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.     

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 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.     

Guidelines for consideration for surgical repair of vesicoureteral reflux

Vesicoureteral reflux (VUR) is a risk factor for acute pyelonephritis, which can result in renal scarring (reflux nephropathy), hypertension, end-stage renal disease (ESRD) and complications during pregnancy, In deciding whether to recommend surgical correction of VUR, factors that should be considered include the previous and potential future morbidity of VUR in that individual, the risk of uncorrected VUR, the likelihood of spontaneous resolution or significant reduction in VUR, the efficacy and complications of medical therapy, the morbidity and discomfort associated with serial screening for VUR, the benefits and risks of surgical therapy, and economic factors. Currently, surgical correction is recommended for those who fail medical therapy, or if the child has grade V VUR, bilateral grade IV VUR, moderate VUR associated with a complete duplication anomaly, severe renal scarring, or persistent VUR associated with an ectopic ureterocele, posterior urethral valves or a neuropathic bladder. The current perioperative management of children undergoing ureteroneocystostomy is detailed. In the future, the less invasive alternative of endoscopic therapy will need to be balanced against the changing understanding of the risk of VUR to the individual.     

Vesico-ureteric reflux in Down's syndrome: poor prognosis

Four patients with Down's syndrome and vesico-ureteric reflux (VUR) are reported. VUR was diagnosed in six renal units and three primary nephrectomies were necessary. Three ureters were reimplanted unsuccessfully in two patients. The 50% nephrectomy rate for reflux nephropathy and the 100% failure rate for ureteric reimplantation in Down's syndrome patients are compared with a nephrectomy rate and ureteric reimplantation failure rate of around 1% for primary VUR in other children.     

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.     

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.     

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.     

Studies on reflux nephropathy--clinical investigation of renal lesions

Renal biopsies were performed on 25 patients with reflux nephropathy to clarify the relationship between the pathological findings and clinical parameters. Biopsy specimens were obtained at anti-reflux operation by open renal biopsy. Glomerular lesions were classified as focal, diffuse, segmental and global sclerosis. Tubulo-interstitial changes were defined according to the principle advocated by Cotran and expressed as the percentage of the lesions. The clinical parameters consisted of the grades of VUR, the grades of renal scarring, renal function and the daily urinary protein excretion. A significant relationship was noted between the grades of VUR and those of renal scarring. The percentage of global sclerosis in the kidney revealed a close relationship with the grades of VUR and the percentage of tubulo-interstitial changes but not with the renal function or the daily urinary protein excretion. Focal segmental hyalinosis and/or sclerosis (FSHS) lesions were presented in 3 of 25 cases (12%). The pathological findings of the FSHS lesions had a close relationship with the renal function and the daily urinary protein excretion and the prognosis of the kidney. The other patients without FSHS lesions displayed an unchanged renal function. Based on these observations, it is clear that the prognosis of the patients with vesico-ureteral reflux could be predicted from the histopathological findings; the presence of FSHS lesions suggests a poor prognosis for the kidney. The degree of daily proteinuria represents a useful parameter for evaluating the progression of the reflux nephropathy.     

Outcome of pregnancy in women with a history of vesico-ureteric reflux

OBJECTIVES

To review the evidence relating to the outcome of pregnancy in women with vesico‐ureteric reflux (VUR) or a previous history of VUR and to identify the factors contributing to morbidity in pregnancy, with particular emphasis on the role of renal scarring.

METHODS

Searches were carried out in Medline, Pubmed and MD Consult using various combinations of the keywords including: vesicoureteral reflux and pregnancy, maternal vesicoureteral reflux, vesicoureteral reflux in adulthood, reflux nephropathy and pregnancy. All data quoted in this review are from original articles.

RESULTS

The published studies showed that women with VUR that was not associated with renal scarring had no increase in the incidence of gestational hypertension, pre‐eclampsia or fetal morbidity, regardless of whether their VUR was diagnosed in childhood or adulthood. However, women with VUR and normal kidneys did have higher incidence of urinary tract infection during pregnancy, which was not modified by ureteric re‐implantation. Renal scarring was the primary risk factor for morbidity during pregnancy and this risk was independent of the presence or absence of VUR at the time of pregnancy.

CONCLUSION

The evidence does not support the practice of correcting low‐grade VUR in girls with unscarred kidneys because this will reduce their risk of complications in pregnancy. The presence of renal scarring rather than the presence or absence of reflux is the principal determinant of morbidity during pregnancy.     

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.     

Clinicopathological study of vesicoureteral reflux (VUR)-associated pyelonephritis in renal transplantation

Abstract:  We retrospectively studied the occurrence of vesicoureteral reflux (VUR)-associated pyelonephritis using renal biopsies obtained from the transplanted kidneys, and correlated the histological changes with clinical parameters. Out of a total of 131 renal biopsies performed between 1990 and 2001 on renal transplant patients at the department of Urology of Nagasaki University Graduate School of Biomedical Sciences, 12 patients showed pyuria more than twice in a single year. Seven of these 12 patients were available for determining VUR by voiding cystourethrography (VCUG). Cystoureterography demonstrated VUR in three of seven studied patients with pyuria. A histopathological examination revealed dilatation of both proximal and distal tubules in renal biopsies of transplant patients with VUR, compared to renal biopsies of transplant patients without VUR, or non-transplanted patients with thin membrane disease. One of the patients with VUR showed advanced features of chronic pyelonephritis in four consecutive biopsies at different time points, suggesting a late stage of reflux nephropathy in the transplanted kidney. We conclude from our study that the occurrence of VUR-related pyelonephritis may be one of the important long-term complications in the survival of renal allografts.     

Vesicoureteral reflux and renal scarring. Report of cooperative study of "Progressive renal disease" of Ministry of Health and Welfare

196 cases with vesicoureteral reflux (VUR) from multiple centers were analysed to examine the relationship between VUR and reflux nephropathy. The high correlation (p less than 0.01) was observed between reflux and renal scarring. Even in cases in whom VUR was not demonstrated at the time of testing, renal scarring of various degrees was recognized, suggesting either co-existed hypoplastic kidney or pre-existed infection. The renal scarring, but not VUR, had a significant correlation with proteinuria and hypertension. Retrospective analysis shows that the surgical treatment was closely related to the degree of renal scarring but not to the degree of reflux. Renal scarring progressed even when reflux did not become worse, which is probably accounted for by the presence of pyelonephritis. Although frequency of pyelonephritis decreased significantly (p less than 0.01) from 0.60 +/- 0.89 to 0.084 +/- 0.305 times/patient. year after anti-reflux surgery, renal scarring progressed in 13 kidneys (5.8%). Seven of the 13 kidneys became worse due to the surgical failure. The scar progression was recognized in the remaining six kidneys (three patients) including adult cases despite the successful surgical correction of reflux. Our study points to the urged need for a prospective clinical trial designed for the study of the pathological and clinical background of progressive renal failure in VUR.     

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.     

Reflux nephropathy and reflux glomerulopathy

The several problems of reflux nephropathy and reflux glomerulopathy are reviewed and discussed. From my own experience of primary vesicoureteral reflux (VUR) in 901 children and secondary VUR in 195 children I would like to stress my cherished opinion that for the treatment of VUR all clinical and subclinical infravesical obstruction should first be ruled out.     

Vesico-uretero-renal reflux and the kidney

The most frequent complications of non-obstructive vesico-uretero-renal reflux (VUR) are segmental renal scars. These scars are confined to segments with intrarenal reflux which are, in addition, exposed to bacterial infection. Primarily, only gaping collecting duct orifices, confined to compound papillae and mainly situated at the kidney poles, allow intrarenal reflux. Scar contraction and obstruction seem to be able to transform closed collecting duct orifices into gaping ones, thereby enlarging the parenchymal area prone to intrarenal reflux and to renal scarring. Contrary to earlier reports, a recent survey has documented that new scars in children develop with significant frequency beyond 5 years of age. There is a greater tendency for scarring to develop with more severe VUR, but new renal scars can develop with all grades of VUR [27]. Early and adequate antibiotic treatment decreases the extent of scarring. The results of experimental studies in which renal scarring developed in piglets with bladder decompensation resulting from intravesical obstruction but without bacterial infection may be relevant to the few children with proximal urethral valves and hypertonic neurogenic bladders but not to the large number with non-neurogenic detrusor instability or detrusor sphincter dyssynergia. Prospective studies have not shown different recurrence rates of urinary tract infections in medically managed compared with surgically managed children. The frequency of acute pyelonephritic attacks decreased significantly after operation.     

Management of vesicoureteral reflux in children

Background. Vesicoureteral reflux (VUR) in children has been reported in many studies. However, the management of VUR is still controversial. Methods. One hundred and fourteen children with primary VUR were divided into two treatment groups: medical (group A) and surgical (group B). The clinical courses and X-ray films of cystography and intravenous pyelography of these children were reviewed retrospectively, using the International Reflux Study Committee Classification. Results. In children less than 1 year of age, VUR was observed more frequently in boys. However, this ratio was reversed in children aged 2 years or more. Sixty-three percent of all refluxing ureters had reflux of grade III or higher at the initial examination. Spontaneous cessation of VUR was observed in 17% of group A ureters, and all had grade III or less reflux. Renal parenchymal scars were already present at the initial examination in 23% of kidneys with refluxing ureters. Recurrent urinary tract infections became less frequent after anti-reflux surgery. The progression of renal scars and renal growth retardation was observed more frequently in group B children. Conclusions. From these observations, it appeared that surgical management of VUR did not prevent the progression of renal scarring or renal growth retardation. Early detection of and intervention in VUR may prevent the progression of renal scarring and renal growth retardation. However, a multicenter, prospective, randomized controlled study would be necessary to confirm these findings. Received: October 4, 1999 / Accepted: January 15, 2000     

Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symptoms or vesicoureteric reflux

BACKGROUND: The significance of late urinary tract infections (UTIs) after renal transplantation and their association with scarring and graft dysfunction remains controversial. We sought to define the prevalence of renal scarring in allograft recipients with a history of late recurrent UTIs, to determine whether the presence of vesicoureteric reflux (VUR) confers an increased risk of scarring and to establish whether scarring correlates with graft dysfunction. METHODS: Among 307 renal allograft recipients, we identified 56 (18%) with late recurrent UTIs (> or =3/year). A total of 32 patients had undergone further investigation by both 2,3 dimercapto-succinic acid single-photon emission computed tomography (99mTc-DMSA SPECT) scan and micturating cystourethrogram (MCUG). RESULTS: Of the 32 patients, 24 (75%) had scars on 99mTc-DMSA SPECT and 15 (47%) had reflux on MCUG. Thirteen of these 15 patients with reflux (87%) had scars, although there was no significant correlation between number of scars and degree of reflux. Eleven of 17 patients (65%) with UTIs but without VUR had scars, as did 12 of 14 (86%) with previous graft pyelonephritis. The pattern of scarring (typically multiple focal cortical defects) suggested infection as the cause. This pattern was not seen in a contemporary cohort with vascular occlusions and was rarely seen in patients with chronic allograft nephropathy. Scarring was not associated with inferior graft survival (median follow-up, 15 years). CONCLUSIONS: In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux.     

Utility of SPECT DMSA renal scanning in the evaluation of children with primary vesicoureteral reflux

OBJECTIVES: DMSA renal scanning is more sensitive than ultrasound in detecting renal parenchymal scars. We proposed to determine the utility of single-photon emission computed tomography (SPECT) dimercaptosuccinic acid (DMSA) renal scanning in children with primary vesicoureteral reflux (VUR). METHODS: During a 24-month period, we evaluated the charts of 368 patients who had undergone SPECT DMSA renal scanning for primary VUR. Patients were divided into three age groups: (a) less than 1 year, (b) between 1 and 5 years, and (c) older than 6 years. Renal scars were deemed severe or focal. The data were analyzed to evaluate the utility of SPECT DMSA scanning in children with primary VUR and to determine the indications for performing SPECT DMSA. We also evaluated the sensitivity of recent renal ultrasound technology in detecting focal and diffuse scars. RESULTS: One hundred twenty-eight patients were younger than 1 year at presentation. These included 24 cases that were detected prenatally. One hundred eighty-five were between the ages of 1 and 5 years, and 55 were 6 years or older. Reflux nephropathy at presentation was found in 99 (26.9%) of 368 patients. DMSA scanning changed the treatment in only 13 patients (3.5%). When scarring was diffuse, ultrasound examination correlated 100% with DMSA scanning; when focal scarring was present, the correlation was poor. CONCLUSIONS: Our results suggest that DMSA scans should be tailored to children who have ultrasound abnormalities, high-grade reflux, or recurrent breakthrough urinary tract infections. These guidelines will result in a substantial cost savings and a significant decrease in radiation exposure.     

Vesicoureteric reflux and renal injury

Renal injury associated with the intrarenal reflux (IRR) of urine that is either infected, under high pressure, or both, is a major cause of severe hypertension during childhood and adolescence and of chronic renal insufficiency in patients less than 30 years of age. Many, but not all, adolescent and adult patients with reflux nephropathy (RN) give a history of urinary tract infection (UTI) or unexplained fevers in infancy or early childhood, when the kidney is thought to be at greatest risk of injury. Although vesicoureteric reflux (VUR) is observed more commonly in infants than children with UTI, it is rare in uninfected patients at any age and should never be considered a normal finding during human development. Renal scarring may not be obvious in radiographic or radionuclear studies to medical management alone, no definite benefit of one over the other was observed, regardless of the grade of VUR. Moreover, progressive renal injury in scarred kidneys has been noted even after VUR had been corrected, when infection had been prevented, and while hypertension had been controlled satisfactorily. Focal glomerular sclerosis, a lesion found in patients with proteinuria and RN, has been identified not only in scarred kidneys, but also may be seen in contralateral, unscarred kidneys without VUR, which might suggest a humoral factor or, perhaps, a hyperfiltration phenomenon. RN is one of the most frequent causes of end-stage renal disease (ESRD) in children, adolescents, and young adults, which is potentially preventable. However, prevention will depend on early identification of patients at risk--infants and young children after the first UTI and siblings of patients with VUR--aggressive and effective treatment of UTI, minimizing intravesical pressure, and education of patients, parents, and physicians.