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Nephrotic Syndrome in Adult Black South Africans: HIV-Associated Nephropathy as the Main Culprit

Ikechi G. Okpechi, MBBS, FWACP, PhD, Cert Nephrol (SA) Phys; Brian L. Rayner, MB ChB, FCP(SA), MMed; Charles R. Swanepoel, MB ChB, FRCP (Edin)

Background: Glomerular diseases, accompanied by nephrotic syndrome, contribute significantly to end-stage renal disease (ESRD) worldwide. We sought to show the distribution and frequency of biopsy-proven causes of nephrotic syndrome in native black Africans attending the Groote Schuur Hospital in Cape Town, South Africa. Methods: We retrospectively reviewed the biopsy data of 294 black South Africans with biopsy-proven cause of nephrotic syndrome in Cape Town over a 10-year period. Nephrotic proteinuria was accepted as urine protein excretion of at least 3.5 g in 24 hours. Glomerular diseases were classified into primary and secondary types. Serum creatinine concentrations were stratified into 3 levels to reflect the degree of renal dysfunction at the time of presentation. The frequency and distribution of disease were recorded according to age and gender. Results: Young adults (40 years of age) constituted 74.1% of the study population. Secondary glomerular diseases were more frequent (58.8%) and human immunodeficiency virus­ associated nephropathy (HIVAN) was observed as the leading cause of nephrotic syndrome in both males and females (42.8%). Most patients with HIVAN (73.6%) presented for the first time with severe renal impairment and more than half of patients with non-HIVAN glomerular diseases presented with an abnormal serum creatinine. Of the primary glomerular diseases, mesangiocapillary glomerulonephritis was the commonest cause of the nephrotic syndrome (19.0%), while IgA nephropathy was the least common cause (1.7%). Conclusions: HIVAN is a major cause of nephrotic syndrome in black South Africans and may be responsible for the rising incidence of ESRD in Africa. Keywords: Africa n kidney n HIV/AIDS J Natl Med Assoc. 2010;102:1193-1197

Author Affiliations: Renal Unit, Groote Schuur Hospital and University of Cape Town, South Africa. Correspondence: Ikechi G. Okpechi, MBBS, FWACP, PhD, Cert Nephrol (SA) Phys, E13 Renal Unit, Groote Schuur Hospital and University of Cape Town, Observatory, 7925, Cape Town, South Africa ([email protected]).

ephrotic syndrome is characterized by a urinary protein loss equal to or exceeding 3.5 g/1.73 m2 of body surface area per day.1 This definition also includes the presence of the clinical manifestations arising from heavy loss of urinary proteins, such as edema, hypoalbuminemia, hyperlipidemia, lipiduria, and a hypercoagulable state. Reports from most parts of the world have shown that nephrotic syndrome represents a significantly large proportion of patients manifesting with different forms of renal disease.2-9 Patterns of glomerular diseases that lead to nephrotic syndrome continue to change in different parts of the world due to changing patterns of infection, improvement in the treatment of diseases, and other environmental factors.10,11 In Africa, malaria, human immunodeficiency virus (HIV), hepatitis B and C, tuberculosis, and parasitic infections (such as schistosomiasis) are common and may all be factors that significantly predispose to renal disease. About 30 to 40 years ago, proliferative glomerulonephritis and membranous glomerulonephritis12 were the common causes of nephrotic syndrome in black South Africans, while in other parts of Africa quartan malaria nephropathy was largely identified to be responsible.13,14 Over the years, there has been little update on the etiology of nephrotic syndrome in many African countries despite the epidemic of diseases such as HIV along with an enhanced capacity to diagnose and , treat rheumatologic diseases such as systemic lupus erythematosus. The aim of this study is to show the distribution and frequency of biopsy-proven causes of nephrotic syndrome in native black Africans attending the Groote Schuur Hospital in Cape Town, South Africa.

INTRODUCTION

N

METHODS

This study was approved by the University of Cape Town research ethics committee. We retrospectively reviewed the data of 294 black South African patients who presented to Groote Schuur Hospital from January 2000 to December 2009 with nephrotic-range proteinuria (3.5 g/24 hr) and who underwent a renal biopsy to

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determine the cause of disease. We documented the demographic, clinical, and relevant biochemical details of each patient at the time of renal biopsy (age, gender, presence of edema, presence of hypertension, serum creatinine, albumin and cholesterol, and urine proteincreatinine ratio). Kidney biopsy specimens were stained and analyzed by light microscopy, immunohistochemistry, and electron microscopy. Glomerular diseases were classified as primary or secondary. Primary disease was considered if the patient's serology was negative for HIV, hepatitis B and C, syphilis, antineutrophil cytoplasmic antibodies, antinuclear antibodies, and if there was no known associated systemic disease at the time of renal biopsy. Primary glomerular diseases were classified into 8 pathologies: minimal-change disease, mesangial proliferative glomerulonephritis, mesangiocapillary glomerulonephritis, membranous glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, crescentic and necrotizing glomerulonephritis (not fulfilling the criteria for systemic disease) and postinfectious glomerulonephritis. Secondary glomerular diseases included lupus nephritis, HIV-associated nephropathy (HIVAN), diabetic nephropathy, any nephropathy associated with hepatitis B or C virus infection, amyloidosis, hypertensive nephrosclerosis, preeclampsia, systemic vasculitis, and pauci-immune crescentic glomerulonephritis. Specifically, HIVAN was diagnosed when the histology showed combined features of focal segmental glomerulosclerosis, podocyte hypertrophy, microcystic dilatation of the tubules with variable tubular atrophy, and a variable extent of interstitial fibrosis.

Table 1. Baseline Demographic and Clinical Features of the Patients Variable Age, y 40 >40 Females, % Serum creatinine, mol/L 110 mol/L 111-200 mol/L > 200 mol/L Serum albumin, g/L 15 g/L 16-25 g/L >25 g/L 24-Hour urine protein excretion 10.0 g >10.0 g Cholesterol, mmol/L Edema present, % Hypertension present, % No. of renal biopsies 2000-2004 2005-2009 Value 33.9 ± 12.0 74.1% 25.9% 54.8 375.5 ± 422.9 30.3% 20.7% 49.0% 22.8 ± 7.9 21.0% 44.0% 35.0% 10.0 ± 6.5 62.8% 37.2% 7.0 ± 3.5 68.4 39.8 115 (39.1) 179 (60.9)

To provide age comparisons with kidney disease types, the patients were divided into 2 age categories: those aged less than 40 years and patients aged at least 40 years. Renal diseases were also classified according to gender. By stratifying the levels of serum creatinine, we classified renal function as normal (serum creatinine, 110 mol/L), mild impairment (serum creatinine, 111200 mol/L), and severe impairment (serum creatinine, >200 mol/L). The data were analyzed with the SPSS statistical package version 11.0 (SPSS Inc, Chicago, Illinois). The frequencies of cases were expressed as percentages. c2 Test was used to test for differences in frequency of disease between males and females and between the 2 age categories. P value was taken as significant if less than .05.

STATISTICS

RESULTS

The baseline demographic and clinical features of the patients are shown in Table 1. The mean age of the patients at time of biopsy was 33.9 ± 12.0 years, 74.1% of all the subjects were classified as young adults (40 years of age), and there were slightly more females (54.8%). Most of the patients (49.0%) already had severe renal impairment at the time of biopsy with 65.0% having serum albumin that was less than 25 g/L.

Table 2. Frequency of Causes of Nephrotic Syndrome Frequency of Occurrence N (%) 121 (41.2) 6 (5.0) 19 (15.7) 19 (15.7) 2 (1.7) 8 (6.6) 23 (19.0) 18 (14.9) 15 (12.4) 11 (9.0) 173 (58.8) 74 (42.8) 23 (13.3) 16 (9.2) 12 (6.9) 10 (5.8) 8 (4.6) 30 (17.4)

Type of Glomerular Disease Primary GN Cresentic GN Chronic GN/end-stage kidney Focal segmental glomerulosclerosis IgA nephropathy Minimal-change disease Mesangiocapillary GN Membranous GN Mesangial proliferative GN Postinfectious GN Secondary GN HIV-associated nephropathy Lupus nephritis Diabetic nephropathy Membranous GN Chronic GN/end-stage kidney Mesangiocapillary GN Othersa

Abbreviations: GN, glomerulonephritis; HIV, human immunodeficiency virus.

a

Others included amyloidosis, secondary crescentic GN, secondary focal segmental glomerulosclerosis, hypertensive nephrosclerosis, myeloma kidney, secondary mesangial proliferative GN, and preeclampsia.

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Edema was absent in 31.6% of the patients. The number of biopsies increased by 55.7% over the study period. We observed a higher frequency of secondary glomerular diseases (58.8%) than primary glomerular diseases, which occurred in 41.2% of the patients (Table 2). Of the primary glomerular diseases, mesangiocapillary glomerulonephritis was the most common, with a frequency of 19.0%. Focal segmental glomerulosclerosis and membranous glomerulonephritis occurred in 15.7% and 14.9% of the patients, respectively, while IgA nephropathy had the least frequency of occurrence (1.7%) (Table 2). HIVAN was the most common secondary glomerular disease leading to the nephrotic syndrome (42.8%). Lupus nephritis and diabetic nephropathy were found in 13.3% and 9.2%, respectively, while secondary membranous glomerulonephritis and mesangiocapillary glomerulonephritis were observed in 6.9% and 4.6%, respectively, of the patients. HIVAN occurred more commonly in young males (29.0%) than in older males (12.1%), young females (28.8%), or older females (16.3%) (Table 3). Also, mesangiocapillary glomerulonephritis occurred significantly more in young males than in young females (15.0% vs 5.9%, p = .023), and in keeping with the gender distribution of systemic lupus erythematosus, lupus nephritis occurred significantly more in young females (p < .0001). The distribution of other glomerular diseases is as shown in Table 3. Table 4 shows the causes of the nephrotic syndrome along with the mean creatinine and proportions of patients stratified according to the different serum

creatinine concentrations. Most patients with HIVAN (73.6%; p < .0001) presented with severe renal impairment (serum creatinine >200 mol/L) at the time of biopsy. Most patients with the non­HIV-related glomerular disease (focal segmental glomerulosclerosis, mesangiocapillary glomerulonephritis, membranous glomerulonephritis, lupus nephritis, minimal-change disease, and mesangial proliferative glomerulonephritis) mostly presented with mild or severe renal impairment (Table 4). All the patients with IgA nephropathy presented early (serum creatinine 110 mol/L). It is reported that glomerular diseases account for up to 90% of end-stage renal disease (ESRD) in the United States.15 In some parts of Africa, the hospital admission rate for the nephrotic syndrome is reported to be 100 times more than that in Europe and the United States.16 Given the level of poverty and poor infrastructure in most of Africa, along with the increasing challenge of tackling the epidemic of ESRD, an understanding of the patterns of glomerular diseases may be useful in the reduction of ESRD through appropriate intervention. This study has shown that in black South Africans: (1) secondary glomerular diseases are more common than primary glomerular diseases; (2) HIVAN is the leading cause of nephrotic proteinuria; and (3) most patients with glomerular disease already have severe renal impairment at the time of hospital presentation. In developing countries, glomerular disease is more likely

DISCUSSION

Table 3. Distribution of the Causes of Nephrotic Syndrome by Age and Gender Females, % (n = 161) Causes of Nephrotic Syndrome Primary glomerular diseases Mesangiocapillary GNa Membranous GN Focal segmental glomerulosclerosis Chronic GN/end-stage kidney Minimal-change disease Mesangial proliferative GN Crescentic GN Postinfectious GN IgA nephropathy Secondary glomerular diseases HIV-associated nephropathy Lupus nephritisb Diabetic nephropathy Othersc

a b c

Males, % (n = 133) 40 y (n = 100) 65.0 15.0 7.0 11.0 14.0 3.0 7.0 3.0 4.0 1.0 35.0 29.0 ­ ­ 6.0 >40 y (n = 33) 64.4 18.2 6.1 6.1 12.1 3.0 6.1 6.7 6.1 ­ 35.6 12.1 3.0 9.1 11.4

40 y (n = 118) 45.6 5.9 6.8 5.1 7.6 4.2 6.8 5.9 2.5 0.8 54.4 28.8 15.3 3.4 6.9

>40 y (n = 43) 39.7 7.0 4.7 9.3 4.7 2.3 4.7 2.3 4.7 ­ 60.3 16.3 9.3 20.9 13.8

Abbreviations: GN, glomerulonephritis; HIV, human immunodeficiency virus. p = .023 for males and females 40 years of age. p < .0001 for males and females 40 years of age. Others included amyloidosis; secondary focal segmental glomerulosclerosis, hypertensive nephrosclerosis, myeloma kidney, and preeclampsia.

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to occur as a complication of an infection or infestation than in developed countries, where primary glomerular diseases have been shown to account for a large proportion of glomerular diseases and the nephrotic syndrome.2,3,6,17,18 In the past, quartan malaria nephropathy was reported as a major cause of the nephrotic syndrome in many parts of sub-Saharan Africa;13,14 recent reports no longer support this association.11,19 The burden of HIV infection in sub-Saharan Africa is well known, and HIV-related kidney disease may now be the leading cause of ESRD in these parts of the world. A recent study has shown that HIV/AIDS was the major communicable disease identified to account for a high death rate in adults aged 15 to 64 years in Cape Town and its surrounding districts in a period (2001-2006) when the number of deaths attributed to nephritis/nephrosis was reported to have risen sharply20,21 by an astounding 67%. It is therefore not surprising that HIVAN was the most common cause of the nephrotic syndrome in patients in our study. It has previously been extrapolated (using data from the United States) that the number of people with HIVAN in Africa could well be between 0.9 to 3.1 million, making it a dominant contributor to ESRD in Africa.22,23 Secondary glomerular diseases such as membranous glomerulonephritis and mesangiocapillary glomerulonephritis were also predominantly due to infections and were mainly seen in patients with HIV infection and hepatitis B and C infections. Our study is important, as it shows that HIVAN is a major player in renal disease within Africa. In other registries from Europe, Asia, North America, and South America2-4,6,17,18 HIVAN is seldom reported as a cause of

kidney disease, therefore making it an important diagnosis from an epidemiological point of view. This study also shows that a large number of our patients have severe renal impairment at the time of presentation. Wauters et al24 have identified 4 reasons why patients with kidney disease often present late to the nephrologist: (1) disease-related factors (acute illness or asymptomatic disease); (2) patient-related factors (denial, comorbid conditions, or low socioeconomic status); (3) physician-related factors (primary care physicianrelated or policy of renal unit); and (4) health care system­related factors (limited access to care or limited access to specialized care). The consequences of late presentation are well documented and include higher morbidity and mortality and increased cost to the health care system due to hospitalizations and procedures.25 South Africa may have the best health care system in all of Africa; however, late presentation to our centers is often from patient-related factors8 such as socioeconomic status or patients who first go to seek alternative medicine care from a native healer (sangoma).26 Mesangiocapillary glomerulonephritis was the most common primary glomerular disease leading to nephrotic proteinuria in our study population (19.0%), while IgA nephropathy was the least (1.7%). The low frequency of IgA nephropathy confirms a previous study from our center by Swanepoel et al27 but disproves the notion that IgA nephropathy does not occur in blacks. However, we believe this stems from our biopsy policy, which excludes obvious uncomplicated cases of IgA nephropathy from undergoing a renal biopsy. This

Table 4. Causes of Nephrotic Syndrome and Levels of Serum Creatinine at Time of Renal Biopsy Serum Creatinine, mol/L Causes of Nephrotic Syndrome Primary glomerular diseases Mesangiocapillary GN Membranous GNa Focal segmental glomerulosclerosis Chronic GN/end-stage kidneyb Mesangial proliferative GNa Minimal-change diseasea Crescentic GN Postinfectious GN IgA nephropathy Secondary glomerular diseases HIV-associated nephropathyb Lupus nephritis Diabetic nephropathy Amyloidosis

a b

Mean, mol/L 192.7 ± 155.9 109.5 ± 109.1 176.5 ± 89.8 771.7 ± 650.9 213.4 ± 293.5 126.3 ± 70.8 290.6 ± 236.8 372.6 ± 324.3 50.0 ± 22.7 580.9 198.4 338.1 177.6 ± ± ± ± 445.9 177.4 384.6 139.4

110 mol/L, % 111-200 mol/L, % >200 mol/L, % 41.4 36.8 30.4 ­ 36.8 50.0 7.7 18.2 100.0 16.7 47.8 18.8 40.0 31.0 42.1 30.4 6.9 42.1 40.0 38.5 18.2 ­ 9.7 13.0 43.8 40.0 27.6 21.1 39.1 93.1 21.1 10.0 53.8 63.6 ­ 73.6 39.1 37.5 20.0

Abbreviations: GN, glomerulonephritis; HIV, human immunodeficiency virus. p < .05. p < .0001.

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limited renal biopsy policy also applies to diabetic patients with nephropathy (except if they have an unusual clinical presentation, eg, those with active urinary sediments) and could therefore explain the low frequency seen in our study.

CONCLUSIONS

As glomerular diseases contribute significantly to the global incidence of ESRD, measures targeted at early identification and treatment of these diseases is imperative. This may be truer for developing countries that are less likely to cope with the burden of ESRD. While the provision of tools and skills to enable many renal centers in Africa to perform and interpret renal biopsies will be very helpful, centres with these skills and tools may need to be more aggressive with an outreach program. Such an outreach program should provide a histological interpretation service ­ either directly or via the internet. This will lead to early detection and treatment of disease. Also, as it is important to emphasize the need for early referral of patients, factors found to be responsible for late presentation need to be effectively and rapidly improved to avoid the detrimental effects of advanced disease with uncontrolled nephrosis. Finally, as many countries roll out anti-retroviral medications to combat HIV, it should be policy to assess for kidney disease at the time HIV is diagnosed and at regular intervals once therapy is commenced. We wish to thank our colleagues in the renal unit for their support.

ACKNOwLEDGEMENTS

REFERENCES

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8. Van Rensburg BWJ, van Staden AM, Rossouw GJ, Joubert G. The profile of adult nephrology patients admitted to the Renal Unit of the Universitas Tertiary Hospital in Bloemfontein, South Africa from 1997 to 2006. Nephrol Dial Transplant. 2010;25:820-824. 9. Naicker S. End-stage renal disease in sub-Saharan and South Africa. Kidney Int. (Suppl) 2003;83:S119-S122. 10. Reshi AR, Bhat MA, Najar MS, et al. Etiological profile of nephrotic syndrome in Kashmir. Indian J Nephrol. 2008;18:9-12. 11. Olowu WA, Adelusola KA, Adefehinti O, Oyetunji TG. Quartan malariaassociated childhood nephrotic syndrome: now a rare clinical entity in malaria endemic Nigeria. Nephrol Dial Transplant. 2010;25:794-801. 12. Seedat YK. Nephrotic syndrome in the Africans and Indians of South Africa. A ten-year study. Trans R Soc Trop Med Hyg. 1978;72:506-512. 13. Kibukamusoke JW, Hutt MSR,Wilks NE. The nephrotic syndrome in Uganda and its association with quartan malaria. Q J Med. 1967;36:393­408. 14. Seggie J, Davies PG, Ninin D et al. Patterns of glomerulonephritis in Zimbabwe: survey of disease characterized by nephrotic proteinuria. Q J Med. 1984;209:109­118. 15. US Renal Data System USRDS 2003 Annual Data Report: Atlas of EndStage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2003. 16. Seggie JL, Adu D. Nephrotic syndrome in the tropics. In: Cameron JS, Glassock RJ, eds. The nephrotic syndrome. New York: Marcel Dekker, 1988:653-696. 17. Rychlík I, Jancová E, Tesar V, et al. The Czech registry of renal biopsies. Occurrence of renal diseases in the years 1994­2000. Nephrol Dial Transplant. 2004;19:3040­3049. 18. Li LS, Liu ZH. Epidemiologic data of renal diseases from a single unit in China: Analysis based on 13,519 renal biopsies. Kidney Int. 2004;66:920­923. 19. Doe JY, Funk M, Mengel M, Doehring E, Ehrich JH. Nephrotic syndrome in African children: lack of evidence for `tropical nephrotic syndrome'? Nephrol Dial Transplant. 2006;21:672-676. 20. Mayosi BM, Flisher AJ, Lalloo UG, Sitas F, Tollman SM, Bradshaw D. The burden of non-communicable diseases in South Africa. Lancet. 2009;374:934-947. 21. Statistics South A. Mortality and causes of death statistical release in South Africa, 2006. Findings from Death Notification. P0309.3. Pretoria: Statistics South Africa, 2008. 22. Naicker S, Han TM, Fabian J. HIV/AIDS--dominant player in chronic kidney disease. Ethn Dis. 2006;16:S2-56-60. 23. Fabian J, Katz I, Gerntholtz T, Goetsch S, Naicker S. Chronic kidney disease in human immunodeficiency virus infection. Panminerva Med. 2007;49:51-66. 24. Wauters JP, Lameire N, Davison A, Ritz E. Why patients with progressing kidney disease are referred late to the nephrologist: on causes and proposals for improvement. Nephrol Dial Transplant. 2005;20:490-496. 25. Schmidt RJ, Domico JR, Sorkin MI, Hobbs G. Early referral and its impact on emergent first dialyses, health care costs, and outcome. Am J Kidney Dis. 1998;32:278-283. 26. Swanepoel CR, Blockman M, Talmud J. Nephrotoxins in Africa. In: De Broe me, Porter GA, eds. Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals. New York, USA: Springer, 2008;859­870. 27. Swanepoel CR, Madaus S, Cassidy MJ, et al. IgA nephropathy--Groote Schuur Hospital experience. Nephron. 1989;53:61-64. n

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