Prevention of UTI in children with VU reflux: management controversies

1. Prevention of UTI in children with VU reflux: management controversies Moshe Efrat MD September 2006

2. Vesicoureteral Reflux (VUR) Retrograde passage of urine from bladder to upper urinary tract VUR = most common urologic abnormality in kids 1% newborns 30 - 45% of children with UTI UTI (upper) = most common serious bacterial infection of children in the developed world in the age of conjugate pneumococcal and H. flu vaccines (Israel is not there yet!! � why?)

3. Two clinical presentations VUR Prenatal: male > female, VUR diagnosed prenatally (by US) Severe VUR common Significant rates spontaneous resolution, but Renal hypoplasia and dysplasia frequent Increased risk renal failure and hypertension Postnatal: Mostly female Presents as febrile UTI Spontaneous resolution is a function of age and grade and if 1 or 2 sided

4. VUR - grading GRADING � The International Reflux Study Group standardized grading the severity of VUR based on findings from a contrast voiding cystourethogram (VCUG). Grade I � Reflux only fills the ureter without dilation. Grade II � Reflux fills the ureter and the collecting system without dilation. Grade III � Reflux fills and mildly dilates the ureter and the collecting system with mild blunting of the calyces. Grade IV � Reflux fills and grossly dilates the ureter and the collecting system. One-half of the calyces are blunted. Grade V � Massive reflux grossly dilates the collecting system. All the calyces are blunted with a loss of papillary impression and intrarenal reflux may be present . There is significant ureteral dilation and tortuosity.

7. Principles of management Premise: VUR can cause upper UTI by bringing bacteria to the kidneys Results: renal scarring, loss of parenchyma ? reflux nephropathy: Potential for hypertension, decreased renal function, proteinuria, renal failure/ end stage renal disease Management: based on - Identification of kids with VUR Prevention of renal damage due to reflux

8. How to prevent damage due to VUR? Medical vs surgical approach Not clear which is more effective! Medical: VUR resolves spontaneously by age 4 -5 years Continuous antibiotics ? sterile urine VUR with sterile urine is assumed benign Most appropriate antibiotics: TMP-SMX, nitrofurantoin Not �-lactams!?!? Why? � Increased bacterial resistance

9. More concerns about medical therapy Long-term antibiotics may ? complications: minor to severe - including bone marrow suppression, Stevens-Johnson syndrome Adherence (compliance) Breakthrough infection Need to monitor reflux with either VCUG or radionuclide cystography (RNC), both with discomfort and radiation

10. The main controversy Does antibiotic prophylaxis of kids with VUR really prevent recurrent upper UTI and concomitant renal scarring? Over the last 5-6 years this has been increasingly questioned / debated and to a certain extent studied�

12. Antibiotic prophylaxis (ABP) - studies Background: ABP recommended for all grades VUR Most studies to date: compare [ABP with surgery] to ABP alone, or compare ABP with surgery Meta-analysis (Wheeler, et al, Arch Dis Child 2003; 88:688-594): 1 randomized, controlled study found no difference in UTI risk with ABP, either continual or intermittent, vs no ABP No large, randomized, prospective trials comparing ABP+ with ABP- in VUR!!!

16. Aims Evaluate the role of VUR in affecting frequency and severity of UTI and renal scarring after APN Determine whether ABP reduces frequency and/or severity of UTI and/or prevents renal parenchymal damage in patients with mild-moderate VUR (grades I, II, III only)

17. The study Randomized, controlled study N= 236 children, 3 months � 18 years APN = acute pyelonephritis: pyuria, fever, positive culture (>105) + DMSA confirmation All tested for VUR by VCUG ? 2 groups: 113 VUR grades I-III and 115 no VUR After initial treatment for APN, both groups randomized: +/- antibiotic prophylaxis (ABP)

19. Conclusion: antibiotics do not prevent APN nor renal scarring in patients with mild or no VUR!!! Results: Overall UTI recurrence 20.1% - ABP: recurrence 22.4% VUR, 23.3% no VUR (NS) +ABP: recurrence 23.6% VUR, 8.8% no VUR (NS, but close, p=0.63) Most recurrences at 9-12 months, most cystitis (DMSA nl), APN only 5.5% No clear-cut advantage for +ABP All recurrences were with resistant bacteria! More APN in +VUR than in -VUR (8 vs 4, but NS)

20. Results, continued 6/8 recurrent APN were in VUR grade III 2/8 in grade II, none in grade I 4 recurrences in non-VUR (2 ABP+, 2 ABP-) Cystitis also VUR III, II >>VUR I Renal scars: Only 5.9% developed scars (1 year F/U only!) 7 VUR+, 6 VUR- (NS) Similar scarring rates ABP+ and ABP- (NS) Increased scarring with increase grade VUR (NS) No difference in scarring in VUR vs non-VUR

22. The Editorial:

23. Fact or fantasy I The study is highly problematic: 1 year follow-up only 1 year follow-up required, no ITT analysis in those not completing 1 year Low incidence APN Low rate renal scarring Non-standardized ABP: either trimethoprim-sulfamethoxazole (TMP-SMX) or nitrofurantoin no placebo given to controls

24. Fact or fantasy II Therefore, too few patients, too short a time period, and maybe the wrong population (VUR I-III), maybe wrong antibiotics - to reach conclusions of significance� Current study: trend for more UTI and more scarring with increasing grades of VUR� III > II > I Important: no evaluation of severe VUR (grades IV, V) Therefore results are not applicable to these patients !

25. Discussion UTI pathogenesis related to bacterial binding to uroepithelial receptors ? No reason to think that VUR increases UTI incidence, but� Reasonable to think that VUR increases APN (vs lower UTI) incidence in those with propensity for UTI = trend but not significant in some studies Scarring is a function of APN and not sterile reflux: good evidence exists

26. ABP should prevent recurrent UTI � few good data to support this! 2 potential barriers to successful ABP for UTI: Adherence (compliance) difficult over years, also antibiotic adverse effects, though rare, increase with exposure time Maybe recurrences mostly at 9-12 months indicate decline in adherence? Emergence of antimicrobial resistance

27. Which drugs are used? Nitrofurantoin or TMP-SMX Theory: absorption high in the in GI tract - colon flora not �exposed� = protected from antibiotics ? little induction of resistance Problem � are areas where TMP-SMX cannot be used: high % GI flora resistant (Israel?) Other agents (e.g. �-lactams) are theoretically poor choices Colonic bacteria exposed to low AB levels Within weeks ? GI colonized primarily with bacteria inherently or newly resistant

28. Another issue Is there any proof that prevention of UTI by continuous ABP prevents scarring better than very early initiation of therapy for APN? No studies performed

29. Possible solutions? Use rotating ABP schedule parallel to ABP for chronic lung disease, switching drug q2-4 weeks Few data for UTI, some potentially encouraging Use non-antibiotic prophylaxis e.g. methenamine mandelate When urine pH <6, methenamine ? formic acid (like formaldehyde) Problem: urine acidification required

30. Suggestions? Additional studies required: To clarify ABP use in VUR grades I,II, III ? Larger, better designed, longer F/U, ITT� To study VUR grades III, IV, V Until new data: For all (?) VUR (severe > moderate > mild), continue using ABP (or surgery for high grade, non-resolving VUR) If TMP-SMX inappropriate epidemiologically, maybe nitrofurantoin should be used > others

31. What about previous studies? Not a lot of data Good systematic review of data available up to 2005�

36. Our questions: antibiotics, yes or no, which, and when? Medical vs surgical therapy? Not clear! Meta�analysis (Wheeler, et al, Arch Dis Child 2003; 88:688-594(: found 7 randomized, controlled studies, ABP vs surgery, n = 859 4 studies: no difference after 5 years 2 studies: less febrile UTI, at 5 years, surgery (10%) vs ABP (22%) But no difference in scarring!

37. Meta-analysis, continued 4 studies: no differences in scarring after 5 years 5% overall risk of new scars by DMSA 4 studies: no differences in renal growth 2 studies: no difference in hypertension or end-stage renal disease Lack of information about surgical vs medical adverse events!!

38. Conclusions 9 reimplantations required to prevent 1 febrile UTI! No reduction in rate of renal scarring! Hardly seems wise to prefer surgical therapy Except?...

40. Rationale AUA guidelines Low grade VUR, VUR in very young kids ? good chance spontaneous resolution so prefer ABP The older kids get or the higher grade the VUR, ABP still recommended but surgery is an option especially if bilateral disease or renal scarring exists Only in children =6 years old with grade V VUR is surgery preferred since the likelihood of spontaneous resolution is very low

41. If ABP follow-up� Close monitoring to identify breakthrough Urine-analysis and cultures whenever UTI possible Surveillance cultures q 3-4 months RNC > VCUG monitoring of VUR ~ yearly

43. So, in conclusion� Until new data: For all (?) VUR (severe > moderate > mild)� continue using ABP or surgery for high grade, non-resolving VUR Nitrofurantoin preferred!?

44. Thanks! Questions? Comments? Protests?