Cochrane Database of Systematic Reviews

Interventions for primary vesicoureteric reflux (Review)

Williams G, Hodson EM, Craig JC

Williams G, Hodson EM, Craig JC.

Interventions for primary vesicoureteric reflux.
Cochrane Database of Systematic Reviews 2019, Issue 2. Art. No.: CD001532.
DOI: 10.1002/14651858.CD001532.pub5.

www.cochranelibrary.com

Interventions for primary vesicoureteric reflux (Review)

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Interventions for primary vesicoureteric reflux

Gabrielle Williams1 , Elisabeth M Hodson2 ,3 , Jonathan C Craig3,4

1 Analytics Assist, NSW Ministry of Health, North Sydney, Australia. 2 Sydney School of Public Health, The University of Sydney,
Sydney, Australia. 3 Cochrane Kidney and Transplant, Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead,
Australia. 4 College of Medicine and Public Health, Flinders University, Adelaide, Australia

Contact address: Elisabeth M Hodson, Cochrane Kidney and Transplant, Centre for Kidney Research, The Children’s Hospital at
Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. [email protected].

Editorial group: Cochrane Kidney and Transplant Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 2, 2019.

Citation: Williams G, Hodson EM, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database of Systematic Reviews
2019, Issue 2. Art. No.: CD001532. DOI: 10.1002/14651858.CD001532.pub5.

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Vesicoureteric reflux (VUR) results in urine passing retrograde up the ureter. Urinary tract infections (UTI) associated with VUR have
been considered a cause of permanent renal parenchymal damage in children with VUR. Management has been directed at preventing
UTI by antibiotic prophylaxis and/or surgical correction of VUR. This is an update of a review first published in 2004 and updated in
2007 and 2011.
Objectives
The aim of this review was to evaluate the available evidence for both benefits and harms of the currently available treatment options
for primary VUR: operative, non-operative or no intervention.
Search methods
We searched the Cochrane Kidney and Transplant Specialised Register to 3 May 2018 through contact with the Information Specialist
using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically
designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings, and searching the International Clinical
Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria
RCTs in any language comparing any treatment of VUR and any combination of therapies.
Data collection and analysis
Two authors independently determined study eligibility, assessed quality and extracted data. Dichotomous outcomes were expressed as
risk ratios (RR) with 95% confidence intervals (CI) and continuous data as mean differences (MD) with 95% CI. Data were pooled
using the random effects model.
Main results
Thirty four studies involving 4001 children were included. Interventions included; long-term low-dose antibiotics, surgical reimplan-
tation of ureters, endoscopic injection treatment, probiotics, cranberry products, circumcision, and oxybutynin. Interventions were
used alone and in combinations. The quality of conduct and reporting of these studies was variable, with many studies omitting crucial
methodological information used to assess the risk of bias. Only four of the 34 studies were considered at low risk of bias across all
Interventions for primary vesicoureteric reflux (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
fields of study quality. The majority of studies had many areas of uncertainty in the risk of bias fields, reflecting missing detail rather
than stated poor design.

Low-dose antibiotic prophylaxis compared to no treatment/placebo may make little or no difference to the risk of repeat symptomatic
UTI (9 studies, 1667 children: RR 0.77, 95% CI 0.54 to 1.09; low certainty evidence) and febrile UTI (RR 0.83, 95% CI 0.56 to
1.21; low certainty evidence) at one to two years. At one to three years, antibiotic prophylaxis made little or no difference to the risk
of new or progressive renal damage on DMSA scan (8 studies, 1503 children: RR 0.73, 95% CI 0.33 to 1.61; low certainty evidence).
Adverse events were reported in four studies with little or no difference between treatment groups (1056 children: RR 0.94, 95% CI
0.81 to 1.08; ), but antibiotics increased the likelihood of bacterial drug resistance threefold (187 UTIs: RR 2.97, 95% CI 1.54 to
5.74; moderate certainty evidence).

Seven studies compared long-term antibiotic prophylaxis alone with surgical reimplantation of ureters plus antibiotics, but only two
reported the outcome febrile UTI (429 children). Surgery plus antibiotic treatment may reduce the risk of repeat febrile UTI by 57%
(RR 0.43, 95% CI 0.27 to 0.70; moderate certainty evidence). There was little or no difference in the risk of new kidney defects
detected using intravenous pyelogram at 4 to 5 years (4 studies, 572 children, RR 1.09, 95% CI 0.79 to 1.49; moderate certainty
evidence)
Four studies compared endoscopic injection with antibiotics alone and three reported the outcome febrile UTI. This analysis showed
little or no difference in the risk of febrile UTI with endoscopic injection compared to antibiotics (RR 0.74, 95% CI 0.31 to 1.78; low
certainty evidence). Four studies involving 425 children compared two different materials for endoscopic injection under the ureters
(polydimethylsiloxane (Macroplastique) versus dextranomer/hyaluronic acid polymer (Deflux), glutaraldehyde cross-linked (GAX)
collagen (GAX) 35 versus GAX 65 and Deflux versus polyacrylate polyalcohol copolymer (VANTRIS)) but only one study (255
children, low certainty evidence) had the outcome of febrile UTI and it reported no difference between the materials. All four studies
reported rates of resolution of VUR, and the two studies comparing Macroplastique with Deflux showed that Macroplastique was
probably superior to dextranomer/hyaluronic acid polymer (3 months: RR 0.50, 95% CI 0.33 to 0.78; 12 months: RR 0.54 95% CI
0.35 to 0.83; low certainty evidence)

Two studies compared probiotic treatment with antibiotics and showed little or no difference in risk of repeat symptomatic UTI (RR
0.82 95% CI 0.56 to 1.21; low certainty evidence)

Single studies compared circumcision with antibiotics, cranberry products with no treatment, oxybutynin with placebo, two different
surgical techniques and endoscopic injection with no treatment.

Authors’ conclusions

Compared with no treatment, the use of long-term, low-dose antibiotics may make little or no difference to the number of repeat
symptomatic and febrile UTIs in children with VUR (low certainty evidence). Considerable variation in the study designs and subsequent
findings prevented drawing firm conclusions on efficacy of antibiotic treatment.

The added benefit of surgical or endoscopic correction of VUR over antibiotic treatment alone remains unclear since few studies
comparing the same treatment and with relevant clinical outcomes were available for analysis.

PLAIN LANGUAGE SUMMARY

Interventions for primary vesicoureteric reflux

What is the issue?

Vesicoureteric reflux (VUR) is the backflow of urine from the bladder up the ureters to the kidney. People with VUR are thought to
be more likely to get urinary tract infections (UTIs) involving the kidney tissue, which may cause permanent kidney damage. Current
treatment options include surgical reimplantation of the ureters, long-term antibiotics, endoscopic correction by subureteric injection
of a substance (injection into the bladder under the ureter), complementary medicines, or a combination of interventions

What did we do?

A literature search identified all randomised studies comparing different treatment options in children with vesicoureteric reflux. Results
along with study design details were extracted and compiled. Studies comparing similar treatments and outcomes had data pooled to
Interventions for primary vesicoureteric reflux (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
obtain an estimate of effect on outcomes such as repeat urinary tract infection with illness, urinary tract infection with fever and kidney
damage.
What did we find?
A total of 34 randomised studies, involving 4001 children were identified and underwent data extraction and analysis. The most
frequent comparisons were for long-term, low-dose antibiotics with no treatment (8 studies) or placebo (4 studies) and antibiotics
versus surgical reimplantation of ureters plus antibiotics (7 studies). Other treatments looked at endoscopic correction by injection
compared with antibiotics (3 studies), different materials for endoscopic correction (2 studies) circumcision (1 study), probiotics (1
study), cranberry product (1 study), and oxybutynin (2 studies).
Meta-analysis of similar studies found that long-term low-dose antibiotic treatment compared with no treatment may lead to little or
no difference in the risk for repeat UTIs in children with VUR. Associated side effects were infrequent and minor, but prophylaxis was
associated with a threefold increased risk of bacterial resistance to the treatment drug in later infections. Surgery decreased the number
of repeat UTIs with fever, but did not change the number of children developing UTI with illness or kidney damage. Many studies
did not contribute to the meta-analysis as they failed to report relevant outcomes or were single studies examining a treatment option
not used by other studies or combinations of treatments.
Conclusions
Long-term low-dose antibiotic treatment in children with VUR makes little or no difference to the risk of repeat UTI causing a person
to be unwell. Surgery may reduce the risk of repeat UTI with fever however this is based on two studies of 429 children who may
not represent the majority and may not bear true in a more general group of children with VUR. Complementary therapies such as
probiotics and cranberry were trialled in single or two studies and do not provide evidence of sufficient certainty to support or deny
their use.

Interventions for primary vesicoureteric reflux (Review)

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.