Vesicoureteral Reflux: The Difficulty of Consensus OR Why Can t We All Just get Along?

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1 Vesicoureteral Reflux: The Difficulty of Consensus OR Why Can t We All Just get Along? J Brandt MD MPH Pediatric Nephrology, UNMSOM Family Practice Grand Rounds 2/14/2012

3 Why do we worry about VUR? 3 % of U.S. children experience a urinary tract infection each year. Urinary tract infection is the most common bacterial disease during the first 3 months of life 3 and accounts for approximately 6 % of febrile illnesses in infants % of children with a urinary tract infection have VUR 2. Overall, an estimated 1-2 % of children have VUR. Some VUR patients develop chronic kidney damage. 5-10% of Pediatric ESRD is due to Reflux Nephropathy 2. Bourchier, Abbott and Maling, 1984; Drachman, Valevici and Vardy, Krober, Bass, Powell, et al., Hoberman, Chao, Keller, et al.,1993

4 What is VUR? VUR is retrograde flow of urine from the bladder into the ureter and/or renal pelvis. This retrograde flow may be seen with a full bladder, only with voiding, or at low bladder volumes in severe cases.

5 VUR Primary VUR VUR in the absence of increased bladder pressure, ureteral, bladder or urethral anomalies. Secondary VUR VUR secondary to a high pressure bladder or significant utereteral anomalies Anatomic: Posterior urethral valves Functional: Dysfunctional voiding or neurogenic bladder.

6 Primary VUR Most mild VUR is usually due to a short ureteral tunnel in the bladder wall.

7 Secondary VUR VUR associated with other urinary tract malformations. Texas pediatric surgical associates,

8 Reflux, Infection and Scar formation Lim R AJR 2009;192: by American Roentgen Ray Society

9 Epidemiology of VUR Most VUR (>50%) is diagnosed following a febrile UTI By puberty 2% of boys and 8% of girls will have a UTI. ~30% of children with a febrile UTI before puberty have VUR. Boys Girls < 1 year of age are more likely to find VUR after UTI compared to girls. More likely to have high grade VUR, secondary VUR and renal damage. Overall have higher incidence of VUR (75% of pts with 1 VUR). Are more likely to have normal kidneys when 1 st evaluated. Are more likely to have associated dysfunctional voiding.

10 Antenatal Hydronephrosis and VUR 40% of VUR is diagnosed during antenatal hydronephrosis evaluation 36% of children with antenatal hydronephrosis have urinary tract pathology 13% is VUR. Overall, VUR tends to be of higher grade than those found after UTIs. Girls > Boys It is unclear if these children have a different risk of recurrent UTI and scarring than those diagnosed after UTI. Lee RS, Antenatal Hydronephrosis as a Predictor of Postnatal Outcome: A Meta-analysis. Pediatrics 2006, 118;586 AUA VUR guidelines 2010

11 Incidence of VUR on screening of Antenatal Hydronephrosis* 13% * Studies where all infants had both ultrasound and vcug postnatally AUA 2010

12 Renal Damage* by VUR Grade with Antenatal hydronephrosis 6.2% 47.9% *DMSA AUA VUR guidelines 2010

13 Genetics Genetic predisposition Family clustering of VUR is common 27-51% of siblings of VUR patients Up to 66% of children of parents or twin with VUR. VUR is more common and of higher grade in Caucasians compared to Blacks. Possible loci have been postulated on multiple chromosomes, but no consensus on the chromosomal major loci has been found Puri P, Nat. Urol Rev 8, (2011)

14 Voiding Cystourethrogram Grading of VUR : Grading correlates with the degree of renal injury and the likelihood of spontaneous resolution

15 Diagnosis- VCUG

16 VCUG and Sedation A normal voiding phase is needed for a complete and reliable VCUG. VCUG can be performed successfully in most patients without sedation. Child life specialist can be very helpful in alleviating anxiety and discomfort about bladder catheterization. If sedation absolutely necessary, midazolam and Nitrous Oxide have the less interference with bladder emptying than Propofol. Sedation will prolong procedure and recovery time. Lim R, AJR 2009; 192:

17 Natural History of VUR: Many cases Self-Resolve. Grade V VUR rarely resolves without surgery. Pediatrics Apr;103(4 Pt 1):

18 Factors in Resolution of VUR Race Renal Scars(RD) Grade of VUR Dysfunctional voiding (DV) Silva JM, Brit J Urology 2006

19 The Importance of Bowel/Bladder Dysfunction in VUR 44% 13% All patients received CAP AUA 2010

20 Does VUR increase Risk of Kidney damage? Renal scarring risk after acute pyelonephritis* VUR vs. no VUR. Odds ratio = 2.8 *Risk of acute and permanent DMSA cortical abnormalities following acute pyelonephritis

21 VUR Therapy If VUR predisposes to Renal Infection and Scar formation, then the goal of VUR treatment is to: 1. Prevent kidney infections. 2. Prevent scar formation.

22 Therapy Options for VUR If most VUR will self-resolve we have 3 reasonable options for management: 1. Passive: Treat any episode of febrile UTI 2. Active: Prevent infections with Antibiotic Prophylaxis 3. Active: Prevent infections by Surgical Correction

23 VUR Treatment History: s Observational studies showed: Recurrent UTIs where associated with increased scarring risk and chronic kidney damage. Continuous antibiotic prophylaxis (CAP) decreased the risk of Recurrent UTIs. Surgical correction could repair VUR and prevent future infections.

24 s: The Great Debate: Antibiotic Prophylaxis or Surgery International Reflux Study in Children (IRSC) Designed to determine if antibiotic prophylaxis or surgery was the superior in treating grade III-IV VUR. Less recurrent pyelonephritis seen with surgery. NO difference in new renal scars by DMSA : Antibiotics 17% vs Surgery 16%

American Urological Assoc. 1997 Adopted by the AAP in 1999 1. Antibiotic prophylaxis (CAP) first. 2.

25 American Urological Assoc Adopted by the AAP in Antibiotic prophylaxis (CAP) first. 2. Yearly VCUG, RUS 3. Surgical repair if: - Recurrent UTI. - High grade VUR. - Lack of VUR resolution.

26 VUR History s: Association between UTI-VUR-Renal scars observed 1990s Guidelines suggest surgery or antibiotic prophylaxis for VUR management s: Antibiotic prophylaxis and Surgery equivalent for VUR management When did we show that Treatment (antibiotics or surgery) are superior to No Treatment?

27 The Modern Era Antibiotics Prophylaxis vs. No Treatment Does antibiotic prophylaxis prevent recurrent pyelonephritis or new renal scars in VUR?

28 Continuous Antibiotics Prophylaxis (CAP) Study Intervention Outcome Results Antibiotic benefit? Quality Garin 2006 Abx vs no Rx: VUR 1-3 N= 113 Scars / pyelo Gr 1-2: No effect of abx Gr 3: less UTI w abx Maybe in Grade 3 -Poor randomization -Low power - Mix of 1 & 2 VUR Pennesi 2006 Abx vs no Rx: VUR 2-4 N=100 Scars / pyelo No effect of abx No Low power Roussey- Kessler 2008 Abx vs no Rx: VUR 1-3 N=225 UTI Girls: No effect Boys: Less UTI w abx Maybe in boys Low power Montini 2008 Abx vs no Rx after UTI (VUR & no VUR) N=338 UTI No effect No Low power for VUR PRIVENT 2009* Abx vs placebo after UTI (VUR & no VUR) N=578 UTI Fewer UTI w abx Fewer febrile UTI w abx Yes -Good overall power -Low power for VUR group No effect of abx prophylaxis seen in 4 small studies. Abx appear to reduce risk of UTI in 1 well powered study, but not VUR specific. * Only study considered low risk of bias by Cochrane

29 Remember the Type 2 Error? Trials finding no difference between outcome groups are at risk of a Type 2 error: Risk of finding no difference in your study sample when a true difference exists Seen when study power is low (small sample size).

30 Very confusing! What do our Experts Recommend?

NICE (British) and European Guidelines 2007-09 UTI in children Multiple risk groups < 3 mos or > 3 mos.

31 NICE (British) and European Guidelines UTI in children Multiple risk groups < 3 mos or > 3 mos. pre-verbal vs verbal. 3yr to 6 yr Typical vs. Atypical vs. Recurrent UTI Next update scheduled after RIVUR complete NICE clinical guideline 54

32 2011

33 Cochrane Abx vs Placebo: No change in # Symptomatic UTI at 1-2 yrs No benefit of Antibiotics Not Significant

34 Cochrane Fewer Renal Scars with Antibiotic prophylaxis Significant

35 2011 Compared with no treatment, long-term low-dose antibiotics DID NOT reduce the # of repeat symptomatic UTIs in children with VUR. Abx prophylaxis did reduce the risk of new or progressive renal damage, but NNT = 8 Considerable heterogeneity, with only one adequately blinded study (Privent). Most studies looked at Grade 1-3 VUR, a few Grade 4 and none Grade 5

36 AAP 2011 No benefit to Prophylactic Antibiotics in preventing recurrent febrile UTIs in infants age 2-24 mos with Grade I to IV VUR. Looked at same trials as Cochrane, restricted to age 2m-2yr, plus several low quality studies rejected by Cochrane. Looked only at Age 2 mos to 2 years Applies only to first UTI. VCUG not recommended after the first UTI unless: Ultrasound shows kidney, bladder, ureteral anomaly Recurrence of a febrile UTI.

38 RIVUR Study

39 VUR Diagnostics Recs UNM After 1 st febrile UTI Boys: Renal Ultrasound + VCUG (and/or DMSA). Evaluate for Voiding Dysfunction BP, Ht/Wt, UA Serum Cr if RUS, BP abnormal or proteinuria found Girls: Renal Ultrasound, UA, BP Ht/Wt Evaluate for Voiding Dysfunction or other risks Consider VCUG or DMSA if no Voiding dysfunction or other risks. VCUG and serum Cr if RUS abnormal

40 VUR Treatment Recs UNM Grade 1-2 No antibiotics If hx of recurrent febrile UTI: consider antibiotic prophylaxis. Treat dysfunctional voiding Grade 3-5 Use abx prophylaxis and consult with Pediatric Urologist/Nephrology Treat any dysfunctional voiding aggressively. At follow-up RUS and Urine protein quantitation every 1-2 years VCUG every 1-2 years to assess resolution of VUR. If VCUG refused, consider DMSA renogram to assess scarring. If recurrent UTIs occur, change therapy (start/change abx or move to surgery) If VUR Gr IV-V or any grade after age 5 yrs consider surgical repair. If recurrent UTIs occur, repeat VCUG and/or DMSA sooner and consider repair.

41 Sibling Risk- AUA recs Risk of VUR in sibling 30% Risk of Renal Cortical damage (DMSA) in Sibling 20% If prior Hx of UTI 35% If No UTI Hx 12% Recommendation: VCUG if evidence of renal scarring on ultrasound or if history of UTI in the sibling. Option: Given that the value of identifying and treating VUR is unproven, an observational approach without screening for VUR may be taken for siblings of children with VUR, with prompt treatment of any acute urinary tract infection and subsequent evaluation for VUR. AUA 2010

42 References AAP SUBCOMMITTEE ON URINARY TRACT INFECTION and STEERING Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months. Pediatrics, 128;595, 2011 National Institute for Health and Clinical Excellence. Urinary Tract Infection in Children: Diagnosis, Treatment, and Long-term Management: NICE Clinical Guideline 54.; at: Pennesi M, et al. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritisband renal scars? A randomized, controlled trial. Pediatrics. 2008; 121(6). Available at: cgi/content/full/121/6/e1489 Garin EH, et al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics. 2006;117(3): Montini G,, et al. Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial. Pediatrics. 2008;122(5): Roussey-Kesler G,, et al. Antibiotic prophylaxis for the prevention of recurrent urinary tract infection in children with low grade vesicoureteral reflux: results from a prospective randomized study. J Urol. 2008;179(2): Craig J, et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med. 2009; 361(18): Nagler EVT, et al. Interventions for primary vesicoureteric reflux (Review). Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD DOI: / CD pub4.

Recurrent Pediatric UTI Revisited 2013

Recurrent Pediatric UTI Revisited 2013 PIDSP 21.2.2013 Shai Ashkenazi, MD, MSc Medicine changes constantly Some aspects of the standard practice of ~40 years are probably not valid and need to be changed