|Year : 2019 | Volume
| Issue : 2 | Page : 61-70
Vesicoureteral reflux and recurrent urinary tract infections
Jitendra Meena, Pankaj Hari
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||4-Dec-2019|
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Vesicoureteral reflux (VUR) refers to backflow of urine from the bladder into the upper urinary tract. Children with high-grade VUR are at risk of recurrent urinary tract infections (UTIs). It is commonly associated with bladder–bowel dysfunction, necessitating treatment because it further increases the risk of recurrent UTI and results in delayed resolution of VUR. Almost one-third of patients with VUR diagnosed following UTI show renal scarring. It is debated whether scarring in VUR is entirely acquired following UTI or due to dysplasia. The efficacy of antibiotic prophylaxis has been variable for the prevention of UTI in children with VUR. A meta-analysis suggests that it might be of some benefit in preventing UTI, but not renal scarring and at cost of bacterial resistance. Due to questionable efficacy and potential risk, use of antibiotic prophylaxis should be based on risk stratification rather than mere presence of reflux. In view of lack of significant improvement in long-term outcomes with current available interventions, there is ongoing debate on the aggressiveness of algorithms for diagnosing VUR following UTI. Long-term complications of VUR include proteinuria, hypertension, and end-stage renal disease. As opposed to previous assumption, the risk of end-stage renal failure and hypertension is fairly small with scarring following UTI.
Keywords: Antibiotic prophylaxis, bladder–bowel dysfunction, reflux nephropathy, urinary tract infection
|How to cite this article:|
Meena J, Hari P. Vesicoureteral reflux and recurrent urinary tract infections. Asian J Pediatr Nephrol 2019;2:61-70
| Introduction|| |
Vesicoureteric reflux (VUR) is the retrograde passage of urine into the upper urinary tract, during detrusor contraction at micturition. In the absence of lower urinary tract outlet obstruction and neurogenic bladder, it is considered to be primary. Primary VUR is regarded as a risk factor for urinary tract infections (UTIs) and postinfectious scarring. In most patients, VUR including higher grades undergoes spontaneous resolution over a period of time. VUR has been shown to be associated with renal scarring, referred to as reflux nephropathy; 7%–17% of end-stage renal disease (ESRD) is reported to be associated with primary VUR.,,
There is a strong association of bladder–bowel dysfunction (BBD), VUR, and UTI. Treatment strategies for VUR include surgical re-implantation of ureters or endoscopic injection of a bulking agent at the ureterovesical junction or medical treatment with low-dose antibacterial prophylaxis with the aim of preventing UTI and consequent scarring. Considerable research has been conducted on the optimal treatment for VUR, and studies have improved the understanding on renal damage associated with VUR. Milder grades of VUR are considered innocuous. Further, it is increasingly recognized that aggressive therapies for VUR may not affect renal damage or development of ESRD. As VUR is detected on investigations that are carried out after an episode of UTI, there is debate on the need for detailed evaluation protocols for UTI. This review focuses on an evidence-based approach to the diagnosis and management of VUR.
| Epidemiology|| |
Conventionally, the prevalence of VUR is presumed to be 1%. However, a study on normal infants and children found reflux in 28% on micturating cystourethrography (MCU). Other studies in children without predisposing conditions show VUR in 0%–30%. As VUR may be subclinical, resolves with time, and requires MCU for diagnosis, determining the prevalence would require subjecting all newborns to an invasive procedure that is not possible. VUR is often diagnosed following evaluation of one or more UTI. In a large retrospective study, the prevalence of VUR was estimated at 37% in children with UTI and 34% without UTI. A large meta-analysis estimated the incidence of VUR in siblings and offspring of patients with VUR at 27.4% and 35.7%, respectively. Variability in the reported prevalence of VUR is largely due to design, selection bias, and methods used for its diagnosis. Researchers believe that ~1% prevalence of VUR is conservative, with a more reliable estimate of 10%–40%., VUR is also diagnosed in children who are evaluated for chronic kidney disease (CKD), hypertension, renal stones, and rarely for proteinuria.
| Etiology of Primary Vur|| |
Several mechanisms are proposed to explain the pathogenesis of primary VUR. The key event in the development of kidney and ureters is the ureteric budding from the Wolffian duct and its reciprocal interaction with the metanephric mesenchyme. Accordingly, cephalad ureteric budding results in laterally displaced ureteric orifice, shorter length of intravesical ureter with loss of valve mechanism preventing reflux. VUR is seen in syndromes associated with genes of the ureteric budding pathway. Loss of ureteral peristalsis and bladder dysfunction are proposed to contribute to the occurrence and persistence of VUR.
| Genetics|| |
Significantly higher incidence of VUR among monozygotic (80%–100%) and fraternal (35%–50%) twins, siblings (27%–50%), and offspring (66%) of affected individuals suggests an underlying genetic basis. Feather et al. found autosomal dominant inheritance with linkage to chromosome 1 in most but not all families and concluded that VUR phenotype may result from alteration in several genes. Other inheritance patterns include autosomal recessive and X-linked inheritance. Results of genetic studies in different populations suggest that VUR is a genetically heterogeneous disease. A large genome-wide linkage and association study implicated 10q26 region as a major contributor to the primary nonsyndromic VUR.
| Reflux Nephropathy: Secondary to Urinary Tract Infection or Hypodysplasia|| |
Children with high-grade reflux show more renal damage at diagnosis than those with grade I–II VUR.,, Renal scarring (reflux nephropathy) is defined by chronic tubulointerstitial inflammation and fibrosis and best diagnosed on intravenous pyelography or dimercaptosuccinic acid (DMSA) scintigraphy, with the latter being more sensitive. As most patients with VUR are diagnosed following one or more episodes of UTI, it is assumed that scarring is due to previous infection (s). However, patients have been diagnosed with renal scars even in the absence of UTI; scarring is presumed secondary to congenital hypodysplasia [Table 1].,
Some investigators propose that much of the scarring associated with VUR leading to end-stage renal failure are secondary to hypodysplasia. On the other hand, renal scars following UTI are generally small and innocuous [Table 1]. Majority of hypodysplasia associated with VUR are seen as large areas of parenchymal damage or small poorly functioning kidneys on scintigraphy, predominantly in boys with high-grade reflux.
It is suggested that hypodysplasia associated with VUR is the result of a developmental anomaly, with an abnormal ureterovesical junction and histological evidence of focal/diffuse renal dysplasia. Abnormal ureteric budding is proposed to be a key factor in pathogenesis. As interaction of ureteric bud with the metanephros is important in nephrogenesis, variations in genes associated with the ureteric budding pathway are important. Studies in minipig model of surgically induced VUR have also reported that sterile reflux alone may cause renal scars., These findings were not confirmed in other animal models.
| Post-Infection Scarring|| |
VUR promotes the ascent of bacteria into the renal pelvis, resulting in pyelonephritis. Reactive oxygen metabolites released by neutrophils, in response to bacterial infection, have been shown to induce renal scarring or fibrosis in animal models. Animal studies using mouse models with VUR show that sustained infection with uropathogenic Escherichia coli is required to induce scar formation in VUR. Post-infection scarring is commonly reported in girls, in contrast to congenital dysplasia that occurs more often in boys [Table 1]. Most randomized trials show that the risk of new scar formation in children with VUR not receiving antibiotic prophylaxis, and followed up in controlled environment, is low at 2%–8%,,,, except the Swedish trial where it was 32%.
The long-term consequences of post-infection scarring are difficult to assess. The risk of end-stage renal failure following UTI is low, at ~1/10,000 cases. Follow-up of Gothenburg cohort using ambulatory blood pressure monitoring found no difference in hypertension in children with or without renal scars. The risk of pregnancy-related complications in women with renal scarring was reported to be high in one study, and similar to those without scarring in another., Thus, as opposed to previous assumptions, it appears that post-infection scarring leads to fewer complications in children and adults.
| Vur and Urinary Tract Infection|| |
VUR is believed to be an important risk factor for recurrent UTI. VUR was present in 30%–40% children following evaluation of an episode of UTI. Girls, with VUR, are more commonly diagnosed following an episode of UTI when compared to boys; this sex preponderance is absent in infants <6 months old. The risk of recurrent UTI was 25% in patients with VUR, compared to 17% without VUR. Patients with antenatally diagnosed VUR show lower incidence of UTI, compared to patients with VUR and prior UTI.,
During an episode of UTI, on DMSA scintigraphy, 67% of patients with primary VUR show 1.5 times higher evidence of acute pyelonephritis than those without VUR. The increased risk is due to exposure of renal parenchyma to infected urine that results in rapid progression from cystitis to pyelonephritis. Patients with VUR are also at risk of renal scars, compared to those without VUR; the risk is higher in patients with dilating reflux. Patients in the RIVUR trial had almost twofold higher incidence of renal scars than those without VUR.
| Vur and Bladder Bowel Dysfunction|| |
BBD results from poor voiding technique, in which bladder contractions are suppressed by inappropriate contraction of pelvic floor muscles and external sphincter. Consequently, voiding pressure is increased, and this results in incomplete voiding and defecation. Rectal distension in constipation can compress the adjacent bladder neck and trigonal region, resulting in detrusor overactivity and voiding dysfunction., Incomplete voiding and increased uropathogenic bacteria in gut in the setting of BBD increase the risk of recurrent UTI in children., Clinical features in the spectrum of BBD include urinary incontinence, enuresis, urgency, frequency, hesitancy, voiding postponement, constipation, and encopresis. While dysfunctional voiding scoring system is a useful tool to detect BBD, functional constipation is diagnosed based on the Rome IV criteria., BBD has been reported in 30%–50% of patients with primary VUR, which is significantly higher than that in healthy children.,,, Impact of BBD on patients with primary VUR is multiple, which include risk of recurrent UTI and renal scars, delayed spontaneous resolution of VUR, and low success rate of interventions (antibiotic prophylaxis, surgical re-implantation, and endoscopic injection).
| Investigations|| |
Majority of VUR are diagnosed following an episode of UTI. The aim of imaging studies is to identify anomalies that predispose a child to pyelonephritis and to detect evidence of renal scarring.
Ultrasound is not sensitive to detect all patients with hydronephrosis or hydroureter secondary to VUR. It also has unsatisfactory sensitivity for acute pyelonephritis and renal scarring. Doppler analysis of ureteric jet when urine fills the bladder has been suggested for the diagnosis of VUR; its utility in practice is unclear. Voiding urosonography utilizes administration of microbubbles through a bladder catheter for the diagnosis of VUR; the test is not widely used.
MCU is the gold standard for diagnosis as it permits grading of VUR and defines lower tract anatomy. Disadvantages include radiation exposure, need for bladder catheterization, and possible introduction of infection. The diagnostic is increased by cyclic procedures, i.e., filling the bladder and having the child void two or more times. Cyclic MCU involves unacceptably high radiation burden. While direct radionuclide cystography (DRCG) is an alternative for the diagnosis and evaluation of VUR, it also requires bladder catheterization. Radionuclide cystography has a lower radiation exposure compared to MCU. However, anatomical and urethral resolution is unsatisfactory.
99Tc-dimercaptosuccinic acid scintigraphy
Renal imaging with DMSA is sensitive and specific for the diagnosis of acute pyelonephritis, with reduced radiotracer uptake due to cortical ischemia and tubular dysfunction. For detecting renal scarring, the scan is ideally performed 4–5 months after the UTI.
| Imaging After The first Episode of Urinary Tract Infection for Detecting Vur|| |
UTI is so common that many children with no urinary tract abnormality would be subjected to investigations without benefit; a “high-risk” approach is required. Recommendations for imaging following UTI are based on the assumption that detection of urologic abnormalities at an early age will lead to improved outcomes. Over the years, physicians have tried to minimize the use of MCU as it involves radiation and discomfort of urethral catheterization. Thus, renal ultrasonography, MCU, and DMSA scan are recommended in young infants, whereas MCU is avoided between 1 and 5 years of age. The latter recommendation is based on the top-down approach, which recently has been extended to young infants. This approach involves performing DMSA scan during an episode of UTI, which assumes that the presence of abnormal DMSA scan findings suggests the underlying VUR. As DMSA scan involves exposure to radiation, researchers have used C-reactive protein and procalcitonin (>0.5 ng/mL) to identify high-risk patients and improve the yield of scintigraphy. Studies in infants show that DMSA scans were abnormal with dilating VUR only. Milder reflux that may be missed by this approach, is assumed to not to be contributing to renal scarring.
Various guidelines for imaging following first UTI are summarized in [Table 2]. The diagnostic yield of imaging protocols is higher with stringent guidelines, but with questionable benefits. We propose an algorithm for evaluation after the first UTI in [Figure 1]. MCU is suggested for the evaluation of infants less than 6 months old, in patients with atypical UTI (see footnote of [Table 2]) or if the physician suspects previous episodes of undiagnosed UTI.
|Table 2: Guidelines for imaging after the first febrile urinary tract infections|
Click here to view
|Figure 1: Suggested algorithm for the diagnosis of vesicoureteric reflux (VUR) following urinary tract infection (UTI). *Consider micturating cystourethrography (MCU) in patients with atypical UTI (as defined in legend of Table 2) and in those younger than 6 months of age.#DMSA scan is performed 4-6 months after the last UTI to look for scarring. BBD: Bladder bowel dysfunction|
Click here to view
| Medical Therapy: Antibacterial Prophylaxis|| |
A Cochrane review concluded that there was no difference in the incidence of UTI and renal scarring in children treated with either surgery or long-term antibiotic prophylaxis. Being noninvasive, the latter became the cornerstone of therapy for VUR. However, it was seen that the evidence to support long-term antibiotic prophylaxis for the prevention of UTI was weak and more randomized controlled studies were needed.
In the last two decades, several randomized controlled trials have compared antibiotic prophylaxis with no treatment or placebo for the prevention of UTI in children with and without VUR [Table 3].,,, Initial studies involving children with absent or lesser grades of VUR demonstrated similar rates of recurrent UTI in the treatment versus no treatment groups. Garin et al. showed that compared to untreated children, the risk of pyelonephritis was higher in those receiving antibiotic prophylaxis. Although statistically insignificant, Pennesi et al. also found a trend favoring more UTI in children on antibiotic prophylaxis. The Swedish Reflux Study reported on 203 children, 1 to 2 year old with grade III–IV VUR, who were randomized to antibiotic prophylaxis, surgical correction, or observation., Reduced frequency of UTI was found in girls in the treatment compared to observation groups. No treatment benefit was observed in boys. These trials were not placebo controlled and did not report adherence to treatment and were considered to have high risk of bias.
|Table 3: Summary of randomized controlled trials in patients with vesicoureteral reflux|
Click here to view
Three recent randomized placebo-controlled trials have low risk of bias. The PRIVENT trial (ACTRN12608000470392) on 576 children with absent or any grade of VUR showed benefit of 6% with antibiotic prophylaxis. The RIVUR trial (NCT00405704) showed that antibiotic prophylaxis reduced recurrences of UTI by 50%. Benefits were more in children with febrile UTI and in those with BBD. Benefits of prophylaxis were not significant in grade III–IV VUR and in the absence of BBD, but chiefly limited to girls with VUR and BBD. The trial from India (CRG110600097) showed higher risk of symptomatic UTI in children with VUR treated with cotrimoxazole prophylaxis, compared to placebo.
The overall incidence of UTI in children with VUR detected following evaluation of antenatal hydronephrosis is low. The role of antibiotic prophylaxis in these patients is unclear; the PREDICT trial (NCT02021006) is expected to provide insight. A recent Cochrane systematic review including all the randomized controlled trials published till date shows that there is no benefit of antibiotic prophylaxis in preventing symptomatic UTI in children with VUR. Analysis of studies with low risk of bias also did not find any difference between antibiotic prophylaxis and placebo.
As per 2011 guideline of the Indian Society of Pediatric Nephrology, antibiotic prophylaxis is recommended up to 5 years of age in patients with high grade (III–V) VUR and up to 1 year in low-grade VUR. Guidelines from other expert groups do not specify the duration of antibiotic prophylaxis. Based on the current evidence, we suggest that children with high-grade VUR and no BBD should receive prophylaxis until the age of 2–3 years [Figure 2].
|Figure 2: Suggested algorithm for the management of patients with primary vesicoureteral reflux (VUR). VUR diagnosed during the evaluation of antenatal hydronephrosis (ANH),#VUR diagnosed following an episode of urinary tract infection (UTI). ABP: Antibiotic prophylaxis, BBD: Bladder–bowel dysfunction|
Click here to view
Antibacterial prophylaxis and post-infection renal scarring
The risk of post-infection scarring in most controlled trials has been below 10%. Most recent studies, except the Swedish study, failed to show significant difference in the occurrence of new or progression of the existing renal damage.,,,, However, all these studies were primarily designed to examine the recurrence of UTI rather than renal scarring. As the rate of acquired scarring is low, it is impractical to conduct a trial with this as the primary outcome.
Why is the efficacy of antimicrobial prophylaxis inconsistent?
Published cohorts of children with VUR on antibiotic prophylaxis differ in baseline characters and methodology. The differences in the efficacy of antimicrobial prophylaxis might be due to differences in the phenotypes of VUR, such as sex, severity of VUR, scarring, and presence of BBD. More than 90% of patients in studies from the USA have been girls, whereas the proportions of girls ranged from 52% to 65% in studies from Europe and Australia. In contrast, majority of VUR diagnosed in India (67%) and Japan included boys (83%). While most patients in RIVUR trial had grade I–III VUR and scarring was present in <5%, patients in other studies had modest baseline scarring, ranging from 40% to 57%.,,,,, Antibiotic prophylaxis was not found to be useful in cohorts comprising of predominantly boys with high-grade VUR and baseline renal scarring.
VUR is recognized as a heterogeneous condition with regional and genetic differences. Differences in demographic and clinical features could explain variability in the effectiveness of antibiotic prophylaxis in various studies. Combining data of different phenotypes of VUR in meta-analyses to derive treatment recommendations should be viewed with caution.
Safety of antibacterial prophylaxis
While antimicrobial prophylaxis may prevent UTI in children with VUR, this benefit may be mitigated by rise in microbial resistance. Controlled trials of antimicrobial prophylaxis show that the incidence of antimicrobial resistance ranges from 16% to 36%.,,,, There was an overall threefold higher risk of drug resistance in patients receiving antibiotic prophylaxis. Resistant infections are twice as likely to be associated with higher morbidity and mortality and associated with increased health-care costs.
Recommendations for antibacterial prophylaxis
Recommendations from various international societies are summarized in [Table 4]. While prophylaxis is associated with reduced morbidity related to UTI, it does not reduce the risk of renal scarring and its consequences, and is at cost of antimicrobial resistance. A prudent way is the use of prophylaxis based on risk stratification, rather than mere presence of VUR.
|Table 4: Guidelines for antibiotic prophylaxis in vesicoureteral reflux and recurrent urinary tract infection|
Click here to view
Risk stratification for the management of VUR
BBD, young age, female sex, high-grade reflux, and presence of baseline scarring are chief risk factors for recurrent UTI in patients with primary VUR. Hidas et al. proposed a risk model for the prediction of breakthrough UTI based on various clinical parameters. They showed that 2-year risk for breakthrough UTI was 8.6%, 26.0%, and 62.5% in low-, intermediate-, and high-risk groups, respectively. The RIVUR trial data were recently re-analyzed using a risk classification system, in which circumcised boys or girls with nondilating VUR in the absence of BBD were categorized as low risk for recurrent UTI. Re-analysis showed that high-risk patients had significantly higher proportion of recurrent UTI (31.5%) than those with low-risk (19.2%) patients, and that antibiotic prophylaxis was only effective in preventing recurrences in the former. There were no differences in terms of renal scarring between high- and low-risk groups. These results indicate the need to consider risk stratifying and using antimicrobial prophylaxis to selected patients with VUR [Table 5].
|Table 5: Risk stratification for recurrent urinary tract infection in vesicoureteral reflux|
Click here to view
Other measures for preventing recurrent urinary tract infection in VUR
A recent systematic review did not find enough evidence on the efficacy of probiotics for preventing UTI in children with VUR. The role of cranberry juice in this context was also uncertain. One randomized trial on the role of circumcision did not find differences in risk of UTI and renal scarring in these patients.
| Surgical Treatment for Vur|| |
Surgical management has failed to show superiority to antibiotic prophylaxis in terms of prevention of recurrent UTI, renal scarring, and progression to CKD. Surgical therapy is not considered as the first-line for the management of VUR. Currently, the chief indication for surgery is repeated episodes of breakthrough UTI, despite adequate management of BBD while on antibiotic prophylaxis. Chief surgical approaches include ureteric re-implantation or periureteral endoscopic injection of bulking agents.
With open surgical re-implantation, the success rate of correction of primary VUR is 97%–99%. Rarely, ureteral stricture secondary to ischemia of distal ureter has been reported following surgical re-implantation. The update of Cochrane systematic review on primary intervention for the management of patients with VUR concludes that surgery plus antibiotic prophylaxis reduced the risk of recurrent febrile UTI by 57% compared to antibiotics alone. However, ureteric re-implantation does not reduce the risk of new renal scars detected at 4–5 years.
Endoscopic injection of bulking agents
This procedure involves injection of a bulking agent in the subtrigonal area at vesicoureteric junction with an aim of stopping backflow of urine into the ureters. Dextranomer hyaluronidase (Deflux®) is the preferred bulking agent for endoscopic management of VUR.,,, A meta-analysis of all studies involving endoscopic therapy has reported success rate of 78.5% for grades I–II, 72% for grade III, 63% for grade IV, and 51% for grade V reflux. A recent Cochrane review did not find any significant difference in the risk of recurrent febrile UTI with endoscopic therapy compared with antibiotic prophylaxis.
| Sibling Screening|| |
The familial nature of VUR is well known with a reported prevalence of 27.4% in siblings and 35.7% in offspring. It has been reported that siblings with VUR have more benign course than index patients diagnosed to have VUR following UTI. In view of the benign course, screening of asymptomatic siblings and offspring of reflux patients is debatable. The European Association of Urology recommends that all parents should be informed about the high prevalence of VUR in siblings. They recommend screening of siblings with ultrasound scan; MCU is advised for patients with abnormalities on ultrasound.
| Follow-Up of Children With Vur|| |
Patients with VUR should be kept on long-term follow-up, with an aim to detect and treat recurrent UTI and complications related to VUR (renal scarring, hypertension, and proteinuria). The American Urological Association (2010) guidelines recommend annual follow-up visits till the resolution of VUR. Each visit should include physical examination; measurement of blood pressure, weight, and height; and urinalysis for proteinuria. Routine urine microscopy and culture is not advised, unless patients are symptomatic.
Although guidelines recommend annual ultrasonography, studies doubt the utility of this investigation in changing the strategy of management., DRCG is preferred to MCU to examine for resolution of VUR. DRCG is advised every 2 years, but less frequent monitoring is required for patients with dilating (grade III–V) reflux and BBD who show lower rates of resolution. Routine DMSA scan to identify new renal scars is not advised, except in patients who have breakthrough UTI.
| Spontaneous Resolution of Vur|| |
Majority of VUR resolves over time. The postulated mechanism includes elongation of the intramural ureter with bladder growth, resulting in restoration of the valve mechanism of ureterovesical junction and stabilization of bladder dynamics. In a prospective study, reflux disappeared or was reduced to grade I in 71% of children with dilating reflux at 10-year follow-up. The probability of resolution is impacted by several factors including grade of reflux, laterality, sex, mode of presentation (UTI vs. prenatal hydronephrosis or sibling screening), and presence of BBD. Those children in whom VUR is diagnosed during the evaluation of antenatal hydronephrosis show higher rates of resolution. A nomogram has been proposed for predicting the rates of resolution. Resolution rate was 72% in grade I, 61% in grade II, 49% in grade III, and 32% in grades IV and V. The VUR index, which predicts its resolution, has been developed and validated for children <2 years old. This index is likely to help in risk stratification and facilitate individualized care. The time of resolution of reflux is faster for lower grades as opposed to dilating VUR. In a large retrospective study with a mean follow-up of 76 months, the median time to resolution of grade I–II reflux was 38 months, for grade III, 98 months, and for grade IV/V, 156 months.
| Long-Term Complications|| |
Renal parenchymal injury in patients with VUR results in persistent proteinuria that increases the risk of progression to CKD. These patients initially manifest with microalbuminuria, which progresses to proteinuria, and finally impaired renal function. The severity of proteinuria correlates with the severity of renal scarring in children with reflux nephropathy.,
About 10%–30% of patients with reflux nephropathy show hypertension., Patients with reflux nephropathy may have accompanying dysplasia, explaining the higher prevalence of hypertension in these patients.
End-stage renal disease
Reflux nephropathy accounts for ~8%–21% of all ESRD in children. In the latest North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) report, reflux nephropathy was a cause of CKD in 5.1% patients. The frequency of ESRD in children with VUR is low, varying between 1.5% and 9%., Despite prevalent therapeutic interventions, the proportion of patients with ESRD attributed to reflux nephropathy has not changed in the Australia New Zealand Registry and in NAPRTCS over the past decades., These findings suggest that most end-stage failure is due to hypodysplasia, which cannot be modified by the management of VUR.
Proteinuria, hypertension, higher grades of reflux (IV–V), bilateral renal scarring, and hypodysplasia are risk factors for progression to ESRD., However, patients with VUR and normal DMSA scintigraphy at diagnosis do not show progressive kidney disease.
| Conclusions|| |
The management of children with primary VUR is complex and controversial. Renal damage in primary VUR is either due to renal hypodysplasia or post-infection scarring. The illness in patients with VUR with hypodysplasia is generally severe and associated with hypertension and risk of progressive kidney disease. Evidence suggests that antibiotic prophylaxis may not prevent recurrences of UTI and the risk of renal scarring and its consequences (hypertension and renal failure) while increasing the risk of antimicrobial resistance. Therefore, the approach for diagnosing VUR following UTI has become less intensive. Robust evidence is needed for risk stratification-based management of patients with VUR.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Craig JC, Irwig LM, Knight JF, Roy LP. Does treatment of vesicoureteric reflux in childhood prevent end-stage renal disease attributable to reflux nephropathy? Pediatrics 2000;105:1236-41.
Miklovicova D, Cornelissen M, Cransberg K, Groothoff JW, Dedik L, Schroder CH. Etiology and epidemiology of end-stage renal disease in Dutch children 1987-2001. Pediatr Nephrol 2005;20:1136-42.
Hari P, Singla IK, Mantan M, Kanitkar M, Batra B, Bagga A. Chronic renal failure in children. Indian Pediatr 2003;40:1035-42.
RIVUR TrialInvestigators. Hoberman A, Greenfield SP, Mattoo TK, Keren R, Mathews R, Pohl HG, et al
. Antimicrobial prophylaxis for children with vesicoureteral reflux. N
Engl J Med 2014;370:2367-76.
Arant BS Jr. Vesicoureteric reflux and renal injury. Am J Kidney Dis 1991;17:491-511.
Köllermann MW, Ludwig H. On vesico-ureteral reflux in normal infants and children. Z Kinderheilkd 1967;100:185-91.
Williams G, Fletcher JT, Alexander SI, Craig JC. Vesicoureteral reflux. J Am Soc Nephrol 2008;19:847-62.
Hannula A, Venhola M, Renko M, Pokka T, Huttunen NP, Uhari M. Vesicoureteral reflux in children with suspected and proven urinary tract infection. Pediatr Nephrol 2010;25:1463-9.
Skoog SJ, Peters CA, Arant BS Jr., Copp HL, Elder JS, Hudson RG, Khoury AE, et al
. Pediatric vesicoureteral reflux guidelines panel summary report: Clinical practice guidelines for screening siblings of children with vesicoureteral reflux and neonates/Infants with prenatal hydronephrosis. J Urol 2010;184:1145-51.
Tullus K. Vesicoureteric reflux in children. Lancet 2015;385:371-9.
Feather SA, Malcolm S, Woolf AS, Wright V, Blaydon D, Reid CJ, Flinter FA, et al
. Primary, nonsyndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome 1. Am J Hum Genet 2000;66:1420-5.
Schedl A. Renal abnormalities and their developmental origin. Nat Rev Genet 2007;8:791-802.
Puri P, Gosemann JH, Darlow J, Barton DE. Genetics of vesicoureteral reflux. Nat Rev Urol 2011;8:539-52.
Darlow JM, Darlay R, Dobson MG, Stewart A, Charoen P, Southgate J, Baker SC, et al
. Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux. Sci Rep 2017;7:14595.
van EerdeAM, Duran K, van RielE, de KovelCG, Koeleman BP, Knoers NV, Renkema KY, et al
. Genes in the ureteric budding pathway: Association study on vesico-ureteral reflux patients. PLoS One 2012;7:e31327.
Ransley PG, Risdon RA, Godley ML. High pressure sterile vesicoureteral reflux and renal scarring: An experimental study in the pig and minipig. Contrib Nephrol 1984;39:320-43.
Nguyen HT, Bauer SB, Peters CA, Connolly LP, Gobet R, Borer JG, Barnewolt CE, et al
. 99m technetium dimercapto-succinic acid renal scintigraphy abnormalities in infants with sterile high grade vesicoureteral reflux. J Urol 2000;164:1674-8.
Hari P, Hari S, Sinha A, Kumar R, Kapil A, Pandey RM, Bagga A, et al
. Antibiotic prophylaxis in the management of vesicoureteric reflux: A randomized double-blind placebo-controlled trial. Pediatr Nephrol 2015;30:479-86.
Paltiel HJ, Mulkern RV, Perez-Atayde A, Connolly LP, Zurakowski D, Treves ST, Atala A, et al
. Effect of chronic, low-pressure, sterile vesicoureteral reflux on renal growth and function in a porcine model: A radiologic and pathologic study. Radiology 2000;217:507-15.
Bowen SE, Watt CL, Murawski IJ, Gupta IR, Abraham SN. Interplay between vesicoureteric reflux and kidney infection in the development of reflux nephropathy in mice. Dis Model Mech 2013;6:934-41.
Roberts JA, Roth JK Jr., Domingue G, Lewis RW, Kaack B, Baskin G. Immunology of pyelonephritis in the primate model. V. Effect of superoxide dismutase. J Urol 1982;128:1394-400.
Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol 2010;184:286-91.
Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ, McTaggart SJ, Hodson EM, et al
. Antibiotic prophylaxis and recurrent urinary tract infection in children. N
Engl J Med 2009;361:1748-59.
Roihuvuo-Leskinen HM, Vainio MI, Niskanen KM, Lahdes-Vasama TT. Pregnancies in women with childhood vesicoureteral reflux. Acta Obstet Gynecol Scand 2015;94:847-51.
Wennerström M, Hansson S, Hedner T, Himmelmann A, Jodal U. Ambulatory blood pressure 16-26 years after the first urinary tract infection in childhood. J Hypertens 2000;18:485-91.
Hollowell JG. Outcome of pregnancy in women with a history of vesico-ureteric reflux. BJU Int 2008;102:780-4.
Chen JJ, Mao W, Homayoon K, Steinhardt GF. A multivariate analysis of dysfunctional elimination syndrome, and its relationships with gender, urinary tract infection and vesicoureteral reflux in children. J Urol 2004;171:1907-10.
Keren R, Shaikh N, Pohl H, Gravens-Mueller L, Ivanova A, Zaoutis L, Patel M, et al
. Risk factors for recurrent urinary tract infection and renal scarring. Pediatrics 2015;136:e13-21.
Bower WF, Yeung CK. A review of non-invasive electro neuromodulation as an intervention for non-neurogenic bladder dysfunction in children. Neurourol Urodyn 2004;23:63-7.
Papachristou F, Printza N, Kavaki D, Koliakos G. The characteristics and outcome of primary vesicoureteric reflux diagnosed in the first year of life. Int J Clin Pract 2006;60:829-34.
Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: A systematic review. Pediatrics 2010;126:1084-91.
McKenna PH, Herndon CD, Connery S, Ferrer FA. Pelvic floor muscle retraining for pediatric voiding dysfunction using interactive computer games. J Urol 1999;162:1056-62.
Ambartsumyan L, Siddiqui A, Bauer S, Nurko S. Simultaneous urodynamic and anorectal manometry studies in children: Insights into the relationship between the lower gastrointestinal and lower urinary tracts. Neurogastroenterol Motil 2016;28:924-33.
Giramonti KM, Kogan BA, Agboola OO, Ribons L, Dangman B. The association of constipation with childhood urinary tract infections. J Pediatr Urol 2005;1:273-8.
Mulvey MA, Schilling JD, Martinez JJ, Hultgren SJ. Bad bugs and beleaguered bladders: Interplay between uropathogenic Escherichia coli
and innate host defenses. Proc Natl Acad Sci U S A 2000;97:8829-35.
Yang S, Chua ME, Bauer S, Wright A, Brandström P, Hoebeke P, Rittig S, et al
. Diagnosis and management of bladder bowel dysfunction in children with urinary tract infections: A position statement from the International Children's Continence Society. Pediatr Nephrol 2018;33:2207-19.
Drossman DA, Hasler WL. Rome IV-functional GI disorders: Disorders of gut-brain interaction. Gastroenterology 2016;150:1257-61.
Farhat W, Bägli DJ, Capolicchio G, O'Reilly S, Merguerian PA, Khoury A, et al
. The dysfunctional voiding scoring system: Quantitative standardization of dysfunctional voiding symptoms in children. J Urol 2000;164:1011-5.
Logvinenko T, Chow JS, Nelson CP. Predictive value of specific ultrasound findings when used as a screening test for abnormalities on VCUG. J Pediatr Urol 2015;11:176.e1-7.
Leung VY, Metreweli C, Yeung CK. The ureteric jet Doppler waveform as an indicator of vesicoureteric sphincter function in adults and children. An observational study. Ultrasound Med Biol 2002;28:865-72.
Darge K. Voiding urosonography with ultrasound contrast agents for the diagnosis of vesicoureteric reflux in children. I. Procedure. Pediatr Radiol 2008;38:40-53.
Shaikh N, Borrell JL, Evron J, Leeflang MM. Procalcitonin, C-reactive protein, and erythrocyte sedimentation rate for the diagnosis of acute pyelonephritis in children. Cochrane Database Syst Rev 2015;1: CD009185.
Wheeler D, Vimalachandra D, Hodson EM, Roy LP, Smith G, Craig JC. Antibiotics and surgery for vesicoureteric reflux: A meta-analysis of randomised controlled trials. Arch Dis Child 2003;88:688-94.
Williams G, Hodson EM, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2019;2:CD001532.
Greenfield SP, Cheng E, DeFoor W, Kropp B, Rushton HG, Skoog S, et al
. Vesicoureteral reflux and antibiotic prophylaxis: why cohorts and methodologies matter. J Urol 2016;196:1238-43.
Nagler EV, Williams G, Hodson EM, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2011; 15:6:CD001532.
Indian Society of Pediatric Nephrology, Vijayakumar M, Kanitkar M, Nammalwar BR, Bagga A. Revised statement on management of urinary tract infections. Indian Pediatr 2011;48:709-17.
Garin EH, Olavarria F, Garcia NietoV, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: A multicenter, randomized, controlled study. Pediatrics 2006;117:626-32.
Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, Minisini S, et al
. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008;121:e1489-94.
Moriya K, Mitsui T, Kitta T, Nakamura M, Kanno Y, Kon M, Nishimura Y, et al
. Early discontinuation of antibiotic prophylaxis in patients with persistent primary vesicoureteral reflux initially detected during infancy: Outcome analysis and risk factors for febrile urinary tract infection. J Urol 2015;193:637-42.
Nakai H, Kakizaki H, Konda R, Hayashi Y, Hosokawa S, Kawaguchi S, Matsuoka H, et al
. Clinical characteristics of primary vesicoureteral reflux in infants: Multicenter retrospective study in Japan. J Urol 2003;169:309-12.
Roussey-Kesler G, Gadjos V, Idres N, Horen B, Ichay L, Leclair MD, Raymond F, 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;179:674-9.
Holmberg SD, Solomon SL, Blake PA. Health and economic impacts of antimicrobial resistance. Rev Infect Dis 1987;9:1065-78.
Hari P, Bagga A. Antimicrobial prophylaxis for children with vesicoureteral reflux. N
Engl J Med 2014;371:1071-2.
Wang ZT, Wehbi E, Alam Y, Khoury A. A reanalysis of the RIVUR trial using a risk classification system. J Urol 2018;199:1608-14.
Piepsz A, Tamminen-Möbius T, Reiners C, Heikkilä J, Kivisaari A, Nilsson NJ, Sixt R, et al
. Five-year study of medical or surgical treatment in children with severe vesico-ureteral reflux dimercaptosuccinic acid findings. International reflux study group in Europe. Eur J Pediatr 1998;157:753-8.
Sheu JC, Huang YH, Chang PY, Wang NL, Tsai TC, Huang FY. Results of surgery for vesicoureteral reflux in children: 6 years' experience in an Asian country. Pediatr Surg Int 1998;13:138-40.
O'Donnell B, Puri P. Technical refinements in endoscopic correction of vesicoureteral reflux. J Urol 1988;140:1101-2.
Leonard MP, Canning DA, Peters CA, Gearhart JP, Jeffs RD. Endoscopic injection of glutaraldehyde cross-linked bovine dermal collagen for correction of vesicoureteral reflux. J Urol 1991;145:115-9.
Atala A, Peters CA, Retik AB, Mandell J. Endoscopic treatment of vesicoureteral reflux with a self-detachable balloon system. J Urol 1992;148:724-7.
Diamond DA, Caldamone AA. Endoscopic correction of vesicoureteral reflux in children using autologous chondrocytes: Preliminary results. J Urol 1999;162:1185-8.
Elder JS. Therapy for vesicoureteral reflux: Antibiotic prophylaxis, urotherapy, open surgery, endoscopic injection, or observation? Curr Urol Rep 2008;9:143-50.
Parekh DJ, Pope JC4th
, Adams MC, Brock JW3rd
. The use of radiography, urodynamic studies and cystoscopy in the evaluation of voiding dysfunction. J Urol 2001;165:215-8.
Tekgül S, Riedmiller H, Hoebeke P, Kočvara R, Nijman RJM, Radmayr C, et al
. EAU guidelines on vesicoureteral reflux in children. Eur Urol 2012;62:534-42.
Peters CA, Skoog SJ, Arant BS, Copp HL, Elder JS, Hudson RG, et al
. Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol 2010;184:1134-44.
Lowe LH, Patel MN, Gatti JM, Alon US. Utility of follow-up renal sonography in children with vesicoureteral reflux and normal initial sonogram. Pediatrics 2004;113:548-50.
Rudzinski JK, Weber B, Wildgoose P, Lorenzo A, Bagli D, Farhat W, Harvey E, et al
. Does routine ultrasound change management in the follow-up of patients with vesicoureteral reflux? Can Urol Assoc J 2013;7:E467-9.
Wennerström M, Hansson S, Jodal U, Stokland E. Disappearance of vesicoureteral reflux in children. Arch Pediatr Adolesc Med 1998;152:879-83.
Upadhyay J, McLorie GA, Bolduc S, Bägli DJ, Khoury AE, Farhat W. Natural history of neonatal reflux associated with prenatal hydronephrosis: Long-term results of a prospective study. J Urol 2003;169:1837-41.
Kirsch AJ, Arlen AM, Leong T, Merriman LS, Herrel LA, Scherz HC, et al
. Vesicoureteral reflux index (VURx): A novel tool to predict primary reflux improvement and resolution in children less than 2 years of age. J Pediatr Urol 2014;10:1249-54.
Silva JM, Diniz JS, Lima EM, Vergara RM, Oliveira EA. Predictive factors of resolution of primary vesico-ureteric reflux: A multivariate analysis. BJU Int 2006;97:1063-8.
Morita M, Yoshiara S, White RH, Raafat F. The glomerular changes in children with reflux nephropathy. J Pathol 1990;162:245-53.
Goonasekera CD, Shah V, Dillon MJ. Tubular proteinuria in reflux nephropathy: Post ureteric re-implantation. Pediatr Nephrol 1996;10:559-63.
Bell FG, Wilkin TJ, Atwell JD. Microproteinuria in children with vesicoureteric reflux. Br J Urol 1986;58:605-9.
Wallace DM, Rothwell DL, Williams DI. The long-term follow-up of surgically treated vesicoureteric reflux. Br J Urol 1978;50:479-84.
Simoes e Silva AC, Silva JM, Diniz JS, Pinheiro SV, Lima EM, Vasconcelos MA, Pimenta MR, et al
. Risk of hypertension in primary vesicoureteral reflux. Pediatr Nephrol 2007;22:459-62.
Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiology of chronic kidney disease in children. Pediatr Nephrol 2012;27:363-73.
Meena J, Sinha A, Hari P, Dinda AK, Khandelwal P, Goswami S, et al
. Pediatric kidney transplantation: Experience over two decades. Asian J Pediatr Nephrol 2018;1:22-8. [Full text]
Silva JM, Santos Diniz JS, Marino VS, Lima EM, Cardoso LS, Vasconcelos MA, Oliveira EA, et al
. Clinical course of 735 children and adolescents with primary vesicoureteral reflux. Pediatr Nephrol 2006;21:981-8.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]