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.     

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.     

Primärer vesikoureteraler Reflux

The never ending discussion about the diagnostics and treatment of vesicoureteral reflux (VUR) now includes arguments for diagnostic nihilism as well as invasive diagnostics and therapy, which is reminiscent of the debate on prostate cancer in adulthood. The common goal of all currently competing diagnostic strategies and approaches is the prevention of renal scars by the most effective and least burdensome approach. There is a difference between acquired pyelonephritic scars with VUR (acquired reflux nephropathy) and congenital reflux nephropathy (primary dysplasia) which cannot be influenced by any therapy. The VUR can be verified by conventional radiological voiding cystourethrography (VCUG), by urosonography, radionuclide cystography or even by magnetic resonance imaging (MRI). The guidelines of the European Association of Urology/European Society for Paediatric Urology (EAU/ESPU) recommend radiological screening for VUR after the first febrile urinary tract infection. Significant risk factors in patients with VUR are recurrent urinary tract infections (UTI) and parenchymal scarring and the patients should undergo patient and risk-adapted therapy. Infants with dilating reflux have a higher risk of renal scarring than those without dilatation of the renal pelvis. Bladder dysfunction or dysfunctional elimination syndrome represents a well-known but previously neglected risk factor in combination with VUR and should be treated prior to any surgical intervention as far as is possible. Certainly not every patient with VUR needs therapy. The current treatment strategies take into account age and gender, the presence of dysplastic or pyelonephritic renal scars, the clinical symptoms, bladder dysfunction and frequency and severity of recurrent UTI as criteria for the therapy decision. The use of an antibacterial prophylaxis as well as the duration is controversially discussed. Endoscopic therapy can be a good alternative to antibacterial prophylaxis or a surveillance strategy in patients with low grade VUR. In patients with dilating VUR and given indications for surgery, endoscopic treatment can be offered. However, parents should be completely informed about the significantly lower success rate of endoscopic therapy compared to open surgical procedures. The open surgical techniques guarantee the highest success rates and should be used in patients with a dilating VUR and high risk of renal damage.     

MANAGEMENT OF VESICO-URETERIC REFLUX IN MYELODYSPLASIA NEUROGENIC BLADDER

During the period 1978–87, 22 patients with myelodysplasia had surgery for vesico-ureteric reflux (VUR) and seven patients with VUR were managed non-operatively. Clean intermittent catheterization was an integral part of the management in both the operated and non-operated cases. The majority of patients had reflux-related upper tract changes pre-operatively. but alter operation the urinary tract was stabilized in all but one kidney which was lost. Tranverse advancement ureteric reimplantation or the pull-through technique provided satisfactory results, giving a total of 29 refluxing units managed surgically.     

Infections and vesicoureteral reflux

Vesicoureteral reflux (VUR) is a common condition in children. It may cause and maintain urinary tract infections, eventually leading to progressive renal damage and end-stage renal disease. Ideally, VUR should be detected and treated before renal scarring occurs. Although fetal hydronephrosis on antenatal ultrasound may be the first indicator, the role of further diagnostic investigations in these newborns is still controversial. Because VUR is an inherited condition, offspring of women with a family history of VUR and urinary tract infection should be screened closely for early detection of VUR. Once diagnosed, however, the optimal management of VUR (i.e. medical or surgical treatment) remains controversial. Evidence-based treatment recommendations, like the American Urological Association guidelines, may aid physicians in their therapeutic decision making, but cannot replace personal experience or surgical skill.     

Gene discovery and vesicoureteric reflux

Vesicoureteric reflux (VUR) is a congenital urinary tract defect caused by abnormal insertion of the ureter within the bladder wall. This leads to a defective ureterovesical junction in which urine flows retrogradely from the bladder to the kidneys. Although VUR is associated with recurrent urinary tract infections, renal malformations, hypertension, and reflux nephropathy, its relationship to each of these clinical entities is poorly understood. Mutations in genes expressed by the developing kidney and urinary tract can cause VUR in mice, and some of these same genes have been identified in humans with VUR. By discovering the genes that are associated with VUR, new hypotheses will be generated such that, eventually, the relationship between VUR and its complications will be understood.     

Fetal vesicoureteric reflux

We present an analysis of 30 patients with fetal vesicoureteric reflux (VUR) from a series of 107 patients with prenatally diagnosed urinary tract anomalies. In 13 patients (Group 1) the fetal VUR was the only urinary tract abnormality. In 17 patients (Group 2) the fetal VUR was combined with other urinary tract problems. In 14 of 46 refluxing renal units there was no evidence of upper tract dilatation on a pre- and post-natal ultrasound examination. Any infant with postnatal urinary tract dilatation needs full urological investigations, including a micturating cystogram. A normal postnatal ultrasound examination does not exclude fetal VUR.     

Use of collagen injections for vesicoureteral reflux in transplanted kidneys

Reports in the literature suggest the incidence of vesicoureteral reflux (VUR) in transplanted kidneys to range from 2-79%. Collagen injections have been used with reported success rates of up to 65% to prevent VUR into native orifices in children, but have not been studied in transplant neo-orifices. We evaluated the use of collagen injections in seven patients with transplant kidney neo-orifices who displayed grades II-IV VUR and seemed to be related to symptomatic urinary tract infections (UTIs). Postoperative VCUGs obtained at 2 months showed improvement in the grade of reflux in four of seven (57.1%) patients; one (14.3%), no change; and two (28.6%), worse reflux. All patients also redeveloped symptomatic UTIs after collagen injection. We conclude that the use of collagen injections in kidney transplant neo-orifices did not prevent VUR. Although prevention of VUR may have been achieved short term, VCUG examinations 2 months after initial injection revealed persistent reflux. Etiologies for failure to prevent VUR may be the readily absorbable nature of collagen, technical aspects of the procedure, the degree of reflux, and anatomic differences between native orifices (which lie on a well-supported trigone) and transplant neo-orifices (which lie on the posterior wall with less support).     

A 14-year follow-up of conservative treatment for vesico-ureteric reflux

OBJECTIVE: To determine renal function in patients with vesico-ureteric reflux (VUR) during 14 years of conservative treatment (no surgery). PATIENTS AND METHODS: Sixty patients with VUR were consecutively included between 1981 and 1982. The degree of VUR was determined by conventional voiding cysto-uretherography (VCUG) after 3 months of prophylactic antibiotics. The VUR was grade I-IV, with grades III and IV characterized as high-grade VUR. In all patients, any urinary tract infections and bladder-urethral dysfunction were treated. Renal function and reflux were monitored by renal and bladder scintigraphy using 123I-hippuran and the glomerular filtration rate (GFR) was determined using the plasma clearance of 51Cr-ethylaminediamine tetra-acetic acid. RESULTS: Of the 60 patients who entered the study, 51 were followed for a mean of 13.7 years; nine patients were lost to follow-up. None of the patients underwent antireflux surgery. All patients were in good health and normotensive (except two with borderline hypertension). Of the 51 patients 21 had low-grade, 21 unilateral high-grade and nine bilateral high-grade reflux. In those with low-grade reflux both the mean renal split function on the most refluxing kidney and the GFR remained stable during the whole monitoring period. Eighteen patients who had a persistent reduction in renal split function or initially had had a significantly reduced functional share to the most refluxing kidney had their GFR re-assessed in adolescence. However, the body surface-corrected GFR remained constant. Total GFR and single kidney GFR increased significantly. CONCLUSION: A conservative treatment regimen in patients with VUR can ensure stable kidney function, although kidneys with a lower renal function at referral seem to have an impaired functional growth potential.     

Vesicoureteral reflux and reflux nephropathy

Primary vesicoureteral reflux (VUR) is the commonest congenital urological abnormality in children, which has been associated with an increased risk of urinary tract infection (UTI) and renal scarring, also called reflux nephropathy (RN). In children, RN is diagnosed mostly after UTI (acquired RN) or during follow-up for antenatally diagnosed hydronephrosis with no prior UTI (congenital RN). The acquired RN is more common in female children, whereas the congenital RN is more common in male children. This observation in children might help explain the differences in the clinical presentation of RN in adults, with males presenting mostly with hypertension, proteinuria, and progressive renal failure as compared with females who present mostly with recurrent UTI and have a better outcome. Known risk factors for RN include the severity of VUR, recurrent UTI, and bladder-bowel dysfunction; younger age and delay in treatment of UTI are believed to be other risk factors. Management of VUR is controversial and includes antimicrobial prophylaxis, surgical intervention, or surveillance only. No evidence-based guidelines exist for appropriate follow-up of patients with RN.     

The impact of vesicoureteral reflux treatment on the incidence of urinary tract infection

Vesicoureteral reflux (VUR) is a heterogeneous disease and its management remains one of the most controversial topics in pediatrics. Management options include surveillance, antibiotics, and surgery. The approval of dextranomer/hyaluronic acid (DHA) as a bulking agent by the Food and Drug Administration was followed by wide acceptance of endoscopic techniques as a major tool in the management of reflux. Pyelonephritis rather than VUR is the most common cause of kidney damage in children. It should be emphasized that the primary goal of diagnosing and treating VUR should be preventing this complication. There are no sufficient data in the literature to address the impact of the different treatment modalities on the incidence of febrile urinary tract infections (feb-UTIs) denoting pyelonephritis, with very few studies evaluating endoscopic treatment in light of this clear and well-defined outcome. The fact that we can correct the anatomy at the vesicoureteral junction with a simple and relatively safe outpatient procedure does not justify offering it to all patients. In this review, we attempt to critically evaluate the available literature pertaining to the impact of different treatment modalities on reducing the incidence of febrile UTIs and kidney damage, with a special emphasis on endoscopic treatment.     

Prognostic value of the acute DMSA scan in children with first urinary tract infection

We attempted to verify in a group of 101 children with first urinary tract infection whether it was possible to identify groups of patients with different risks of developing renal scarring by taking into account both the extent of kidney involvement documented in the acute phase of infection using a dimercaptosuccinic acid (DMSA) scan, and the presence or absence of vesicoureteral reflux (VUR). The frequency of persistent lesions in kidneys with mild-moderate lesions (less than 50% of kidney involvement) in the presence of VUR or in non-refluxing kidneys was similar (P=0.1447), while the frequency of persistent lesions in kidneys with severe lesions in the presence of VUR was significantly higher than the frequency of persistent lesions in non-refluxing kidneys (P=0.0089). The extent of kidney involvement and the presence of VUR make possible the identification of different categories of risk of scarring: in the ”low risk group” (normal kidney with/without VUR) the risk of scarring is 0%; in the ”intermediate risk group” (mild lesions with/without VUR; extensive lesions without VUR) the risk of scarring is between 14% and 38%, while in the ”high risk group” (extensive lesions with VUR) the risk of scarring is 88%. Quantifying the risk of scarring could help in planning the treatment or in modifying the later strategy. Received: 5 June 2000 / Revised: 23 January 2001 / Accepted: 24 April 2001     

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.     

Split renal function does not change after successful treatment in children with primary vesico-ureteric reflux

OBJECTIVE: To evaluate the renal growth pattern in patients with primary vesico-ureteric reflux (VUR) using long-term measurements of split renal function with 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy. PATIENTS AND METHODS: In all, 712 children aged < 16 years (466 boys and 246 girls) with primary VUR were referred to our hospital from July 1991 to December 2000. VUR was diagnosed by voiding cysto-urethrography. The patients were treated either surgically (group 1) or conservatively (group 2) and followed with serial 99mTc-DMSA scintigraphy for up to 10 years. There were 942 examinations in 367 of 712 patients who had repeat scintigraphy. Patients with secondary VUR, VUR to a solitary or fused kidney, or upper urinary tract obstruction, were excluded. Five of 298 patients (1.7%) who had ureteric reimplantation had a febrile urinary tract infection (UTI) soon after surgery but none recurred (recurrence is an indication for surgery in children with VUR); there was no febrile UTI in the 69 patients in group 2. Planar scintigraphy with 99mTc-DMSA was used to assess the absolute uptake (AU) of each kidney, measured as a percentage of the injected dose, and the relative uptake (RU = AU of each kidney/AU of both kidneys) calculated. The initial examination was at least 4 weeks after any febrile UTI in most patients. Serial studies were conducted 1 year after surgery and then biannually in group 1. In group 2 the DMSA scan was repeated every 2-3 years. The change in split renal function was compared with the RU of the right kidney. RESULTS: The RU of the right kidney at the initial scan correlated closely with those on repeated scans in both groups. The correlation coefficients were 0.99 in group 1 and 0.94-0.97 in group 2 at every study. The change of RU remained within 0.05 in all patients after treatment. CONCLUSIONS: Under strict control of UTI, split renal function in children with primary VUR does not change. There may be no possibility of accelerated or compensatory growth of the kidney with reflux nephropathy, but no concern about deterioration and atrophy either.     

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.     

The role of imaging in urinary tract infections

The aim of imaging in urinary tract infections (UTI) is to detect conditions that must be corrected to avoid imminent deterioration of kidney function, or to prevent recurrent infections and long-term kidney damage. The most threatening conditions are obstruction of an infected upper tract and abscesses of the genitourinary system. An image-guided percutaneous drainage can be lifesaving. The role of imaging in small children with UTI is controversial in terms of the importance of anatomical and functional disorders in relation to the preventive measures to be taken. In newborns identified with hydronephrosis during pregnancy or by neonatal screening, vesicoureteral reflux (VUR) and renal scarring are congenital and not caused by infection. Most of these patients are males and the VUR is of a higher grade than VUR detected in girls after the first UTI. Imaging in children with UTI should only be ordered after a thorough evaluation of the risk of renal damage and the benefits of preventive measures. In adult females, no imaging is necessary in cystitis, while ultrasonography and plain films are recommended in acute pyelonephritis. Since uncomplicated UTI in men is rare, diagnostic imaging should be started early to rule out complicating factors in the urinary tract. In prostatitis, vesiculitis, epididymitis and orchitis the role of imaging is to rule out abscess formation and testicular malignancies.     

Urinary tract infections,VUR, and autosomal dominant polycystic kidney disease

This case series of 16 patients with autosomal dominant polycystic kidney disease (ADPKD) describes 4 girls who presented with a urinary tract infection (UTI). Radiological evaluation revealed that each of these patients had vesicoureteral reflux (VUR). The frequency of VUR was significantly higher in the patients with ADPKD compared with otherwise healthy age-matched children who underwent testing after a UTI (100% versus 15%, P<0.002). These findings suggest VUR is an associated somatic anomaly in children with ADPKD that may contribute to the occurrence of UTI in this patient population.     

Summary of recent AUA guidelines for the management of vesicoureteral reflux in children

VUR is a common condition and it is a predisposing factor for pyelonephritis, and reflux nephropathy, which can cause end stage renal disease in children. Given the consequences and sequelae of UTI and VUR, and due to lack of consensus regarding management of this common condition, the American Urological Association (AUA) developed treatment guidelines for children with VUR in 1997 and 2012 to help physicians better manage children with VUR. In this review, the summary of the 1997 and 2012 AUA guidelines are discussed with a focus on the 2012 report. Recommendations about evaluation and management of children under and above one year with VUR, with and without bladder/bowel dysfunction, screening of siblings of patients with VUR, screening of the neonate/infant with prenatal hydronephrosis, and follow up of the children with VUR are discussed in this review. The identification and management of VUR in these groups, provide the potential opportunity to prevent renal damage and decrease the risk of UTI and pyelonephritis. According to these guidelines, risk assessment of renal injury/scarring in the individual patient based upon clinical factors is critical, and interventions should be appropriate to the risk profile. Informing families and healthcare providers of the potential risk of pyelonephritis and renal scarring and allowing them to participate in decision making is considered important.     

Vesicoureteric reflux is not a benign condition

Renal parenchymal defects may be congenital, usually associated with dilated vesicoureteric reflux (VUR), or they may appear in previously normal kidneys and be caused by reflux nephropathy due to VUR combined with urinary tract infection (UTI). A piglet model defined that the 70% of children with VUR and vulnerable pyramids would scar rapidly with their first UTI. Because most defects are present at first imaging after a UTI, and from the lack of benefit from apparently reasonable clinical interventions, many now believe that most defects are congenital, their association with VUR being a shared dysplasia rather than causal. Consequently, guidelines now argue for less assiduous management. These conclusions ignore adult human transplant evidence, adult pig studies, and clinical anecdotes, which indicate that scars may develop in infant kidneys quicker than urine culture can confirm the diagnosis, and that reflux nephropathy has no age limit. Its rarity over 4 years suggests that most vulnerable children develop scars before then, despite all medical efforts. I argue that preventing such scarring will require better diagnosis of infant UTI, quicker treatment, reliable imaging of scars and VUR, and subsequent protection until VUR resolves. To make a difference, we need more assiduous management, not less, and cannot afford to consider VUR to be a benign condition.     

Urinary calcium and uric acid excretion in children with vesicoureteral reflux

Urolithiasis is relatively common in children, and identifiable predisposing factors for stone formation, including metabolic and structural derangements, can be established in most cases. Vesicoureteral reflux (VUR) is a common cause of kidney stone formation. The pathophysiological mechanism of urolithiasis in reflux is related to urinary tract infection and urinary stasis, both of which promote urinary crystal formation, but metabolic causes, such as crystallurias (mostly hypercalciuria), may also be involved in this process. However, few studies on urinary calcium and uric acid excretion in children with VUR have been conducted. We have studied the frequency of hypercalciuria and hyperuricosuria in children with VUR and compared the results with those from a control group. The VUR group comprised 108 children with VUR (19 boys, 89 girls; age range 3 months to 12 years), and the control group comprised 110 healthy children without any history of reflux or urinary tract infection (30 boys, 80 girls; age range 2 months to 12 years). Fasting urine was analyzed for the calcium/creatinine (Ca/Cr) and uric acid/creatinine (UA/Cr) ratios. Hypercalciuria was more frequently diagnosed in the VUR patients than in the control group (21.3 vs. 3.6%; P = 0.0001). Significant differences between the two groups were also found for the mean Ca/Cr and UA/Cr ratios (P = 0.0001 and P = 0.0001, respectively). No differences were found in the urinary Ca/Cr or UA/Cr ratios related to VUR grading or unilateral/bilateral VUR in the patient group, with the exception of those for hypercalciuria and mild VUR (P = 0.03). The association of urinary stones and microlithiasis in the VUR group was 29.6%. Our results demonstrate that the frequency of hypercalciuria and hyperuricosuria was higher in pediatric patients with VUR than in healthy children. Knowing this relationship, preventive and therapeutic interventions for stone formation in VUR could be greatly expanded.