Vesico-ureteric reflux: using mouse models to understand a common congenital urinary tract defect

Vesico-ureteric reflux (VUR) is a common congenital urinary tract defect in which urine flows retrogradely from the bladder to the kidneys because of an abnormally formed uretero-vesical junction. It is associated with recurrent urinary tract infections, renal hypo/dysplasia, reflux nephropathy, hypertension, and end-stage renal disease. In humans, VUR is genetically and phenotypically heterogeneous, encompassing diverse renal and urinary tract phenotypes. To understand the significance of these phenotypes, we and others have used the mouse as a model organism and this has led to the identification of new candidate genes. Through careful phenotypic analysis of these models, a new understanding of the genetics and biology of VUR is now underway.     

Vesicoureteral reflux and bladder dysfunction

The relationship between vesicoureteral reflux and bladder dysfunction is inseparable and has long been emphasized. However, the primary concern of all physicians treating patients with vesicoureteral reflux is the prevention of renal scarring and eventual deterioration of renal function.Bladder dysfunction, urinary tract infection and vesicoureteral reflux are the three important factors which are closely related to each other and contribute to the formation of renal scar. Especially, there is ongoing discussion regarding the role of bladder dysfunction in the prognosis of both medically and surgically treated vesicoureteral reflux. The effect of bladder dysfunction on VUR is mostly via inadequate sphincter relaxation during infancy which is closer to immature bladder dyscoordination rather than true dysfunction. But after toilet training, functional obstruction caused by voluntary sphincter constriction during voiding is responsible through elevation in bladder pressure, thus distorting the architecture of bladder and ureterovesical junction. Reports suggest that voiding phase abnormalities in lower urinary tract dysfunction contributes to lower spontaneous resolution rate of VUR. However, filling phase abnormalities such as involuntary detrusor contraction can also cause VUR even in the absence of dysfunctional voiding. With regards to the effect of bladder dysfunction on treatment, meta-analysis reveals that the cure rate of VUR following endoscopic treatment is less in children with bladder bowel dysfunction but there is no difference for open surgery.The pathophysiology of bladder dysfunction associated with UTI can be explained by the ‘milk-back’ of contaminated urine back into the bladder and significant residual urine resulting from functional outlet obstruction. In addition, involuntary detrusor contraction can decrease perfusion of the bladder mucosa thus decreasing mucosal immunity and creating a condition prone to UTI. In terms of renal scarring, dysfunctional voiding seems to be more closely related to renal damage in association with VUR than overactive bladder. However, studies show that UTI can induce renal scarring even without VUR present and urodynamic abnormalities are quite often detected in these cases. Whether reflux of sterile urine in bladder dysfunction can cause significant renal scarring, especially when intrarenal reflux is present remains controversial. Another issue that warrants further research is the direct relationship between bladder dysfunction and renal scarring, since some reports suggest that these two conditions share a common genotype.Recently some studies have suggest VUR as a causal factor of bladder dysfunction, supported by the fact that bladder dysfunction resolves after injection therapy of VUR. Further study with more objective evaluation of bladder dysfunction may be needed.     

Embryology and genetics of primary vesico-ureteric reflux and associated renal dysplasia

Congenital anomalies of the kidney and urinary tract, as well as primary vesico-ureteric reflux (VUR) and associated renal dysplasia, are the most relevant causes of end-stage renal failure in the pediatric population. In vivo and in vitro experimental studies have allowed the identification of several genes involved both in ureteric bud branching, ureteric elongation and insertion into the bladder, and in nephrogenesis. It has been proposed that both renal and ureteral abnormalities, as well as the associated renal hypo-dysplasia, may derive from a common mechanism as the result of a dysregulation of the normal developmental program. The large homologies between mice and the human genome suggest that the same genes could be involved both in rodent and human VUR. Furthermore, epidemiological observations suggest that not only syndromic but also isolated VUR is an inherited trait. Linkage analysis for homologous mouse genes in humans, genome-wide linkage studies in multigenerational families and association studies by polymorphisms support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. The present teaching paper is an overview of the embryology and genetics of primary VUR and associated congenital reflux nephropathy.     

Vesicoureteric reflux and reflux nephropathy: from mouse models to childhood disease

Vesicoureteric reflux (VUR) is a common congenital urinary tract defect that predisposes children to recurrent kidney infections. Kidney infections can result in renal scarring or reflux nephropathy defined by the presence of chronic tubulo-interstitial inflammation and fibrosis that is a frequent cause of end-stage renal failure. The discovery of mouse models with VUR and with reflux nephropathy has provided new opportunities to understand the pathogenesis of these conditions and may provide insight on the genes and the associated phenotypes that need to be examined in human studies.     

Vesicoureteral reflux

Vesicoureteral reflux (VUR), the retrograde flow of urine from the bladder toward the kidney, is common in young children. About 30% of children with urinary tract infections will be diagnosed with VUR after a voiding cystourethrogram. For most, VUR will resolve spontaneously; 20% to 30% will have further infections, but few will experience long-term renal sequelae. Developmentally, VUR arises from disruption of complex signaling pathways and cellular differentiation. These mechanisms are probably genetically programmed but may be influenced by environmental exposures. Phenotypic expression of VUR is variable, ranging from asymptomatic forms to severe renal parenchymal disease and end-stage disease. VUR is often familial but is genetically heterogeneous with variability in mode of inheritance and in which gene, or the number of genes, that are involved. Numerous genetic studies that explore associations with VUR are available. The relative utility of these for understanding the genetics of VUR is often limited because of small sample size, poor methodology, and a diverse spectrum of patients. Much, if not all, of the renal parenchymal damage associated with end-stage disease is likely to be congenital, which limits the opportunity for intervention to familial cases where risk prediction may be available. Management of children with VUR remains controversial because there is no strong supportive evidence that prophylactic antibiotics or surgical intervention improve outcomes. Furthermore, well-designed genetic epidemiological studies focusing on the severe end of the VUR phenotype may help define the causal pathway and identify modifiable or disease predictive factors.     

Characteristics of the hydrodynamic situation in the urinary tract in vesico-ureteral reflux based on an analysis of a general type of equation of the linear transport model

Upper urinary tract urodynamics are described through a linear deterministic chamber model. An analysis of possible urodynamic variants in vesico-ureteral reflux (VUR), using a mathematical model, has suggested that hydrodynamic situation in the refluxing ureter will be dependent on vesical and ureteral activity where ureterovesical incompetence and VUR are of similar grades. Where ureteral anatomy and function remain fairly intact, urinary regurgitation under high pressure shall be accompanied by the development of a considerable intraureteral hypertension. Besides, VUR-associated urodynamic disorder must have an obstructive component whose markedness will depend on the extent of arterial motor impairment, intravesical hypertension or a combination of the two. Urodynamic and radioisotopic studies have completely confirmed the theoretical postulations. In second- or third-degree VUR, for example, the highest intraureteral pressure developed in children with uninhibited bladder, while in fourth-degree VUR the bladder showed no response to gradual intravesical pressure rise. Urodynamic disturbance was already shown to have a functional/obstructive component in those cases of second-degree VUR where the bladder was uninhibited and be free of it in cases of normal bladder reflex and third-degree VUR.     

Relationship between febrile urinary tract infection and urodynamics in myelodysplastic children with vesicoureteral reflux

OBJECTIVE: We conducted a retrospective study in order to identify factors that may predict the incidence of febrile urinary tract infection (UTI) in myelodysplastic children with vesicoureteral reflux (VUR). METHODS: A total of 23 myelodysplastic children with persistent VUR who were managed by clean intermittent catheterization (CIC) were eligible for this study. Any factors, including urodynamic parameters and urinary tract abnormalities, that may have been associated with the incidence of febrile UTI were evaluated using both univariate analysis and multiple logistic regression analysis. RESULTS: Of 23 patients, 10 (43%) had had one or more episodes of febrile UTI. Both univariate and multivariate analyses showed a statistically significant relationship between low bladder compliance (<10 ml/cm H(2)O) and episodes of febrile UTI. CONCLUSION: These results demonstrated that the urodynamics linked to bladder function disorder in the filling phase appear to be correlated with the incidence of febrile UTI in myelodysplastic children with VUR who are managed by CIC.     

Nicht neurogene Blasenfunktionsst?rungen und vesikoureteraler Reflux bei Kindern

Various types of bladder dysfunction are associated with urinary tract infection, renal damage and vesicoureteral reflux (VUR). In this article the influence of functional bladder disturbances such as detrusor instability (overactive bladder, OAB) and bladder sphincter dyssynergia (dysfunctional voiding), on the resolution of vesicoureteral reflux are reviewed. In summary, it is important to distinguish between children with dysfunctional voiding (increased activity of the pelvic floor during voiding) and those with OAB (detrusor overactivity during filling) because the latter has less effects on VUR.     

膀胱输尿管反流的精准诊治进展

膀胱输尿管反流( VUR)是儿童最为常见的泌尿系统疾病,该病使患儿更易出现肾盂肾炎,是儿童尿路感染后肾脏疤痕形成的最重要的风险因素。到目前为止,对VUR的诊断及治疗仍有很多争议,其争议内容主要是围绕着哪些儿童应该评估反流的有无,以及一旦确诊VUR时哪些儿童又应该接受治疗及接受何种治疗。VUR是一种遗传性疾病,但是该病具有种族差异性、遗传异质性等特点,迄今为止国际上尚没有公认的、一致的主要致病基因。明确不同基因突变所致的VUR的研究,有助于做出肾疤痕形成是先天性还是后天性的判断,从而在临床做出精确诊断及精准治疗。     

The need for ureteric re‐implantation during augmentation cystoplasty: video‐urodynamic evaluation

Study Type – Therapy (case series)
Level of Evidence 4

OBJECTIVE

To evaluate video‐urodynamic (VUD) results before and after surgery in children with high‐pressure, low‐compliance bladders and vesico‐ureteric reflux (VUR), who had augmentation cystoplasty with no antireflux surgery, hypothesising that in these patients, poor preoperative bladder dynamics is not always the cause of the associated VUR, as VUR persists in some patients.

PATIENTS AND METHODS

We assessed objective VUD criteria where antireflux surgery might potentially be necessary to avoid reflux after augmentation, and retrospectively evaluated the clinical consequences of persistent VUR and compared it to those whom VUR resolved. In all, 19 patients with VUR and hypocompliant bladders (mean age 11.4 years, range 5–21) had augmentation ileocystoplasty. Lower urinary tract function was assessed before surgery and at 3 and 6 months afterward with VUD. Symptomatic febrile urinary tract infections (UTIs) and progressive renal scarring on scintigraphy were retrospectively evaluated in all patients.

RESULTS

VUR persisted in nine patients despite a low‐pressure bladder. In all patients with persistent VUR, VUD at 6 months after surgery showed that VUR started at low bladder volumes (mean 29.6 mL, range 19–52) and low pressures (mean 14.6 cmH₂O, range 9.6–25) when compared to the group with no persistent VUR. Before surgery VUD showed that reflux started at the beginning of the filling phase (mean 14.8 mL, range 8–33) with very low intravesical pressures (mean 7.8 cmH₂O, range 4–17) in these nine patients. During the follow‐up febrile UTIs were significantly more frequent in the group with persistent VUR. One patient had progressive renal scarring on scintigraphy after cystoplasty.

CONCLUSION

Preoperative VUD findings might be a very important predictor of the spontaneous resolution of VUR. In these patients concomitant VUR should be corrected simultaneously during bladder augmentation if it starts at low pressures on preoperative VUD, as persistence of VUR can induce scarring from febrile UTIs.     

Indirect radionuclide cystography: a sensitive technique for the detection of vesico-ureteral reflux

The detection or exclusion of vesico-ureteral reflux (VUR) has classically been by micturating cystourethrography (MCUG). Radionuclide cystography will detect VUR but fails to provide the same detailed anatomical informations as MCUG. This study allowed a comparison of indirect radionuclide cystography (IRC) and MCUG in 65 children. Renal reflux was detected by IRC in 32% of renal units, while VUR was seen in 36% by MCUG. When a comparison was made with MCUG, IRC had a sensitivity of 74.1% and a specificity of 90.5%. The markedly reduced radiation dose, avoidance of a bladder catheter plus the ability to monitor the urinary tract constantly during the entire procedure should ensure that IRC is the examination of choice in follow-up studies for VUR in all toilet-trained children.     

Risk factors for febrile urinary tract infection in children with myelodysplasia treated by clean intermittent catheterization

OBJECTIVE: To identify the factors involved in the incidence of febrile urinary tract infection (UTI) in a retrospective study of children with myelodysplasia who were treated by clean intermittent catheterization. METHODS: A total of 76 myelodysplastic children were included in the present study. Any factors, including urodynamic parameters and urinary tract abnormalities, that may have been associated with the incidence of febrile UTI were evaluated using both a univariate analysis and a multiple logistic regression analysis. RESULTS: Of the 76 patients, 19 (25%) had one or more episodes of febrile UTI. A univariate analysis showed low bladder compliance (<10 mL/cmH2O), detrusor overactivity, bladder trabeculation and the presence of vesico-ureteral reflux (VUR) to be significant factors in the incidence of febrile UTI. The presence of detrusor overactivity and a low bladder compliance, in addition to the presence of VUR, were found to be significant factors for the incidence of febrile UTI using a multivariate analysis. CONCLUSION: These results demonstrate that, in addition to VUR, urodynamics linked to bladder storage function disorder appear to be directly correlated with the cause of febrile UTI in children with myelodysplasia.     

Vesicoureteral reflux and reflux nephropathy

Vesicoureteral reflux is an anatomic abnormality, mostly affecting a pediatric population, which may be the second leading cause of end-stage renal failure. Most cases of reflux are due to abnormalities in the insertion of the ureters into the bladder, either congenital or acquired. Most commonly, VUR is discovered during routine evaluation of urinary tract infections, but may also be present in patients with severe hypertension or chronic renal failure. The diagnosis is confirmed radiologically, utilizing either voiding cinecystography or radioisotopic methods. VUR can result in renal failure through scarring secondary to 'chronic pyelonephritis' or through a glomerulopathy, possibly immune in origin. In most series, the glomerulopathy is felt to be the cause of the end-stage renal failure. Treatment of VUR includes conservative (medical) management with the hope that maturation of the ureterovesical junction will cure reflux. Surgical therapy is reserved for those patients in whom this maturation is not expected to occur or in those whose urinary infections cannot be controlled. In those patients who have developed the glomerulopathy secondary to VUR, surgery may not halt the progression of the renal disease. VUR in a transplanted kidney may result in a higher risk of loss of the graft due to glomerulopathy or chronic rejection.     

Contrast-enhanced ultrasound voiding cystography as a screening examination for vesicoureteral reflux in the follow-up of renal transplant recipients: a new approach.

BACKGROUND: The aim of the study was to evaluate a new diagnostic procedure, ultrasound contrast-enhanced voiding cystography (USVC), for vesicoureteral reflux (VUR) in renal transplant recipients and to compare it with radionuclide voiding cystography (RVC). METHODS: Twenty-three renal transplant recipients with recurrent urinary tract infection were investigated simultaneously by RVC and USVC. After catheterization, the empty bladder was filled with normal saline (mean 250+/-30 ml) and 30-45 mBq of (99m)Tc-labelled colloid. At the end of filling the bladder, 19.5 ml of galactose-based, microbubble-containing echo-enhancing agent, at a concentration of 200 mg/ml, was instilled. During the filling and voiding phases the movement of the radiotracer was recorded by a gamma camera and the presence of microbubbles in the urinary tract by ultrasound. RVC was used to detect and grade the degree of VUR. RESULTS: Nuclear studies identified VUR in 16 (69.6%) of 23 recipients with recurrent urinary tract infection: VUR grade I in three (13%) recipients, grade II in eight (34.8%) and grade III in five (21.7%) using a simplified grading system. USVC with contrast-enhancement detected VUR in 14 (60.9%) recipients. Overall sensitivity and specificity of contrast-enhanced USVC was 75 and 71%, respectively. Statistical analysis showed that the accuracy of this procedure increased with higher grades of VUR and its sensitivity reached 100% for detection of VUR grade III. CONCLUSION: In our preliminary study, contrast-enhanced USVC has proved to be an effective examination, with the same accuracy rate as RVC in detecting grade III VUR episodes with low diagnostic accuracy for low reflux grades.     

Therapy insight: What nephrologists need to know about primary vesicoureteral reflux

Vesicoureteral reflux (VUR) is the abnormal, retrograde flow of urine from the bladder to the upper urinary tract. This disease affects about 1% of otherwise normal children, 30-50% of those who present with urinary tract infections, and approximately 10% with prenatally diagnosed hydronephrosis. Over the past 50 years, tremendous progress has been made in the diagnosis, treatment and management of VUR. The realization that VUR is probably a component of generalized dysfunction of the lower urinary tract (i.e. dysfunctional elimination syndrome) has further enhanced understanding of the disease. This Review covers basic pathogenesis, diagnosis, management, clinical presentation, and current controversies surrounding VUR.     

Risk factors for renal scarring in children and adolescents with lower urinary tract dysfunction

Risk factors for renal scarring in children with lower urinary tract dysfunction (LUTD) were evaluated. The medical records of 120 patients were assessed concerning gender, presence of vesicoureteric reflux (VUR), bladder capacity, detrusor overactivity, residual urine, febrile urinary tract infection (UTI), bacteriuria, constipation, detrusor sphincter incoordination (DSI), high detrusor pressure at maximal cystometric capacity (PMCC), low compliance, and thickness and trabeculation of the bladder wall. Renal scarring was diagnosed by ^99mtechnetium-dimercaptosuccinic acid renal scan (DMSA). Renal scarring was detected in 38 patients (31%). VUR, UTI, decreased bladder capacity, urinary residue, and trabeculated and thick bladder wall were associated with scarring at univariate analysis. Multivariate analysis showed VUR (P < 0.0001) as the independent risk factor for renal scarring. Thickness of the bladder wall was a marginal risk factor (P  = 0.07). Although UTI was not a risk factor, it was associated with VUR (P  = 0.03). In our analysis, VUR was the main risk factor; however, renal scarring was probably due to multifactorial causes, as VUR was associated with UTI.     

Non-invasive screening for vesicoureteric reflux: a realistic aim?

Summary The prevention of reflux nephropathy by screening will likely prove to be an elusive aim. Possible non-invasive screening tests include urinary analysis for microproteins, colour Doppler ultrasound and real-time ultrasound. However, it is likely that real-time ultrasound, in practice the only feasible screening tool, would fail to detect the large group of children whose vesicoureteric reflux (VUR) does not give rise to detectable dilatation. Routine ultrasound scanning of the fetal urinary tract in pregnancy constitutes a de facto screening programme. However, it has become apparent that prenatal ultrasound results in the detection of high-grade VUR in a population of boys rather than in the numerically more important population at risk: girls with low-grade VUR. Investigating infants with mild pelvic and pelvicaliceal dilatation for VUR might improve the sensitivity of prenatal ultrasound as a screening test, but the potential benefits of detecting VUR in this group of infants would have to be weighed against unnecessary micturating cystography in a large number of normal children. Presently, considerable clinical and experimental evidence indicates that urinary infection plays the major role in the aetiology of reflux nephropathy. By detecting asymptomatic VUR in early childhood, an effective screening programme could be expected to reduce the considerable burden of morbidity that is associated with the condition. Unfortunately, a reliable screening test remains a distant goal.     

Evidence-based medicine and vesicoureteral reflux

Vesicoureteral reflux (VUR) remains one of the most controversial subjects in paediatric urology. Much literature has been published on VUR, making the understanding of this anomaly and its treatments quite opaque. Evidence-Based Medicine (EBM) should be helpful to clarify the various VUR approaches contained in the 6224 titles found on Medline using the keywords "vesicoureteral reflux" and "vesicoureteric reflux". These articles were critically reviewed and graded according to EBM scorings, with regard to their methodological designs. This review of VUR literature suggests that most of our knowledge is based on publications with a low level of evidence, and that EBM lacks arguments to support recommendations for VUR diagnostic and treatment. It appears yet that antenatal dilatation of the urinary tract and symptomatic urinary tract infections (UTI) justify VUR screening. Surgery should be discussed in recurrent UTIs or deterioration of renal function. There is no consensus in case of persistent asymptomatic VUR regarding indication and duration of antibio-prophylaxis, and selection of radical treatment.     

EAU Guidelines on vesicoureteral reflux in children

Context

Primary vesicoureteral reflux (VUR) is a common congenital urinary tract abnormality in children. There is considerable controversy regarding its management. Preservation of kidney function is the main goal of treatment, which necessitates identification of patients requiring early intervention.

Objective

To present a management approach for VUR based on early risk assessment.

Evidence acquisition

A literature search was performed and the data reviewed. From selected papers, data were extracted and analyzed with a focus on risk stratification. The authors recognize that there are limited high-level data on which to base unequivocal recommendations, necessitating a revisiting of this topic in the years to come.

Evidence synthesis

There is no consensus on the optimal management of VUR or on its diagnostic procedures, treatment options, or most effective timing of treatment. By defining risk factors (family history, gender, laterality, age at presentation, presenting symptoms, VUR grade, duplication, and other voiding dysfunctions), early stratification should allow identification of patients at high potential risk of renal scarring and urinary tract infections (UTIs). Imaging is the basis for diagnosis and further management. Standard imaging tests comprise renal and bladder ultrasonography, voiding cystourethrography, and nuclear renal scanning. There is a well-documented link with lower urinary tract dysfunction (LUTD); patients with LUTD and febrile UTI are likely to present with VUR. Diagnosis can be confirmed through a video urodynamic study combined with a urodynamic investigation. Early screening of the siblings and offspring of reflux patients seems indicated.Conservative therapy includes watchful waiting, intermittent or continuous antibiotic prophylaxis, and bladder rehabilitation in patients with LUTD. The goal of the conservative approach is prevention of febrile UTI, since VUR will not damage the kidney when it is free of infection. Interventional therapies include injection of bulking agents and ureteral reimplantation. Reimplantation can be performed using a number of different surgical approaches, with a recent focus on minimally invasive techniques.

Conclusions

While it is important to avoid overtreatment, finding a balance between cases with clinically insignificant VUR and cases that require immediate intervention should be the guiding principle in the management of children presenting with VUR.