolar-ATPase B1 subunit in distal tubular acidosis: Novel mutations and mechanisms for dysfunction. Kidney Int 73: 1151­1158, 2008

57. Walsh S, Shirley D, Wrong O, Unwin R: Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride. Kidney Int 71: 1310 ­1316, 2007 58. Bonny O, Rubin A, Huang C, Frawley W, Pak C, Moe O: Mechanism of urinary calcium regulation by urinary magnesium and pH. J Am Soc Nephrol 19: 1530 ­1537, 2008 59. Evan A, Lingeman J, Coe F, Shao Y, Miller N, Matlaga B, Phillips C, Sommer A, Worcester E: Renal histopathology of stone-forming patients with distal renal tubular acidosis. Kidney Int 71: 795­ 801, 2007 60. Ren H, Wang M, Chen X, Zhang W, Pan X, Wang X, Lin Y, Zhang S, Chen N: Renal involvement and followup of 130 patients with primary Sjogren's syndrome. J Rheumatol 35: 278 ­284, 2008 ¨ 61. D'Cruz S, Chauhan S, Singh R, Sachdev A, Lehl S: Wasp sting associated with type 1 renal tubular acidosis. Nephrol Dial Transplant 23: 1754 ­1755, 2008 62. Khositseth S, Sirikanaeret A, Khopraset S, Opastiakul S, Kingwatanakul P, Thongoppinkhun W, Yenchitsomanus P: Hematological abnormalities in patients with distal renal tubular acidosis and hemoglobinopathies. Am J Hematol 83: 465­ 471, 2008 63. Jamard B, Allard J, Caron P, Corberand J, Blanchard A, VargasPoussou R, Mahou S, Constantin A, Cantagrel A, Mazieres B, Laroche M: Distal renal tubular acidosis and ovalocytosis: A case report. Osteoporos Int 19: 119 ­122, 2008 64. Walsh S, Borgese F, Gabillat N, Unwin R, Guizouarn H: Cation transport activity of anion exchanger 1 (AE1) mutations found in inherited distal renal tubular acidosis (dRTA): structure-function implications for AE1. Am J Physiol Renal Physiol 295: F343­F350, 2008

Hyponatremia

Isotonic and Hypertonic Hyponatremia

Nonhypotonic hyponatremia can be recognized by the presence of an "osmolar gap"--a difference between the measured plasma osmolality and the osmolality calculated from the plasma sodium concentration, blood urea nitrogen (BUN), and blood glucose. If the laboratory reports the concentration of these solutes in mmol/L, then the calculated osmolality equals the doubled sodium concentration (so as to account for sodium's accompanying anions) plus the millimolar concentrations of urea and glucose. If the BUN and glucose are expressed in mg/dl, then these concentrations are converted to mmol/L by dividing the BUN by 2.8 and blood glucose by 18. The presence of an osmolar gap in a patient with hyponatremia usually means that the patient has pseudohyponatremia or that hyponatremia is caused by the presence of excessive concentrations of a non­sodium-effective osmole in the circulation. An osmolar gap is also present when the plasma contains high concentrations of ethanol, methanol, or isopropyl alcohol; however, these solutes are not effective osmoles (i.e., they do

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not osmotically attract water from cells, and they do not cause hyponatremia). Patients with azotemia and hyponatremia may have a normal or high plasma osmolality, but they do not have an osmolar gap. Urea is not an effective osmole unless its concentration is changing rapidly because of urea infusion or dialysis. Attention to the "effective osmolality" (i.e., the plasma osmolality minus the osmotic contribution of urea) may help in the evaluation of these patients.

approach to circumvent the problem of pseudohyponatremia is first to estimate plasma water from the formula plasma water content (%) 99.1 (0.1 L) (0.07 P) [equation 1],

Pseudohyponatremia

Sodium's biologic effects are determined by its concentration in plasma water. Thus, "true hyponatremia" or "hypotonic hyponatremia" is characterized by a decreased concentration of sodium in the aqueous phase of plasma. Plasma is normally 93% water and 7% proteins and lipids. Hyperproteinemia or hyperlipidemia decreases the fraction of the plasma sample that is aqueous. Under these conditions, each volume of plasma measured will contain less Na (because Na is present only in plasma water), and most automated clinical laboratory determinations will report an artifactually low plasma sodium concentration despite a normal sodium concentration in plasma water--a phenomenon called "pseudohyponatremia." Potentiometric methods have come into widespread use because of advances in ion-sensitive electrodes (ISEs). Instruments for routine chemical analysis typically use indirect ISEs to measure sodium levels. With an indirect ISE, the plasma sample is diluted before the actual measurement is obtained, and the plasma sodium concentration is then determined by correcting for the dilution degree and by assuming that plasma water equals 93% of the total sample volume; therefore, the sodium level as determined by indirect ISE will be artificially low when the plasma water content is 93%. Instruments used for measuring arterial blood gases use direct ISE without any dilution and measure the activity of sodium in the water phase only. Thus, pseudohyponatremia does not occur when the measurement is made with direct ISE (sometimes called "direct potentiometry"). These differences in method should be taken into account to explain discrepancies between results obtained with classical biochemistry analyzers and with blood gas apparatus, and they can be exploited in evaluating patients in whom pseudohyponatremia is suspected. In the absence of a direct-reading ISE system, an

where L and P refer to the total lipid and protein concentrations in g/L, respectively, and then to adjust this value to the normal value for plasma water content of 93% (1­3); however, values that are obtained by directreading ISEs are likely to be more accurate than calculated values that are based on protein and lipid concentrations using equation 1. Nguyen et al. (1) induced pseudohyponatremia in the laboratory by dissolving saltfree albumin in human plasma to vary the plasma protein concentration from 7.4 to 28.4 g/L. The investigators then measured the plasma water content gravimetrically (by drying). Then they compared the directly measured water content of the samples with a calculated value based on equation 1 (based on plasma lipid and protein concentrations) and with a calculated value based on differences between plasma sodium concentrations using direct-reading ISE (which was unaffected by the increased plasma protein concentration) and indirect (with dilution) ISE. The experiment showed that there is excellent agreement between the ISE-determined plasma water content and the gravimetrically determined plasma with no discernible statistical difference between these values but a substantial discrepancy from the value calculated using estimates such as equation 1; therefore, for a given patient, the plasma water content can be determined from the difference between a simultaneous direct and indirect ISE reading. This calculated value could then be used to correct subsequent measurements that are based on indirect ISE, permitting serial sodium concentration measurements for that patient using an automated device. For example, hypergammaglobulinemia is a common finding in HIV-infected patients and is the result of both virus-specific and polyclonal B cell activation. It is also common among patients with cirrhosis and/or hepatitis C infection. Whereas hyponatremia in end-stage liver disease usually is caused by cirrhosis, pseudohyponatremia should be considered in the differential diagnosis for patients with hypergammaglobulinemia and liver disease. Patients who are co-infected with hepatitis C and HIV are especially likely to have high IgG levels. A recent case

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report of a co-infected patient with a polyclonal hypergammaglobulinemia (total protein concentration 11.7 g/dl) nicely illustrates this observation (4). The patient presented with a serum sodium of 119 mEq/L, a plasma osmolality of 290 mOsm/kg, and an osmolar gap of 29 mOsm/kg. In the absence of any other explanation for the osmolar gap, the serum sodium was repeated using direct ISE and was found to be 128 mEq/L, reducing the osmolar gap to 11 mOsm/kg. Thus, the patient had a combination of true hyponatremia (likely caused by diuretics and liver disease) and pseudohyponatremia caused by hyperproteinemia. Using equation 1, the authors calculated the patient's plasma aqueous volume to be 0.90 rather than 0.93. Using a dilution factor based on a plasma water content of 93% rather than 90% led to an underestimation of the plasma sodium concentration when the laboratory measured the serum sodium concentration using an automated indirect ISE method.

Solute-Induced Nonhypotonic Hyponatremia

Hypertonic hyponatremia is caused by abnormally high concentrations of an effective osmole in the circulation, diluting the plasma sodium concentration by osmotically attracting water from cells. Unlike hypotonic hyponatremia, in which cells are swollen, body cells are dehydrated in hypertonic hyponatremia. Hyperglycemia, mannitol infusions, and Ig infusion preparations that contain maltose or sucrose are the most common causes. Hypertonic mannitol and the hypertonic sugars contained in Ig preparations are nephrotoxic. The development of hyponatremia in a mannitol recipient is an early warning sign of mannitol accumulation; treatment with hypertonic saline or other measures aimed at increasing the serum sodium concentration are contraindicated, and early hemodialysis to remove the offending solute is probably the best approach (5). Hyponatremia is a known complication of intravenous Ig (IVIG). Because IVIG has been reported to result in postinfusional hyperproteinemia, IVIG-induced hyponatremia has often been attributed to pseudohyponatremia. More recently, the sugar additives in Ig preparations is an identified major factor in IVIG-related hyponatremia. These additives help prevent Ig aggregation and have reduced the frequency and severity of systemic reactions, but they have also resulted in osmotic renal injury and hyponatremia resulting from an osmotic translocation of cellular water. Thus, hyponatremia resulting from

IVIG is likely to be multifactorial: (1) Pseudohyponatremia secondary to the increased protein phase (associated with an increased osmolal gap), (2) true hyponatremia resulting from sucrose-induced translocation of water from the intracellular compartment to the extracellular compartment (associated with an increased osmolal gap), and (3) true dilutional hyponatremia because of retention of the large volume of solvent required for reconstitution of the IVIG product (associated with a normal osmolal gap). A Greek single-center study retrospectively evaluated a cohort of 66 unselected patients who had idiopathic thrombocytopenic purpura and received 140 courses of IVIG (Sandoglobulin 3%, which contains sucrose) in an average dosage of 35 g/d (2). Acute kidney injury was observed in 10 (15%) of 66 patients. IVIGrelated hyponatremia, defined as a sodium level 134 mmol/L, was only observed in nine (9%) patients, and the lowest serum sodium value was 130 mmol/L. A significant inverse correlation (r 0.308; P 0.01) was found between the changes in serum sodium and creatinine, and the mean reduction in serum sodium concentration in patients with acute kidney injury was significantly (P 0.01) higher than in patients whose renal function remained stable (5.7 versus 2.7 mmol/L). The serum protein concentration increased from 7.2 to 8.9 g/dl, which would be expected to decrease plasma water by 1.1% with a corresponding decrease in plasma sodium by 1.1%, or 1.6 mmol/L from the initial value of 141 mmol/L. This anticipated change of 1.6 mmol/L in sodium concentration, however, was half of the 3.1mmol/L fall in sodium that occurred; the remainder can be attributed to an osmotic shift caused by the sucrose constituent of the IVIG preparation. As with hyperglycemia, the sucrose present in the IVIG decreases the serum sodium concentration by provoking net movement of water out of cells. When renal function is impaired, renal clearance of sucrose diminishes, magnifying this effect. Rather similar findings were found in two patients with renal failure described by Nguyen et al. (3). After IVIG, both patients had 5- to 6-mEq/L differences between indirect ISE- and direct ISE-measured plasma sodium concentrations (suggesting an element of pseudohyponatremia), but, in both cases, the DSE values were low and therefore reflective of "true hyponatremia" secondary to IVIG (i.e., a low sodium concentration in plasma water). The authors noted that impaired water excretion and the large water load provided by IVIG (a 2-g/kg dose for a 70-kg patient provides 2.33 L of water)

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can cause "true hyponatremia." Without measuring the plasma osmolality with an osmometer as well as the plasma sodium by DSE, one cannot distinguish between hypotonic hyponatremia caused by positive water balance and hypertonic or isotonic hyponatremia caused by retained sucrose or a combination of the two. Although hypertonic and isotonic hyponatremia are "true hyponatremia" in the sense that they represent sodium concentrations that are low in the extracellular fluid in vivo, therapeutic measures to increase the plasma sodium concentration are not indicated. Isotonic hyponatremia may complicate transurethral prostate surgery when isosmotic or hypo-osmotic irrigants abruptly enter the circulation via the surgically disrupted prostatic venous plexus. A similar syndrome can complicate endoscopic intrauterine surgery. In these cases, the solute responsible for the low plasma sodium concentration is rapidly absorbed with water so that the plasma osmolality is not increased and there is no water shift from cells. Rather, there is an expansion of the extracellular space with fluid, and as long as the absorbed solute remains extracellular, the water that is absorbed with the solute remains extracellular as well, diluting the plasma sodium concentration. Depending on the osmolality of the irrigant, the plasma osmolality either remains unchanged or falls slightly. Accumulation of glycine, the most commonly used irrigant, causes neurotoxicity because of direct effects of the amino acid itself and because of the hyperammonemia that results from its metabolism. Use of nonconducting nonelectrolyte irrigants (glucose, mannitol, glycine, or sorbitol) was introduced because the use of electrocautery contraindicated conductive solutions such as isotonic saline as an irrigant. Water was initially used in lieu of saline, but because of reports of hemolysis, renal failure, and sometimes fatal circulatory collapse, other solutions were developed. Although the safety of pure water as an irrigating solution in prostate surgery remains controversial, this fluid is still commonly used in some countries. A study of 1600 prostatectomies in a single center in Iran found only a 2.5% incidence of clinically significant hyponatremia (serum Na 130 mmol/L) and a 1% incidence of severe hemolysis with no deaths (6). The newly developed bipolar electrocautery resectoscope permits isotonic saline as an irrigant and avoids both the hypotonic hyponatremia caused by water absorption and the isotonic hyponatremia caused by solutes that containing nonelectrolyte solutes (7­9).

References

1. Nguyen MK, Ornekian V, Butch AW, Kurtz I: A new method for determining the plasma water content: Application in pseudohyponatremia. Am J Physiol Renal Physiol 292: F1652­F1656, 2007 2. Daphnis E, Stylianou K, Alexandrakis M, Xylouri I, Vardaki E, Stratigis S, Kyriazis J: Acute renal failure, translocational hyponatremia and hyperkalemia following intravenous immunoglobulin therapy. Nephron Clin Pract 106: c143­ c148, 2007 3. Nguyen MK, Rastogi A, Kurtz I: True hyponatremia secondary to intravenous immunoglobulin. Clin Exp Nephrol 10: 124 ­126, 2006 4. Garibaldi BT, Cameron SJ, Choi M: Pseudohyponatremia in a patient with HIV and hepatitis C coinfection. J Gen Intern Med 23: 202­205, 2008 5. Yun JJ, Cheong I: Mannitol-induced hyperosmolal hyponatraemia. Intern Med J 38: 73, 2008 6. Moharari RS, Khajavi MR, Khademhosseini P, Hosseini SR, Najafi A: Sterile water as an irrigating fluid for transurethral resection of the prostate: Anesthetical view of the records of 1600 cases. South Med J 101: 373­375, 2008 7. Michielsen DP, Debacker T, De Boe V, Van Lersberghe C, Kaufman L, Braeckman JG, Amy JJ, Keuppens FI: Bipolar transurethral resection in saline: An alternative surgical treatment for bladder outlet obstruction? J Urol 178: 2035­2039, discussion 2039, 2007 8. Gilleran JP, Thaly RK, Chernoff AM: Rapid communication: Bipolar PlasmaKinetic transurethral resection of the prostate: Reliable training vehicle for today's urology residents. J Endourol 20: 683­ 687, 2006 9. Ho HS, Yip SK, Lim KB, Fook S, Foo KT, Cheng CW: A prospective randomized study comparing monopolar and bipolar transurethral resection of prostate using transurethral resection in saline (TURIS) system. Eur Urol 52: 517­522, 2007

Hypotonic Hyponatremia

Brain Responses to Hyponatremia

Hypotonic hyponatremia causes swelling of all body cells, but it is particularly harmful in the brain because of the limitations posed by the rigid skull. As the brain swells in a confined space, blood flow is impaired, potentially causing ischemia, infarct, excitotoxicity, and neuronal death. In rare cases, brain herniation through the foramen magnum affects brain stem function, causing death by respiratory and cardiac arrest. Fortunately, the brain responds to hyponatremia in ways that limit the amount of swelling (1,2). Within minutes, the increase in hydrostatic pressure increases the flow of sodium-rich interstitial fluid into the cerebrospinal fluid and from there to the general circulation. Soon after, brain cells respond with a volume regulatory response that diminishes the degree of cell swelling. The ability to regulate cell volume is an ancient trait conserved throughout evolution in animal cells from most species. Volume control is evidently essential to preserve a variety of cell functions. When cells are exposed to a hypotonic environment, they first swell and then activate a mechanism of volume regulatory decrease (RVD), in which osmotically active solutes are extruded followed by water. The osmolytes involved in RVD are

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the main intracellular ions K and Cl and a large number of small organic molecules, known as organic osmolytes. Organic osmolytes are considered to act as "compatible" or "nonperturbing" cell solutes that function as osmoregulators without severely compromising cell function; cells release them in response to hypotonicity and import them in response to hypertonicity or correction of hypotonicity. By extruding electrolytes and organic osmolytes, cells can achieve a low intracellular osmolality-- equal to that of plasma--without a large increase in cell water. Changes in osmolyte concentrations, both inorganic and organic, can be quite large, and they can virtually eliminate brain swelling despite very severe hyponatremia. In animals that have completely adapted to hyponatremia, brain concentrations of organic osmolytes can decrease by 40 to 90%, whereas chloride and potassium concentrations decrease by 10 to 20%. The brain is separated from the systemic circulation by the blood­ brain barrier, which impedes the entry of substances that are not lipid soluble (2,3). Anatomically, the barrier consists of tight junctions between vascular endothelial cells that interface with glial cells (astrocytes) whose foot processes abut the endothelial cells of brain capillaries. In hyponatremia, water enters the brain primarily through the astrocytic endfeet. In experimental models, water is shunted through the astrocytes, which swell to more than double their normal size, whereas neurons maintain their cell volume; astrocytes that are close to blood vessels increase their volume by a factor of 2 to 3, whereas astrocytes with no obvious relation to blood vessels fail to show a volume increase (4). Water channels, particularly aquaporin 4 (AQP4), permit water to cross the blood­ brain barrier in response to osmotic gradients. Recent evidence suggests that the AQP4 water channels influence the severity of cerebral edema that occurs in response to acute hyponatremia and other insults. Knockout mice that do not express AQP4 develop less brain swelling in response to acute experimental hyponatremia, and selective deletion of AQP4 from the astrocytic endfeet that surround brain microvessels is also protective against brain swelling (4,5). Conversely, transgenic mice overexpressing AQP4 have exaggerated brain swelling, with an increase in intracranial pressure nearly twice that of controls, often producing brain herniation and death (6). Recently, multiple polymorphisms in the human AQP4 gene have been identified, some of which affect water flow; these findings suggest that there may be genetic variability in the susceptibility to brain swelling from acute hyponatremia (7).

The blood­ brain barrier consists of tight junctions between vascular endothelial cells that interface with glial cells (astrocytes) whose foot processes abut the endothelial cells of brain capillaries. In hyponatremia, water enters the brain through the astrocytic endfeet. Astrocytes close to blood vessels swell to more than double their normal size, whereas neurons maintain their cell volume. Water channels, particularly AQP4, permit water to cross the blood­ brain barrier in response to osmotic gradients. The reason that astrocytes swell more than neurons in response to hypotonicity may relate to greater expression of AQP4 in astrocytes or to a more efficient operation of volume regulation in neurons as compared with astrocytes. Consistent with the latter hypothesis, Purkinje cells in the cerebellum have been shown to release a large amount of taurine, which is transferred to neighboring astrocytes. As a consequence of this taurine translocation, neurons preserve their volume, whereas astrocytes swell (1,2). Taurine, a sulfur-containing amino acid, is the most abundant free amino acid in mammalian tissue. Maintenance of the large intracellular taurine pool requires cellular amino acid uptake from the blood against a substantial concentration gradient, because the concentration of taurine is 100-fold less in the plasma than in the tissues. Taurine is present in high concentrations in most animal cells, largely free in the cytosol. It is metabolically inert and not a protein constituent. Compared with other osmolytes, taurine responds to osmotic swelling with the lowest release threshold and the largest amount released. Taurine efflux occurs through a leak pathway known as volume-sensitive organic anion channel (1,2,8 ­10). Other organic osmolytes that are involved in RVD are a group of small, heterogeneous organic molecules: Amino acids (taurine, glutamate, glycine, and GABA), polyalcohols (sorbitol and myoinositol), amines (creatine, phosphoethanolamine, and glycerophosphorylcholine), and N-acetyl-aspartate. Despite structural differences, these molecules are believed to permeate through the same pathway. Because GABA and glutamate are major neurotransmitters, their release from intracellular pools may affect neuronal excitability.

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Recent evidence has shown the potential importance of G protein­ coupled receptors (GPCRs) in enhancing the release of organic osmolytes from neural cells in response to hypotonicity (1,2). GPCRs represent the largest family of membrane proteins, and approximately 300 such receptors are expressed in the brain. Importantly, receptor activation significantly lowers the osmotic threshold at which osmolyte release occurs, allowing cells to respond to small, physiologically relevant decreases in tonicity. The widespread occurrence of these receptors in the central nervous system and the critical importance of regulating brain cell volume make this observation especially intriguing because it may explain the unique ability of neural cells to resist osmotic swelling. Receptor regulation of volume-dependent osmolyte release means that the adaptation to hyponatremia could be accelerated by specific ligands that are known to activate GPCRs, and it may also explain individual variations in the ability to tolerate hyponatremia. Regulation of osmolyte release has been observed in response to a variety of neurotransmitters or neuromodulators, including neuropeptides (vasopressin, endothelin, and oxytocin), cholinergic and adrenergic agonists, adenosine, ATP, thrombin, and phospholipids; the ligand concentrations required to elicit osmolyte release in vitro are within the range of these compounds found in the central nervous system (2,8 ­10). Organic osmolyte efflux from astrocytes may play a role in the regulation of vasopressin release by the neurohypophesis. Acting through V1a receptors, vasopressin potentiates the volume-dependent release of taurine. Once released, taurine activates glycine receptors on nerve terminals that originate in the supraoptic nucleus and inhibits vasopressin secretion. Thus, the ability of vasopressin to stimulate taurine efflux provides a negative paracrine feedback loop. Vasopressin secretion may also be regulated by adenosine, which inhibits the release of taurine from pituitcytes In response to hypertonicity or after correction of hyponatremia, organic osmolytes are transported into cells. Taurine uptake is mediated by a sodium-dependent transporter (TauT), which uses the Na gradient across the cell membrane to drive taurine accumulation. Myoinositol, another important organic osmolyte, is transported by the sodium-dependent myoinositol transporter. Amino acids are transported by the sodium-coupled neutral amino-acid transporter member 2 (SNAT2). It has been known for many years that these transporters

are upregulated in chronic hypertonicity, a phenomenon that helps to explain the stubborn persistence of accumulated osmolytes in patients with hypernatremia and the resultant cerebral edema that occurs when hypernatremia is corrected too rapidly. Recent evidence suggests that chronic hypotonicity may downregulate these transporters (11).

Chronic hyponatremia downregulates the signaling pathway, regulating expression of the neutral amino acid transporter SNAT2. Oligodendrocytes may rely primarily on amino acid accumulation to recover their cell volume. Any deficiency in tonicity-induced SNAT2 expression would render oligodendrocytes selectively vulnerable after systemic hypertonicity or rapid correction of chronic hyponatremia. This might be the case in osmotic demyelination syndrome. Hyponatremia that develops rapidly ( 24 h) is associated with more severe cerebral edema, more severe neurologic symptoms, and a risk for death from herniation. In experimental models, the brain's adaptation to hyponatremia is completed within approximately 48 h; therefore, many investigators have defined hyponatremia that has evolved over 48 h as "chronic," and more rapidly developing hyponatremia has been called "acute" (12­18).

Brain Responses to Correction of Hyponatremia: Osmotic Demyelination

Depletion of brain organic osmolytes permits survival in chronic hyponatremia and limits the severity of neurologic symptoms, but it may also lead to neurologic injury when the electrolyte disturbance is corrected too rapidly. Perhaps because of downregulation of transporters, organic osmolytes are slow to return to the brain when chronic hyponatremia is corrected. As a result, excessive correction of hyponatremia can cause neurologic complications, which manifest as the osmotic demyelination syndrome (2,17,19 ­23). Clinical manifestations of osmotic demyelination typically emerge 1 d to several days after a large, rapid increase in sodium concentration. Observational studies and reviews of published case reports suggested

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that increases of 10 to 12 mEq/L within 24 h and increases of 18 to 25 mEq/L within 48 h are sufficient to cause the syndrome; patients with alcoholism, liver disease, and malnutrition are most vulnerable to osmotic demyelination and may occasionally be affected by even slower rates of correction (24). Patients and experimental animals with acute hyponatremia ( 24 h duration) have a lower risk for osmotic demyelination and often tolerate large, rapid increases in the serum sodium concentration that are uniformly injurious in the chronic condition (18). In patients who have the osmotic demyelination syndrome and die, brain lesions known as "myelinolysis," characterized by a loss of oligodendrocytes and myelin without inflammation, are found (17). Classically, the lesions are located in the center of the pons ("central pontine myelinolysis"), but similar lesions are often found symmetrically distributed in many regions of the brain where gray and white matter are closely associated ("extrapontine myelinolysis"). The response to correction of chronic hyponatremia is analogous to the response to hypertonicity. In hypertonicity, cells must accumulate organic osmolytes to avoid osmotic shrinkage. With correction of chronic hyponatremia, cells must re-accumulate these osmolytes. Indeed, myelinolysis has been reported in patients who were never known to have hyponatremia and who were subjected to an acute onset of hypertonicity (25). Uremia, which is associated with resistance to myelinolysis, seems to enhance the reuptake of organic osmolytes by the brain, particularly myoinositol; however, patients with hyponatremia and uremia are not immune from osmotic demyelination (20). Exogenous administration of myoinositol during correction of hyponatremia has been shown to reduce the incidence and severity of myelinolysis (17). It has been suggested that shrinkage of brain vascular endothelial cells disrupts their tight junctions, opening the blood­ brain barrier; circulating complement, cytokines, and lymphocytes can then enter the brain, causing oligodendrocyte damage and demyelination. Alternatively, oligodendrocytes might be injured directly by shrinkage, triggering apoptosis. Differences in the way that various populations of brain cells respond to osmotic stress may explain why myelin-producing oligodendrocytes are selectively injured by rapid correction of hyponatremia (26,27). Osmoprotective genes that are involved in cellu-

lar osmoadaptation to hypertonicity are regulated by a specific transcription factor called tonicity-responsive enhancer-binding protein (TonEBP). In the brain, TonEBP is expressed only in neurons, but neurons in various brain regions differ in the degree to which TonEBP responds to hypertonicity (27). Induction of sodium-dependent myoinositol transporter­mRNA labeling (which encodes the myoinositol transporter) seems to occur in non-neuronal cells, presumably astrocytes, where TonEBP is neither expressed nor tonicity induced. Thus, brain cells, even from the same class, activate distinct osmoprotective genes through distinct activation processes to adapt to hypertonicity. Chronic hyponatremia downregulates the signaling pathway, regulating expression of the neutral amino acid transporter SNAT2. Tonicity-induced SNAT2 expression is restricted to oligodendrocytes but occurs in virtually all of them. Oligodendrocytes may rely primarily on amino acid accumulation to recover their cell volume, whereas other brain cells that do not rely on amino acid accumulation through tonicity-induced SNAT2 expression are not affected (26). Any deficiency in tonicity-induced SNAT2 expression would render oligodendrocytes selectively vulnerable after systemic hypertonicity or rapid correction of chronic hyponatremia. This might be the case in osmotic demyelination syndrome. References

1. Fisher SK, Cheema TA, Foster DJ, Heacock AM: Volume-dependent osmolyte efflux from neural tissues: Regulation by G-protein-coupled receptors. J Neurochem 106: 1998 ­2014, 2008 2. Vazquez-Juarez E, Ramos-Mandujano G, Hernandez-Benitez R, Pasantes-Morales H: On the role of G-protein coupled receptors in cell volume regulation. Cell Physiol Biochem 21: 1­14, 2008 3. Ayus JC, Achinger SG, Arieff A: Brain cell volume regulation in hyponatremia: Role of gender, age, vasopressin and hypoxia. Am J Physiol Renal Physiol 295: F619 ­F624, 2008 4. Nase G, Helm PJ, Enger R, Ottersen OP: Water entry into astrocytes during brain edema formation. Glia 56: 895­902, 2008 5. Papadopoulos MC, Verkman AS: Aquaporin-4 and brain edema. Pediatr Nephrol 22: 778 ­784, 2007 6. Yang B, Zador Z, Verkman AS: Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling. J Biol Chem 283: 15280 ­15286, 2008 7. Sorani MD, Zador Z, Hurowitz E, Yan D, Giacomini KM, Manley GT: Novel variants in human aquaporin-4 reduce cellular water permeability. Hum Mol Genet 17: 2379 ­2389, 2008 8. Vazquez-Juarez E, Ramos-Mandujano G, Lezama RA, Cruz-Rangel S, Islas LD, Pasantes-Morales H: Thrombin increases hyposmotic taurine efflux and accelerates ICI-swell and RVD in 3T3 fibroblasts by a src-dependent EGFR transactivation. Pflugers Arch 455: 859 ­ 872, 2008 9. Cruz-Rangel S, Hernandez-Benitez R, Vazquez-Juarez E, LopezDominguez A, Pasantes-Morales H: Potentiation by thrombin of

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10.

11.

12. 13. 14. 15. 16. 17.

18.

19.

20.

21. 22.

23.

24.

25.

26.

27.

hyposmotic glutamate and taurine efflux from cultured astrocytes: Signalling chains. Neurochem Res 33: 1518 ­1524, 2008 Ramos-Mandujano G, Vazquez-Juarez E, Hernandez-Benitez R, Pasantes-Morales H: Thrombin potently enhances swelling-sensitive glutamate efflux from cultured astrocytes. Glia 55: 917­925, 2007 Franchi-Gazzola R, Dall'Asta V, Sala R, Visigalli R, Bevilacqua E, Gaccioli F, Gazzola GC, Bussolati O: The role of the neutral amino acid transporter SNAT2 in cell volume regulation. Acta Physiol 187: 273­283, 2006 Ellison DH, Berl T: Clinical practice: The syndrome of inappropriate antidiuresis. N Engl J Med 356: 2064 ­2072, 2007 Gross P: Treatment of hyponatremia. Intern Med 47: 885­ 891, 2008 Halperin ML, Kamel KS: A new look at an old problem: Therapy of chronic hyponatremia. Nat Clin Pract Nephrol 3: 2­3, 2007 Hoorn EJ, Zietse R: Hyponatremia revisited: Translating physiology to practice. Nephron Physiol 108: 46 ­59, 2008 Lien YH, Shapiro JI: Hyponatremia: Clinical diagnosis and management. Am J Med 120: 653­ 658, 2007 Sterns RH, Silver S, Kleinschmidt-DeMasters BK, Rojiani AM: Current perspectives in the management of hyponatremia: Prevention of CPM. Expert Rev Neurother 7: 1791­1797, 2007 Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH: Hyponatremia treatment guidelines 2007: Expert panel recommendations. Am J Med 120: S1­S21, 2007 Gutenstein M: Osmotic myelinolysis syndrome after treatment of severe deamino arginine vasopressin-associated hyponatraemia: Pitfalls in emergency medicine. Emerg Med Australas 19: 68 ­70, 2007 Huang WY, Weng WC, Peng TI, Ro LS, Yang CW, Chen KH: Central pontine and extrapontine myelinolysis after rapid correction of hyponatremia by hemodialysis in a uremic patient. Ren Fail 29: 635­ 638, 2007 Snell DM, Bartley C: Osmotic demyelination syndrome following rapid correction of hyponatraemia. Anaesthesia 63: 92­95, 2008 Lin CM, Po HL: Extrapontine myelinolysis after correction of hyponatremia presenting as generalized tonic seizures. Am J Emerg Med 26: 632.e5­ 632.e6, 2008 Roh JH, Kim JH, Oh K, Kim SG, Park KW, Kim BJ: Cortical laminar necrosis caused by rapidly corrected hyponatremia. J Neuroimaging May 19, 2008 [epub ahead of print] Georgy V, Mullhi D, Jones AF: Central pontine myelinolysis following `optimal' rate of correction of hyponatraemia with a good clinical outcome. Ann Clin Biochem 44: 488 ­ 490, 2007 O'Malley G, Moran C, Draman MS, King T, Smith D, Thompson CJ, Agha A: Central pontine myelinolysis complicating treatment of the hyperglycaemic hyperosmolar state. Ann Clin Biochem 45: 440 ­ 443, 2008 Maallem S, Mutin M, Gonzalez-Gonzalez IM, Zafra F, Tappaz ML: Selective tonicity-induced expression of the neutral amino-acid transporter SNAT2 in oligodendrocytes in rat brain following systemic hypertonicity. Neuroscience 153: 95­107, 2008 Maallem S, Wierinckx A, Lachuer J, Kwon MH, Tappaz ML: Gene expression profiling in brain following acute systemic hypertonicity: Novel genes possibly involved in osmoadaptation. J Neurochem 105: 1198 ­1211, 2008

Acute Hyponatremia

Although acute hyponatremia is defined biologically by the time course of its evolution, this definition can seldom be applied to patients who develop hyponatremia outside the hospital. Ambulatory patients who present to the hospital with hyponatremia rarely have recent previous laboratory values, and the designation of "acute" hyponatremia is often based on

the circumstances that led to the electrolyte disturbance. For example, hyponatremia in marathon runners, ecstasy users, and psychotic patients with selfinduced water intoxication may be characterized as "acute" because it typically presents after a few hours of unusually large water intakes coupled with impaired water excretion. These patients, like hospitalized patients with iatrogenic hyponatremia, often present with severe neurologic symptoms, and death from herniation in ambulatory patients have been reported almost exclusively in these settings. Unlike patients who have had hyponatremia for 48 h, patients who are known to have hyponatremia of brief duration seem to tolerate a rapid return of their serum sodium concentrations to normal without adverse consequences. As discussed in the previous fluid and electrolyte issue of NephSAP, there are data to suggest that hypoxia impairs the brain's adaptation to hyponatremia, increasing the severity of cerebral edema, which in turn results in neurogenic pulmonary edema and a vicious cycle (1). It has been noted that young women and children account for most reports of fatal or neurologically crippling complications from cerebral edema caused by acute postoperative hyponatremia. One group attempted to explain these clinical observations mechanistically in a recent review of brain cell volume regulation (1). The increased susceptibility of young children is explained by the brain's size (which is full size by age 6) relative to the skull (which does not reach full size until adulthood). Consistent with this hypothesis, acute hyponatremia in young infants whose fontanel is open does not result in herniation. To explain the susceptibility of young women with hyponatremia to fatal cerebral edema, the review suggested that estrogens impair volume regulation by the brain; however, the experimental evidence offered to support this idea is problematic. The review suggested that estrogens regulate water movement and neurotransmission by affecting aquaporin 4 expression; however, the article cited to support this assertion demonstrated that aquaporin 4 regulates the functions of ovarian hormones and neurotransmission and not vice versa (2). The review suggested that estrogens decrease Na-K-ATPase in the brain and that astrocytes rely on active export of cellular sodium by the enzyme in their adaptation to hyponatremia, citing an article published in 1986; however, astrocytes are now known to volume regulate through loss of potassium chloride and organic osmolytes and not by active

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sodium transport (3­ 6). Importantly, there was no difference between brain water and sodium contents in male and female rats that were subjected to acute or chronic hyponatremia (7).

Exercise-Associated Hyponatremia

Exercise-associated hyponatremia (Na 135 mmol/L) is a potentially serious condition reported initially in ultraendurance athletes and more recently in marathon runners (8). Exercise-associated hyponatremia was unknown before 1981, when recommendations for fluid intake during exercise were conservative; it first appeared after publication of a position statement advising athletes to drink as much as possible during exercise (8,9). Athletes may drink large volumes of water before exercise in an attempt to ward off dehydration and, despite large fluid losses during a race, may drink enough fluid to gain weight. Occasionally, some athletes may drink up to 3 L/h in an attempt to produce dilute urine to escape detection of banned drugs in the urine. Although the dangers of these practices are now well recognized and have been emphasized in the sports medicine community, some authors suggested that excessive drinking is still being promoted by the global sports drink industry (9,10). Hew-Butler et al. (11) conducted a comprehensive evaluation of the endocrine secretion of pituitary, natriuretic, and adrenal steroid hormones, as well as cytokines, in 82 well-trained endurance athletes immediately before and after running a 56-km ultramarathon in Cape Town, South Africa. Plasma arginine vasopressin (AVP) concentrations were markedly elevated despite unchanged plasma sodium concentrations for the group as a whole, and AVP levels also increased in those whose plasma sodium levels decreased slightly. Mathematical pathway modeling attributed nonosmotic stimulation of AVP secretion to decreased plasma volume, with potential influence from brain natriuretic peptide, oxytocin, and corticosterone. A linear relationship was found between exercise-induced plasma volume contraction (presumably related to sodium losses from sweat) and plasma aldosterone, indicating that this provided an adequate stimulus to the volume-sensing baroreceptors that provoke AVP secretion. There was a statistically significant mathematical influence of plasma oxytocin on postrace plasma AVP and plasma sodium levels in women but not in men. This finding is intriguing because female gender has been proposed as a risk

factor for morbidity associated with hyponatremia. Significant increases in IL-6 have been reported in runners because actively contracting muscles produce IL-6. Because IL-6 stimulates AVP production in nonexercising humans, IL-6 has been proposed as a cause of inappropriate antidiuretic hormone secretion among runners. The data of this study do not support this hypothesis, however, because higher IL-6 levels were weakly associated with decreased plasma AVP. A similar study of selected Boston marathon runners also failed to show a correlation between IL-6 and AVP levels (12). This study found that AVP was measurable ( 0.5 pg/ml) in seven of 16 runners who developed hyponatremia during the race. Like the individuals with detectable levels of AVP, individuals with hyponatremia and without measurable hormone did not pass urine during the race, suggesting that vasopressin levels were sufficient to impair maximal urine free-water excretion. The investigators suggested that in vitro proteolysis of AVP is the likely explanation for the negative findings in some specimens. Individuals with hyponatremia (Na 135 mmol/L) had lower blood urea nitrogen levels than individuals with high serum sodium levels ( 145 mmol/L), supporting the hypothesis that exercise-induced hyponatremia is caused by fluid intake in excess of losses in the presence of antidiuresis provoked by the nonosmotic secretion of AVP. Similar evidence for nonosmotic release of vasopressin was documented among cyclists who completed a 109-kg race (13). High-urine osmolalities and inappropriate plasma AVP levels have been measured in athletes who were hospitalized with critical hyponatremia associated with exercise (10). Chorley et al. (14) conducted a rigorous study of 96 marathon runners who volunteered for a research project conducted during four Houston marathons. Eighty-seven percent of runners decreased their serum sodium during the race, and 22% had postrace values 135 mmol/L (range 130 to 134 mmol/L); none had hyponatremic symptoms. Those who lost no weight were significantly more likely to develop hyponatremia than those who did lose weight. Those who lost 0.75 kg were 7.03 times more likely to develop hyponatremia than those who lost at least 0.75 kg. Fluid overconsumption was more likely among those who lost less fluid from sweating. Sweat rate is dependent on degree of acclimatization, gender (women sweat less), intensity of exercise, body weight (smaller

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runners sweat less), environmental heat stress, and individual variation. Runners with lower sweat rates (e.g., untrained, lightweight women running under cooler conditions) are more likely to consume more water than they lose, developing hyponatremia. Slower runners were more likely to drink more and more likely to sweat less. The authors proposed that runners who are slower than 5 h 10 min or 60 to 65 kg should be keenly aware of their risk for overconsumption and hyponatremia. Although women weighed less, had less weight loss, had less estimated sweat loss, and had slower finish times than men, female gender was not an independent factor for hyponatremia or lower postrace plasma sodium concentration. Changes in plasma sodium concentration during exercise are determined by net water and net electrolyte balance. Studies undertaken in the field cannot accurately record electrolyte losses, which are likely to be substantial; in a 90-km ultramarathon race, an athlete may lose approximately 8.6 L of sweat. Sweating is a potential source of large sodium losses. Sweat gland adaptations can reduce these losses (15). Sweat glands consist of a secretory coil, which produces an isosmotic precursor sweat, and the reabsorptive duct, which actively reabsorbs salt from the precursor sweat. Sodium reabsorption occurs via an amiloridesensitive sodium channel, and chloride uses the cystic fibrosis transmembrane conductance regulator on the luminal membrane. When sweat production is low, most of the sodium chloride is reabsorbed and very hypotonic sweat appears at the skin surface; however, because the sodium chloride reabsorption rate is limiting, at high sweat rates, the sodium concentration of the sweat increases, exhibiting a linear relationship with the sweat rate. Acclimation to heat increases the reabsorptive capacity so that lower sodium concentrations occur at all sweating rates, but the linear relationship between sweat rate and sodium concentration remains. The mechanism for heat acclimation is unknown, but it is believed to involve aldosterone-mediated increases in Na-K-ATPase and sodium channels in the sweat gland reabsorption duct. Spironolactone (an aldosterone antagonist) increases sweat sodium concentration during heat acclimation. Lower sweat sodium concentrations decrease the likelihood of developing hyponatremia during exercise. Patients with cystic fibrosis, who lack the chloride channel in the reabsorptive duct of the sweat gland, are predisposed to developing hyponatremia when exposed to heat (16).

Baker et al. (17) conducted a rigorous balance study of volunteers who were subjected to treadmill exercise in the heat. Sodium and potassium losses in the urine and in sweat were quantified, and sodium and water intake were varied. The measured serum sodium concentrations (which ranged from 136 to 154 mEq/L) were compared with what would be predicted from known empirical relationships between total body sodium and potassium and total body water using the "Nguyen-Katz" balance equation (18): SNa {[(SNai 23.8)TBWi 1.03 E]/ (TBWi TBW)} 23.8

where SNa is the predicted serum sodium concentration, SNa is the initial serum sodium concentration, E is the net loss of sodium plus potassium, TBW is the initial total body water (assumed to be 0.73 of fat-free mass), and TBW is the change in total body water taken to be the body weight change. Urine sodium losses were small during the 2-h experiment, averaging 6 to 11 mEq, but sweat sodium losses, averaging 112 to 150 mEq, had a significant effect on the serum sodium concentration. The investigators found that the Nguyen-Katz equation accurately predicted the change in serum sodium concentration in those whose fluid intake was adjusted so that they either maintained their weight or lost 2 or 4% of their body weight during exercise; however, when participants overdrank relative to their sweat losses so as to gain 2% of their body weight, the Nguyen-Katz equation was not accurate; among runners who gained weight, the serum sodium concentration did not fall as much as was predicted. By assuming that the body weight change reflects a change in total body water, this analysis ignores the release of bound water as glycogen is used for fuel; each kilogram of glycogen can contain upwards of 3 kg of associated water (8). If loss of body weight overestimates the loss of total body water, then the Nguyen-Katz equation should have predicted sodium concentrations higher than those observed (the opposite of what occurred). As noted by the authors, delayed absorption of ingested water from the gastrointestinal tract would cause the measured serum sodium to be higher than the predicted value (as occurred among those who had to drink enough to exceed their urinary losses and gain weight). Other investigators have noted that marathoners who gain weight during a race do not uniformally develop hyponatremia; in one study, 70% of those

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who overconsumed fluids maintained normal serum sodium concentrations despite external losses that would be expected to be substantial. As detailed in a recent review (8), some authors suggested that athletes are protected from developing hyponatremia because they are able to mobilize sodium from internal stores that otherwise are osmotically inactive. Although this is an intriguing possibility, that some athletes develop more hyponatremia than would be expected from their weight change (which would have to be explained by osmotic inactivation of circulating sodium) seems more consistent with delayed absorption of ingested water and variability in the timing of blood samples. There are conflicting data regarding nonsteroidal anti-inflammatory drug (NSAID) use as an important predisposing factor for exercise-associated hyponatremia. A prospective study of 131 of the 360 runners entered in a 60-km mountain run in New Zealand assessed the effects of nonselective (NSAIDs and cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory medication (COXIBs) in the incidence of exercise-associated hyponatremia (19). Five athletes developed hyponatremia (130 to 134 mmol/ L). As in other studies, hyponatremia was associated with a mean weight gain of 1.32 kg (range 1.5 to 1.6 kg), and serum sodium varied inversely with weight change. Twenty percent of runners had used NSAIDs and 15% had taken COXIBs, whereas 65% did not use either medication. There were no significant differences between NSAID and COXIB users in any measured parameters or between all NSAID and COXIB users when compared with nonusers. It is generally accepted that symptomatic patients with exercise-induced hyponatremia are best treated with 3% saline. Siegel et al. (12) reported data from two previously healthy women who were aged 24 and 32 and collapsed while participating as charity fundraisers in the 2002 Boston and Marine Corps marathons. After endotracheal intubation on arrival at emergency services, isotonic (0.9%) saline was initially infused at 150 ml before serum [Na ] values of 113 and 123 mmol/L were reported. Blood urea nitrogen levels were 10 mg/dl, urine osmolalities were 329 and 121 mOsm/kg H2O, and urine [Na ] was 81 and 25 mEq/L, respectively. AVP and cortisol levels were elevated and thyroid profiles were normal in both cases, consistent with a diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Computed tomography of the brain and chest

radiography showed diffuse cerebral and pulmonary edema, and neither runner survived. By contrast, cases of hypotonic encephalopathy in the 2004 to 2005 Marine Corps and Boston marathons were treated with intravenous infusions of hypertonic (3%) saline at a rate of 1 ml/kg per h, resulting in an increase in serum [Na ] by 4 to 6 mmol/L during the first few hours; two severely affected runners whose encephalopathy rapidly improved without adverse effects were reported. The Second International Exercise-Associated Hyponatremia (EAH) Consensus Development Conference convened in Queenstown, New Zealand (November 2007). A panel of 18 international experts recommended that any athlete with hyponatremia and encephalopathy be immediately treated with a bolus infusion of 100 ml of 3% NaCl to reduce brain edema acutely with up to two additional 100-ml 3% NaCl bolus infusions given at 10-min intervals if there is no clinical improvement. According to the consensus report, the first successful use of a bolus of hypertonic saline was reportedly documented onsite in the 2005 Two Oceans Marathon and subsequently in the Twin Cities Marathon October 2005 in unpublished observations. One published case report documented a rapid clinical response to the administration of 50 ml of 5% saline; however, the patient had only mild hyponatremia and mild symptoms (20).

Self-Induced Water Intoxication in Psychosis

Polydipsia is common among institutionalized psychotic patients, particularly among those with schizophrenia (21,22). Water intake can exceed normal excretory capacity, resulting in large diurnal weight gains and hyponatremia. One study reported a history of hyponatremia among 11% of patients who were admitted to a long-term care unit of a state psychiatric hospital. Selfinduced water intoxication can occur despite an intact ability to excrete maximally dilute urine, or it may be accompanied by impaired water excretion as a result of SIADH. Hallucinations with psychomotor agitation or depression resembling delirious mania or catatonia caused by acute hyponatremia may mimic primary psychiatric symptoms. Several case reports have documented rhabdomyolysis among patients with self-induced water intoxication. A recent study from a single Japanese hospital found evidence of rhabdomyolysis in six (27.3%) of 22 psychotic patients who were hospitalized for acute hyponatremia (mean maximum CK

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level 104,638 IU; range 12,138 to 319,400 IU/L) (23). Two patients developed renal dysfunction with maximum creatinine levels of 2.7 and 6.9 mg/dl (one required hemodialysis). One patient developed extrapontine myelinolysis. There were no deaths. Patients who developed rhabdomyolysis had similar values for presenting serum sodium (116.5 8.0 versus 119.6 8.0 mEq/L) and were equally likely to have presented with seizures (one of six versus four of 16), alcohol intake before admission (one in each group), or overdose of antipsychotic medications (one in each group); however, the six patients with rhabdomyolysis were corrected more rapidly (2.0 1.3 versus 0.9 0.7; P 0.017) and underwent a larger increase in serum sodium concentration in the initial 24 h (21.3 6.0 versus 10.0 4.6 mEq/L; P 0.001) despite being given virtually identical amounts of sodium intravenously (117.7 20.3 versus 119.8 17.3 mEq).

All of the patients with hyponatremia survived without sequelae. Among patients who received isotonic fluids, hypernatremia (145 to 159 mEq/L) developed in 11 patients (an incidence of 7.5%) and hypernatremia did not occur among patients who received hypotonic fluid. The authors concluded that they could not make a recommendation on the basis of these data and suggested a controlled trial. A small, double-blind, randomized, controlled trial compared 0.9% saline with 4% dextrose and 0.18% saline (dextrose saline), at either the traditional maintenance fluid rate or two thirds of that rate in 50 pediatric patients (37 surgical) and found a 3-mEq/L greater fall in sodium in patients who received hypotonic fluid (27). The incidence of hyponatremia was not significantly affected by the fluid administration rate. References

1. Ayus JC, Achinger SG, Arieff A: Brain cell volume regulation in hyponatremia: Role of gender, age, vasopressin. and hypoxia. Am J Physiol Renal Physiol 295: F619 ­F624, 2008 2. Sun XL, Ding JH, Fan Y, Zhang J, Gao L, Hu G: Aquaporin 4 regulates the effects of ovarian hormones on monoamine neurotransmission. Biochem Biophys Res Commun 353: 457­ 462, 2007 3. Fisher SK, Cheema TA, Foster DJ, Heacock AM: Volume-dependent osmolyte efflux from neural tissues: Regulation by G-protein-coupled receptors. J Neurochem 106: 1998 ­2014, 2008 4. Vazquez-Juarez E, Ramos-Mandujano G, Hernandez-Benitez R, Pasantes-Morales H: On the role of G-protein coupled receptors in cell volume regulation. Cell Physiol Biochem 21: 1­14, 2008 5. Ringel F, Plesnila N: Expression and functional role of potassiumchloride cotransporters (KCC) in astrocytes and C6 glioma cells. Neurosci Lett 442: 219 ­223, 2008 6. Kimelberg HK: Supportive or information-processing functions of the mature protoplasmic astrocyte in the mammalian CNS? A critical appraisal. Neuron Glia Biol 3: 181­189, 2007 7. Verbalis JG: Hyponatremia induced by vasopressin or desmopressin in female and male rats. J Am Soc Nephrol 3: 1600 ­1606, 1993 8. Rosner MH, Kirven J: Exercise-associated hyponatremia. Clin J Am Soc Nephrol 2: 151­161, 2007 9. Beltrami F, Hew-Butler T, Noakes T: Drinking policies and exerciseassociated hyponatraemia: Is anyone still promoting overdrinking? Br J Sports Med 42: 496 ­501, 2008 10. Hew-Butler T, Ayus JC, Kipps C, Maughan RJ, Mettler S, Meeuwisse WH, Page AJ, Reid SA, Rehrer NJ, Roberts WO, Rogers IR, Rosner MH, Siegel AJ, Speedy DB, Stuempfle KJ, Verbalis JG, Weschler LB, Wharam P: Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007. Clin J Sport Med 18: 111­121, 2008 11. Hew-Butler T, Jordaan E, Stuempfle KJ, Speedy DB, Siegel AJ, Noakes TD, Soldin SJ, Verbalis JG: Osmotic and nonosmotic regulation of arginine vasopressin during prolonged endurance exercise. J Clin Endocrinol Metab 93: 2072­2078, 2008 12. Siegel AJ, Verbalis JG, Clement S, Mendelson JH, Mello NK, Adner M, Shirey T, Glowacki J, Lee-Lewandrowski E, Lewandrowski KB: Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion. Am J Med 120: 461 e11­ e17, 2007 13. Hew-Butler TD, Dugas JP, Noakes TD, Verbalis JG: Changes in plasma arginine vasopressin concentrations in cyclists participating

Postoperative Hyponatremia

Vasopressin levels are increased for 2 d after surgical procedures; therefore, hypotonic fluid administration in the postoperative period risks acute iatrogenic hyponatremia. Postoperative hyponatremia is a major problem in pediatric populations, for whom traditional prescribing practices based on guidelines developed 50 yr ago still prevail in many medical centers (24). Because of postoperative deaths from hyponatremia in young children, a nationwide educational effort has been undertaken in the United Kingdom to change prescribing practices; however, prescription of hypotonic fluid remains common. A crosssectional survey of 17 English hospitals on all children who received intravenous fluids during 1 d of a specified week in December 2004 showed that 77 of 99 children were given hypotonic solutions and 38% received 105% of fluid requirements; 21 of 86 children with available data had hyponatremia (25). Fluid management of pediatric patients continues to be guided by theoretical concerns that isotonic maintenance fluids carry a risk for hypernatremia. Au et al. (26) conducted a retrospective analysis of 145 postoperative admissions to a pediatric intensive care unit; 80% of patients had been given isotonic fluid postoperatively, and 20% had been given hypotonic fluid (none more dilute than 0.3% saline). Moderate hyponatremia ( 130 mEq/L) was found in 12 patients who received hypotonic fluids (two were 125 mEq/L) and in one patient who received isotonic fluid.

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14.

15.

16.

17.

18. 19.

20.

21. 22.

23.

24.

25.

26.

27.

in a 109 km cycle race. Br J Sports Med July 15, 2008 [epub ahead of print] Chorley J, Cianca J, Divine J: Risk factors for exercise-associated hyponatremia in non-elite marathon runners. Clin J Sport Med 17: 471­ 477, 2007 Buono MJ, Claros R, Deboer T, Wong J: Na secretion rate increases proportionally more than the Na reabsorption rate with increases in sweat rate. J Appl Physiol 105: 1044 ­1048, 2008 Augusto JF, Sayegh J, Malinge MC, Illouz F, Subra JF, Ducluzeau PH: Severe episodes of extra cellular dehydration: An atypical adult presentation of cystic fibrosis. Clin Nephrol 69: 302­305, 2008 Baker LB, Lang JA, Kenney WL: Quantitative analysis of serum sodium concentration after prolonged running in the heat. J Appl Physiol 105: 91­99, 2008 Kurtz I, Nguyen MK: A simple quantitative approach to analyzing the generation of the dysnatremias. Clin Exp Nephrol 7: 138 ­143, 2003 Page AJ, Reid SA, Speedy DB, Mulligan GP, Thompson J: Exerciseassociated hyponatremia, renal function, and nonsteroidal antiinflammatory drug use in an ultraendurance mountain run. Clin J Sport Med 17: 43­ 48, 2007 Hew-Butler T, Anley C, Schwartz P, Noakes T: The treatment of symptomatic hyponatremia with hypertonic saline in an Ironman triathlete. Clin J Sport Med 17: 68 ­ 69, 2007 Siegel AJ: Hyponatremia in psychiatric patients: Update on evaluation and management. Harv Rev Psychiatry 16: 13­24, 2008 Dundas B, Harris M, Narasimhan M: Psychogenic polydipsia review: Etiology, differential, and treatment. Curr Psychiatry Rep 9: 236 ­ 241, 2007 Morita S, Inokuchi S, Yamamoto R, Inoue S, Tamura K, Ohama S, Nakagawa Y, Yamamoto I: Risk factors for rhabdomyolysis in self-induced water intoxication (SIWI) patients. J Emerg Med April 23, 2008 [epub ahead of print] Moritz ML, Ayus JC: Hospital-acquired hyponatremia: Why are hypotonic parenteral fluids still being used? Nat Clin Pract Nephrol 3: 374 ­382, 2007 Armon K, Riordan A, Playfor S, Millman G, Khader A: Hyponatraemia and hypokalaemia during intravenous fluid administration. Arch Dis Child 93: 285­287, 2008 Au AK, Ray PE, McBryde KD, Newman KD, Weinstein SL, Bell MJ: Incidence of postoperative hyponatremia and complications in critically-ill children treated with hypotonic and normotonic solutions. J Pediatr 152: 33­38, 2008 Yung M, Keeley S: Randomised controlled trial of intravenous maintenance fluids. J Paediatr Child Health November 25, 2007 [epub ahead of print]

Chronic Hyponatremia

Epidemiology

Conclusions about costs and outcomes in hyponatremia are sometimes drawn from billing data, using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. A comparison of inpatient hospital discharge records with inpatient laboratory data reported a sensitivity of 30% for even the strictest definition of hyponatremia ( 115 mmol/L). Because that study did not address the validity of coding for hyponatremia outside the inpatient setting, Shea et al. (1) sought to examine the validity of ICD-9-CM diagnosis codes for hyponatremia identification in an outpatient managed care pop-

ulation. Patients who were undergoing dialysis were excluded, and a correction factor for blood glucoses 300 mg/dl was used. A total of 40,668 outpatient serum sodium laboratory results were identified as hyponatremic (serum sodium 136 mmol/L). The sensitivity of ICD-9-CM codes for hyponatremia in outpatient professional claims within 15 d before or after the laboratory date was 3.5%. Sensitivity values for the 133 mmol/L, 130 mmol/L, and 125 mmol/L strata were 7.5, 13.9, and 29.6%, respectively. The authors concluded that administrative claims are not reliable for use in epidemiologic studies, even for patients with severe hyponatremia. Because only a small percentage of patients with hyponatremia receive an ICD-9-CM diagnosis code for hyponatremia, the same group obtained the results of outpatient laboratory tests on patients who were enrolled in 30 health insurance plans in the United States to determine the medical costs associated with hyponatremia (serum sodium 135 mmol/L) (2). Dialysis patients and patients with serum creatinine 2.0 mg/dl were excluded, and serum sodium concentrations were corrected for hyperglycemia (1.6 mg/dl for every 100-mg/dl increase in blood sugar) when the blood glucose was 300 mg/dl. During the study period, there were 1274 (0.9%) patients with hyponatremia and 3196 (1.9%) with hypernatremia. Controlling for age, gender, region, and comorbidities, hyponatremia was an independent predictor of cost, increasing overall costs by 41.2 to 45.7% and inpatient costs by 76.4 to 95.6%. Costs that were associated with hypernatremia were not significantly different from those that were incurred by patients with normonatremia, and cost increases that were associated with hyponatremia were more than seven times greater than those that were associated with hypernatremia. Because these data were derived from an employerbased, commercially sponsored population and included only health plan members with laboratory data, they are not necessarily generalizable: The elderly are likely to have been underrepresented, as were patients with comorbidities. Zilberberg et al. (3) performed a retrospective cohort study of hospitalized patients to quantify the effect of admission hyponatremia on hospital costs and outcomes. Data were derived from a large administrative database with laboratory components, representing 198,281 discharges from 39 US hospitals. The incidence of hyponatremia ( 135 mmol/L) at admission was 5.5% (n 10,899). Patients with hyponatremia were older

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(65.7 19.6 versus 61.5 21.8 yr; P 0.001) and had a higher number of comorbidities than patients with normonatremia. A higher proportion of patients with hyponatremia required intensive care (17.3 versus 10.9%; P 0.001) and mechanical ventilation (5.0 versus 2.8%; P 0.001) within 48 h of hospitalization. Hospital mortality (5.9 versus 3.0%; P 0.001), mean length of stay (8.6 versus 7.2 d; P 0.001) and costs ($16,502 versus $13,558; P 0.001) were significantly greater among patients with hyponatremia than those without. After adjustment for confounders, hyponatremia was independently associated with an increased need for intensive care unit care, mechanical ventilation, and higher hospital mortality. The authors encouraged studies to explore how prompt correction of admission hyponatremia may affect these outcomes.

Differential Diagnosis of Chronic Hyponatremia

Because nearly all patients with chronic hyponatremia have an abnormality in free water excretion, the diagnostic approach to the electrolyte disturbance seeks to define the cause of that abnormality. Except for patients with severely compromised renal function or impaired renal dilution caused by thiazide diuretics, impaired water excretion usually results from persistent secretion of vasopressin despite osmotic stimuli that would normally suppress secretion of the hormone. Vasopressin-mediated hyponatremia may result from disorders that decrease effective arterial blood volume (thereby provoking a hemodynamic stimulus for vasopressin secretion mediated by volume and pressure receptors), or it may result from vasopressin secretion that is independent of any hemodynamic stimulus. Hemodynamically mediated vasopressin secretion and hyponatremia occur in advanced heart failure and cirrhosis with ascites; these conditions can be easily recognized clinically and are defined by sodium retention and edema. The greater diagnostic challenge comes with the distinction between true hypovolemia caused by sodium depletion from euvolemic hyponatremia, often called the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Because the presence of antidiuretic hormone cannot always be proved in cases of euvolemic hyponatremia, it has been suggested that a better term for the condition is the syndrome of inappropriate antidiuresis (SIAD). Several recent reviews summarized the current state of our knowledge in distinguishing between salt depletion and SIAD. For diagnosing SIAD, the following

criteria are needed: (1) Hypo-osmolality, (2) urine that is less than maximally dilute (i.e., urine osmolality 100 mOsm/kg), (3) absence of diuretics or clinical signs of volume depletion or edema, (4) urine sodium concentration 30 mEq/L (some say 40 mEq/L on an adequate sodium intake), (5) reversal of "sodium wasting" and correction of hyponatremia with water restriction, and (6) absence of severely impaired renal function. Traditionally, a diagnosis of "SIADH" has required that hypothyroidism and adrenal function be normal, a requirement based on the Bartter and Schwartz criteria published in 1967; however, as discussed here, patients with these endocrine disturbances often present clinically with euvolemic hyponatremia with all of the other features of SIAD, and they are likely to respond to vasopressin antagonists. Similarly, there is disagreement as to whether to include drug-induced hyponatremia under the SIAD rubric. These distinctions are largely semantic. From a practical clinical standpoint, drug-induced hyponatremia and hyponatremia caused by endocrine disorders should be part of the differential diagnosis of a patient who fulfills the biochemical and physical examination criteria for SIAD. It is sometimes difficult to distinguish SIAD from hypovolemic hyponatremia on clinical grounds because the volume deficit in sodium-depleted patients has usually been partially repaired by retained water. Physical findings are often nondiagnostic, and azotemia may be lacking. In two studies, approximately half of the patients' hypovolemic hyponatremia was not diagnosed by history and physical examination. The most definitive test for hypovolemic hyponatremia is assessment of the response to isotonic saline; by expanding the extracellular volume, vasopressin secretion is suppressed and the urine becomes dilute. The validity of laboratory tests that are used to distinguish between SIAD and hypovolemic hyponatremia are best measured against this gold standard. Spot urine samples reveal urine sodium concentrations 30 mEq/L in most saline-responsive patients with hyponatremia and 30 mEq/L in most patients with SIAD; however, in older patients, who may be slower to adapt to hypovolemia with sodium retention, urine sodium concentrations may be as high as 50 to 60 mEq/L in patients with volume depletion. Fractional excretion of sodium (FENa), which requires measurement of the creatinine (creat) and sodium (Na) concentrations in concurrent urine (U) and plasma (P) samples may be helpful in these patients:

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FENa

UNa/PNa/Ucreat/Pcreat

A FENa 0.5% supports a diagnosis of volume depletion. The FENa can be supplemented with measurements of the fractional excretion (FE) of urea and uric acid, which requires the concurrent measurement of these substances in the plasma and urine. Thus, the FE of urea (FEurea) can be computed from the plasma and urine urea concentrations as follows: FEurea Uurea/Purea/Ucreat/Pcreat

FEuric acid in SIAD is mediated by V1 receptors. The high FEuric acid in SIAD also is influenced by the chronicity of hyponatremia and the GFR.

SIAD versus Cerebral Salt Wasting

In the early 1950s, before the pathophysiology of SIAD was understood, a few patients who had neurologic disease and continued to excrete sodium in their urine despite hyponatremia were reported; although these patients did not have hypotension, they were described as having "cerebral salt wasting" (CSW) (4). After the description of SIADH in 1957, urinary sodium losses in patients with hyponatremia and neurologic disease were generally attributed to a physiologic response to an expanded intravascular volume caused by primary water retention. In 1981, contracted isotopically measured blood volumes were found in patients with hyponatremia and subarachnoid hemorrhage, and the finding was attributed to CSW. The term CSW was resurrected primarily in the neurosurgery and critical care literature. Many neurointensivists now accept that CSW is a common if not the most common cause of hyponatremia among their patients (5­10). To make a valid diagnosis of "salt wasting," evidence of inappropriate urinary salt losses and a reduced "effective arterial blood volume" is required (4,8). The CSW literature relies on several criteria for volume depletion: Direct determinations of blood and plasma volume, negative sodium balance, clinical impressions, plasma levels of arginine vasopressin (AVP) and natriuretic peptides, and responses to therapy. As discussed in a recent editorial, none of these measures can define hypovolemia unambiguously (4).

In a recent series of sodium-depleted patients with hyponatremia, 30% had a UNa 30% (and therefore might have received a misdiagnosis of SIAD). All of these patients had a FENa 0.5%; however, 42% of patients with SIAD had a FENa 0.5%. Combined use of FENa and FEurea was proposed, with FENa 0.5% and FEurea 55% defining SIAD; however, a subsequent study showed that these limits were unreliable in patients with low urine outputs (defined by U/P creatine ratios 140). A FENa 0.15% or FEurea 45% in such patients identified those who were unresponsive to isotonic saline. As noted, the therapeutic response to isotonic saline is the closest thing we have to a gold standard for a SIAD diagnosis. The distinction should not be based solely on the plasma sodium concentration (PNa) response to isotonic saline; in one study, 29% of patients with sodium depletion failed to increase their PNa by 5 mEq/L after 2 L of saline, whereas 30% of patients with SIAD did increase their PNa by 5 mEq/L. A rapid increase in FENa to 0.5% after 2 L of isotonic sodium without correction of PNa (or appropriate dilution of the urine) supports a SIAD diagnosis. The response of PNa to isotonic saline is related to the baseline urine osmolality. Patients with a urine osmolality of approximately 300 mOsm/kg increased their PNa after isotonic saline, whereas patients with a urine osmolality 530 mOsm/kg respond with a decrease in PNa. The fractional excretion of uric acid is higher in patients with SIAD because of decreased proximal tubular reabsorption at presecretory and postsecretory sites. Plasma uric acid levels of 4 mg/dl and FEuric acid 12 or 16% have been proposed as criteria for a SIAD diagnosis; however, potomania, diuretics, and renal salt wasting may duplicate these findings. Desmopressin-induced hyponatremia increases FEuric acid to a much lower degree than as vasopressininduced hyponatremia, suggesting that increased

To make a valid diagnosis of "salt wasting," evidence of inappropriate urinary salt losses and a reduced "effective arterial blood volume" is required. The literature on cerebral salt wasting relies on several criteria for volume depletion: Direct determinations of blood and plasma volume, negative sodium balance, clinical impressions, plasma levels of AVP and natriuretic peptides, and responses to therapy. None of these measures can define hypovolemia unambiguously. Elevated levels of natriuretic peptides, ostensibly of cerebral origin, have helped fuel the idea that hyponatre-

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mia in neurologic disease is related to "salt wasting"; however, so-called brain natriuretic peptide usually is of cardiac origin; in a recent study, jugular venous sampling in suspected CSW did not support cerebral release of the peptide (11). Elevated natriuretic peptides are also consistent with a diagnosis of SIAD with secondary natriuresis caused by volume expansion with water (12). Patients with subarachnoid hemorrhage or other acute neurologic injuries respond with an increase in catecholamines, causing venoconstriction; as a result, the arterial circulation would be overfilled, leading to a pressure natriuresis and a decrease in plasma volume. Renin and aldosterone levels are low in patients with purported CSW, a finding that could be a primary cause of salt wasting, but also could be a response to an overfilled circulation (4). Fludrocortisone has been shown to be effective in decreasing urinary sodium losses and increasing the serum sodium concentration in patients who have hyponatremia and are believed to have CSW (13,14); however, parenteral preparations of fludrocortisone are not available for clinical use. In a series from Japan, where fludrocortisone was first proposed as a therapy for CSW, 13 patients with traumatic brain injury and hyponatremia that was resistant to sodium replacement (serum sodium 129.3 1.5 mEq/L) were given high-dosage hydrocortisone (300 mg every 12 h) as a substitute for fludrocortisone; hyponatremia normalized over 2 d. Before hydrocortisone treatment, urinary sodium losses averaged 563.5 95.9 mEq/d, and urine volume was 3.3 0.7 L/d. After the hydrocortisone treatment, sodium excretion fell significantly to 204.8 74.7 mEq/d, and urine volume fell significantly to 2.2 0.4 L/d. To follow up these findings, the same group conducted a multicenter, randomized, placebo-controlled trial of hydrocortisone (300 mg every 6 h for 10 d and then tapered) given prophylactically to prevent hyponatremia among patients with subarachnoid hemorrhage (15). Fluid intake was adjusted to achieve positive fluid balance and to maintain central venous pressure within 8 to 12 cmH2O. Seventy-one patients (placebo group n 36; hydrocortisone group n 35) entered the study. Sodium excretion (P 0.04), urine volume (P 0.04), and the amount of fluid and orally ingested water were reduced in the group that received hydrocortisone. The serum sodium concentration and plasma osmolarity were significantly higher in the hydrocortisone group (P 0.001), remaining above 140 mEq/L and approximately 290 mOsm/kg; however, control subjects do not seem to

have developed hyponatremia. There was no significant difference in the incidence of symptomatic cerebral vasospasm or in overall outcome. Hyperglycemia, hypokalemia, and hypoproteinemia were significantly more common in the hydrocortisone group (P 0.001); two patients developed gastrointestinal hemorrhage and one developed congestive heart failure in the hydrocortisone group. No patients had surgery or permanent sequelae because of adverse events. In our opinion, the investigators have not shown that steroid therapy has significant advantages over hypertonic saline given in adequate dosages.

Symptoms of Chronic Hyponatremia

Chronic hyponatremia should not be equated with "asymptomatic" hyponatremia; a high percentage of patients with serum sodium concentrations 125 mmol/L have symptoms of fatigue, vomiting, confusion, dysarthria, gait disturbances, or lethargy. Patients with chronic hyponatremia and very low serum sodium concentrations or underlying neurologic conditions may occasionally present with seizures, stupor, or coma; however, asymptomatic, mild chronic hyponatraemia is a more common finding and is associated with a risk for the development of worsening hyponatraemia and more serious neurologic symptoms. Even patients who seem to be "asymptomatic" can be shown to be neurologically impaired on formal testing. In a 3-yr retrospective survey in a single hospital, Bissrum et al. (16) identified 31 patients who were hospitalized with neurologic symptoms attributable to hyponatremia (average serum sodium 118.8 mmol/L). A large majority (70.9%) of these patients had preexisting untreated hyponatremia believed to be asymptomatic. The authors next investigated the prevalence of presumed asymptomatic hyponatraemia in the outpatient setting. Of 27,496 patients analyzed, 14% had serum sodium levels 134 mEq/L, and 4% had values 130 mEq/L. "Asymptomatic" hyponatremia has been associated with an increased risk for falls. Despite the absence of clinically apparent symptoms, hyponatremia impairs performance on both attention and tandem gait tests to a similar degree as that produced by a blood alcohol level of 0.06%, and these tests are restored to normal with correction of hyponatremia. These findings provide a rationale for therapeutic interventions for all patients with hyponatremia, re-

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gardless of symptoms, with an attempt to maintain a near-normal serum sodium concentration.

Despite the absence of clinically apparent symptoms, hyponatremia impairs performance on both attention and tandem gait tests to a similar degree as that produced by a blood alcohol level of 0.06%, and these tests are restored to normal with correction of hyponatremia. These findings provide a rationale for therapeutic interventions for all patients with hyponatremia, regardless of symptoms, with an attempt to maintain a near-normal serum sodium concentration. Further support for therapeutic intervention was provided by a case-control study of 513 cases of bone fracture after falling in ambulatory patients who were aged 65 yr and treated in a university hospital (17). The prevalence of hyponatremia (serum sodium 135 mEq/L) among patients with bone fracture after falling was 13.06 versus 3.90% in age- and gender-matched control subjects. Hyponatremia was mild and asymptomatic in all patients (mean serum sodium 131 3 mEq/L) and in most cases was drug induced (36% diuretics, 17% selective serotonin reuptake inhibitors) or from idiopathic SIADH (37%). Of the 67 patients with hyponatremia and bone fractures, only one had hyponatremia mentioned as a diagnosis in the medical record or discharge summary; many were discharged with uncorrected hyponatremia, and 25% had no measurement of the serum sodium at discharge. Four patients with hyponatremia had recurrent bone fractures.

Beer Potomania

Hyponatremia has been observed in people who drink large quantities of beer, so-called "beer potomania." Beer has a very low sodium and protein content; therefore, unless it is ingested with food, it provides little solute for excretion in the urine. The overall rate of solute excretion profoundly influences the capacity for water excretion, because the urine flow rate equals the rate of solute excretion divided by the urine osmolality (18). For any given urine osmolality, solute excretion sets the ceiling for how much water is actually excreted. Normally, 50 to 100 mmol of urea is produced each day by catabolism, and dietary protein

intake provides the rest; every 10 gm of protein provides approximately 50 mmol of urea for excretion. On a salt- and protein-rich diet that provides 900 mOsm of solute for excretion, 12 L of free water will be cleared daily at a urine osmolarity (Uosm) of 60 mOsm/L. On a diet that consists primarily of beer that provides only 300 mOsm of solute for excretion, free water clearance would be only 4 L/d. It should be noted that this calculation provides a value for free water clearance, whereas electrolyte-free water clearance is a better predictor of the effect of urine output on the plasma sodium concentration. Electrolyte-free water clearance is calculated by replacing urine and plasma osmolarity with their concentrations of sodium plus potassium. Because a beer diet contains little sodium or potassium, the value for electrolyte-free water would be closer to 5 L/d. Enthusiastic beer drinkers can consume 5 L/d, exceeding urinary water losses, causing hyponatremia. Traditionally, beer potomania is attributed to solute-limited water excretion with normal diluting ability; however, a single observation that the urine osmolality is low may not accurately reflect what occurred during the development of hyponatremia. Sanghvi et al. (19) reported two beer drinkers who had profound hyponatremia (100 and 104 mmol/L) and initially presented with inappropriately concentrated urine (218 and 547 mOsm/kg). After small amounts of intravenous fluid, urine osmolalities fell to 48 and 71 mOsm/kg, and a massive water diuresis emerged. If the urine osmolalities had not been measured before intravenous fluid, then one could have concluded erroneously that hyponatremia developed despite an intact ability to dilute the urine; hyponatremia might have been attributed to self-induced water intoxication, with an acute onset and a well-tolerated rapid resolution of hyponatremia. In fact, beer drinkers usually have chronic hyponatremia with transiently impaired water excretion resulting from the nonosmotic release of vasopressin caused by volume depletion from gastrointestinal losses, alcohol withdrawal, nausea, or medications. A low solute intake and consequent limited delivery of the glomerular filtrate to the distal nephron allows the urine to be concentrated at low levels of vasopressin; the ability to dilute the urine maximally can be restored with very little volume resuscitation. A review of 20 previously published cases of hyponatremia that resulted from beer poto-

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mania showed that only six included urine osmolality measurements and three in which those values were maximally dilute (19). Hyponatremia in these cases was very severe (14 of 20 110 mmol/L; eight of 20 105 mmol/L), and hypokalemia was frequent (13 of 20 3 mmol/L). Osmotic demyelination was documented in one of the authors' two cases (after correction by 15 mmol/L in 24 h and 24 mmol/L in 48 h) and in at least three of the cases in the literature. The authors advocated matching urinary water losses with D5W to avoid excessive correction, a strategy that was successful in one of their cases and unsuccessful in another. Alternatively, urinary water losses could have been controlled by giving desmopressin; this strategy is discussed later in this section.

Table 1. Principal causes and underlying mechanisms of drug-induced SIAD

Increased hypothalamic vasopressin secretion antidepressants SSRIs serotonin and norepinephrine reuptake inhibitors tricyclics monoamine oxidase inhibitors antipsychotic agents phenothiazines butyrophenones (haloperidol) antiepileptic drugs carbamazepine oxcarbazepine sodium valproate anticancer agents vincristine and vinblastine intravenous cyclophosphamide melphalan ifosfamide methotrexate opiates miscellaneous IFN- and levamisole pentostatin mAb Potentiation of vasopressin action on the collecting duct antiepileptic drugs carbamazepine lamotrigine intravenous cyclophosphamide antidiabetic drugs chlorpropamide tolbutamide nonsteroidal anti-inflammatory drugs Direct antidiuretic action desmopressin (DDAVP) oxytocin (Pitressin)

Drug-Induced Hyponatremia

Drug-induced hyponatremia is becoming the most common cause of hyponatremia seen in clinical practice. A host of drugs have been identified, and the subject has been recently reviewed (20). Thiazide diuretics are the most common cause of community-acquired hyponatremia. Most patients are elderly with a female preponderance; individuals with a low body mass are most likely to be affected. The pathophysiology is not completely understood but includes sodium and potassium depletion, vasopressin-mediated water retention, transcellullar cation exchange resulting from hypokalemia, magnesium depletion, and a direct effect of the diuretic on the renal diluting site. Acute hyponatremia may be seen in individuals who consume large amounts of water. Serum uric acid levels are often low, and thiazide-induced hyponatremia may mimic SIAD; therefore, unless there is strong evidence to suggest an underlying SIAD cause, an extensive diagnostic search for other causes should be postponed for 2 to 3 wk. It should be remembered, however, that thiazides may aggravate hyponatremia that is caused by other conditions. Other than diuretics, drugs can impair renal dilution by one of three basic mechanisms: Increased central release of AVP, resetting the osmostat to lower the threshold for AVP secretion, or increased sensitivity of the collecting duct to AVP. The various drugs that commonly cause hyponatremia and their probable underlying mechanisms are listed in Table 1. Because they are used so commonly, selective serotonin reuptake inhibitors (SSRIs) have become the most important cause of drug-induced hyponatremia other than thiazide diuretics. Older age and concomi-

tant use of diuretics are the most important risk factors, and hyponatremia has been reported to affect up to 32% of susceptible individuals. Although hyponatremia typically presents within the first 2 wk of starting therapy, one study showed that 29% of patients who presented with SSRI-induced hyponatremia did so 3 mo after starting the drug (21). The cause of SSRI-induced SIAD is still unknown. Although the drugs are thought to be highly selective in their effect on serotonin reuptake, there is some evidence that they inhibit reuptake of dopamine and norepinephrine, which may induce AVP release (21). A high incidence

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of drug-induced SIAD with a rapid onset of hyponatremia has been documented in patients treated with Venlafaxine, a serotonin and norepinephrine reuptake inhibitor (21a). As with diuretics, younger patients with psychogenic polydipsia may develop hyponatremia on SSRIs, and a history for excessive water or beer drinking should be obtained before prescribing these medications. Carbamazepine is a widely known cause of hyponatremia and is thought to increase the sensitivity of the renal tubule to normal plasma levels of AVP, and another antiepileptic drug, lamotrigine, has been reported to have a similar action; carbamazepine has also been reported to cause the reset osmostat variant of SIAD (20). Oxcarbazepine, which has a lower incidence of drug interactions than carbamazepine, has come into widespread use. The incidence of hyponatremia resulting from oxcarbazepine was found to be 9.2% (serum sodium 119 to 133 mEq/L) in a retrospective study of 414 patients with epilepsy; serum sodium values 125 mEq/L were found in only two patients (22) Desmopressin, a selective vasopressin 2 (V2) receptor agonist, was recently used to treat nocturia and the syndrome of nocturnal polyuria in both elderly and pediatric patients (23,24). Multiple case reports of symptomatic hyponatremia in these patients have appeared in the literature. One study showed that among patients aged 65, a baseline serum sodium value below normal carries a high risk for developing clinically relevant hyponatremia, even with oral desmopressin administration. As a result of concerns about hyponatremia, the US Food and Drug Administration (FDA) published a warning about the use of desmopressin, particularly for primary nocturnal enuresis treatment in children. The FDA reported 61 cases of hyponatremia-related seizures, two of which were fatal; 25 of these cases occurred in children. Many affected patients had been using other medications that affect water excretion, primarily SSRIs and thiazide diuretics. Similarly, in 2007, several European Union countries decided to remove the indication of nocturia in the elderly for nasal formulations of desmopressin because of the increased risk for hyponatremia. A study of prescribing patterns in Sweden found a marked increase in filled prescriptions for desmopressin in patients who were older than 60 yr after the drug was approved for enuresis treatment in that country in 2002. More than half of patients who were given

desmopressin were also given other agents that are known to increase the risk for hyponatremia, including diuretics, tricyclic antidepressants, SSRIs, chlorpromazine, carbamazepine, loperamide, and nonsteroidal anti-inflammatory drugs (24).

Tumor-Associated Hyponatremia

Most tumors that produce vasopressin ectopically are small cell lung cancers. Hyponatremia occurs at presentation in small cell lung cancer in 15 to 30% of cases, whereas up to 70% of patients have increased high levels of plasma vasopressin that normalize with therapy. SIAD resulting from ectopic secretion of vasopressin also occurs in patients with head and neck cancer. These tumors are usually located in the oral cavity and less often in the larynx, nasopharynx, hypopharynx, nasal cavity, maxillary sinus, pharyngeal space, salivary glands, and oropharynx. Ectopic hormone secretion has been reported in a handful of other tumors, primarily in isolated case reports, including olfactory neuroblastoma, small cell neuroendocrine carcinomas, adenoid cystic carcinomas, and undifferentiated carcinomas and sarcomas. Antineoplastic therapy with vincristine, vinblastine, and cyclophosphamide are widely known causes of hyponatremia, possibly because of cytotoxicity that affects paraventricular and supraoptic neurons. Cerebral metastases from a variety of tumors may cause hyponatremia that has been variably attributed to SIAD and cerebral salt wasting. Nephrotoxicity because of cisplatinum causes renal salt wasting and hypovolemic hyponatremia. Hyponatremia with salt wasting can also be caused by adrenal metastases in advanced breast cancer, colon cancer, and adrenal lymphoma. Approximately one third of patients with hyponatremia associated with small cell lung cancer have no evidence of ectopic vasopressin secretion and express atrial natriuretic peptide. Occult neoplasms are sometimes found to be the cause of what seems to be "idiopathic" SIADH. In most cases, these tumors become apparent soon after the discovery of hyponatremia. Olfactory neuroblastomas, although rare, may present with SIADH and can remain occult for many years; particularly in young patients with "idiopathic" SIADH, an examination of the sinuses may be warranted (25).

Pneumonia

The association between pneumonia and hyponatremia was first described in 1962, but there have

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been few studies to define this relationship. Nair et al. retrospectively reviewed a 342-patient cohort treated in their hospital over 2 yr with data gathered as part of a 2-yr project to develop a standardized communityacquired pneumonia order set (25a). Admission serum sodium concentrations ranged from 122 to 175 mEq/L, and 27.9% of patients had hyponatremia ( 135 mEq/ L). Patients with hypernatremic tended to be nursing home residents, reflecting impaired thirst associated with advanced age and dementia. Hyponatremia occurred among patients who were not from nursing homes and was equally common in men and women; it usually was mild on admission, but 4.1% of the cohort had admission serum sodium concentrations 130 mEq/L. Patients with hyponatremia had significantly higher heart rate and white blood cell (WBC) count and were more likely to have a pneumonia severity index of 4 or 5, but, surprising, their arterial PO2 and oxygen saturation were nearly identical to those of the patients with normonatremia. A heart rate 100 with a WBC count 15,000 carried a 48.9% likelihood of developing hyponatremia. Multivariate analysis showed that hyponatremia severity index was the only independent risk predictor for hyponatremia. As has been true for many disorders, hyponatremia was associated with longer hospital stays and hospital mortality (9.5 versus 3.4%), most likely reflecting the severity of the pneumonia rather than morbidity from the usually mild and asymptomatic hyponatremia. Between the second and eighth hospital days, 10.5% of patients developed hyponatremia (122 to 135 mEq/L), and only nine patients with hospital-acquired hyponatremia had sodium levels 130 mEq/L. Hospitalacquired hyponatremia was equally likely to occur in men and women, was not related to the severity of the pneumonia or hypoxia, but was associated with the choice of intravenous fluid; the incidence of hyponatremia after use of isotonic fluid was 3.9 versus 14.5% with hypotonic fluid. It is interesting that patients who received no intravenous fluid were nearly as likely as those who received intravenous hypotonic fluid to develop hyponatremia in the hospital. A study of 108 children with community-acquired pneumonia of varying severity found a 45.4% incidence of hyponatremia ( 135 mEq/L), which was mild ( 130 mEq/L) in 92% of cases. Patients with hyponatremic had higher temperature and WBC count than patients with normonatremia and were more likely to express inflammatory markers than those

with normonatremia. Hyponatremia did not affect length of stay (26).

Endocrine Disorders

Data are conflicting regarding the incidence and pathogenesis of hyponatremia in hypothyroidism (27,28). The appearance of hyponatremia during withdrawal of thyroid hormone replacement and resolution of hyponatremia with thyroid replacement supports an etiologic role of hypothyroidism in the electrolyte disturbance. To improve uptake of radioactive iodine in thyroid carcinoma, levothyroxine is sometimes withdrawn and a low-iodine diet is administered. Shakir et al. (27) reported five patients who had papillary or follicular thyroid carcinoma and developed symptomatic hyponatremia during this maneuver. Baseline serum sodium levels had been normal before replacement therapy withdrawal. The patients presented with a variety of complaints, including weakness, dizziness, fainting spells, lethargy, and/or nausea in association with serum sodium concentrations ranging from 110 to 121 mmol/L. Despite hyponatremia, the plasma renin activity and serum aldosterone levels were suppressed, indicating volume expansion, consistent with a diagnosis of SIAD. The hyponatremia responded to fluid restriction and normalized after thyroid hormone replacement. Lung or cerebral metastases (present in four of the patients) may have contributed to hyponatremia. Autoimmune polyendocrine syndrome type 2, or Schmidt syndrome, is characterized by the association of autoimmune Addison disease with autoimmune thyroid disease and/or type 1 diabetes. When hypothyroidism and hypoadrenalism coexist, hyponatremia seems to be more severe than when either of these diseases occur in isolation (29). Hypopituitarism because of Sheehan syndrome occurs as a result of ischemic pituitary necrosis from severe postpartum hemorrhage; it is more common in developing countries. Kurtulumus et al. (30) reported five elderly multiparous women (mean age 69; range 62 to 78 yr) who had a history of complicated delivery and presented with hyponatremia (serum sodium 128 mEq/L) as a result of previously undiagnosed Sheehan syndrome (for up to 42 yr after the initial event). Longstanding unrecognized Sheehan syndrome was unmasked in one patient who developed hyponatremia (123 mEq/L) 2 d after treatment with pegylated interferon for hepatitis C (31).

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Although Addison disease (combined aldosterone and cortisol deficiency) and hypopituitarism (isolated cortisol deficiency) are widely recognized causes of hyponatremia, isolated hypoaldosteronism is seldom mentioned as a cause. Talapatra et al. (32) reported on three patients who were aged 64 to 82 and presented with hyponatremia (serum sodium 128, 116, and 117 mEq/L) and high-normal serum potassium concentrations (5.0 to 5.2 mEq/L). Renal function was near normal, urine osmolalities ranged from 370 to 658, and urine sodium concentrations were 30, 128, and 170 mEq/L. The patients had normotension but had orthostatic changes in BP, which in one case was symptomatic. All patients had low plasma aldosterone levels and normal cortisol levels; two patients had low plasma renin values (the third was on lisinopril). On low dosages of fludrocortisone (50 to 100 g/d), the patients gained weight, postural changes in BP resolved, serum potassium concentrations fell, and serum sodium concentrations returned to normal.

hyponatremia. During the clinical course, hyponatremia was seen in 27% of cases and was classified as severe in 6%; the proportion of patients with seizures, impaired consciousness, hydrocephalus, and stroke in patients with normonatremia and patients with severe or mild hyponatremia was similar. Treatment for hyponatremia was given for 16 (29%) of 55 episodes of severe hyponatremia and 26 (13%) of 206 episodes of mild hyponatremia. Despite this nonaggressive therapeutic approach, hyponatremia resolved in 79% of cases within 3 d, and neither mild nor severe hyponatremia was associated with death or neurologic sequelae.

Traumatic Brain Injury

Hyponatremia has been shown to be a common complication of traumatic brain injury, affecting 13.7 to 33% of patients in two small published series. Moro et al. confirmed these findings in a retrospective analysis of 298 patients who had traumatic brain injury and were admitted during 12 mo to a single hospital in Japan; 50 (16.8%) developed hyponatremia (33b). Hyponatremia was not observed among the 63 patients with cerebral concussion, the 49 patients with skull fracture, or the eight patients with traumatic subarachnoid hemorrhage; however, hyponatremia was common among patients with cerebral contusion (n 48 [48%]), acute and chronic subdural hematoma (n 16 [25%] and n 88 [16%]), and acute epidural hematoma (n 16 [25%]). Most patients developed hyponatremia within 3 d of injury; however, some patients developed hyponatremia after 8 d. No patients developed diabetes insipidus. Hyponatremia was associated with longer hospital stay (P 0.001) and bad outcome (P 0.02).

Meningitis

Hyponatremia is a frequent complication of bacterial meningitis (6). Brouwer et al. conducted a nationwide observational cohort study in the Netherlands of 696 episodes of community-acquired acute bacterial meningitis assessed prospectively in 671 patients (32a). The authors found a surprisingly benign prognosis. Hyponatremia was defined as mild (130 to 135) or severe ( 130 mmol/L). Hyponatremia was present on admission in 30% of patients and was classified as severe in 6%; the lowest serum sodium on admission was 120 mEq/L. Hyponatremia was significantly more common in Listeria meningitis (73%) than with other infecting organisms (in other series, comparably high rates of hyponatremia have been described in tuberculous and group A streptococcal meningitis, which was not encountered in this cohort) (33). Symptoms of headache, seizures, and impaired consciousness on admission occurred with equal frequency among patients with severe hyponatremia, mild hyponatremia, and normonatremia; however, a longer duration of symptoms ( 24 h) was more common among patients with hyponatremia. Cerebrospinal fluid opening pressures were measured in 216 of 696 patients, but there was no association between high cerebrospinal fluid pressure and hyponatremia. Likewise, the proportion of patients with cerebral edema on computed tomography was similar among patients with and without

Cirrhosis

In severe hepatic cirrhosis, reduced effective circulating volume because of arterial splanchnic vasodilation leads to baroreceptor-mediated nonosmotic stimulation of vasopressin release and an impaired ability to excrete electrolyte-free water (34). Reduced sodium delivery to the distal tubule because of a low GFR and/or increase of proximal sodium reabsorption adds to susceptibility to hyponatremia of patients with cirrhosis. The prevalence of hyponatremia (defined as a serum sodium 130 mmol/L) has been reported to be 21.6% in patients with cirrhosis (35). Hyponatremia should theoretically pose a risk to patients hyperam-

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monemia, who often have low-grade cerebral edema because of glutamine accumulation in the brain. Consistent with this prediction, hyponatremia increases the probability of developing hepatic encephalopathy. Hyponatremia also increases morbidity and mortality from hepatic transplantation and is associated with osmotic demyelination in the postoperative period because of the large increase in sodium concentration associated with the procedure (35). When V2 receptor antagonists become clinically available, they may prove useful in hyponatremia management among patients with cirrhosis. Gines et al. (36) conducted a multicenter, double-blinded, randomized, controlled trial that compared placebo with fixed dosages (5, 12.5, or 25 mg once daily) of satavaptan, a highly selective V2 receptor antagonist, in 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium 130 mmol/L). Treatment continued for 14 d, during which all patients continued to receive spironolactone. Satavaptan improved the control of ascites, reducing body weight and abdominal girth significantly more than placebo. The serum sodium concentration was significantly higher than placebo in all treatment groups, and, at the highest dosage used (25 mg once daily), the serum sodium had increased by 6.6 4.3 mmol/L after 5 d versus 1.3 4.2 mmol/L in control subjects. The number of patients who showed an increase in serum sodium of 5 mmol/L during the first 5 d ranged from 54 to 61% in satavaptan-treated patients and 18% in patients who received placebo. Thirst was significantly more common in the treatment groups, whereas the frequency of other adverse effects did not differ from that of control subjects. The drug did not affect BP. In some patients, the increase in urine volume was striking. In fact, 11 patients who were treated with satavaptan had urine outputs of 5 L/d at some point during the study. There were no changes in serum creatinine concentration in any of the satavaptan-treated patients compared with placebo. A rapid increase in serum sodium (defined as 8 mmol/L in this high-risk population) was observed in four of 28 patients who were given with placebo and nine of 82 patients who were treated with conivaptan; no patient developed neurologic complications.

Heart Failure

Hyponatremia is a common complication of leftsided heart failure, and several studies have shown that

it is an independent mortality predictor (37­ 40). Gheorghiade et al. (37) followed patients who had heart failure and were enrolled in a study of the effectiveness of pulmonary catheterization (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE]) for 180 d after discharge to compare outcomes among patients with persistent hyponatremia (n 71), corrected hyponatremia (n 32), and normonatremia (n 327). Patients with persistent hyponatremia had a higher risk for postdischarge mortality and rehospitalization for heart failure than patients with normonatremia despite similar clinical improvements (weight loss, improved symptoms, and hemodynamic changes); however, although there was a trend for improved outcomes in patients with corrected hyponatremia compared with those with persistent hyponatremia, this did not reach statistical significance. Patients who have heart failure and have hyponatremia have higher circulating levels of neurohormones (catecholamines, renin, angiotensin II, aldosterone, and vasopressin) than individuals with normonatremia and are more likely to have prerenal azotemia. It is therefore possible that hyponatremia is simply a marker of increased neurohormonal activation and more severe disease. Conversely, it also is possible that the volume regulatory responses of myocytes responding to hypotonicity might be maladaptive or that vasopressin itself, through its action on cardiac and coronary V1a receptors, might have adverse effects (41). Hyponatremia in heart failure is mediated by vasopressin, and it responds to vasopressin antagonists. The availability of orally active vasopressin antagonists has made it possible to conduct long-term outcome studies to compare corrected with uncorrected hyponatremia. In the acute and chronic therapeutic impact of a vasopressin antagonist in chronic heart failure (ACTIV in CHF) study, there were no differences in 60-d outcomes in patients who had heart failure and were treated with tolvaptan (a V2 receptor antagonist) compared with placebo. A post hoc analysis of this study suggested that patients with corrected hyponatremia had a lower mortality compared with placebo (42). At hospital discharge, 45 (66.2%) of 68 patients with hyponatremia had improvements in serum sodium levels of 2 mEq/L. Patients who had hyponatremia and whose serum sodium concentration improved had a mortality rate of 11.1% at 60 d after discharge, compared with a 21.7% mortality rate in the

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17 patients with persistent hyponatremia; however, in the much larger Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), 2072 patients who had heart failure and were treated with tolvaptan had virtually identical clinical outcomes (overall mortality, cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure) compared with 2061 patients who received placebo (43). Given that only 8% of the trial's study population had hyponatremia, however, the question of whether correction of hyponatremia will improve prognosis in heart failure remains open. Even if survival is not improved, patients with hyponatremia and heart failure are likely to benefit in other ways (subtly improved cognitive function and a reduced risk for falls) from sustained normalization of their serum sodium concentration. Evidence of benefit from increased urine output in patients with normonatremia and heart failure is unconvincing. Hyponatremia in right heart failure has received much less attention. Forfia et al. (44) found that 13 of 40 patients who had primary pulmonary hypertension and were evaluated in a referral center had hyponatremia (mean 132.4 4.4 mEq/L; range 119 to 136) at the time of cardiac catheterization. Patients with hyponatremia (serum sodium 136 mEq/L) were significantly more symptomatic, were more likely to be hospitalized, had more peripheral edema (69 versus 26%; P 0.009), had higher hospitalization rates (85 versus 41%; P 0.009), and had higher right atrial pressure (14 6 versus 9 3 mmHg; P 0.001) than patients with normonatremia. Patients with hyponatremia had a 10fold higher mortality rate than patients with normonatremia; all 10 patients with a serum sodium 135 mEq/L died during the 2-yr follow-up, whereas no patient with a serum sodium 140 mEq/L died. Diuretic use had no bearing on the relationship between hyponatremia and outcome, and the prognostic significance of hyponatremia persisted after adjustment for functional class, treatment status, and renal function, and it was independent of hemodynamic, echocardiographic, and clinical markers of poor outcome.

Treatment Options for Hypotonic Hyponatremia

Treatment Goals. Although the treatment of hyponatremia has often been called "controversial," a general consensus has emerged (45­53). There is longstanding agreement that the serum sodium concentration should be increased rapidly among patients

who present with severe neurologic symptoms or whose risk for herniation is high (e.g., a known acute onset of hyponatremia, presence of intracranial pathology) and that this requires hypertonic saline administration. There is also general agreement that, especially for patients with chronic hyponatremia, the magnitude of correction over 24 and 48 h should be limited to avoid iatrogenic injury. There are still some differences in the details of these general principles. For clear-cut hyponatremic emergencies associated with acute hyponatremia, some authors recommended correction by 1 to 2 mEq/L per h by infusing 3% saline at 1 to 2 ml/kg per h, whereas others advocated bolus infusions of hypertonic saline. Data from patients who had normonatremia and neurosurgical emergencies suggested that a 5-mmol/L increase will reliably reverse impending herniation (see the Hypernatremia section), and a rapid infusion of hypertonic saline should cause a greater increase in sodium concentration of the arterial blood perfusing the brain (51). Thus, the bolus strategy may make the most sense. For patients who present with seizures, one group infuses 3 mmol of hypertonic NaCl per liter of total body water (3 ml/kg 3% saline in a young woman) per hour for 2 h (51). Even if seizures have stopped, bolus infusion is still used because of the risk that the serum sodium concentration may fall: (1) Seizures are known to increase transiently the plasma sodium concentration because of an internal water shift into muscle cells caused by an increase in intracellular solute, and there is a theoretical risk that water might return to the plasma from muscle cells postictally, lowering the plasma sodium concentration; and (2) in patients who have developed hyponatremia by drinking water rapidly (e.g., psychotic patients, runners, ecstasy users), delayed absorption from the intestinal tract can lower the serum sodium concentration. Once the acute emergency has been dealt with expeditiously and aggressively, this group advocates limiting the overall daily correction to 8 mmol/L, similar to the goal for patients with chronic hyponatremia (51). Although virtually all authors agree that overcorrection of hyponatremia risks iatrogenic brain damage, there is not uniformity of opinion as to what overcorrection is; however, differences seem to be narrowing. Whereas one author once suggested that correction of hyponatremia was not harmful unless the increase in serum sodium concentration exceeded 25 mmol/L in

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48 h, his more current recommendation is to limit correction over 48 h to 15 to 20 mmol/L (a standard that is consistent with a 48-h limit of 18 mmol/L suggested by others) (52). Not all authors mention a 24-h limit. Although this was once set at 12 mmol/L per d, reports of osmotic demyelination at slower rates of correction have led to recommendations for a 24-h limit of 8 to 12 mmol/L (49). These should be regarded as limits not to be exceeded rather than therapeutic goals. To avoid overshooting the mark, a "target" of 8 mmol/L per d has been suggested by several authors. For patients at high risk for osmotic demyelination (patients with alcoholism, liver disease, or malnutrition), even slower daily rates of correction may be indicated. Water Restriction. Restriction of water intake can be an effective treatment for mildly symptomatic chronic hyponatremia if there is enough electrolytefree water excretion in the urine. Electrolyte-free water clearance is computed by multiplying the ratio of sodium and potassium concentrations in the urine and plasma (the urine:plasma electrolyte ratio) by the urine flow rate. The urine:plasma electrolyte ratio alone on a spot urine sample (omitting urine output) is sufficient to estimate electrolyte-free water clearance . If the ratio is 0.5, then electrolyte-free water clearance is high and the plasma sodium concentration can be expected to increase acceptably if water is restricted; if it is between 0.5 and 1.0, then electrolyte-free water clearance is low but still positive, and, to be effective, water intake must be drastically reduced; if it is 1.0, then electrolyte-free water clearance is negative, the plasma sodium concentration may actually fall without intervention, and fluid restriction alone will be ineffective (54). Increasing solute intake may augment water restriction's effectiveness as a treatment for hyponatremia. A recent editorial review illustrated this point using patient data derived from the literature (18). For example, consider a patient who has a fixed urine osmolarity of 664 mOsm/L caused by SIAD because of lung cancer and whose diet provides 600 mOsm/d solute. If the concentration of sodium plus potassium in his urine were 166 mEq/L, then the urine-electrolyte ratio would be 1.0 and hyponatremia will worsen no matter how much fluid intake is restricted. Administering urea (or more dietary protein) to double solute excretion from 600 to 1200 mOsm/d would also double his urine flow, diluting the urine sodium and

potassium concentrations in half. As a result, electrolyte-free water excretion becomes positive; however, large dietary protein intakes may not be achievable, and urea is not readily available as a therapeutic choice in North America; it may also not suit the North American palate. Alternatively, a high salt intake combined with water restriction allows the electrolyte concentration of what is ingested to match the electrolyte concentration of what is excreted in the urine. Combining a high salt intake with furosemide, which decreases urine osmolality, can be an effective strategy. Hypertonic Saline. Hypertonic saline has been used to treat hyponatremia since the first description of its use in 1938; however, there is a paucity of data to guide clinicians. Dosing guidelines have therefore been derived from anecdotal clinical experience and physiologic principles. Most patients who are hospitalized for hyponatremia have mild to moderate symptoms. If they have features of SIAD and are expected to be or have been shown to be resistant to isotonic saline, then administration of hypertonic saline may be indicated. Among patients with mildly symptomatic chronic hyponatremia, hypertonic saline can be infused at much slower rates than are used for acute water intoxication. A retrospective study of all 62 patients who had hyponatremia and received hypertonic saline at a single medical center showed that despite a low rate of infusion (mean 23.5 ml/h, interquartile range 17.0 to 32.2 ml/h), frequent adjustments in the rate of infusion, and in some cases administration of D5W as an antidote, the serum sodium concentration often increased by more than would be predicted and by more than the prescribers intended: Correction exceeded 12 mEq/L at 24 h in 11% of the cases, and 10% corrected by 18 mEq/L within 48 h (55). By hospital policy, all patients were treated under the supervision of nephrologists who sought to maintain correction rates within these guidelines. The magnitude of correction within 48 h was directly correlated with the plasma sodium concentration, with more severe hyponatremia associated with more rapid correction. The Adrogue-Madias formula is widely used to predict the effect of an intravenous infusate on the serum sodium concentration (SNa): SNa after 1 L of infusate (infusate [Na] SNa)/(total body water 1)

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In patients with a plasma sodium concentration 120 mEq/L, the actual increase in plasma sodium exceeded the increase predicted by the formula in 74% of the patients; the average ratio of actual to expected was 1.7 0.2, and actual correction was as much as five times predicted. In approximately half the cases, a documented water diuresis could account for the excessive correction. A number of conditions temporarily or reversibly impair water excretion. Once the impairment resolves, excretion of dilute urine increases the serum sodium concentration by much more than would be predicted by calculations that ignore urine output. Multifactorial causes of hyponatremia are common, and it is often difficult to determine which factor is controlling or to predict which patients will respond to volume repletion, the passage of time, or discontinuation of medications with a water diuresis. For example, Mohmand et al. (55) described an 87-yr-old who was taking thiazides (which would be expected to correct with volume repletion) and was admitted with a serum sodium of 106 mEq/L 2 wk after starting an SSRI antidepressant (a common cause of drug-induced SIAD). Despite stopping her medications and infusion of 0.9% saline with potassium supplements, the serum sodium increased by only 3 mEq/L during the first 14 h and urine output was 60 ml/h; therefore, with the assumption that she had SIAD, 3% saline was prescribed at 20 ml/h. A few hours later, a water diuresis developed with a urine osmolality of 90 mOsm/kg. Hypertonic saline was discontinued after 120 ml had been administered (enough to increase the serum sodium by a calculated 3 mEq/L); however, primarily because of the water diuresis, the serum sodium increased 15 mEq/L in 18 h. Drescher et al. (56) described a similar patient who presented with seizures, a serum sodium of 100 mmol/L, urine osmolality of 271, and urine sodium of 39 mmol/L (Figure 2). A SIAD diagnosis prompted administration of 3% saline; however, in the first hour of the infusion, the urine output increased to 750 ml/h and urine osmolality fell to 68 mOsm/kg. Despite stopping hypertonic saline and infusing D5W, the serum sodium concentration continued to increase. As more history emerged, investigators learned that the patient was psychotic and had been drinking large volumes of water while taking thiazide diuretics. Her transiently concentrated urine on presentation was attributed to an effect of her

seizure or nausea or might also have reflected an effect of thiazides.

Figure 2. An example of a reversible defect in water excretion. A young woman with severe hyponatremia (serum sodium 100 mmol/L) and seizures associated with previously unrecognized polydipsia and thiazides. The initial laboratory data suggest SIAD, but after receiving 70 ml of 3% saline over 1 h, the urine became dilute and the serum sodium concentration increased by more than intended despite an attempt to replace urine losses with 5% dextrose in water. Reprinted with permission from Elsevier (The Lancet, 2008, Vol 371, page 2144; ref. 59).

Vasopressin Receptor Antagonists. The main effects of AVP on water balance are mediated through V2 receptors in the renal collecting ducts. Stimulation of V2 receptors upregulates renal expression of aquaporin 2 water channels and initiates their insertion into the cellular membranes of the renal collecting duct, increasing water reabsorption. AVP also affects vascular tone and platelet activity by stimulating V1A receptors. Vasopressin receptor antagonists, collectively known as the "vaptans," provide a new approach to the treatment of hyponatremia. Anticipation of the availability these agents has sparked the publication of several recent reviews, including an editorial in the last fluid and electrolyte edition of NephSAP (48,54,57). Conivaptan, which blocks both the V2 and V1A receptors, is currently the only drug of its class available for use in the United States, although mozavaptan has been approved for use in paraneoplastic SIADH in Japan. In humans, 99% of conivaptan is bound by plasma proteins, over a wide plasma concentration range. A potent inhibitor of CYP3A4, conivaptan interacts with many medications, including the statins

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(simvastatin, lovastatin, atorvastatin, rosuvastatin, ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir). Because of concern about serious drug­ drug interactions if the drug were used for prolonged periods, the FDA approved only the intravenous form of conivaptan for the short-term management of euvolemic hyponatremia and hyponatremia because of heart failure in hospitalized patients. Conivaptan is contraindicated in hypovolemic hyponatremia (because the antagonism of the V1A receptor could cause hypotension) and in patients with hyponatremia caused by cirrhosis with ascites (for fear of precipitating hepatorenal syndrome, a disorder ameliorated by agonists of the V1A receptor). A number of orally active V2 receptor antagonists are in clinical trials and may potentially be approved for outpatient treatment of hyponatremia. As yet, there is little published experience with conivaptan, currently the only FDA approved vaptan. Zeltser et al. (58) conducted a placebo-controlled trial of 84 hospitalized patients with euvolemic or hypervolemic (congestive heart failure) hyponatremia (serum sodium 115 to 130 mmol/L). Patients were assigned to receive intravenous placebo or conivaptan administered as a 30-min, 20-mg loading dose followed by a 4-d continuous infusion of either 40 or 80 mg/d conivaptan. Conivaptan significantly increased the plasma sodium concentration by a variety of measures over placebo, and it increased electrolyte-free water clearance, whereas placebo did not. The drug was generally well tolerated, although infusion-site reactions led to the withdrawal of 3% of patients who were given the 40-mg dose and 15% of patients who were given the 80-mg dose. As would be expected for a V1A receptor antagonist, conivaptan infusion at either dosage was associated with significant but clinically unimportant changes in supine systolic and diastolic BP, and postural hypotension occurred in five of 55 patients who received conivaptan and none of the 29 patients who received placebo. Two patients in each of the groups given conivaptan-- but none in the placebo group-- experienced excessive correction of hyponatremia (at 40 mg/d 13 mmol/L over 24 h and 8 mmol/L over 4 h; at 80 mg/d 25 mmol/L over 24 h and 12 mmol/L after 24 h); overcorrection did not lead to neurologic symptoms suggestive of osmotic demyelination. Verbalis et al. (59) conducted a subgroup analysis of the 56 patients who had euvolemic hyponatremia (SIAD) and participated in the original trial.

All but one of the 19 patients who received conivaptan had significantly higher serum sodium concentrations than placebo after the first day of therapy, and these averaged 5.70 0.90 mEq/L in the 40-mg/d group and 6.40 0.95 mEq/L in the 80-mg/d group. Only one patient in the subgroup experienced excessive correction (12 mmol/L over 24 h). The authors suggested that 4 d of intravenous conivaptan could be a useful therapy for patients who are hospitalized with transient SIAD, as seen with surgical procedures, acute pneumonia, respiratory failure, or subarachnoid hemorrhage. More data are needed for patients with subarachnoid hemorrhage; if, as is commonly believed, these patients have hypovolemia because of cerebral salt wasting, then the hypotensive effect of the drug could adversely affect cerebral perfusion. If the drug were combined with isotonic saline, however, then this theoretical risk could be avoided. Rianthorn et al. reported a novel use of conivaptan in a 13-yr-old patient who had SIAD associated with an anaplastic large cell lymphoma and required large volumes of intravenous fluid to prevent tumor lysis syndrome (59a). The increase in free water clearance allowed the administration of isotonic saline at 3 L/m2 per d, and the serum sodium concentration increased from 121 to 129 mmol/L over 24 h. Vaptans are a welcome addition to our therapeutic armamentarium. They make it possible to treat patients who have hyponatremia and heart disease without saline, and they will greatly simplify outpatient treatment of hyponatremia. For patients with seizures or coma, hypertonic saline remains the drug of choice. There has been no experience with giving hypertonic saline and vaptans together, but this is a theoretically attractive maneuver. For patients with moderate neurologic symptoms from severe hyponatremia, vaptans are an option, but they must be used with caution to avoid overcorrection. Clinicians who use these agents must focus their attention on the urine output and must be prepared to replace urinary water losses when therapeutic goals have been reached. Desmopressin for Overcorrection. As discussed earlier, a water diuresis often emerges during the treatment of hyponatremia, risking inadvertent overcorrection. There are several settings in which this can occur: (1) Volume resuscitation in patients with excess vasopressin because of hypovolemia or low solute intakes; (2) discontinuation of thiazide diuretics or drugs that cause SIAD; (3) cortisol replacement in

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patients with adrenal insufficiency; and (4) spontaneous resolution of a reversible cause of SIAD, such as nausea, hypoxia, or recent surgery. In three separate case reports of individual patients, desmopressin was successfully used therapeutically to relower the serum sodium concentration after inadvertent overcorrection of hyponatremia and the onset of symptoms suggestive of osmotic demyelination. Perianayagam et al. (60) reported their experience with desmopressin in 20 patients as a therapeutic agent to avoid overcorrection of hyponatremia and to relower the plasma sodium concentration after inadvertent overcorrection before symptoms of osmotic demyelination could appear. Hyponatremia was multifactorial in most cases, and, with few exceptions, the cause of water retention was eliminated during the course of hospitalization; thiazide diuretics and SSRIs, alone or in combination, were causative factors in 11 cases. Six patients were given desmopressin acetate as a rescue maneuver after the 24-h limit of 12 mmol/L had already been reached or exceeded; correction was prevented from exceeding the 48-h limit of 18 mmol/L in five of the six (the exception had exceeded the goal before desmopressin was given). Fourteen patients were given desmopressin acetate in anticipation of overcorrection after the plasma sodium concentration had increased by 1 to 12 mmol/L. In all 14 patients who were treated with desmopressin acetate as a preventive measure, correction was prevented from exceeding either the 24- or 48-h limit. After desmopressin acetate was administered, the plasma sodium concentration of 14 of the 20 patients fell by 2 to 9 mmol/L. In all six patients who were treated after overcorrection and five patients who were treated prophylactically, the plasma sodium concentration was actively lowered again by the concurrent administration of desmopressin acetate and 5% dextrose in water; no serious adverse consequences from this maneuver were observed. In most cases, desmopressin was administered subcutaneously or intravenously in 1- or 2- g doses. The authors recommended a dosing interval of 6 to 8 h to avoid escape from the drug and the unwanted reemergence of a water diuresis. References

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59. Verbalis JG, Zeltser D, Smith N, Barve A, Andoh M: Assessment of the efficacy and safety of intravenous conivaptan in patients with euvolaemic hyponatraemia: Subgroup analysis of a randomized, controlled study. Clin Endocrinol (Oxf) 69: 159 ­168, 2008 59a. Rianthavorn P, Cain JP, Turman MA: Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH. Pediatr Nephrol 2008 60. Perianayagam A, Sterns RH, Silver SM, Grieff M, Mayo R, Hix J, Kouides R: DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol 3: 331­336, 2008

Hypernatremia and Diabetes Insipidus

Basic Mechanisms of Osmoregulation

Although osmoregulatory systems in humans and other mammals strive to maintain a set point of constant plasma osmolality, rapid fluctuations occur around that set point because of changes in the rates of water intake and water loss (through the skin or urine) and because of variations in sodium intake and excretion rates. Forty minutes of strenuous exercise in the heat or 24 h of water deprivation increases the plasma osmolality by 10 mOsm/kg, whereas drinking the equivalent of two large glasses of water (850 ml) lowers osmolality by approximately 6 mosmol/kg within 30 min. Ingestion of 13 g of salt increases plasma osmolality by approximately 5 mosmol/kg within 30 min (1). Osmotic fluctuation within the 1 to 3% range that is compatible with health controls bodyfluid homeostasis by inducing proportional homeostatic responses through negative feedback. Sensory osmoreceptors actively generate a basal signal at the desired set point and can modulate this signal to encode both the direction and the magnitude of the stimulus (1). Extracellular hyperosmolality stimulates the sensation of thirst to promote water intake, and the release of arginine vasopressin (AVP), also known as antidiuretic hormone, to increase water reabsorption by the renal tubules. It is known that cell shrinkage is required for thirst and AVP release because these responses are evoked by infusions of concentrated solutions that contain membrane-impermeable solutes, which extract water from cells, but not by infusions of solutes that readily equilibrate across the cell membrane (e.g., urea). Osmoreceptors are neurons that can detect changes in extracellular osmolality. The osmotic set point is determined by the resting electrical activity of these cells, and osmotic perturbations result in signals

to downstream neurons by proportional changes in the action-potential firing rate (or firing pattern) (1). Both cerebral and peripheral osmoreceptors contribute to the body fluid balance. Peripheral osmoreceptors have been identified along the oropharynx and the intestinal lumen and in the blood vessels that collect solutes absorbed from the intestines (splanchnic mesentery and hepatic portal vein). Osmoreceptors in these areas can detect the osmotic strength of what is eaten or drunk and, through afferent connections to the central nervous system, can induce anticipatory responses that buffer the effect of ingestion-related osmotic perturbations. Water intake satisfies thirst and decreases vasopressin release before extracellular hyperosmolality is fully corrected, whereas salt ingestion stimulates arginine vasopressin (AVP) release and thirst before plasma osmolality increases. Hypertonic saline infusions directly into the hepatic portal vein can provoke anticipatory osmoregulatory responses in the absence of significant changes in extracellular fluid osmolality (1). Information collected by peripheral osmoreceptors reach the central nervous system through fibers that ascend in the vagus nerve and form synapses in the nucleus tractus solitarius and through peripheral projections of dorsal root ganglion neurons that provide input to the thoracic spinal cord, where first-order synapses are made onto ascending relay neurons in the superficial layers of the dorsal horn (1). Cerebral osmoreceptors are located in circumventricular organs, a brain region that lacks a blood­ brain barrier. The organum vasculosum laminae terminalis (OVLT) located in the anterior region of the third ventricle is a key osmosensing site; functional magnetic resonance imaging studies have shown that the anterior region of the third ventricle becomes activated during the onset of hypertonicity in humans. Osmoreceptor neurons display an intrinsic ability to transduce osmotic perturbations into changes in the rate or pattern of action-potential discharge. Neurons in the OVLT, the subfornic organ, and magnocellular neurosecretory cells in the supraoptic nucleus, can operate as intrinsic osmoreceptors. Most of these cells are proportionally excited by hypertonic stimuli and inhibited by hypo-osmotic stimuli. Thus, the basal electrical activity of these cells effectively encodes the osmotic set point. Unlike many cells in the body, which resist changes in volume through various regulatory mechanisms, magnocellular neuronal cells behave as osmometers, displaying reversible changes in

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volume that are inversely proportional to extracellular fluid osmolality. Osmoreceptor neurons become depolarized when they are exposed to hypertonic conditions, and hypotonic stimuli cause hyperpolarization because of the suppression of a nonselective cation current (1,2). It is thought that a single population of cation channels may mediate osmosensory transduction through modulation of their probability of opening during changes in fluid osmolality. The increase in membrane conductance provoked by a hypertonic stimulus is linked to a cell volume decrease. It is possible that changes in physical strain caused by cell shrinkage could regulate a mechanosensitive channel. Alternatively, the increased concentration of cell solute caused by loss of water from cells could play a role in osmosensory transduction. Experiments in which cell volume was decreased by pipette suction or inflated by increased pipette pressure while maintaining a constant concentration of solute suggested that changes in cell volume are the controlling variable (2). By increasing membrane stretch, hypotonic cell swelling seems to suppress stretch-inhibited channel activity, which reduces cation conductance, hyperpolarizing the cell. Conversely, hypertonic cell shrinkage relaxes membrane stretch, thereby increasing channel activity and membrane cation conductance, depolarizing the cell. Transient receptor potential vanilloid (TRPV) channels may play a role in osmoregulation, affecting osmosensation and the generation of thirst; channels encoded by trpv2 and trpv4 genes are expressed in osmoreceptor neurons, and trpv4 knockout mice drink less water and become hypernatremic and fail to increase AVP secretion normally when injected with hypertonic saline. Osmoreceptor neurons in the supraoptic nucleus also express a variant of TRPV1, in which a portion of the N-terminal domain is truncated. Products of the trpv1 gene may contribute to the intrinsic osmosensitivity of these neurons. Although hypertonicity shrinks osmoreceptor cell volume, in trpv1 / knockout mice, this stimulus no longer increases membrane conductance, membrane depolarization, or firing frequency (Figure 3). Hypertonicityevoked thirst and AVP release are significantly attenuated in trpv1 / mice, and trpv1 / animals maintain a plasma osmolality comparable to that found in rats subjected to 24 h of dehydration. Information derived from peripheral and cerebral osmoreceptors is transmitted to many parts of the brain, where these signals are integrated with sensory

Figure 3. Osmosensory signal transduction. The positions of the OVLT and supraoptic nucleus (SON) relative to other hypothalamic structures in the rodent brain are shown. Hypertonicity depolarizes osmoreceptor neurons in the OVLT of wild-type (WT) animals, increasing their rate of action potential discharge (upper traces in the bottom left inset). These neurons send axonal projections to the SON, where they release the excitatory transmitter glutamate and excite neurons that release vasopressin (VP). OVLT neurons also project to cortical areas such as the insula (Ins) and the anterior cingulate gyrus (AC), which are believed to be involved in the perception of thirst. The depolarization and excitation of VP-releasing neurons in the SON induced by hyperosmolality (upper traces in the top right inset) are caused by the combined action of stretch-inhibited (SI) channels and ionotropic glutamate receptors expressed in these cells. OVLT and SON neurons from TRPV1 gene knockout mice (Trpv1 / ) fail to exhibit the normal responses to hypertonic stimuli (lower sets of traces in the insets). Reprinted by permission from Macmillan Publishers Ltd: Kidney Int 73:811­5, 2008 (ref. 2).

inputs provided by changes in blood volume, BP, extracellular sodium concentration, and body temperature (3). Little is known about the mechanisms by which osmotic and nonosmotic signals are integrated; however, previous work showed that at least six areas of the central nervous system participate in this process. AVP is synthesized by a subset of magnocellular neuronal cells (MNCs) located in the paraventricular and supraoptic nuclei of the hypothalamus. These neurons project axons into the neurohypophysis, where the hormone is released when action potentials stimulate voltage-gated Ca2 influx and exocytosis. The firing rate of MNCs under resting conditions medi-

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ates basal AVP secretion; decreased firing frequency in hypotonicity response inhibits hormone release, and increased frequency in response to hypertonicity enhances it. Taurine release from glia contributes to the osmotic control of firing rate in MNCs, and these neurons also receive synaptic afferents from the nucleus tractus solitarius and from peripheral osmoreceptors and from neurons in the OVLT. Newly synthesized AVP prohormone is packaged into secretory granules and then transported down the supraopticohypophyseal tract to the posterior pituitary (4). During its passage, the prohormone is enzymatically cleaved into AVP, neurophysin, and a C-terminal glycopeptide. Once released, circulating AVP binds to vasopressin V2 receptors on the basolateral membrane of the renal collecting duct, activating a cAMP-mediated signal transduction pathway that results in the insertion of aquaporin 2 (AQP2) water channels in the luminal membrane. AQP2 channels increase the water permeability of the collecting duct, permitting luminal fluid to come into osmotic equilibrium with the surrounding hypertonic renal medulla.

(age 23.7 2.8) men by infusing of hypertonic saline and using positron emission tomography to measure regional cerebral blood flow during the development and then the satiation of thirst. Older and younger men had similar increases in blood osmolality and experienced nearly identical thirst levels as measured on an analogue scale during and after hypertonic saline. The two age groups also exhibited similar patterns of regional blood flow on positron emission tomography scanning; however, when given free access to water, older men drank much less than younger men. Thus, aging did not affect the perception of thirst but rather the satiation of thirst; it remains unknown whether diminished responses to dehydration in older people reflects an effect of age on afferent inputs from the pharynx and intestine or in the central processing of thirst and the satiation process.

Renal Concentrating Mechanism

The glomerular filtrate that enters the proximal tubule has essentially the same osmolality as plasma. Water and solute are absorbed isotonically along the proximal tubule. Water flows out of the S2 segment of the proximal tubule though the proximal tubular cells, a process that is dependent on the presence of AQP1 water channels on the cells' luminal membranes. As the fluid enters the descending limb of the loop of Henle, it is exposed to a higher osmolality in the surrounding interstitial fluid that has been generated by transport in the thick ascending limb of the loop of Henle. AQP1 also provides the route for water flow out of the descending limb and the outer medullary descending vasa recta. Deletion of AQP1 in mice and mutations in AQP1 in humans result in impaired ability to concentrate the urine by interfering with the countercurrent multiplication and exchange that are required for the medullary concentration gradient (5). The ascending thick limb exports sodium chloride from its lumen through an apical membrane Na-K-2Cl co-transporter; however, lacking water channels, this segment is relatively impermeable to water, so salt is reabsorbed without water, diluting the luminal contents and increasing the salt concentration of the surrounding interstitium (6). Fluid that enters the distal tubule becomes isotonic from continued salt and water reaborption as it enters the collecting duct. The luminal membrane of collecting duct principal cells becomes permeable to water in the presence of AVP, which inserts AQP2 water channels in the membrane,

Age-Related Hypodipsia

Aging alters thirst and drinking responses, making older people vulnerable to body fluid imbalance (3). Systemic infusion of hypertonic solutions decrease thirst responses in older men in some but not all studies. Head-out-of-water immersion (which drives water into the intrathoracic cavity, mimicking volume expansion) decreases thirst in young but not in older individuals. Reduced responses to hypovolemia could be explained by changes in baroreceptor function or by higher-order processing of signals generated by changes in blood volume. Regardless of how much thirst they record, older people tend to drink less than their younger counterparts when dehydrated. This aged-related decrease in drinking has been reported after hypertonic infusions and fluid restriction, acutely after exercise, and in response to exercise­ heat acclimation (3). After dehydration, young people drink rapidly until their thirst is satisfied. Thirst satiation occurs before water has been absorbed from the gastrointestinal tract and before the plasma osmolality has fallen; it is controlled by afferent signals from the mouth, pharynx, esophagus, and stomach. Farrell et al. (3) investigated the generation of thirst in 12 older (age 68.1 3.4) and 10 younger

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but it is relatively impermeable to urea. Water exits the cells through AQP3 and AQP4, which are expressed on the basolateral (blood side) membrane of the cortical and outer medullary collecting duct, and AQP4, which is expressed in the inner medullary collecting duct (5). Deletion of AQP3 results in marked polyuria in mice, but, to date, there have been no reports of AQP3 mutations causing polyuria in humans. AQP4 null mice have only a mild concentrating defect, suggesting that most of the water is reabsorbed in the cortical and outer medullary segments of the collecting duct. As the luminal fluid descends in the collecting duct, it becomes more concentrated as water diffuses out, attracted by the high salt concentration of the surrounding interstitium, and the luminal urea concentration rises. The medullary collecting duct is permeable to both water and urea in the presence of AVP, owing to vasopressin-responsive AQP2 water channels and vasopressin-responsive urea channels in its luminal membrane. Urea diffuses out of the medullary collecting duct into the interstitium down its concentration gradient, and the accumulating interstitial urea raises the interstitial osmolality that, in turn, attracts water from the descending limb of the loop of Henle, a segment that is highly permeable to water and relatively impermeable to salt and urea. Because the medullary collecting duct is highly permeable to both water and urea, the final urine has a concentration that is similar to that of the fluid at the bend of the loop of Henle and the deep medullary interstitial tissue, at maximum, approximately 1200 mOsm/kg (6). References

1. Bourque CW: Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci 9: 519 ­531, 2008 2. Sharif-Naeini R, Ciura S, Zhang Z, Bourque CW: Contribution of TRPV channels to osmosensory transduction, thirst, and vasopressin release. Kidney Int 73: 811­ 815, 2008 3. Farrell MJ, Zamarripa F, Shade R, Phillips PA, McKinley M, Fox PT, Blair-West J, Denton DA, Egan GF: Effect of aging on regional cerebral blood flow responses associated with osmotic thirst and its satiation by water drinking: A PET study. Proc Natl Acad Sci U S A 105: 382­387, 2008 4. Loh JA, Verbalis JG: Disorders of water and salt metabolism associated with pituitary disease. Endocrinol Metab Clin North Am 37: 213­234, x, 2008 5. Verkman AS: Dissecting the roles of aquaporins in renal pathophysiology using transgenic mice. Semin Nephrol 28: 217­226, 2008 6. Linshaw MA: Back to basics: Congenital nephrogenic diabetes insipidus. Pediatr Rev 28: 372­380, 2007

absolute or relative free water deficit. In hypovolemic hypernatremia, total body water content is reduced. If there has been a net loss of water with no change in electrolyte balance, then the patient may not exhibit signs of volume depletion unless the deficit is large. If electrolytes have been lost in addition to water, then the patient will have hypotension and azotemia. In hypervolemic hypernatremia, there is a relative free water deficit (i.e., total body water content is either normal or reduced, but the ratio of body electrolyte content [exchangeable sodium plus potassium] is increased because of positive balance of these cations). The relationship among the plasma sodium concentration (PNa), body water, and body electrolyte content was first described empirically by Edelman. Simplistically, that relationship has been reduced to a conceptual equation: PNa Exchangeable (Na K ) Body Water

Hypernatremia

Hypernatremia, a common electrolyte disturbance in hospitalized patients, is characterized by an

The actual equation derived from empirical isotopic measurements has an intercept of 24.30 and a slope of 1.03, and mechanistic explanations have been offered to explain why these values differ from 0 (1). In addition, the relationship is distorted by hyperglycemia. Thus, a rigorous prediction of how the plasma sodium concentration will change during hypernatremia development and during efforts to repair the disturbance requires an equation that incorporates the slope; the intercept; the blood glucose; and changes in water, sodium, and potassium balance (1). In a 2-yr study of all patients who were admitted to a single center in Greece, hypernatremia was identified at admission in 0.5% of patients, and 0.7% developed hypernatremia in the hospital (2). A total of 113 patients with hypernatremia were analyzed. The ages of patients with admission hypernatremia (76.3 12.2) and hospital-acquired hypernatremia (73.9 14.4) were similar. Patients with hypernatremia on admission had a significantly lower mortality rate than those with hospital-acquired hypernatremia (28 versus 48%) despite having higher serum sodium concentrations (160 10 versus 154 2 mmol/L). In all fatal cases, hypernatremia occurred in the setting of serious underlying disease, mainly sepsis or stroke, and 85% of the patients who died had normonatremia at time of death. Thus, it seemed that hypernatremia was a marker for severe underlyling disease rather than a cause of death.

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Defined by a fractional excretion of sodium 0.5% and a blood urea nitrogen/creatinine 40, a large majority (82%) of patients with hypernatremia on admission were classified as having hypovolemic hypernatremia. The most common causes of excessive water loss for this group were fever (84%), mostly resulting from pulmonary infections, uncontrolled diabetes (40%), high environmental temperature (36%), osmotic diarrhea because of lactulose (8%), and furosemide (4%). In almost all cases, water intake was obviously diminished because of altered mental status. Only 45% of patients who developed hypernatremia in the hospital were classified as having hypovolemia, and 5% had marked edema associated with heart failure, cirrhosis, or attempts at volume resuscitation for shock. Sources of water loss in the hospitalized patients were also dominated by fever, primarily because of pulmonary infections (72%), uncontrolled diabetes (30%), osmotic diarrhea from lactulose (10%), and furosemide (9%); in addition, 10% of patients had been treated with mannitol. A study of all patients who were admitted to the medical, surgical, or neurologic intensive care units (ICU) of a university hospital in the Netherlands identified 130 patients who developed hypernatremia in the ICU (serum sodium 156 6 mmol/L) (3). Sepsis, hypokalemia, renal dysfunction, hypoalbuminemia, and the use of mannitol and bicarbonate were more common in patients with hypernatremia compared with those with normonatremia. During hypernatremia, fluid balance was negative in approximately 60% of cases, but in a substantial minority, it was positive. Patients with positive fluid balance received more sodium and potassium but a similar amount of electrolyte-free water, and they tended to have polyuria despite hypernatremia. No patients had been given hypertonic saline. Urinary sodium and potassium losses were not measured, so a quantitative analysis of the changes in fluid and electrolyte balance causing hypernatremia could not be made; however, the authors argued that many patients developed hypernatremic in the ICU by "too much sodium and not enough water" (i.e., large volumes of isotonic fluid coupled with unreplaced water losses caused by hyperglycemia, renal concentrating defects because of hypercalcemia or hypokalemia, renal dysfunction, furosemide, or mannitol). Another factor, which was not mentioned or measured by the investigators, is increased urea excretion caused by catabolism and/or

protein feeding. For fluid overloaded patients with hypernatremia, the proper therapy is water administration (or its parenteral equivalent, 5% dextrose in water) in conjunction with furosemide to achieve negative sodium balance with neutral or negative fluid balance (1,3). The mortality rate among ICU patients with hypernatremia was 48% (five times higher than patients with normonatremia), and they were generally sicker with higher APACHE II and lower Glasgow Coma Scale scores (3). A multivariate analysis identified hypernatremia as an independent risk factor for death (odds ratio 4.3; 95% confidence interval 2.5 to 7.2) as were age and renal dysfunction. Just more than half of the patients with fatal cases had hypernatremia when they died; these patients had a more acute increase in serum sodium concentration compared with other cases (14 versus 6 mmol/L per d; P 0.002) and reached a higher serum sodium level (160 8 versus 155 4 mmol/L). Correction rates did not differ between patients who lived and those who died (3).

Therapeutic Hypernatremia

Hypertonic saline solutions have emerged as a preferable alternative to mannitol to treat increased intracranial pressure (4). Koenig et al. (5) reported a 4-yr single-center study of 63 patients who had normonatremia and were treated for transtentorial herniation (caused by a variety of neurosurgical conditions) with hypertonic saline. Extending a preliminary report, the investigators administered 23.4% saline as a bolus of 30 ml (85.5% of cases) or 60 ml (14.5% of cases). Prompt reversal of clinical signs of herniation (unilaterally or bilaterally dilated, nonreactive pupils associated with a decline in the Glasgow Coma Scale score) was observed in 57 (75%) of 76 events. Among patients with intracranial pressure (ICP) monitors, ICP decreased from 23.3 16.2 to 13.8 10.3 mmHg (P 0.001) within 1 h. Patients with successful reversal of herniation had a higher serum sodium at 1 h (149.8 9.3 mmol/L). Univariate predictors of successful reversal of herniation included an increase in serum sodium of 5 mmol/L and an absolute serum sodium 145 mmol/L. Twenty-two (32.4%) patients survived to discharge, five of whom (8% of the total treated cohort) had minimal to mild disability. The 30-ml bolus of 23.4% saline used in this study is equivalent in sodium content to 240 ml of 3% saline.

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Thus, the treatment is similar to what has been advised for patients with acute hyponatremic emergencies. Larger doses of 23.5% saline were reported in a study of patients who had subarachnoid hemorrhage and were assigned poor clinical grades because of cerebral ischemia caused by vasospasm (6). Infusion of 2 ml/kg over 20 to 30 min, increasing the serum sodium by 11.2 4.0 mmol/L at 1 h, significantly increased cerebral perfusion pressure and decreased ICP by 93%, including six patients whose ICP went lower than 0 after the infusion, suggesting shrinkage of the intracranial contents. It should be noted that 23.4% saline can cause severe extravasation injury and should be administered only in a central vein; its advantage over 3 or 5% solution has not been demonstrated. Aggressive use of hypertonic saline has also been reported in patients with normonatremia and subarachnoid hemorrhage to decrease elevated ICP before signs of transtentorial herniation. In a placebocontrolled study, infusion of 2 ml/kg 7.2% saline in 6% hydroxyethyl starch over 30 min into a central venous catheter was compared with an equal-volume infusion of isotonic saline. Among patients who were given hypertonic saline, the maximum increase in serum sodium averaged 5.6 mmol/L (range 4 to 7 mmol/L) at 30 min and 3.3 mmol/L (range 1 to 5 mmol/L) after 210 min; the serum sodium concentration did not change in patients who were given isotonic saline. In response to hypertonic saline, intracranial pressure decreased significantly, within 1 h of the start of the infusion, by a mean maximum of 5.6 mmHg and increased cerebral perfusion pressure, whereas no change occurred after isotonic saline. As would be expected, the ICP change was less than a previous uncontrolled study by this group, using the same regimen in sicker patients with ICP 20 mmHg. On the basis of these findings and a review of other published observations, the authors now recommend that the initial bolus be 2 ml/kg of the 7% solution. References

1. Nguyen MK, Kurtz I: Correction of hypervolaemic hypernatraemia by inducing negative Na and K balance in excess of negative water balance: A new quantitative approach. Nephrol Dial Transplant 23: 2223­2227, 2008 2. Liamis G, Tsimihodimos V, Doumas M, Spyrou A, Bairaktari E, Elisaf M: Clinical and laboratory characteristics of hypernatraemia in an internal medicine clinic. Nephrol Dial Transplant 23: 136 ­143, 2008 3. Hoorn EJ, Betjes MG, Weigel J, Zietse R: Hypernatraemia in critically

ill patients: Too little water and too much salt. Nephrol Dial Transplant 23: 1562­1568, 2008 4. Himmelseher S: Hypertonic saline solutions for treatment of intracranial hypertension. Curr Opin Anaesthesiol 20: 414 ­ 426, 2007 5. Koenig MA, Bryan M, Lewin JL 3rd, Mirski MA, Geocadin RG, Stevens RD: Reversal of transtentorial herniation with hypertonic saline. Neurology 70: 1023­1029, 2008 6. Tseng MY, Al-Rawi PG, Czosnyka M, Hutchinson PJ, Richards H, Pickard JD, Kirkpatrick PJ: Enhancement of cerebral blood flow using systemic hypertonic saline therapy improves outcome in patients with poor-grade spontaneous subarachnoid hemorrhage. J Neurosurg 107: 274 ­282, 2007

Diabetes Insipidus

Diabetes insipidus (DI) is caused by deficient arginine vasopressin (AVP) secretion (central DI), physiologic inhibition of AVP secretion because of primary water intake (dipsogenic DI), or diminished renal response to the hormone (nephrogenic DI). All polyuric disorders, regardless of whether they are neurogenic, nephrogenic, or psychogenic, are associated with dilation of the renal collecting system and bladder. Chronic renal failure resulting from bilateral hydronephrosis has been reported. Renal and bladder ultrasounds are advisable annually. Scheduled voiding and double voiding can prevent complications (1).

Central DI

Central DI is caused by a variety of acquired or congenital disorders that affect the hypothalamic-posterior pituitary axis, including tumors, trauma, hemorrhage and infarction, granulomatous disease, and pituitary surgery (2,3). Because the synthesis of AVP occurs in the supraoptic and paraventricular nuclei of the hypothalamus, pituitary tumors themselves do not usually cause DI; however, postoperative polyuria occurs in 18 to 31% of patients after transphenoidal surgery. The course of postoperative DI is usually transient but can be permanent or triphasic, as was described in experimental studies of transaction of the pituitary stalk. Permanent DI occurs in only 2 to 10% of patients because 80 to 90% of vasopressin-secreting neurons must be destroyed for this to occur. Transient DI and the first phase of triphasic DI is caused by dysfunction of vasopressin-secreting neurons caused by direct trauma or ischemia. The triphasic pattern is quite rare, occurring in only 3.4% of patients, but it is also quite interesting (2). The first phase of DI, lasting for 5 to 7 d, is followed by syndrome of inappropriate antidiuresis (SIAD) resulting from uncontrolled AVP leakage from degenerating posterior pituitary tissue or from vasopressin-secreting neurons whose axons have

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been severed. Typically, continued administration of hypotonic fluid, started in the first phase to avoid dehydration, results in hyponatremia when an antidiuresis appears in the second phase, which lasts 2 to 14 d. Some patients with more limited damage present with an isolated second phase (i.e., SIAD without previous DI). Once AVP stores are depleted, the third phase of chronic DI begins. Magnetic resonance imaging can facilitate DI diagnosis. The presence of vasopressin and oxytocin is normally revealed by a bright spot in the posterior pituitary on T1-weighted images; the absence of a bright spot can help confirm a diagnosis of postoperative DI. However, the bright spot may not disappear early in the course of the disease, so its presence does not exclude the diagnosis. Desmopressin is the drug of choice for the acute and chronic DI management. The drug promptly reduces urine output, and its effect generally lasts 6 to 12 h. Urine output must be carefully monitored in the early postoperative course, and output of 200 to 250 ml/h with a urine osmolality 200 mOsm/kg or urine specific gravity 1.005 is an indication for a dose of desmopressin (2). Some authors advocated administration of desmopressin on an as-needed basis rather than a fixed schedule (2). In addition to avoiding hyponatremia, this strategy allows detection of decreasing urine output, if SIAD should develop. An alternative strategy is to give a fixed dose of desmopressin frequently and treat the patient as though he or she has SIAD, avoiding hypotonic fluids and giving hypertonic fluids when necessary, or to give continuous infusions of dilute AVP in a dosage of 0.25 to 2.70 mU/kg per h (2). AVP has a half-life of 10 to 20 min, so the continuous infusion approach permits a rapid resolution of antidiuresis if the serum sodium falls too low. Regardless of the strategy chosen and regardless of whether SIAD occurs, a large series of patients with postoperative DI after transphenoidal surgery found that 8.4% of patients developed hyponatremia and 2.1% had symptomatic hyponatremia. Thus, careful monitoring of the serum sodium concentration is mandatory. Central DI is the most common manifestation of neuroendocrine sarcoidosis (4,5); however, the central nervous system is involved in only 5% of patients with sarcoid, making this an uncommon disorder. A longterm study of nine patients with known sarcoidosis and hypothalamic involvement by magnetic resonance imaging found that all patients had anterior pituitary

dysfunction, especially hypogonadism, which was universally present, and diabetes insipidus developed in seven (4). Although brain parenchymal lesions improved in response to steroids, the hormone deficiencies were irreversible, suggesting permanent destruction of the pituitary or hypothalamic cells by granulomas.

Adipsic DI

When vasopressin secretion and thirst both are impaired, affected patients are vulnerable to recurrent episodes of hypernatremia. Once called "essential hypernatremia," the disorder is now called "central DI with deficient thirst" or "adipsic DI." A recent review of the literature identified a total of 70 patients with central DI and deficient thirst in 41 studies (6). Reported causes include congenital/developmental conditions (predominantly septo-optic dysplasia; 20%), germinoma (17%), rupture or clipping of anterior communicating artery aneurysms (14%), craniopharyngioma (13%), pinealoma (4%), Langerhans cell histiocytosis (4%), neurosarcoidosis (3%), head trauma (3%), cytomegalovirus encephalitis (3%), nonfunctioning pituitary adenoma (3%), macroprolactinoma (1%), and toluene exposure (1%). Small perforating arterial branches from the anterior communicating artery supply the hypothalamic osmoreceptors that mediate thirst and vasopressin release, explaining why patients with aneurysms that involve this artery sometimes develop adipsic DI (6,7). Most patients with adipsic DI caused by anterior communicating artery aneurysms retain the ability to secrete vasopressin and concentrate their urine in response to a decrease in arterial BP (100% of the five patients who have been studied); this response is mediated by baroreceptors in the aortic arch, carotid arteries, and atria. Patients with adipsic DI from craniopharyngioma (0% of four patients studied) are less likely to retain baroceptor-mediated vasopressin secretion. All patients reported in the literature had features of central DI; they were unable to concentrate their urine when dehydrated or after hypertonic saline but were able to concentrate the urine in response to exogenous vasopressin or desmopressin (6,7). Thirst was absent despite an intact sensorium and free access to water. The diagnosis of adipsic DI can be confirmed in a dehydrated patient or during hypertonic saline infusion by measuring plasma vasopressin by radio-

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immunoassay and by quantifying thirst using an analog scale; however, these tests are seldom required in routine clinical practice. Patients who have central DI and whose thirst is intact maintain normal serum sodium levels despite extremely large urine outputs, provided that they have free access to water and are physically able to drink. By contrast, patients with adipsic DI are prey to life-threatening dehydration, renal failure, and seizures. Severe hypernatremia is common, with serum sodium levels ranging from 148 to 221 mEq/L. Seventeen (24%) patients in the literature experienced seizures (most because of hyponatremia), and 44 (63%) patients had been admitted at least once with hypernatremia or hyponatremia. Acute renal failure (3%) and rhabdomyolysis (4%) are serious but less commonly reported complications (6,7). Anterior pituitary dysfunction was documented in 46 (72%) of 64 patients, including panhypopituitarism in 28 (44%) patients and partial defects in anterior pituitary hormone secretion in 18 (28%) patients. Patients with adipsic DI associated with anterior communicating aneurysms were significantly less likely than patients with craniopharyngioma, germinoma, or congenital/developmental conditions to have panhypopituitarism (6,7). Other hypothalamic abnormalities were identified in 23 (33%) patients, including disturbances of appetite (16 patients) and temperature regulation (10 patients). In addition, 56 patients (80% of the entire cohort) had neurologic abnormalities related to their underlying condition (vision loss, hemiplegia, short-term memory deficits, or cognitive dysfunction). A carefully documented single-center series of 13 patients with adipsic DI (cited in the previously mentioned literature review) found a high mortality rate at a young age (7). A review of death certificates suggested that the cause of death was respiratory failure resulting from sleep apnea. Symptomatic obstructive sleep apnea was recognized among more than half of the patients. In addition, a high percentage of patients experienced thromboembolic events, serious obesity, and seizure disorders. Two patients were admitted with symptomatic hyponatremia, one case after a binge on cider, with continued vasopressin. All of the patients in this series had polyuria ( 4 L/d), and, indeed, this feature was one of the criteria used to define the disorder; however, some patients exhibit more subtle abnormalities of osmoregulation, most commonly an upward resetting of the osmotic

thresholds for vasopressin secretion and thirst (6 ­ 8). Such patients are protected from extreme hypernatremia by their ability to experience thirst and elaborate a concentrated urine at higher plasma osmolalities than normal. Because patients with an upwardly reset osmostat may not have oliguria when they have hypernatremia, their underlying DI may not be recognized. In this series, patients with adipsic DI caused by anterior communicating artery aneurysms had brisk AVP responses to hypotension, indicating intact supraoptic and paraventricular nuclei and normal-functioning posterior pituitary glands. This finding suggests a lesion in the osmoreceptors in the anterior hypothalamus. Patients with adipsic DI associated with tumors had undergone extensive surgery that had created lesions in the neurohypophesis as well as the osmoreceptors. Treatment of patients with adipsic DI includes desmopressin for patients with polyuria at high normal serum sodium concentrations; regimens of scheduled fluid drinking should be recommended to all patients. In one report, a behavior modification approach was used successfully to ensure adequate fluid intake in a patient with severe amnesia. Fluid intake must be adjusted by monitoring of body weight and serum sodium levels while taking into account variations in ambient temperature. Because of the high incidence of thrombosis (most likely a complication of plasma volume contraction and hyperviscosity), routine use of prophylactic heparin is advisable during periods of dehydration. Holley et al. (9) reported a 44-yr-old man with extreme hypernatremia (208 mmol/L) as a result of adipsic DI, caused by a gunshot wound to the head at age 18. Computed tomography revealed a residual projectile fragment near the third ventricle. Presumably, the severe hypernatremia was related to working in the heat (an ambient temperature of 42°C was recorded on the day of his admission). A 19-L water deficit was replaced over 4 d, gradually decreasing the serum sodium concentration. At a serum sodium of 147 mmol/L, his urine osmolality was 743 mOsm/kg, consistent with hypodipsia and partial central DI--an upwardly reset (hypertonic) osmostat. The patient made a full neurologic recovery.

Acquired Nephrogenic DI

Lithium. One of every 1000 people in the United States is treated with lithium, and approximately one

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fourth of them develop polyuria (10). Undoubted, lithium is the most important cause of nephrogenic DI. Lithium inhibits vasopressin-stimulated translocation of cytoplasmic aquaporin 2 (AQP2) to the luminal membrane of the collecting duct by inactivating adenyl-cylase and inhibiting protein kinase A­induced phosphorylation of cytoplasmic AQP2 (10). Polyuria because of lithium is associated with downregulation of AQP2 and AQP3 gene expression and decreased trafficking of the vasopressin-regulated water channel AQP2 to the apical membrane of the collecting duct. Patients with lithium-induced nephrogenic DI excrete less cAMP and less AQP2 in their urine (11). There is also evidence that lithium downregulates expression of the urea transport proteins, which could contribute to decreased concentrating ability by diminishing the concentration gradient in the renal medulla. In addition to its effects on water and urea channels, longterm use of lithium causes major changes in the cellular composition of the collecting duct, reducing the percentage of principal cells, which are the sites for regulated water reabsorption. Proteins that are involved in cell death, apoptosis, cell proliferation, and morphology are altered after 1 to 2 wk of lithium treatment, suggesting that these proteins may play a role in the remodeling of the collecting duct associated with lithium treatment (12). It has been known for nearly 50 yr that thiazide diuretics paradoxically decrease urine output in lithium-induced and congenital nephrogenic DI. In rats with lithium-induced nephrogenic DI, hydrochlorothiazide upregulates AQP2 and the Na-K-2Cl transporter in the ascending limb (which is responsible for creating the medullary concentration gradient). Nonsteroidal anti-inflammatory drugs, which are also known to decrease polyuria clinically, also increase the abundance of AQP2 and Na-K-2Cl transporter in lithiumtreated rats (13). Recently, mineralocorticoids have been shown to affect experimental nephrogenic DI as a result of lithium. Aldosterone administration dramatically increases urine production (an effect that is associated with decreased expression of AQP2 on luminal membranes of the collecting duct), whereas administration of the mineralocorticoid receptor blocker spironolactone decreased urine output and increased AQP2 expression (14). Aldosterone and spironolactone have similar effects on the subcellular distribution of AQP2 in vasopressin-deficient polyuric Brattleboro rats, suggesting that the mineralocorticoid

effect is related to the absence of vasopressin signaling rather than to lithium per se. To date, these observations have been limited to lithium-treated experimental animals; it is not yet known whether spironolactone would be a useful treatment for humans with lithiuminduced nephrogenic DI. The epithelial sodium channel (ENaC) is the entrance pathway for lithium into collecting duct principal cells. ENaC shows high selectivity for both sodium and lithium ions, and the channel is upregulated by aldosterone and is inhibited by spironolactone. Amiloride is known to inhibit lithium uptake by the collecting duct and has been used clinically to treat nephrogenic DI caused by lithium. A study of 45 patients who were on long-term lithium and 42 control subjects with a mood disorder but no lithium treatment showed impaired urine-concentrating ability and reduced urinary AQP2 and cAMP excretion correlated with the duration of lithium therapy. Eleven of the patients were enrolled in a randomized, placebo-controlled trial to investigate the action of amiloride (10 mg/d for 6 wk) on desmopressin-stimulated urineconcentrating ability and AQP2 excretion. After 6 wk of amiloride therapy but not after placebo, urine osmolality after desmopressin increased by 64.5 8.0% (P 0.05) in association with increased urinary AQP2 excretion (10). Hypercalcemia and Hypercalciuria. Calcium receptors (CaR) expressed on the basolateral membrane of the thick ascending limb and the luminal membrane of collecting duct can affect the ability to concentrate the urine, and hypercalcemia causes polyuria. CaR activation by hypercalcemia inhibits the Na-K-2Cl transporter on the ascending limb, reducing the medullary concentration gradient in a manner analogous to furosemide (15). A high luminal calcium concentration has been shown to activate the CaR, reducing coupling efficiency between the vasopressin 2 (V2) receptor and adenylate cyclase via a calmodulin-dependent mechanism in cultured cortical collecting duct cells (16). Congenital Nephrogenic DI. X-linked nephrogenic DI is primarily a disease of males, whereas female heterozygotes may have mild polyuria and polydipsia because of skewed inactivation of the X chromosome (1). X-linked DI is caused by a loss-of-function mutation of the gene that encodes the V2 receptor (AVPR2). A total of 193 disease-causing mutations of AVPR2 have been identified, 95 of which result in a

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misfolded protein that becomes trapped in the endoplasmic reticulum, unable to reach the basolateral cell membrane of the cell, where it can function as a vasopressin receptor. There is a great deal of interest in developing pharmacologic chaperones to promote escape of the misfolded protein from the endoplasmic reticulum. Vasopressin analogues can bind with misfolded receptors, causing them to refold, escaping the endoplasmic reticulum and reaching the plasma membrane, where endogenous vasopressin can subsequently displace the analogue and activate the receptor. Administration of an investigational V1a vasopressin antagonist, SR49059, which seems to act as a chaperone, slightly increased urine osmolality in five patients with nephrogenic DI (1). Other potential strategies for treating the disease include activation of the nitric oxide­ cGMP signaling pathway, which may play a role in AQP2 trafficking; sildenafil, a selective inhibitor of cGMP phosphodiesterase, increases intracellular cGMP and increases insertion of AQP2 in the apical membrane of principal cells in the outer medullary collecting duct but not the cortical collecting duct, the major site of water reabsorption (17). Nephrogenic DI, resulting from mutations of the gene encoding AQP2, was first recognized in a Dutch male patient with nephrogenic DI that did not seem to be X linked; the patient responded to desmopressin with an increase in factor VIII, von Willebrand factor, and tissue-type plasminogen and a decrease in BP. These normal V2 receptor­mediated responses suggested that extrarenal receptors were intact. Subsequently, the patient was found to harbor two point mutations in the AQP2 gene on chromosome 12, encoding the AQP2 water channel. Approximately 10% of patients with congenital nephrogenic DI have mutations of the AQP2 gene; of these, 90% have recessively inherited disease. To date, 39 mutations in AQP2 have been reported, and 32 are associated with recessive nephrogenic DI. In the recessive form of the disease, polyuria and polydipsia are present at birth, whereas in the much rarer dominant form, these features appear in the second year of life or later. Gene mutations, which have now been identified in seven families, are inherited as a recessive trait. Urine osmolality in the recessive disease never exceeds 200 mOsm/kg, whereas, in the dominant form, higher urine osmolality can be found, and some patients respond to desmopressin or dehydration with a transient increase in urine osmolality. AQP2 proteins in

dominant nephrogenic DI have mutations in the COOH terminus of the protein; they are functional water channels that are mis-sorted, failing to reach the luminal membrane of principal cells in the collecting duct, moving instead to other parts of the cell, where most of them are retained by lysosomes, stored in other vesicles, or routed to the basolateral membrane. Strategies to increase basolateral membrane AQP2 abundance by reducing their removal by endocytosis are currently under investigation; statins are potential candidates for this strategy (17). Some patients with congenital nephrogenic DI have a mild phenotype that responds to AVP. One variant of autosome recessive disease manifest by marked polyuria and polydipsia responded to desmopressin with a modest improvement in urine osmolality and a subjective improvement in polyuria and thirst. Presumably, the mutant water channel was partially functional and was better able to route to its target apical membrane in response to antidiuretic hormone (18). Nocturnal Enuresis and Nocturnal Polyuria. Nocturnal enuresis and nocturnal polyuria are related disorders that affect children and elderly patients, respectively. Neither syndrome is well understood, and they both share elements of vasopressin deficiency and impaired response to vasopressin. Both have been treated with desmopressin, and, as discussed previously, this sometimes causes hyponatremia. Nocturnal enuresis is a children's disease characterized by urine loss during the night at an age when bladder control is usually present. Normally, urine production at night is reduced by a nocturnal increase in vasopressin secretion, which may be blunted in children with enuresis. In addition, approximately 40% of children with enuresis have hypercalciuria, which may reduce the response to vasopressin by reducing the amount of AQP2 that reaches the luminal membrane in response to the hormone (15). In children who have enuresis and whose nocturnal vasopressin levels are lower than that of control children, the day-night ratio of AVP2 is approximately twice as high as in children without enuresis. When low nocturnal vasopressin levels are associated with hypercalciuria, the day-night ratio of AQP2 is nearly three-fold normal. Treatment of patients who have hypercalciuria with a low-calcium diet and desmopressin restores the day-night AQP2 ratios to normal, and with suspension of the low-calcium diet, bedwetting recurred despite

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continued therapy with desmopressin. The failure of patients to awake before, during, or after voiding is not well explained by either low levels of vasopressin or mild nephrogenic DI caused by hypercalciuria. Robben et al. (19) described two patients with primary nocturnal enuresis and co-segregating nephrogenic DI caused by mutations in the AQP2 gene and one patient with a co-segregating mutation in the AVPR2 gene. Despite the mutations and despite continuing large urine volumes at night, enuresis responded to desmopressin; on the drug, the patients aroused in response to the sensation of a full bladder and went to the bathroom. In the patient with the AVPR2 gene mutation, urinary calcium levels were low. These findings suggest that success of desmopressin in nocturnal enuresis is not dependent on the urine-concentrating mechanism, activation of the V2 receptor, or insertion of AQP2 in the luminal membrane. The authors suggested that desmopressin acts on the V1b receptor, which has a similar affinity for desmopressin as the V2R receptor and is localized in the brain. The affect of specific agonists for this receptor awaits further study. Nocturnal polyuria is a syndrome that occurs primarily in older patients and in which the day-night ratio of urine production is altered in a manner similar to that seen in children with nocturnal enuresis. Although urine output is normal, more than one third of urine output occurs at night, and, in some affected patients, urine production at night may exceed that during the day. Low nocturnal levels of AVP have been found in some but not all patients. References

1. Bichet DG: Vasopressin receptor mutations in nephrogenic diabetes insipidus. Semin Nephrol 28: 245­251, 2008 2. Loh JA, Verbalis JG: Diabetes insipidus as a complication after pituitary surgery. Nat Clin Pract Endocrinol Metab 3: 489 ­ 494, 2007 3. Loh JA, Verbalis JG: Disorders of water and salt metabolism associated with pituitary disease. Endocrinol Metab Clin North Am 37: 213­234, x, 2008 4. Bihan H, Christozova V, Dumas JL, Jomaa R, Valeyre D, Tazi A, Reach G, Krivitzky A, Cohen R: Sarcoidosis: Clinical, hormonal, and magnetic resonance imaging (MRI) manifestations of hypothalamic-

5.

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18. 19.

pituitary disease in 9 patients and review of the literature. Medicine (Baltimore) 86: 259 ­268, 2007 Miyoshi T, Otsuka F, Takeda M, Inagaki K, Otani H, Ogura T, Ichiki K, Amano T, Makino H: An elderly patient with sarcoidosis manifesting panhypopituitarism with central diabetes insipidus. Endocr J 54: 425­ 430, 2007 Mavrakis AN, Tritos NA: Diabetes insipidus with deficient thirst: Report of a patient and review of the literature. Am J Kidney Dis 51: 851­ 859, 2008 Crowley RK, Sherlock M, Agha A, Smith D, Thompson CJ: Clinical insights into adipsic diabetes insipidus: A large case series. Clin Endocrinol (Oxf) 66: 475­ 482, 2007 Hayashi T, Murata M, Saito T, Ikoma A, Tamemoto H, Kawakami M, Ishikawa SE: Pathogenesis of chronic hypernatremia with dehydrated and non-dehydrated states in hypothalamic space-occupying lesions. Endocr J 55: 651­ 655, 2008 Holley AD, Green S, Davoren P: Extreme hypernatraemia: A case report and brief review. Crit Care Resusc 9: 55­58, 2007 Bedford JJ, Weggery S, Ellis G, McDonald FJ, Joyce PR, Leader JP, Walker RJ: Lithium-induced nephrogenic diabetes insipidus: Renal effects of amiloride. Clin J Am Soc Nephrol 3: 1324 ­1331, 2008 Wilting I, Baumgarten R, Movig KL, van Laarhoven J, Apperloo AJ, Nolen WA, Heerdink ER, Knoers NV, Egberts AC: Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration. Eur J Pharmacol 566: 50 ­57, 2007 Nielsen J, Kwon TH, Christensen BM, Frokiaer J, Nielsen S: Dysregulation of renal aquaporins and epithelial sodium channel in lithium-induced nephrogenic diabetes insipidus. Semin Nephrol 28: 227­244, 2008 Kim GH, Choi NW, Jung JY, Song JH, Lee CH, Kang CM, Knepper MA: Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2. Am J Physiol Renal Physiol 294: F702­F709, 2008 Nielsen J, Kwon TH, Frokiaer J, Knepper MA, Nielsen S: Lithiuminduced NDI in rats is associated with loss of alpha-ENaC regulation by aldosterone in CCD. Am J Physiol Renal Physiol 290: F1222­ F1233, 2006 Procino G, Mastrofrancesco L, Mira A, Tamma G, Carmosino M, Emma F, Svelto M, Valenti G: Aquaporin 2 and apical calciumsensing receptor: New players in polyuric disorders associated with hypercalciuria. Semin Nephrol 28: 297­305, 2008 Bustamante M, Hasler U, Leroy V, de Seigneux S, Dimitrov M, Mordasini D, Rousselot M, Martin PY, Feraille E: Calcium-sensing receptor attenuates AVP-induced aquaporin-2 expression via a calmodulin-dependent mechanism. J Am Soc Nephrol 19: 109 ­116, 2008 Bouley R, Hasler U, Lu HA, Nunes P, Brown D: Bypassing vasopressin receptor signaling pathways in nephrogenic diabetes insipidus. Semin Nephrol 28: 266 ­278, 2008 Linshaw MA: Back to basics: Congenital nephrogenic diabetes insipidus. Pediatr Rev 28: 372­380, 2007 Robben JH, Sze M, Knoers NV, Eggert P, Deen P, Muller D: Relief of nocturnal enuresis by desmopressin is kidney and vasopressin type 2 receptor independent. J Am Soc Nephrol 18: 1534 ­1539, 2007

NephSAP

NephSAP Review Panel

Georgi Abraham, MD Sri Ramachandra Medical College and Hospital Chennai, India Pablo H. Abrego, MD, FASN Marshfield Clinic Wausau, WI Anil K. Agarwal, MD, FASN Ohio State University Columbus, OH Kamal E. Ahmed, MD, FASN Yuma Nephrology, PC Yuma, AZ Adel E. Berbari, MD American University of Beirut-Medical Center Beirut, Lebanon Bruce E. Berger, MD University Hospitals, Case Medical Center Cleveland, OH Paul Bolin, MD Brody School of Medicine at East Carolina University Greenville, NC Mauro Braun, MD Cleveland Clinic Florida Weston, FL Laurence E. Carroll, MD, FASN Hypertension & Kidney Specialists Lancaster, PA Jorge Cerda, MD, FASN Capital District Renal Physicians Albany, NY Chokchai Chareandee, MD, FASN Regions Hospital St. Paul, MN Mahmoud El-Khatib, MD, PhD, FASN University of Cincinnati Cincinnati, OH Lynda A. Frassetto, MD, FASN University of California at San Francisco San Francisco, CA Duvuru Geetha, MD Johns Hopkins University Baltimore, MD

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Volume 8, Number 2, March 2009

The Editorial Board of NephSAP extends its sincere appreciation to the following reviewers. Their efforts and insights have helped to improve the quality of this postgraduate education offering. Richard N. Hellman, MD Indiana University School of Medicine Indianapolis, IN R. Morrison Hurley, MD University of British Columbia Vancouver, BC, Canada Ekambaram Ilamathi, MD, FASN Suffolk Nephrology Consultant Stony Brook, NY Sharon L. Karp, MD Indiana University School of Medicine Indianapolis, IN Pranay Kathuria, MD, FASN University of Oklahoma College of Medicine Tulsa, OK Quresh T. Khairullah, MD, FASN St. Clair Specialty Physicians Detroit, MI Ramesh Khanna, MD University of Missouri, Columbia Columbia, MO Edgar V. Lerma, MD, FASN University of Illinois at Chicago College of Medicine Chicago, IL Philippe Madhoun, MD Chu Charleroi Pairach Pintavorn, MD, FASN East Georgia Kidney and Hypertension Augusta, GA Paul H. Pronovost, MD, FASN Yale University School of Medicine Waterbury, CT Mohammad A. Quasem, MD, FASN State University of New York Binghampton, NY Venkat Ramanathan, MD, FASN Baylor College of Medicine Houston, TX Robert Richardson, MD University of Toronto and Toronto General Hospital Toronto, ON, Canada Bijan Roshan, MD Joslin Diabetes Center Harvard Medical School Boston, MA Mohammad G. Saklayen, MD Wright State University Dayton, OH Ramesh Saxena, MD, PhD University of Texas Southwestern Medical Center Dallas, TX Gaurang M. Shah, MD Long Beach VA Healthcare System Long Beach, CA Neil E. Soifer, MD, FASN Lakeside Nephrology, LTD Chicago, IL Harold Szerlip, MD, FASN Medical College of Georgia Augusta, GA Luigi Vernaglione, MD M. Giannuzzi Hospital Manduria, Italy Antonio R. Vilches, MD, PhD Instituto Universitario Cemic Buenos Aires, Argentina

Charleroi, Belgium

Jolanta Malyszko, MD, FASN Medical University Bialystok, Poland Hanna W. Mawad, MD, FASN University of Kentucky Lexington, KY Pascal Meier, MD, FASN Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland Jacob Mooij, MD, PhD Al Hada Hospital Taif, Saudi Arabia Mamiko Ohara, MD, FASN Kameda Medical Center Chiba, Japan

NephSAP

Program Mission and Objectives

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Volume 8, Number 2, March 2009

The mission of the Nephrology Self-Assessment Program (NephSAP) is to regularly provide a vehicle that will be useful for clinical nephrologists who seek to renew and refresh their clinical knowledge and diagnostic and therapeutic skills. This Journal consists of a series of challenging, clinically oriented questions based on case vignettes, a detailed Syllabus that reviews recent publications, and an Editorial on an important and evolving topic. Taken together, these parts should assist individual clinicians undertaking a rigorous self-assessment of their strengths and weaknesses in the broad domain of nephrology.

Accreditation and Credit Designation

The American Society of Nephrology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASN designates this educational activity for a maximum of 8.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Continuing Medical Education (CME) Information

Date of Original Release: March 2009 Examination Available Online: Monday, March 9, 2009 CME Credit Eligible Through: February 28, 2010 Answers: Correct answers with explanations will be posted on the ASN website in March 2010 when the issue is archived. UpToDate Links Active: March and April 2009 Core Nephrology question links active: March, April, and May 2009. CME Credit: 8.0 AMA PRA Category 1 CreditsTM Target Audience: Nephrology Board and recertification candidates, practicing nephrologists, and internists. Method of Participation: Read the syllabus that is supplemented by original articles in the reference lists, and complete the online self-assessment examination. Examinations are available online only after the first week of the publication month. There is no fee. Each participant is allowed two attempts to pass the examination ( 75% correct). Your score and a list of question/s (by number) answered incorrectly can be printed immediately. Your CME certificate can be printed immediately after passing the examination. Answers and explanations are provided ONLY with a passing score on the first or second attempt. Your ASN transcript will be updated in 6 to 8 weeks after passing the examination. Instructions to access the Online CME Center to take the examination and complete the evaluation: Access the ASN website: www.asn-online.org Click on "CME" tab at the top of the homepage and then click on the Online CME Center icon to go to the login page. After login, click on the icon for "NephSAP" Select a topic and click on "Start Now" On the CME Information page, click on "Continue" On the MOC page, select whether or not you want MOC points. On the next page, click on "Examination Questions/Evaluation" to answer the questions. Your score and a list of question numbers answered incorrectly can be printed immediately. Follow the prompts to retake the examination if you failed, or print your certificate and the correct answers if you passed. You can retake the examination at any time. Each participant is allowed two attempts.

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Volume 8, Number 2, March 2009

Instructions to Obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points: Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:

Be certified by ABIM in internal medicine and/or nephrology and must be enrolled in the ABIM­MOC program via the ABIM website (www.abim.org). Pass the self-assessment examination within the timeframe specified in this issue of NephSAP. Designate the issue for MOC points by clicking on the MOC link on the CME certificate page after passing the examination. You will be leaving the ASN-CECity site and transferring the information directly to the ABIM in real-time. Provide your ABIM Certificate ID number and your date of birth. You will receive a confirmation message from the ABIM indicating the receipt of your information. MOC points will be applied to only those ABIM candidates who have enrolled in the program. It is your responsibility to complete the ABIM MOC enrollment process.

Instructions to access the ASN website, NephSAP, and the UpToDate link

Compatible Browser: The ASN website (asn-online.org) has been formatted for cross-browser functionality, and should display correctly in all modern web browsers. We recommend that you use Internet Explorer. Monitor Settings: The ASN website was designed to be viewed in a 1024 768 or higher resolution.

Technical Support: If you are having difficulty viewing any of the pages, please refer to the ASN technical support page for possible solutions. If you continue having problems, contact Hal Nesbitt at [email protected] UpToDate provides an additional source of information that should help you answer up to 5 selected NephSAP questions from each issue. The link is free and will remain active for the first 60 days after publication for each issue. On the ASN home page, double click on the NephSAP link (NephSAP cover) on the bottom side of the page. On the NephSAP page, click on the UpToDate button on the left hand side to access the current links.

NephSAP

Disclosure Information

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Volume 8, Number 2, March 2009

The ASN is responsible for identifying and resolving all conflicts of interest prior to presenting any educational activity to learners to ensure that ASN CME activities promote quality and safety, are effective in improving medical practice, are based on valid contents, and are independent of the control from commercial interests and free of commercial bias. All faculty are instructed to provide balanced, scientifically rigorous and evidence-based presentations. In accordance with the disclosure policies of the Accreditation Council for Continuing Medical Education (ACCME) as well as guidelines of the Food and Drug Administration (FDA), individuals who are in a position to control the content of an educational activity are required to disclose relationships with a commercial interest if (a) the relation is financial and occurred within the past 12 months; and (b) the individual had the opportunity to affect the content of continuing medical education with regard to that commercial interest. For this purpose, ASN consider the relationships of the person involved in the CME activity to include financial relationships of a spouse or partner. Peer reviewers are asked to abstain from reviewing topics if they have a conflict of interest. Disclosure information is made available to learners prior to the start of any ASN educational activity. Agarwal, Rajiv--Grants/research support: Abbott; Consultant/Scientific advisor: Rockwell Medical, Watson Pharma; Honoraria: Abbott, Astra-Zeneca, Merck Berns, Jeffrey S.--Consultant: Baxter, Affymax; Advisory Board: Amgen, Litholink Cohen, David J.--Grants/research support: Novartis, Roche; Honoraria: Roche Fishbane, Steven--none Fuchs, Elissa (Medical Editor)--none Glassock, Richard J.--Consultant: Aspreva, FibroGen, Novartis, Genentech, Keryx, Quest Diagnostics/Nichols Institute, Science Partners; Honoraria: Visiting professorships at various medical schools; Ownership Interests: LaJolla Pharmaceutical; Paid Expert Testimony: Various legal firms regarding product reliability; Royalties: Lippincott Williams and Wilkins, Textbook of Nephrology; Scientific Advisor or Membership: American Renal Associates, Aspreva, Los Angeles Biomedical Institute, University Kidney Research Associates Goldfarb, Stanley--Consultant: Lupitold, Omeros; Ownership Interests: Polymedix; Honoraria: GE Healthcare, Fresenius; Expert Testimony: Bayer; Editorial Board: Journal of Clinical Investigation Martin, Kevin J.--Grants/research support/honoraria: Abbott; Advisory Board: Abbott, Cytochroma Mehrotra, Rajnish--Grants/research support: Amgen, Baxter, Shire; Consultant: Novartis; Honoraria: AMAG, Baxter Healthcare, Shire Murray, Patrick T.--Grants/research support: Biosite, GlaxoSmithKline, NxStage Medical; Consultant: Scios; Honoraria: GE Healthcare; Advisory Board: NxStage Medical, Quantum Biotechnologies Nachman, Patrick H.--Grants/research support: Otsuka Palevsky, Paul M.--none Palmer, Biff F.--Honoraria: Boehringer Ingelheim, Norvartis Sterns, Richard H.--Consultant: Astellas, Otsuka; Honoraria: Astellas, Otsuka; UpToDate; Scientific advisor: UpToDate Textor, Stephen C.--Honoraria: Visiting professorships; Editorial Board Membership: Journal of the American Society of Nephrology; Royalties: Lippincott Williams and Wilkins, Handbook of Kidney Transplantation Townsend, Raymond R.--Consultant: Abbott Laboratories, Atcor Medical, GlaxoSmithKline; Research support: Novartis; Honoraria: Bristol Myers-Squibb, Pfizer; Other financial relationship: UpToDate, PIER (ACP/ASIM) Vella, John P.--none Editorial authors: Ackerman, Teresa F.--none Artunc, Ferruh--none Boini, Krishna--none Kempe, Daniela S.--none Lang, Florian--none Vallon, Volker--none Review Commentary Author: Berl, Tomas--Grants/research support/scientific advisor: Otsuka; Honoraria: Astellas

Nephrology Self-Assessment Program - Vol 8, No 2, March 2009

Nephrology Self-Assessment Program

Examination Questions

Instructions to obtain 8 AMA PRA Category 1 CreditsTM Credit expiration date: February 28, 2010

Continuing Medical Education (CME) Information

Date of Original Release: March 2009 Examination Available Online: Monday, March 9, 2009 CME Credit Eligible Through: February 28, 2010 Answers: Correct answers with explanations will be posted on the ASN website in March 2010 when the issue is archived. UpToDate Links Active: March and April 2009 Core Nephrology question links active: March, April, and May 2009. CME Credit: 8.0 AMA PRA Category 1 CreditsTM Target Audience: Nephrology Board and recertification candidates, practicing nephrologists, and internists. Method of Participation: Read the syllabus that is supplemented by original articles in the reference lists, and complete the online self-assessment examination. Examinations are available online only after the first week of the publication month. There is no fee. Each participant is allowed two attempts to pass the examination ( 75% correct). Your score and a list of question/s (by number) answered incorrectly can be printed immediately. Your CME certificate can be printed immediately after passing the examination. Answers and explanations are provided ONLY with a passing score on the first or second attempt. Your ASN transcript will be updated in 6 to 8 weeks after passing the examination. Instructions to access the Online CME Center to take the examination and complete the evaluation: Access the ASN website: www.asn-online.org Click on "CME" tab at the top of the homepage and then click on the Online CME Center icon to go to the login page. After login, click on the icon for "NephSAP" Select a topic and click on "Start Now" On the CME Information page, click on "Continue" On the MOC page, select whether or not you want MOC points. On the next page, click on "Examination Questions/Evaluation" to answer the questions. Your score and a list of question numbers answered incorrectly can be printed immediately. Follow the prompts to retake the examination if you failed, or print your certificate and the correct answers if you passed. You can retake the examination at any time. Each participant is allowed two attempts.

Instructions to Obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points: Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria:

Be certified by ABIM in internal medicine and/or nephrology and must be enrolled in the ABIM­MOC program via the ABIM website (www.abim.org). Pass the self-assessment examination within the timeframe specified in this issue of NephSAP. Designate the issue for MOC points by clicking on the MOC link on the CME certificate page after passing the examination. You will be leaving the ASN-CECity site and transferring the information directly to the ABIM in real-time. Provide your ABIM Certificate ID number and your date of birth. You will receive a confirmation message from the ABIM indicating the receipt of your information. MOC points will be applied to only those ABIM candidates who have enrolled in the program. It is your responsibility to complete the ABIM MOC enrollment process. 154

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Volume 8, Number 2, March 2009 ­Fluid, Electrolyte, and Acid-Base Disturbances

1. A 47-yr-old man presents with new-onset ascites. He has a significant history of heavy alcohol use during the past several years. His last drink was approximately 12 h ago. On physical examination, BP is 110/70 mmHg, pulse is 110, and respiratory rate is 28. Spider angiomas are noted on the skin. The abdomen shows shifting dullness, and there is 2 peripheral edema. Laboratory examination shows the following: Na 130 mEq/L, K 2.8 mEq/L, Cl 90 mEq/L, HCO3 14 mEq/L, phosphate 3.5 mg/dl, calcium 6.5 mg/dl, and magnesium 1.6 mg/dl. Urine and serum ketones are positive. The patient is admitted and treated with thiamine, folic acid, and multivitamins followed by maintenance fluids with D5% 1/2NS. Approximately 18 h after admission, the patient is restless and agitated and complains of severe weakness. The serum phosphate concentration is 0.9 mg/dl. Which ONE of the following is TRUE regarding the change in serum phosphate in this patient? A. On admission, total-body phosphate was likely normal. B. Alcoholic ketoacidosis tends to cause a shift of phosphate into cells. C. Respiratory alkalosis that develops in association with alcohol withdrawal shifts phosphate into cells. D. The weakness is likely due to hypermagnesemia developing during the hospitalization. 2. A 38-yr-old man with a known history receives a diagnosis of chronic liver disease secondary to hepatitis C. He is treated with a 24-wk course of pegylated IFN- -2a, combined with ribavirin. He tolerates the therapy without complications. Four weeks after completing treatment, he begins to complain of episodic weakness in the proximal limbs, particularly in the early-morning hours. He states that on one occasion, his weakness suddenly became worse immediately after completing a 30-min run on a treadmill. One day before admission, he developed sudden weakness after finishing his dessert at a work-associated banquet. He is on no medications. Physical examination reveals the following: BP 140/70 mmHg, pulse 120, and respiratory rate (RR) 18. There is no ophthalmopathy or lymphadenopathy. The thyroid gland is normal on palpation. He is noted to have severe symmetrical proximal weakness in the thighs (1/5) with intact distal muscle power. Laboratory examination reveals the following: White blood cell (WBC) count 7.8 mm3, Hg 13.5 gm/dl, Na 142 mEq/L, K 2.1 mEq/L, Cl 104 mEq/L, HCO3 23 mg/dl, creatinine 1.0 mg/dl, and blood urea nitrogen (BUN) 15 mg/dl. Urine chemistries are as follows: Na 96 mEq/L, K 10 mEq/L, and Cl 110 mEq/L. The thyroid stimulating hormone is 0.1 IU/ml. Which ONE of the following statements is TRUE regarding the underlying cause of weakness in this patient? A. This disorder tends to occur more frequently in women. B. The patient should be immediately started on acetazolamide for treatment of the weakness. C. Pegylated IFN was likely responsible for precipitating this disorder. D. The serum magnesium is likely to be increased. E. High K intake is known to exacerbate this disorder. 3. A 68-yr-old man presents 2 wk after having undergone surgical treatment for a hip fracture. During the past 3 to 4 d, he has noticed abdominal distention and diarrhea. Physical examination shows decreased bowel sounds and a mildly tender abdomen but no rebound tenderness. Abdomen percussion is tympanitic. Imaging studies reveal a markedly dilated colon with no small intestine dilation. Laboratory findings

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show the following: Na 151 mEq/L, K 1.9 mEq/L, Cl 120 mEq/L, and HCO3 16 mEq/L. Despite the use of a rectal tube for drainage of stool and flatus, the patient continues to manifest colonic distention, and a diagnosis of colonic pseudo-obstruction is made. Over 8 wk, the patient's gastrointestinal manifestations resolve spontaneously. Which ONE of the following findings is characteristic of the diarrhea found in patients with colonic pseudo-obstruction? A. Secretory diarrhea as a result of inhibition of active intestinal absorption of NaCl B. Secretory diarrhea as a result of active Cl secretion followed by passive Na secretion C. Markedly increased stool osmotic gap D. Secretory diarrhea as a result of active colonic K secretion 4. A 58-yr-old man with type 2 diabetes and stage 3 chronic kidney disease receives a diagnosis of transitional cell carcinoma of the bladder. He has received chemotherapy and radiation therapy during the past year for treatment of this disorder. His clinical course has been complicated by the development of an enterocutaneous fistula. The surgical team now recommends that the patient undergo a radical cystectomy. Given the likelihood of extensive pelvic fibrosis and presence of the fistula, the surgeons are concerned that the procedure will be complicated. The surgeons inform the patient that a urinary diversion into the bowel will be performed, but the segment of bowel used can be determined only at the time of the procedure. Preoperative laboratory examination shows the following: Na 138 mEq/L, K 4.7 mEq/L, Cl 100 mEq/L, HCO3 22 mEq/L, and creatinine 1.8 mg/dl. The patient undergoes the procedure without complications. Repeat laboratory examination 7 d after the procedure shows the following values: Na 138 mEq/L, K 2.9 mEq/L, Cl 85 mEq/L. HCO3 36 mEq/L, pH 7.51, and creatinine 1.7 mg/dl. On the basis of postoperative laboratory values, which ONE of the following seg-

ments of bowel did the surgeon use for the urinary diversion procedure? A. Stomach B. Jejunum C. Ileum D. Sigmoid colon 5. A 33-yr-old African American man with sickle cell disease presents with severe back pain typical of sickle cell crisis. His medical history is pertinent for frequent episodes of hemolytic crisis. The patient was not on diuretic therapy. Physical examination shows an anxious man in mild discomfort with BP of 156/94 mmHg, pulse 98, RR 22. There is scleral icterus. Lung examination shows basilar crackles, and he has hepatomegaly and trace peripheral edema. Laboratory examination shows hematocrit of 21%, reticulocyte count of 12%, and total bilirubin of 38 mg/dl. Chemistry studies reveal the following: Na 136 mEq/L, K 2.2 mEq/L, Cl 85 mEq/L, HCO3 29 mEq/L, and creatinine 0.6 mg/dl. Urine studies reveal the following: Na 63 mEq/L, K 49 mEq/L, Cl 58 mEq/L, plasma renin activity 1.1 ng/ml per h (3 to 9 ng/ml per h), and aldosterone 2 ng/dl (n 10). The patient is treated with exchange transfusion and given K supplements to correct the hypokalemia. BP at the time of discharge is 118/78 Hg, and laboratory studies show a total bilirubin of 8 mg/dl and a serum potassium of 4.1 mEq/L off potassium supplements. Five months later, the patient is readmitted with a hemolytic crisis. BP is again noted to be increased at 158/98 mmHg. Laboratory examination shows a total bilirubin of 45 mg/dl. The serum potassium is 2.1 mEq/L. A transtubular K gradient at this time shows a value of 12. The serum aldosterone is 2.5 ng/dl. Which ONE of the following is the BEST explanation for the recurrent hypokalemia in this patient? A. Liddle syndrome B. Shift of K into cells C. Acquired deficiency of 11 -hydroxysteroid dehydrogenase II

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D. Surreptitious loop diuretic use E. Dexamethasone-suppressible hyperaldosteronism 6. A 45-yr-old man with ESRD presents to the emergency department with the chief complaint of palpitations and weakness. He has been stable on dialysis for 2 yr. He had an aortic valve replacement as a result of rheumatic aortic stenosis approximately 4 yr ago. Physical examination shows a pleasant, slightly anxious man in no acute distress. The BP is 100/65 mmHg, and the pulse is 180 bpm. An electrocardiogram shows atrioventricular nodal reentrant tachycardia. Laboratory examination shows the following: Na 136 mEq/L, K 8.2 mEq/L, Cl 100 mEq/L, HCO3 19 mEq/L, creatinine 12 mg/dl, BUN 68 mg/dl, hemoglobin 8.1 g/dl, lactate dehydrogenase 512 U/L (normal 100 to 190 U/L), and indirect bilirubin 4.5 mg/dl. Hyperkalemia has not been an issue for this patient before. His most recent Kt/V is 1.5. His diet is unchanged, and he has not missed any dialysis treatments. Which ONE of the following is the BEST explanation for the hyperkalemia in this patient? A. Recirculation in vascular access B. Use of an angiotensin-converting enzyme inhibitor (ACEI) C. Hemolysis as a result of shear stress across the prosthetic aortic valve D. Disseminated intravascular coagulation secondary to methycillin-resistant Staphylococcus aureus E. Occult hyperthyroidism 7. Which ONE of the following is TRUE regarding the risk for developing hyperkalemia in association with packed red blood cell transfusion? A. Hyperkalemia risk is related to the number but not the rate of red blood cell transfusions. B. Washing cells before transfusion increases hyperkalemia risk.

C. Increasing the amount of additive solution minimizes hyperkalemia risk. D. Hyperkalemia risk is increased with use of irradiated blood. E. Hyperkalemia risk is inversely related to the duration of blood storage. 8. A 14-yr-old boy was observed to collapse on a tennis court during a midmorning practice session. He was conscious and oriented but unable to move his arms or legs. He stated that his last meal was at 7:00 the night before. The weakness spontaneously resolved during the course of 2 h. His history was significant for several other episodes of intermittent weakness that all resolved within 30 to 45 minutes after onset. On several of these occasions, the weakness occurred after the ingestion of large quantities of orange juice. Physical examination reveals the following: BP 130/80 mmHg, pulse 86, RR 18, cranial nerves intact, and 1/5 strength in all major muscle groups. The sensory examination is normal. Laboratory values that were obtained 30 min after collapse reveal the following: Na 143 mEq/L, K 5.7 mEq/L, Cl 100 mEq/L, HCO3 22 mEq/L, and creatinine 0.9 mg/dl. Which ONE the following statement is correct regarding treatment of the underlying disease in this patient? A. The patient should be prescribed a blocker to reduce the frequency of attacks. B. ACEI therapy will decrease the frequency of attacks. C. He should initiate exercise or eat a highcarbohydrate meal to abort attacks. D. Albuterol inhaler is likely to worsen the acute weakness. 9. A 38-yr-old woman with a strong family history of cardiovascular diseases and hypertension recently received a diagnosis of essential hypertension. Her BP on three separate measurements averages 154/94 mmHg. Current medications include a daily multivitamin and birth control pills. The physical examination and laboratory examination are normal. Because the patient is using birth control pills, her primary care phy-

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sician was comfortable prescribing lisinopril 10 mg/d. One month later, the patient returns for follow-up. BP is 142/88 mmHg. Laboratory examination shows the following: Na 140 mEq/L, K 5.5 mEq/L, Cl 100 mEq/L, HCO3 22 mEq/L, creatinine 0.8 mg/dl, and BUN 10 mg/dl. The physician refers the patient to a nephrologist for hyperkalemia evaluation. Which ONE of the following is the MOST likely risk factor for hyperkalemia development after prescribing an ACEI for this patient? A. High-grade bilateral renal artery stenosis B. Pseudohypoaldosteronism type II C. Acquired adrenal insufficiency D. Mineralocorticoid-blocking activity in birth control pill E. Daily ingestion of bananas 10. A 65-yr-old man is referred for evaluation of an increased serum creatinine and hyperkalemia. The patient complains of intermittent abdominal pain during the past month. Medications include lisinopril/hydrochlorothiazide 10/25 mg/d for hypertension treatment for the past 7 yr. His medical history is significant only for a motor vehicle accident 8 mo ago, in which he sustained a retroperitoneal bleed. Laboratory studies at the time of discharge are normal. Physical examination reveals BP of 158/94 mmHg and pulse of 92 bpm. The remainder of the examination is significant only for mild periumbilical tenderness. Laboratory examination reveals the following: WBC 9.0 mm3, hematocrit 32%, Na 138 mEq/L, K 5.9 mEq/L, Cl 108 mEq/L, HCO3 19 mEq/L, creatinine 2.3 mg/dl, and BUN 38 mg/ dl. Urinalysis reveals specific gravity 1.010 trace protein, 0 to 1 red blood cells, and 0 to 1 WBC. An abdominal sonogram shows normalsized kidneys with slight enlargement of the urinary pelvis on both sides. There is no hydroureter. Which ONE of the following is the MOST likely cause of the development of hyperkalemia and renal failure in this patient? A. Pseudohypoaldosteronism type 1

B. Use of over-the-counter nonsteroidal antiinflammatory drugs C. Urinary obstruction D. ACEI therapy E. Use of the herb Chan Su 11. A 38-yr-old man presents for evaluation of chronic weakness. His family history is strongly positive for hypertension. Physical examination is remarkable only for a BP of 148/100 mmHg. Laboratory studies reveal the following: Na 141 mEq/L, K 6.0 mEq/L, Cl 109 mEq/L, HCO3 19 mEq/L, and creatinine 0.9 mg/dl. Urine studies reveal he following: Na 75 mEq/L, K 20 mEq/L, and Cl 98 mEq/L. Subsequent workup discloses that the patient has pseudohypoaldosteronism type II. Which ONE of the following is correct regarding this patient's clinical disorder? A. The patient's hypertension would likely be resistant to treatment with hydrochlorothiazide. B. Plasma renin activity and aldosterone levels both are increased. C. K excretion in response to NaCl loading is normal. D. An immunoblot assay would show increased urinary abundance of the Na-Cl co-transporter. E. The patient is likely to have an inactivating mutation in the NaCl co-transporter in the distal convoluted tubule. 12. A 5-yr-old boy is brought to the emergency department because he complains of light-headedness upon standing. The parents tell the physician that their son has received a diagnosis of a condition that causes potassium problems, but they do not recall the name of the disease. A great grandfather is said to have experienced a similar condition. The patient has required oral salt supplementation as well as some other medicine designed to help correct abnormalities in blood potassium, but the family has run out of both medications. Physical examination shows a BP of 95/70 mmHg that decreases to 80/55 mmHg upon standing. Serum chemistries show

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the following: Na 135 mEq/L, K 6.5 mEq/L, Cl 105 mEq/L, HCO3 16 mEq/L, glucose 105 mg/ dl, creatinine 1.0 mg/dl, and BUN 35 mg/dl. An arterial blood gas shows a pH of 7.33 and a PCO2 of 32. Which ONE of the following diagnoses is MOST likely in this case? A. Pseudohypoaldosteronism type II B. Pseudohypoaldosteronism type I C. Liddle syndrome D. Hyporeninemic hypoaldosteronism related to diabetic nephropathy E. Long-term use of nonsteroidal anti-inflammatory drugs 13. A 38-yr-old man is referred for evaluation of hypertension. He tells you that his father has hypertension and has problems with high K in his blood. Physical examination shows a BP of 150/100 mmHg. Laboratory examination shows the following: Na 140 mEq/L, K 6.2 mEq/L, Cl 110 mEq/L, HCO3 16 mEq/L, creatinine 1.1 mg/dl, and BUN 14 mg/dl. Plasma renin activity and aldosterone levels are markedly suppressed. He is placed on hydrochlorothiazide, and 3 wk later his BP and serum chemistries have largely normalized. Genetic analysis shows that he has an inactivating mutation of the WNK4 protein. Which ONE of the following is correct regarding Ca2 homeostasis in this patient? A. A 24-hr urinary Ca2 excretion is elevated. B. A 24-hr urinary Mg2 excretion is decreased. C. Urinary Ca2 excretion in this patient is unaffected by thiazide diuretics. D. The activity of the selective Ca2 channel TRPV5 is increased. E. Urinary Ca2 handling would be the same with an activating mutation of WNK1. 14. A 30-yr-old woman is referred for evaluation of a goiter. When she was 14 yr old, she had a thyroid operation in which part of a goiter was removed. She was euthyroid at that time and has remained euthyroid. She states that she has had

impaired hearing since childhood, and a recent examination by an otolaryngologist showed enlargement of the endolymphatic duct and sac. BP is 110/70 mmHg. The remainder of the physical examination is normal. Her baseline laboratory examination is normal. The patient is placed on 12.5 mg of hydrochlorothiazide in an attempt to treat the inner ear disorder. Two weeks later, the patient presents with marked weakness and orthostasis. Laboratory examination shows the following: Na 129 mEq/L, K 1.7 mEq/L, Cl 70 mEq/L, HCO3 44 mEq/L, pH 7.52, creatinine 1.1 mg/dl, and BUN 35 mg/dl. Which ONE of the following disorders BEST accounts for the findings in this case? A. Gitelman syndrome. B. Pseudohypoaldosteronism type II C. Congenital chloridorrhea D. Pendred syndrome E. Liddle syndrome 15. A 77-yr-old woman develops increased intraocular pressure after cataract surgery and is treated with 2.5 L of 20% mannitol intravenously and oral ibuprofen for pain. Her history includes congestive cardiac failure, hypertension, and mild renal impairment with baseline creatinine of 1.5 mg/dl. Her regular medications include captopril and furosemide. On day 4, she develops confusion, dyspnea, and anuria. Chest x-ray shows acute pulmonary edema. Laboratory data reveal the following: serum sodium of 112 mEq/L, urea of 37 mg/dl, glucose of 90 mg/dl, creatinine of 3.2 mg/dl, and a serum osmolality of 326 mOsm/kg. That same afternoon, she develops multiple seizures that require urgent ventilation in an intensive care unit. Which ONE of the following is the BEST emergency therapeutic intervention? A. 100 ml 3% saline bolus intravenously followed by continuous veno-venous hemodiafiltration using replacement fluid adjusted to a sodium concentration of 130 mEq/L B. 40-mg bolus of conivaptan intravenously C. Furosemide intravenously plus 3% saline at 1 ml/kg per h until the serum sodium is 118 mEq/L

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D. Continuous veno-venous hemodiafiltration using replacement fluid adjusted to a sodium concentration of 118 mEq/L E. Conventional hemodialysis against a dialysate with a sodium concentration of 140 mEq/L 16. A 72-yr-old woman who has multiple sclerosis and weighs 50 kg receives 400 mg/kg intravenous immunoglobulin infused for 3 h. At the end of the infusion, she has an acute and dramatic worsening of neurologic symptoms. She is suddenly unable to bear weight or coordinate arm and leg movements and describes paresthesias and hyposthesias of all extremities. Blood chemistries are normal except for a serum sodium of 130 mEq/L. Which ONE of the following is the BEST treatment for this patient? A. 3% saline in 50-ml bolus B. 3% saline in 150-ml bolus C. 3% saline at 50 ml/h for 4 h D. 0.9% saline, 1000 ml, infused as rapidly as possible with furosemide 80 mg intravenously E. Make patient nil per os and observe 17. A 50-yr-old man with hemophilia complicated by HIV/AIDS and cirrhosis caused by hepatitis C is admitted for renal failure. He is treated with furosemide and spironolactone for management of ascites and sulfamethoxazole and trimethoprim for prophylaxis against Pneumocystis jiroveci pneumonia. There is no history of alcoholism. On admission, BP is 98/62 mmHg, and physical examination shows scleral icterus, stigmata of cirrhosis, an abdominal fluid wave, and pitting edema of his lower extremities. He is alert and oriented but has asterixis. Laboratory data show serum Na 128 mEq/L, K 5.7 mEq/L, Cl 95 mEq/L, CO2 23 mEq/L, BUN 49 mg/dl, glucose 110 mg/dl, and creatinine 2.3 mg/ dl, and plasma osmolality 290 mOsm/kg. Urine osmolality is 580 mOsm/kg. Other laboratory values included urine Na 53 mEq/L, random cortisol 25 g/dl, uric acid 14.2 mg/dl, serum triglycerides 50 mg/dl, total cholesterol 95 mg/dl, total protein

11.7 gm/dl, and albumin 2.4 gm/dl. Which ONE of the following is the MOST likely cause of the patient's hyponatremia? A. Addison disease B. Trimethroprim therapy C. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) D. Pseudohyponatremia 18. An infant is born at 27 wk gestation. Laboratory examination 24 h after birth shows a serum K concentration of 6.5 mEq/L. Urine output is 1.5 ml/kg per h. The patient is given a diagnosis of early-onset nonoliguric hyperkalemia in a very low birth weight infant. Which ONE of the following is TRUE regarding hyperkalemia in this infant? A. It is likely the result of excess sodium reabsorption proximal to potassium secretory sites in the premature kidney. B. It is likely due to immaturity in development of aldosterone production in the premature adrenal gland. C. The maxi-K channel is expressed in the distal nephron before the ROMK secretory channel. D. There is a relative predominance of apical H-K-ATPase compared with ROMK in the neonate. 19. A 55-yr-old woman presents with a subarachnoid hemorrhage caused by a saccular aneurysm originating from the anterior communicating artery. Three days after surgical clipping of the aneurysm, the patient develops polyuria (urine output up to 300 ml/h) and increasing confusion. Serum sodium level is 165 mEq/L. Serum concentrations of potassium, calcium, and glucose are normal, and urine osmolality is 122 mOsm/ kg. Administration of 2 g of desmopressin subcutaneously decreases urine output to 50 ml/h, and the serum sodium concentration is normalized with 0.45% saline. Intranasal desmopressin is prescribed in a dosage of 20 g twice daily, and she is discharged to an intermediate-care facility with a serum sodium con-

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centration of 140 mEq/L. One week later, her serum sodium is found to be 156 mEq/L. Which ONE of the following is the BEST intervention? A. Administer desmopressin subcutaneously 2 g twice daily. B. Increase the intranasal desmopressin dosage to 40 g twice daily. C. Increase the dose interval of desmopressin to 20 g three times daily. D. Continue the present dosage of desmopressin and reduce dietary sodium. E. Continue the present dosage of desmopressin and implement a regimen of timed oral fluid intake. 20. A 44-yr-old man is admitted from home 3 d after working outside in the extreme heat (42°C). He had come home with a headache and nausea and had been unable to eat or drink for 3 d. On admission, he is unresponsive with a BP of 80/54 mmHg and a temperature of 38.9°C. Mucous membranes are dry, and skin turgor is poor. Plantar reflexes are extensor bilaterally. Laboratory data show the following: serum Na 208 mEq/L, K 3.0 mEq/L, BUN 30 mg/dl, and creatinine 2 mg/dl. A computed tomography scan of the head reveals a retained bullet fragment, believed secondary to a gunshot wound at age 18 near the third ventricle. He is given 3 L of isotonic saline followed by 0.45% saline. Urine output is 4.2 L on the second hospital day, when his serum sodium is 155 mEq/L. After recovery, a water deprivation test is performed. At a serum osmolality of 325 mOsm/kg and serum sodium concentration of 147 mEq/L, urine osmolality is 743 mOsm/kg, urine sodium is 190 mEq/L, and he expresses no desire for water. Which ONE of the following is the MOST likely diagnosis? A. Adipsia with normal vasopressin secretion B. Adipsia with complete central diabetes insipidus (DI) C. Adipsia with partial central DI D. Dehydration as a result of heat exposure with temporary resetting of the osmostat

E. Psychiatric disturbance with surreptitious salt ingestion 21. A 28-yr-old woman undergoes trans-sphenoidal resection of a large pituitary tumor. The first day after surgery, she begins to complain of thirst, and her urine output is 500 ml/h. Serum sodium is 150 mEq/L, and urine specific gravity is 1.003. A diagnosis of central DI is made, and she is started on 1 g of desmopressin subcutaneously, every 12 h. Urine output decreases to 25 ml/h and urine specific gravity increases to 1.018, and by the second postoperative day, her serum sodium is 140 mEq/L. On the sixth hospital day, the serum sodium decreases to 127 mEq/L and desmopressin is discontinued. Urine output is 1L/d for the next 3 d. On the ninth day, she begins to complain of extreme thirst, urine output increases to 300 ml/h, the serum sodium increases to 145 mEq/L, plasma osmolality is 298 mOsm/kg, and the urine specific gravity is 1.004. An magnetic resonance imaging scan shows no pituitary bright spot. Which ONE of the following statements is the BEST explanation for this sequence of events? A. The patient is a slow acetylator of desmopressin. B. The patient has episodic secretion of a vasopressin inhibitor from residual pituitary tumor. C. The fluctuating urine output is caused by episodic secretion of vasopressin from a temporarily dysfunctional osmoreceptor, and syndrome of inappropriate antidiuresis is likely to recur in the next 3 d. D. The patient had SIADH on day 6 to 9 and now has permanent DI as a result of injury to the pituitary stalk. E. The patient developed transient DI on the first and ninth hospital days, and this is likely to resolve in the next 2 wk. 22. A 65-yr-old woman with a history of a schizoaffective disorder has been treated with lithium 400 mg/d for the past 20 yr. She developed aphasia 4 yr ago secondary to a sagittal vein

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thrombosis. She is now admitted because of fever and a change in mental status. Physical examination reveals the following: BP 90/50 mmHg, heart rate 120 bpm, temperature 39°C, dry mucous membranes, clear lungs, and no edema. Laboratory data reveal the following: Serum Na 148 mEq/L, K 3.6 mEq/L, Cl 114 mEq/L, CO2 28 mEq/L, BUN 26 mg/dl, creatinine 0.6 mg/dl, and calcium 13.5 mg/dl. Urine and blood cultures are positive for Escherichia coli. Computed tomographic scan of the abdomen shows nonobstructing calcium stones. Lithium is discontinued, and she is treated with isotonic saline, antibiotics, and pamidronate. Five days later, she is alert, normotensive, and afebrile. Urine output is 5 L/d. Serum calcium is 9.5 mg/dl, and serum sodium is 148 mEq/L. Urine osmolality is 180 mOsm/kg. After desmopressin, urine osmolality increases to 230 mOsm/kg. Which ONE of the following is the BEST explanation for her polyuria? A. Psychogenic polydipsia B. Central DI C. Osmotic dieresis D. Nephrogenic DI as a result of lithium 23. A 40-yr-old woman is admitted with the worst headache of her life. Physical examination reveals weight of 56 kg and BP of 170/60 mmHg. Meningeal signs are present, but the rest of the examination is nonrevealing. Admission laboratory values show the following: Na 140 mEq/L, K 3.9 mEq/L, Cl 105 mEq/L, CO2 22 mEq/L, BUN 17 mg/dl, creatinine 1.0 mg/dl, and hematocrit 37%. Computed axial tomography of the brain shows a small subarachnoid hemorrhage. During the first 6 d of hospitalization, she is treated with nimodipine and 0.9% saline at 200 ml/h. Gradually the serum sodium concentration falls to 125 mEq/L. Mannitol 12.5 g is administered, and saline is continued. The next day, BP is 148/66, and weight is 58 kg. She is alert and oriented but complains of a headache. Laboratory data on day 6 reveal the following: Na 124 mEq/L, K 4.2 mEq/L, Cl 91 mEq/L, CO2 22

mEq/L. BUN 11 mg/dl, creatinine 0.9 mg/dl, glucose 260 mg/dl, and hematocrit 34. Serum osmolality is 260 mOsm/kg; urine osmolality is 800 mOsm/kg. Urine values include the following: Na 240 mEq/L, K 20 mEq/L, and output 200 ml/h. Which ONE of the following is the MOST likely cause of her hyponatremia? A. Pseudohyponatremia B. Translocational hyponatremia as a result of mannitol C. SIADH D. Cerebral salt wasting 24. A 32-yr-old woman with von Willebrand disease is treated with preoperative desmopressin before cesarean section for a term pregnancy. Intravenous fluids are discontinued 24 h after delivery. Three days after surgery, she is alert, oriented, and eating and drinking normally. She is observed walking unsteadily to the nursing station, when she falls and experiences a brief seizure. Laboratory data show a serum sodium of 108 mEq/L, and computed tomography scan of the head is normal. It is discovered that desmopressin had inadvertently been continued in a dose of 2 g every 8 h for the past 3 d. She is treated with 3% saline at 40 ml/h (0.5 ml/kg per h). Eight hours later, the serum sodium is 119 mEq/L and she is awake but confused. Which ONE of the following therapies should be instituted at this time? A. Continue 3% saline at 40 ml/h B. 100-ml bolus of 3% saline and then discontinue intravenous fluids C. Stop 3% saline and start 0.9% saline at 100 ml/h D. Stop 3% saline and administer desmopressin E. Stop 3% saline and restrict fluids 25. A 20-yr-old woman is referred for recurrent bouts of weakness associated with hypokalemia. She occasionally has used laxatives to lose weight but denies recent history of vomiting or diarrhea. She

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does not use illicit drugs and is HIV negative. BP is 110/80 supine and 92/70 upright; the remainder of the examination is normal. Laboratory values are as follows: Na 135 mmol/L, K 2.0 mmol/L, Cl 80 mmol/L, HCO3 40 mmol/L, plasma aldosterone 32 ng/dl, and plasma renin activity 40 ng/ml per h. Urine values are as follows: Na 50 mmol/L, K 20 mmol/L, Cl 5 mmol/L, and pH 7.5.

Which ONE of the following is the MOST likely cause of the laboratory abnormalities? A. Recent abuse of ipecac B. Recent ingestion of loop diuretics C. Bartter syndrome D. Gitelman syndrome E. Laxative abuse

Nephrology Self-Assessment Program - Vol 8, No 2, March 2009

Nephrology Self-Assessment Program

Core Knowledge Questions

Fluid, Electrolyte, and Acid-Base Disturbances

The Core Knowledge questions feature 5 multiple choice questions which are designed to test knowledge of core aspects of clinical nephrology and are therefore more useful in preparing for Board certification, recertification and future inservice examinations. The questions and answers are available in each issue of NephSAP and on the NephSAP page on the ASN website by clicking on the Core Nephrology Questions button. Each question is associated with an UpToDate link that will remain active for the first 3 months after publication. The Editors believe that this feature enhances the utility of NephSAP as a comprehensive self study, self-assessment program for ASN members. 1. A young man is found to have hypertension and hypokalemia. A resident taking a careful history discovers that the patient is extremely fond of European licorice. Which ONE of the following genetic defects produces a similar syndrome? A. A mutation in the gene for the inwardly rectifying potassium channel ROMK B. A mutation in the gene for the basolateral chloride channel CLC-Kb C. A mutation in the gene for the NaCl co-transporter D. A mutation in the gene for 11 -hydroxysteroid dehydrogenase E. A chimeric gene with portions of the 11 -hydroxylase gene and the aldosterone synthase gene

2. A 45-yr-old previously healthy woman who weighs 50 kg undergoes surgery for a ruptured ovarian cyst. During surgery, she is given 2 L of lactated Ringer solution, and she is given 5% dextrose in 0.45% NaCl with 20 mEq/L KCl at 250 ml/h postoperatively. Forty-eight hours after surgery, she complains of headache and vomiting. BP is 140/80 mmHg. She is alert and oriented, and the general physical and neurologic examinations are unremarkable. Laboratory data reveal the following: Serum Na 115 mEq/L, plasma osmolality 241 mOsm/kg H2O, and urine osmolality 850 mOsm/kg H2O. The patient is not taking anything by mouth. In addition to stopping the 5% dextrose in 0.45% NaCl infusion, which ONE of the following would be the MOST appropriate treatment? A. 5% dextrose in 0.9% saline with 20 mEq KCl at 50 ml/h B. 5% dextrose in 0.9% saline with 20 mEq KCl at 250 ml/h C. 3% saline at 100 ml/h plus intravenous furosemide until serum sodium concentration is 132 mEq/L D. 3% saline at 50 ml/h plus intravenous furosemide until the serum sodium is 120 mEq/L 3. A 40-yr-old man with ESRD that requires hemodialysis presents with proximal muscle weakness. The serum potassium is 8 mEq/L, and an electrocardiogram shows peaked T waves. Which ONE of the following agents would lower his serum potassium concentration most quickly? A. B. C. D. E. Calcium gluconate intravenously Propranolol intravenously Kayexalate in sorbitol orally Sodium bicarbonate intravenously Glucose and insulin intravenously

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4. A homeless man is discovered unconscious in the park and is brought to the emergency department. He wreaks of alcohol, is unkempt, and is incoherent. Physical examination shows a BP of 90/50 mmHg, heart rate of 120 bpm, temperature of 39°C, slight scleral icterus and dullness, and bronchial breath sounds over the right lower lung fields. Laboratory data reveal the following: Serum Na 131 mEq/L, K 2.9 mEq/L, Cl 70 mEq/L, CO2 21 mEq/L, blood urea nitrogen 34, creatinine 1.4 mg/dl, glucose 240 mg/dl, serum osmolality 320 mOsm/kg H2O, serum ketones weakly positive, pH 7.53, PaCO2 25 mmHg, PaO2 60 mmHg, and serum albumin 3.8 g/dl. Which ONE of the following choices BEST describes his acid-base disturbance? A. Metabolic acidosis B. Respiratory alkalosis C. Metabolic acidosis and respiratory alkalosis D. Metabolic acidosis and metabolic alkalosis E. Metabolic acidosis, metabolic alkalosis, and respiratory alkalosis 5. A 9-yr-old girl complains of profound weakness, dizziness, and polyuria. She is taking no medications and has no gastrointestinal complaints. Pertinent clinical finding is BP of 90/50 mmHg with orthostatic dizziness. Laboratory data reveal the following: Na 140 mEq/L, K 2.5 mEq/L, Cl 100 mEq/L, CO2 33 mEq/L, blood urea nitrogen 25 mg/dl, and creatinine 0.7 mg/dl. A 24-h urine collection reveals the following: Sodium 90 mEq, potassium 60 mEq, Cl 110 mEq, and calcium 280 mg. Plasma renin and aldosterone are elevated. These findings are MOST suggestive of which ONE of the following? A. Adrenal adenoma B. Gitelman syndrome C. Bartter syndrome D. Licorice ingestion E. Hemangiopericytoma

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Answer and Explanation Key

1. Answer: D. A mutation in the gene for 11 -hydroxysteroid dehydrogenase Aldosterone, the most important mineralocorticoid, increases sodium reabsorption and potassium secretion in the distal nephron. Excessive secretion of mineralocorticoids or abnormal sensitivity to mineralocorticoid hormones may result in hypokalemia, suppressed plasma renin activity, and hypertension. The syndrome of apparent mineralocorticoid excess is an inherited form of hypertension in which 11 -hydroxysteroid dehydrogenase is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. Because mineralocorticoid receptors themselves have similar affinities for cortisol and aldosterone, the deficiency allows these receptors to be occupied by cortisol, which normally circulates at much higher plasma levels than aldosterone. Licorice that contains glycyrrhetinic acid mimics the hereditary syndrome because it inhibits 11 -hydroxysteroid dehydrogenase. White PC: 11Beta-hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess. Am J Med Sci 322: 308 ­315, 2001 Brem AS: Insights into glucocorticoid-associated hypertension. Am J Kidney Dis 37: 1­10, 2001 Farman N, Bocchi B: Mineralocorticoid selectivity: Molecular and cellular aspects. Kidney Int 57: 1364 ­1369, 2000 Iida R, Otsuka Y, Matsumoto K, Kuriyama S, Hosoya T: Pseudoaldosteronism due to the concurrent use of two herbal medicines containing glycyrrhizin: Interaction of glycyrrhizin with angiotensin-converting enzyme inhibitor. Clin Exp Nephrol 10: 131­135, 2006 2. Answer: D. 3% saline at 50 ml/h plus intravenous furosemide until the serum sodium is 120 mEq/L The patient has developed hypotonic hyponatremia because of the nonosmotic release of vasopressin caused by the stress of surgery coupled with the intravenous administration of a large volume of hypotonic fluid. Her complaints of headache and vomiting are strongly suggestive of cerebral edema, a complication that has been reported primarily in premenopausal women with postoperative hyponatremia. Because this syndrome may be fatal, prompt, definitive treatment is needed to raise the serum sodium concentration over the next few hours. Neither isotonic saline nor fluid restriction is a satisfactory strategy to accomplish this goal. Extracellular fluid volume expansion created by the postoperative and perioperative fluid will cause the patient to excrete large amounts of sodium in her urine. Vasopressin levels may remain elevated for several days after surgery, which will cause her urine to be concentrated. Thus, the sodium in each liter of isotonic saline that she is given may be excreted in 1 L of urine; the infusate will thus be "desalinated," causing positive water balance and worsening of hyponatremia. Because of her volume-expanded state, the patient may excrete the equivalent of hypertonic saline in her urine even if intravenous fluids are discontinued; as a result, her serum sodium concentration may continue to fall spontaneously. Thus, intravenous hypertonic saline is needed to decrease the severity of cerebral edema and eliminate the risk for herniation. Because hyponatremia has evolved over 48 h, there is some risk for osmotic demyelination if the serum sodium concentration is increased too much ( 18 mEq/L in 48 h). Choice C will raise the serum sodium concentration by 5, 17 mEq/L in 24 h; as postoperative vasopressin levels begin to fall spontaneously, the ensuing water diuresis may result in excessive correction. Because brain swelling of 5 to 10% is incompatible with life, a 5% increase in serum sodium concentration (an increase of 6 mEq/L) is enough to bring the patient out of danger without risking iatrogenic injury from excessive correction. Steele A, Gowrishankar M, Abrahamson S, Mazer CD, Feldman RD, Halperin ML: Postoperative hyponatremia despite near-isotonic saline infusion: A phenomenon of desalination. Ann Intern Med 126: 20 ­25, 1997 Lien YH, Shapiro JI: Hyponatremia: Clinical diagnosis and management. Am J Med 120: 653­ 658, 2007

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3. Answer: E. Glucose and insulin intravenously Calcium gluconate (choice A) is indicated in the treatment of hyperkalemic emergencies because its electrophysiologic effect prevents cardiac arrest. Although the drug works extremely rapidly, it does not actually lower the serum potassium concentration. Propranolol (choice B) is a -adrenergic­ blocking agent that has a mild hyperkalemic effect and is therefore contraindicated in this patient. Kayexalate (choice C) must first reach the rectum to be effective in lowering the serum potassium concentration; when the drug is given orally, it does not work rapidly. Sodium bicarbonate (choice D) is theoretically beneficial because it favors uptake of potassium by cells; however, studies of sodium bicarbonate in patients with ESRD have shown that potassium falls minimally within the first 2 h. Glucose and insulin (choice E) are effective in lowering the serum potassium concentration within minutes. Insulin acts on sodium-potassium ATPase to promote cellular uptake of potassium, an effect that is independent of glucose. Glucose is given concurrently with insulin to avoid hypoglycemia. Evans K, Reddan D, Szczech L: Nondialytic management of hyperkalemia and pulmonary edema among end-stage renal disease patients: An evaluation of the evidence. Semin Dial 17: 22­29, 2004 4. Answer: E. Metabolic acidosis, metabolic alkalosis, and respiratory alkalosis The patient has an alkaline blood pH indicting that he must have either metabolic or respiratory alkalosis. The low PaCO2 in the presence of alkalemia makes the diagnosis of respiratory alkalosis; however, the patient also has a large anion gap (40 mEq/L), which indicates that he must also have a metabolic acidosis. The presence of serum ketones suggests that the metabolic acidosis may be caused in part by alcoholic ketoacidosis, and the presence of an osmolar gap (calculated osmolality 287 versus measured osmolality 320 mOsm/kg) should prompt an evaluation for ethanol, methanol, or ethylene glycol intoxication. Circulating acetone in patients with ketoacidosis will contribute to the osmolar gap despite the extremely large anion gap (28 mEq/L higher than normal); the serum bicarbonate concentration is only 3 mEq/L lower than normal. The discrepancy between the change in the anion gap from baseline and the change in the bicarbonate concentration from baseline is suggestive of a third disturbance, metabolic alkalosis (in this setting, most likely as a result of vomiting), which raised the serum bicarbonate concentration to a higher than normal level before it was reduced by the metabolic acidosis. Kraut JA, Madias NE: Approach to patients with acid-base disorders. Respir Care 46: 392­ 403, 2001 Kraut JA, Madias NE: Serum anion gap: Its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2: 162­174, 2007 5. Answer: C. Bartter syndrome The term Bartter syndrome denotes a group of renal diseases that share a common denominator of metabolic alkalosis and renal potassium wasting without hypertension. Bartter syndrome falls into four subgroups: (1) Antenatal Bartter syndrome (hyperprostaglandin E2 syndrome), (2) the Gitelman variety of Bartter syndrome (Gitelman syndrome), (3) classical Bartter syndrome, and (4) pseudo-Bartter syndrome. This patient is an example of classical Bartter syndrome, characterized by early childhood onset. Symptoms may include polyuria, polydipsia, vomiting, constipation, salt craving, and a tendency to volume depletion. Growth retardation follows if treatment is not initiated. Affected patients have hypokalemic metabolic alkalosis and, unlike patients with Gitelman syndrome, their urinary calcium excretion is elevated. Adrenal adenoma, licorice ingestion, and hemangiopericytoma (choices A, D, and E) all are causes of hypokalemia, but these disorders are associated with hypertension. Seyberth HW: An improved terminology and classification of Bartter-like syndromes. Nat Clin Pract Nephrol 4: 560 ­567, 2008 Shaer AJ: Inherited primary renal tubular hypokalemic alkalosis: A review of Gitelman and Bartter syndromes. Am J Med Sci 322: 316 ­332, 2001

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