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Paediatric Urology

Vesico-ureteral Reflux in Paediatric Patients ­ Update on Treatment

Pa o l o C a i o n e

Chief, Division of Paediatric Urology, and Head, Department of Nephrology-Urology, `Bambino Gesù' Children's Hospital, Rome

Abstract

The pathogenesis and the appropriate treatment of vesico-ureteral reflux (VUR) and correlated nephropathy is still very controversial, despite its frequence in infancy and childhood. We reviewed the pathogenetic hypothesis and the current management options of VUR and related nephropathy. VUR prevalence is estimated at up to 1% of children within three years of age. In newborns and infants, VUR is more severe and frequent in male gender compared with pre-school and school-age girls with recurrent urinary tract infections (UTIs). Renal damage occurs in 40­45% of VUR as a consequence of acquired renal scarring secondary to febrile acending UTIs. Recently, pre-natally determined renal hypodysplasia has been recognised as congenital nephropathy associated with VUR. Appropriate VUR treatment is still not defined, as long-term antimicrobial prophylaxis and early surgery by open or laparoscopic techniques have classically been adopted. Endoscopic treatment by subureteral bulking agents (i.e. dextranomer in jaluronic acid) has recently gained popularity. The role of antimicrobial prophylaxis in presenting UTIs and new renal damage has been discussed and no prophylactic treatment has been advocated. In conclusion, definitive results on the different therapeutic options are still lacking. Correct information and minimally invasive, early endoscopic treatment should be offered, taking into account the preference of the parents. Dysfunctional elimination syndrome requires appropriate urotherapy in any toilet-trained child with abnormal voiding habits.

Keywords

Vesico-ureteral reflux, reflux nephropathy, endoscopic treatment, antimicrobial prophylaxis, urinary tract Infections (UTIs), ureteral re-implantation

Disclosure: The author has no conflicts of interest to declare. Received: 13 May 2009 Accepted: 10 July 2009 Correspondence: Paolo Caione, Primario Divisione Chirurgia Urologica, Direttore Di Dipartimento Nefrologia-Urologia, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S Onofrio, 4, 00165 Rome, Italy. E: [email protected]

Vesico-ureteral Reflux and Related Nephropathy in Infants and Children

The optimal management of vesico-ureteral reflux (VUR) in infants and children remains one of the most controversial questions in paediatric urology. A wide spectrum of therapeutic strategies have been proposed, adopted and sometimes discouraged over the last two to three decades. The new clinical approach to VUR treatment is the result of a significant evolution of new concepts in bladder and lower urinary tract pathophysiology and new knowledge of renal parenchyma damage concerning acquired and congenital reflux nephropathy. VUR is a well-recognised urological abnormality characterised by retrograde urine flow from the bladder to the kidneys through the ureters. Its prevalence is estimated to be up to 1% of children in the first three years of life, with differences between males and females in infancy and school age. 1­4 The significance of VUR in paediatrics has been strongly debated in the last few years. Very few randomised controlled studies have been available until now to confirm the role of VUR in the pathogenesis of recurrent urinary tract infections (UTIs), febrile ascending pyelonephritis and the onset of renal scars. 1,4,5 The refluxing uretero­vesical junction was initially considered only as a consequence of a structural defect of the uretero­trigonal junction. More recently, the observation that

high intravesical pressure occurs during dysfunctional voiding has led researchers to consider that VUR may develop in high-pressure emptying bladders. 3 So far, disorders of the lower urinary tract and VUR have been considered from a functional rather than a structural point of view.

The `Reflux Nephropathy'

Renal damage is present in about 40­45% of VUR in pre-school-age children. It was considered a consequence of acquired renal scarring secondary to febrile ascending UTI. Recent studies have demonstrated that VUR is often associated with congenital nephropathy (renal hypodysplasia), which is determined prenatally6,7 (see Figure 1). Any febrile acute intravenous urography (IVU) that might occur in a child with VUR could cause only limited further parenchymal damage. Males are at greater risk compared with females7 (see Figure 2).

Management of Vesico-ureteral Reflux

Just as the pathogenesis of the consequences of VUR on renal parenchyma is controversial, the appropriate treatment of children with VUR is still debated. Some physicians take a completely nontreatment approach to VUR, while other urologists suggest early surgical intervention using open techniques, and, lastly, minimally invasive procedures such as endoscopic treatment by bulking

© TOUCH BRIEFINGS 2009

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Figure 1: Risk of Chronic Renal Failure in Infants with High-grade Vesico-ureteral Reflux

54% 46%

Figure 3: Voiding Cystourethrogram and Endoscopic Treatment of Left Vesico-ureteral Reflux

A

46% 54%

CRF

No CRF

Among 50 infants presenting high-grade bilateral vesico-ureteral reflux (VUR) detected at <1 year of age, 27 (54%) were at risk of long-term renal failure (chronic renal failure [CRF]).7

Figure 2: Gender Distribution of Chronic Renal Failure in 50 Infants with Bilateral Gross Vesico-ureteral Reflux

35.7% 64.3%

B

C

Males At risk of CRF Not at risk

A: Voiding cystogram of a male boy, four years of age, with recurrent febrile urinary tract infections (UTIs): severe left vesico-ureteral reflux (VUR) with complete extravesicalisation of the uretero­vesical junction. B: Endoscopic treatment of the gross dilated ureteral orifice by metallic needle and ureteral catheter to guide the endoscopic procedure. C: Modified endoscopic view of the ureteral orifice and immediate VUR resolution.

100%

on the basis of an accurate meta-analysis; seven different treatment modalities were recommended depending on the radiological degree of VUR and the clinical features of the patients. 8,9 Below we present the main therapeutic options, which are still under debate.

Antimicrobial Prophylaxis

The basic principle of long-term antimicrobial prophylaxis assumes that VUR tends to spontaneously regress over a three- to 10-year period. Pending this spontaneous solution, UTIs must be prevented by daily administration of low-dose antimicrobial drugs (50 or 30% of therapeutic dose) to reduce the risk of pyelonephritic episodes and new renal scarring.1 Various medications are used. Sulphonamides and nitrofurantoine are commonly given in northern Europe and North America. The advantages of these drugs are their low cost and good stability in solution and at room temperature; however, side effects are also described: allergic reactions, granulocytopenia and gastric intolerance. They are not recommended in young infants and newborns. In other countries, such as as Italy, amoxicillin with clavulanic acid and third-generation oral cephalosporins is preferred. However, the `compliance' of children and parents to long-term administration of antimicrobial medications has been evaluated at less than 20%, and residual antibacterial power is less

Females At risk of CRF Not at risk

Twenty-seven of 42 males presented with chronic renal failure (CRF) (64.3%) compared with none of the eight females.7

agents have recently gained popularity. Long-term antibacterial prophylaxis or treatment of only single episodes of UTIs are adopted by different urologists and nephrologists. Very few randomised prospective studies have been published comparing long-term prophylaxis with conservative observation and prompt treatment of single episodes of UTIs in order to reduce the frequency and severity of febrile UTIs and prevent renal parenchyma damage. 4,5 In 1997, the American Urological Association (AUA) processed specific guidelines for VUR treatment

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EUROPEAN UROLOGICAL REVIEW

Vesico-ureteral Reflux in Paediatric Patients ­ Update on Treatment

than 17% at 12­18 hours. 10,11 The increased risk of bacterial resistance must also be considered. UTIs may occur in up to 42% of children in antimicrobial prophylaxis, and after five years 22% have febrile UTIs. Moreover, VUR tends to disappear slowly over time: after one year of prophylaxis, the disappearance rate was calculated as 37% in grade 2 VUR, 33% in grade 3 VUR and close to 0% in grade 4 VUR.12 In a multicentre study in children by the International Reflux Study Group,13 the spontaneous cure rate of grade 3­4 VUR was less than 20% after five years of prophylaxis and about 52% after 10 years. 14 Repeated voiding cystourethrograms are required during conservative treatment, increasing the concern about the invasiveness of the procedure.

Table 1: One-year Results of Different Treatment Options for Grade 3­4 Vesico-ureteral Reflux

Treatment Options Antibiotic prophylaxis Open surgery Deflux: One injection Two injections 71 84 Cure Rate (%) 33 98

Table 2: Vesico-ureteral Reflux Treatment Options ­ Parental Preference

Treatment Endoscopic treatment Antibiotic prophylaxis Open surgery No determined opinion Preference (%) 80 5 2 13

Open Surgery Repairs

A large number of highly effective open surgical repairs of VUR have been proposed and adopted, beginning with the original description by Guy Laedbetter. The Leadbetter-Politano technique was effective but presented a significant rate of late upper urinary tract obstruction, and is no longer used.15 The most common intravesical repair was proposed by Joseph Cohen in 1975:16 the ureteral hiatus remains the same and the ureter is re-implanted in a transtrigonal submucosal tunnel (`transtrigonal ureteroneocystostomy'). The success rate is very high (95.9% of ureters and 95.1% patients across 86 surveys).8 However, the Cohen technique requires 60­90 minutes of surgery, a few days of hospitalisation with antalgic treatment and bladder catheterisation. A moderate amount of dysuria and frequency is common, and children will miss school and sporting activities for about one month. A failure rate of 3­5% can be expected. In this anatomical position, it is difficult or even impossible to perform retrograde ureteral catheterisation or ureteroscopy, procedures that are significantly more common in the adult population.

On 100 patients with grade 3­4 vesico-uteral reflux (VUR) after six to 12 months of antibacterial prophylaxis.

Figure 4: Rate of Different Therapeutic Options for Treatment of Vesico-ureteral Reflux Over 30 Years

1970

1980 Antimicrobial prophylaxis

1990 Open surgery

2000 Endoscopy

In the Lich and Gregoir extravesical approach,17,18 the bladder muscular wall is incised to expose the mucosa and a longer (3­4cm) submucosal tunnel is created. It may cause minor bladder dysfunction and urinary retention, expecially when the procedure is performed bilaterally. A partial and transient denervation occurring around the ureteral hiatus is the suggested reason for this complication. More recently, there has been interest in performing this technique laparoscopically.19 Although successful in skilled hands, the utility of this approach remains in question given the cost­benefit ratio.

Different therapeutic options for vesico-ureteral (VUR) treatment at our institution over the last three decades. Endoscopic treatment has gained popularity versus long-term antimicrobical prophylaxis and open surgery.

migration of non-biodegradable particles. Similar problems were experienced with Macroplastique ® (Uroplastique, Bruxelles, Belgium). Cross-linked bovine collagen was a valid alternative for some years, but it presented a high resorption rate and a risk of immunogenic reactions. In our experience, adverse reactions have never occurred with this agent.22 The only agent currently approved by the US Food and Drug Administration (FDA) for this purpose ­ and widely adopted in Europe ­ is Deflux® (dextranomer/hyaluronic acid copolymer, QMedd, Uppsala, Sweden), a slowly biodegradable injectable agent that is non-immunogenic and not animal-derived. We adopted Deflux in 1995.12 The experience in our department is 2,400 treated patients and 4,000 ureteral units. Our success rate is about 90% (96% in grade 2 VUR, 91% in grade 3 VUR and 81% in grade 4 VUR). Grade 5 VUR has been also treated by Deflux subureteric and/or intra-ureteric injection, with a success rate of approximately 67%, although a number of children may require two or even three treatments.22 The increased efficacy of endoscopic treatment in

Endoscopic Treatment

Injection of bulking agents under the refluxing ureteral orifice by cystoscopy was first described by Matouscheek in 198120 and pointed out by O'Donnell and Puri from 1984.21 Teflon® paste was initially adopted and the technique was named `STING' (subureteral Teflon injection), alluding to the mosquito puncture. The technique consists of a subureteric implant of a biomaterial, acting as a bulking agent, that increases and stabilises the intravesical length of the distal ureter. A paediatric cystoscope (8­14F) with a operating channel and a rigid or semi-rigid cannula are required. The agent used has changed over time in the search for the ideal. Polytef was not accepted in the US due to the risk of long-distance

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expert hands due to refinement of the techniques means that we do not routinely perform voiding cystourethrogram after treatment; it is requested only if UTIs or ultrasound signs are present. The morbidity is minimal, with the procedure performed on an outpatient basis. Dysuria and side effects are minimal, and the child returns to normal activities within one day. The risk of ureteral obstruction is very rare (fewer than 0.5% of cases) and transient (see Figure 3). In expert hands, Deflux endoscopic treatment today presents similar positive results to open surgery, with minimal invasiveness and discomfort and without the severe adverse effects of open surgery. Compared with antimicrobial prophylaxis, endoscopic treatment with Deflux was demonstrated in our randomised study to be superior (8­10 versus 22%) in terms of the prevention of febrile UTIs12 (see Table 1). prophylaxis was chosen by 5% and open surgery by 2%; 13% of the parents did not express any preference (see Table 2). If the results of different therapeutic options are similar, we have to consider the patient's/parents' preference.23 These results suggest the need for a new algorithm for VUR management in children based on endoscopic treatment as the first choice for intermediate- to high-grade VUR as an efficacious and safe alternative to open surgery. In lower-grade VUR, if the patient is symptomatic with recurrent febrile UTIs, endoscopic treatment represents a valid alternative to long-term antimicrobial prophylaxis or occasional antibiotic administration (see Figure 4).

Conclusion

The best treatment for VUR has still not been determined. In our opinion, immediate treatment of VUR in infants and children using subureteric injection of Deflux is a fascinating new concept. It allows successful repair at the diagnosis of VUR with minimally invasive morbidity, and significantly reduces the rate of newly developed febrile pyelonephritis, renal scarring, annual testing and use of prophylactic antimicrobials. These advantages are more evident within the first two years of life. Anxiety and stress on the family and invasive procedures on the child are also greatly decreased. 23 Accurate medical and behavioural treatment of bladder and bowel dysfunction is necessary if abnormal voiding habits (daytime incontinence, urgency, frequency) and constipation are present in toilet-trained children. 24,25 The urological and nephological approach to the child with VUR has greatly changed in recent years and is still evolving. Congenital renal hypodysplasia is well recognised, and we can reduce the risk of symptomatic UTIs and new renal scarring.26 The advent of minimally invasive and cost-effective endoscopic treatment is strongly modifying the natural history of children suffering from congenital VUR and recurrent febrile UTIs. Dysfunctional elimination syndrome is well recognised in school-age children and requires appropriate uropathy. n

No Prophylactic Treatment but Antimicrobial Therapy for Febrile Urinary Tract Infections

This strategy is based on recent observations of long-term antimicrobial prophylaxis.10,11 Daily intake of an antimicrobial drug for a long period presents low compliance, especially in children. In a recent study by Hensle,11 most children took antibiotics for less than half the year (41.4% of the year). Subtherapeutic doses of antimicrobial drugs could contribute to the onset of bacterial resistance. Garin 4 observed a higher incidence of acute pyelonephritis and new renal scarring in children supposed to receive long-term antimicrobial prophylaxis (12.9 and 9.0%, respectively) compared with those treated occasionally for acute episodes (1.7 and 3.4%, respectively). However, a critical review of the literature data by the Cochrane Renal Group showed no significant difference in terms of the risk of symptomatic IVU or renal damage comparing antimicrobial prophylaxis versus no treatment. A bias of the study could be the small number of enrolled patients.6 A similar experience was recently reported by an Italian multicentre, randomised, prospective study.5 In conclusion, although definitive confirmation is required, the role of antimicrobial prophylaxis in preventing UTIs and new renal scarring is now under discussion.

A New Therapeutic Algorithm

In the absence of definitive results for the different therapeutic options in grade 3­4 VUR, we must offer children and their parents correct information on the different options and consider their preference. At our institution,23 we provide detailed information on the mechanism of action, cure rate, possible complications and pros and cons of the different therapeutic options. The great majority of parents (80%) prefer endoscopic treatment, whereas antibacterial

Paolo Caione is Chief of the Division of Paediatric Urology and Head of the Nephrology-Urology Department at `Bambino Gesù' Children's Hospital in Rome. He is President of the Italian Society of Paediatric Urology (SIUP) and a member of several scientific societies, including the European Society for Paediatric Urology (ESPU), the Italian Society of Urology (SIU), the Italian Society of Paediatric Surgery (SICP), the American Academy of Pediatrics (AAP) urology section and the International Continence Society (ICS). Dr Caione has published more than 550 articles, and is Editor or Co-editor of three monographs on paediatric urology.

1. 2. 3. 4. 5. 6. 7.

Smellie JM, Barratt TM, Chantler C, et al., Lancet, 2001;357:1329­33. Upadhyay J, McLorie GA, Bolduc S, et al., J Urol, 2003;169: 1837­41. Sillen U, Pediatr Nephrol, 1999;13(4):355­61. Garin EH, Olavvara F, Garcia Nieto V, et al., Pediatrics, 2006;117(3):626­32. Montini G, Rigon L, Zucchetta P et al., Pediatrics, , 2008;122(5):1064­71. Hodson EM, Wheeler DM, Vimalchandra D, et al., The Cochrane Library, 2007;3. Caione P Villa M, Capozza N, et al., BJU Int, , 2004;93:1309­12.

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Elder JS, Peters CA, Arant BS Jr, et al., J Urol, 1997;157(5):1846­51. Elder JS, Diaz M, Caldamone A, et al., J Urol, 2006;175(2): 716­22. Panaretto KS, Craig JC, Knight JF, et al., J Paediatr Child Health, 1999;35(5):454­9. Hensle TW, Grogg AL, Eaddy M, Nat Clin Pract Urol, 2007;4(9):462­3. Capozza N, Caione P J Pediatr, 2002;140(2):230­34. , Jodal U, Smellie JM, Lax H, Pediatr Nephrol, 2006;21(6):785­92. Greenfield SP Expert Opin Pharmacother, 2003;4(11):1959­66. , Politano VA, Leadbetter WF, J Urol, 1958;79:932­41.

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

Cohen SJ, Aktuelle Urol, 1975;6:1. Lich R Jn, Howerton LW, Davis LA, J Urol, 1961;86:554­8. Gregoir W, Van Regemorter G, Urol Int, 1964;18:122­36. Shu T, Cisek LJ Jr, Moore RG, J Endourol, 2004;18:441­6. Matouschek E, Urologe A, 1981;20:263­4. O'Donnel B, Puri P Br Med J, 1984;289:7­9. , Capozza N, Lais A, Nappo S, Caione P J Urol, , 2004;172:1626­9. Capozza N, Lais A, Matarazzo E, BJU Int, 2003;92(3):285­8. Koff SA, Wagner TT, Jayanthi VR, J Urol, 1998;160:1019­22. Capozza N, Lais A, Matarazzo E, et al., J Urol, 2002;168(4 Pt 2):1695­8. Capozza N, Caione P Pediatr Nephrol, 2007;22:1261­5. ,

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