Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux. Randomized Intervention for Children with Vesicoureteral Reflux

1. Renal Scarring in the Randomized
Intervention for
Children with Vesicoureteral Reflux
(RIVUR) Trial
Dr Abdullah Alzahrani

2. VUR
• Retrograde passage of urine from the bladder into the
upper urinary tract
• Most common urologic finding in children
• Primary VUR:
▫ most common form, is due to incompetent or inadequate
closure of the ureterovesical junction (UVJ)
• Secondary VUR :
▫ abnormally high pressure in the bladder that results in
failure of the closure of the UVJ during bladder contraction
▫ often associated with anatomic (eg, posterior urethral
valves) or functional bladder obstruction (eg, bladder bowel
dysfunction and neurogenic bladder)

3. VUR

4. VUR

5. Renal Scar

6. DMSA
• Renal scintigraphy using dimercaptosuccinic
acid (DMSA) can be used to detect acute
pyelonephritis and renal scarring
• DMSA is injected intravenously, and uptake by
the kidney is measured two to four hours later.
• Areas of decreased uptake represent
pyelonephritis or scarring.

7. DMSA
Normal kidney Renal scarsAcute PNA

8. DMSA Normal Renal Scarring

9. RIVUR Trial

10. RIVUR Trial
• Many prospective studies have evaluated the role of
antimicrobial prophylaxis in the prevention of UTI
recurrence and renal scarring in children with
primary VUR
• This is the largest prospective, randomized trial for
children with reflux to date, comparing prophylaxis
with placebo
• Of 10,756 children screened, 1,311 (12%) met entry
criteria, 607 enrolled
• Screening and enrollment took place from June
2007 through May 2011

11. RIVUR Trial
• primary outcome of the RIVUR trial was recurrence of a
febrile or symptomatic UTI .
• Secondary outcomes: renal scarring, treatment
failure, renal function, resource utilization, and
development of antimicrobial resistance in stool
flora.
• In 2014 , they published article about primary outcome
• They found a significantly lower risk of UTI recurrence in
children receiving antimicrobial prophylaxis than in those
receiving placebo (RR, 0.55; 95% CI, 0.38 to 0.78).
• This Article will represents a comprehensive evaluation of
renal scarring outcomes in RIVUR trial participants.

12. PICO
• P: children aged 2–71 months with grade 1–4
primary VUR diagnosed after a first or second
febrile or symptomatic UTI
• I: trimethoprim-sulfamethoxazole (TMP-SMZ)
• C: placebo
• O: renal scarring

16. Methods
• Multicenter, randomized, placebo-controlled
trial in 607.
• Study participants were followed up on for 2
years.
• The Data Coordinating Center ensured that all
participants, clinical site investigators, and
radiologists were blinded to randomization
assignment, participants and clinical site
investigators were further blinded to trial
outcome data during the trial.

17. Methods
• Pilot studies were conducted to ensure
uniformity in methods and imaging quality for
DMSA renal scans and VCUG.
• All DMSA renal scans were reviewed
independently by two blinded reference
radiologists and all differences were adjudicated
to obtain a consensus reading between the two.

19. Methods
• RIVUR trial protocol, study participants were scheduled
for three DMSA renal scans.
• The baseline scan was obtained within 2 weeks of
randomization and 112 days from the index UTI.
• A second DMSA scan was obtained within 21 days of
the 12-month follow-up visit.
• The outcome scan was targeted within 10 days of the
study exit visit at 24 months after randomization.
• For all children with treatment failure, the outcome
DMSA scan was obtained approximately 4 months after
meeting criteria for treatment failure.

21. Result
599 children
Normal DMSA
scan 490 children
Abnormal DMSA
scan 109 children
Renal scar 58
New renal scar 40
Bilateral VUR 288
Unilateral VUR
311
Bactrim 298
Placebo 301
1197 kidney
units
Normal DMSA
scan 1081
kidney units
Abnormal
DMSA scan 116
kidney units
Renal scar 63
New renal scar
43

22. Result

23. Result
• Children with any renal scarring were significantly
older than those with no scarring (median age, 26
versus 11 months; P=0.01).
• Significantly more renal scars were noted in children
▫ second febrile or symptomatic UTI before enrollment
(OR, 2.85; 95% CI, 1.38 to 5.92)
▫ toilet-trained children (OR, 2.78; 95% CI, 1.59 to 4.89)
▫ hydronephrosis (OR, 4.61; 95% CI, 2.00 to 10.62)
▫ ureteral duplication (OR, 3.34; 95% CI, 1.43 to 7.81)
▫ higher grades of VUR (OR, 2.79; 95% CI, 1.56 to
5.0)
• Similar results for new scarring versus no scarring

24. Result

25. Result

26. Result

27. Discussion
• Are infants truly at a higher risk of renal scarring
with APN compared with older children, as initially
reported in literature ?
• Recent studies have already questioned this
conventional wisdom by reporting that younger age
may not be a risk factor for renal scarring , the risk
in older children may even be higher .
• In addition, the recommendation by the American
Academy of Pediatrics and National Institute for
Health and Clinical Excellence guidelines to delay
VCUG until the second episode of UTI may need to
be reviewed.

28. Discussion
• incidence of new renal scarring in children
receiving antimicrobial prophylaxis did not
differ from that in patients receiving placebo,
whether in terms of the proportion of children
(6% and 7%) or renal units (4% versus 4%).
• These results are similar to those reported in
other recent studies that evaluated the role of
antimicrobial prophylaxis in reducing the risk of
renal scarring

29. Discussion
• Our study revealed a higher risk of preexisting as well as
new renal scarring in renal units with grade 4 VUR
compared with no VUR or grade 1–3 VUR.
• Scarring was 27 times more likely to be observed in
renal units with grade 4 VUR compared with units with
no VUR (95% CI, 8.3 to 89.6)
• Six times more likely compared with units with grades
1–3 VUR (95% CI, 3.4 to 19.7).

30. Discussion
• Units with grade 4 VUR were 24 times more
likely to have new scarring compared with
units with no VUR (95% CI, 6.4 to 91.2)
• Six times more likely to have new scarring
compared with units with grade 1–3 VUR (95%
CI, 3.2 to 11.7).
• These observations support that high-grade VUR
being a risk factor for preexisting as well as new
renal scarring.

31. Discussion
• Incidental finding of a significant decreasing trend
in mean percentage DMSA uptake in normal renal
units with different grades of VUR in comparison to
renal units with no VUR is interesting.
• If true, it raises the possibility of subtle intrinsic
renal parenchymal abnormality associated with
high-grade VUR affecting DMSA uptake in such
kidneys with no apparent cortical defect.
• This observation needs to be confirmed in a larger
cohort and, more important, in renal units with
grade 5 VUR

32. Conclusion
• Significantly more renal scarring was seen in
relatively older children and in those with a
second episode of febrile or symptomatic UTI
before randomization.
• Preexisting and new renal scars occurred
significantly more in renal units with grade 4
VUR than in those with low-grade or no VUR.
• Antimicrobial prophylaxis did not decrease the
risk of renal scarring.

33. Strengths of study
• Well-designed randomized, double-blind,
placebo-controlled study
• Including strict criteria for UTI
• Standardized interpretation of nuclear studies
• 86 % of children completed followed up
• Largest study till now

34. Limitation of study
• Not designed primarily to evaluate the role of antimicrobial
prophylaxis in preventing scarring as rates of renal
scarring at outcome were low and not reduced by
prophylaxis
▫ Most reflux was low grade ( 80%: II, III)
▫ Exclusion of children with grade 5 VUR
▫ Children were enrolled after first or second UTI only
▫ Parents, instructed to be alert, sought early medical
attention for a diagnosis and treatment of UTI
recurrence
• Follow-up of 1–2 years may have been too short to
determine long-term risk for the development of renal scarring
or the effect of antimicrobial prophylaxis in its prevention.

35. Limitation of study
• Relatively small number of children with renal
scarring limits the scope of this study,
particularly for subgroup analysis.
• Very small number of boys (9%) were enrolled,
limiting applicability of its results to boys
• Only one prophylactic antimicrobial was used ,
the efficacy of other prophylactic antibiotics in
children with VUR remain unknown.