Vesicoureteric reflux is now considered to be due essentially to congenital malformation of the vesicoureteric junction. It is also considered to be a major cause of renal failure in early adult life. The condition is associated with recurrent urinary tract infection and in some instances with renal scarring. When reflux is detected clinically, in the investigation of patients with recurrent urinary tract infection, renal scarring is often already present. The reflux tends to disappear in later childhood.
Vesicoureteric reflux (VUR) is a common childhood condition characterised by regurgitation of urine from the bladder to the kidney. It is the commonest cause of end stage renal failure in children and an important cause in adults. Primary VUR is often familial, suggesting that genetic factors play an important role in its aetiology. Recently, VUR was observed as part of a syndrome, involving optic nerve colobomas and renal anomalies, caused by mutations of the PAX2 gene. PAX2 is a member of the paired box family of genes and is expressed in the ureteric bud and differentiating nephrogenic mesenchyme of the developing kidney. PAX2 has been shown to play a critical role in the development of both the kidney and the ureter. The occurrence of VUR in one family with the PAX2 mutation, and the expression pattern of PAX2 in developing ureteric bud, strongly suggested that PAX2 could be the cause of primary familial VUR. Single strand conformational polymorphism (SSCP) analysis of 23 affected subjects in eight families with primary familial VUR showed no alterations in exons 2-5 of the PAX2 gene. In addition, a polymorphic dinucleotide repeat marker located within the PAX2 gene segregated independently of the disease trait in one large family who primarily had VUR or reflux nephropathy. These results suggest that PAX2 is not a major cause of primary familial reflux.
Measurement of IgG antibodies to Tamm-Horsfall protein (ATHA) in 92 bacteriuric schoolgirls aged 5-12 did not show a significant rise compared with the titres found in the sera of 24 healthy controls. ATHA titres showed no correlation with the presence of vesicoureteric reflux or kidney scarring and it is concluded that measurement of serum ATHA is of no value as a screening procedure for the detection of vesicoureteric reflux.
A review of 105 children with urinary tract infection showed an increasing prevalence of grades II-III vesicoureteric reflux with diminishing age. During infancy reflux was almost always severe, and affected boys as often as girls. Radiologically scarred kidneys were drained by refluxing ureters in 98% of cases. The prevalence of scars also rose significantly with increasinglyly severe reflux. Deterioration of existing scars or new scar formation was seen in 15 children; 18 out of 20 affected kidneys (90%) were associated with grade III vesicoureteric reflux. 2 out of 5 children who developed new scars did so after 5 years of age. Because severe reflux may occasionally be seen in the presence of a normal intravenous urogram, and since the finding of grades II-III vesicoureteric reflux is an indication for chemoprophylaxis, we consider cystourethrography essential in children of all ages with recurrent urinary tract infection. In children under 5 years the increased prevalence of both severe reflux and renal scarring are arguments for regarding cystourethrography as a necessary initial investigation.
Cystography, performed in 26 out of a total of 33 consecutive neonates with imperforate anus, revealed primary vesicoureteric reflux in 12 cases. The reflux was usually pronounced, and was particularly common in females and in infants with urinary tract infections. The incidence of reflux was unrelated to the severity of the anorectal anomaly, and reflux was often demonstrated in patients in whom an intravenous pyelogram had shown an undilated upper renal tract.
A group of patients known to have had vesicoureteric reflux of varying severity in infancy were followed up over a period of five years. Gross vesicoureteric reflux was found to be accompanied by a high incidence of initial and progressive renal damage. Progressive renal damage was not found in infants showing moderate or slight reflux.
We investigated 47 children in whom vesicoureteric reflux was clinically suspected by both conventional radiological and indirect radionuclide cystography. Comparison of the two methods showed no significant difference in their accuracy in detecting vesicoureteric reflux. The advantages and disadvantages of, and indications for, indirect radionuclide cystography are discussed.
Thirty three healthy infants and children with a family history of reflux nephropathy or vesicoureteric reflux in first degree relatives were screened for upper urinary tract abnormalities (renal scarring or pelvicaliceal dilatation) using ultrasound scanning or intravenous urography, or both. In addition, micturating cystourethrography was carried out in all infants and children under 2 years old (n = 20) and in children over 2 years old in whom abnormalities of the upper renal tract (renal scarring) had been found (n = 3). Upper renal tract abnormalities were found in four of the total of 33 children (12%) and vesicoureteric reflux in 12 of the 23 who underwent micturating cystourethrography (52%). Screening of infants and children was acceptable to parents. This approach has enabled the diagnosis of vesicoureteric reflux to be made in an appreciable number of children before the development of urinary tract infections and reflux nephropathy. Prospective follow up of this group will provide more information about the natural history of sterile vesicoureteric reflux.
The voiding cystourethrogram (VCUG) is a widely used study to define lower urinary tract anatomy and to diagnose vesicoureteric reflux (VUR) in children. We examine the technical advances in the VCUG and other examinations for reflux that have reduced radiation exposure of children, and we give recommendations for the use of imaging studies in four groups of children: (1) children with urinary tract infection, (2) siblings of patients with VUR, (3) infants with antenatal hydronephrosis (ANH), and (4) children with a solitary functioning kidney. By performing examinations with little to no radiation, carefully selecting only the children who need imaging studies and judiciously timing follow-up examinations, we can reduce the radiation exposure of children being studied for reflux.
Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component. Here, we report a whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux and reflux nephropathy. We used linkage and family-based association approaches to analyze 320 white families (661 affected individuals, generally from families with two affected siblings) from two populations (United Kingdom and Slovenian). We found modest evidence of linkage but no clear overlap with previous studies. We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A). Family-based analysis detected associations with one single-nucleotide polymorphism (SNP) in the UK families, with three SNPs in the Slovenian families, and with three SNPs in the combined families. A case-control analysis detected associations with three additional SNPs. The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations.
A 29-year-old man developed paraplegia at T-10 level due to road traffic accident in 1972. Both kidneys were normal and showed good function on intravenous urography. Division of external urethral sphincter was performed in 1973. In 1974, cystogram showed retrograde filling of left renal tract, which was hydronephrotic. Left ureteric reimplantation was performed. Following surgery, cystogram revealed marked retrograde filling of left renal tract as before. Penile sheath drainage was continued. In 1981, intravenous urography revealed bilateral severe hydronephrosis. Left ureteric reimplantation was performed again in 1983. Blood pressure was 220/140 mm Hg; this patient was prescribed atenolol. Cystogram showed gross left vesicoureteral reflux. Intermittent catheterisation was commenced in 2001. In 2007, proteinuria was 860 mg/day. This patient developed progressive renal failure and expired in 2012. In a spinal cord injury patient with vesicoureteral reflux, the treatment should focus on abolition of high intravesical pressures rather than surgical correction of vesicoureteric reflux. Detrusor hyperactivity and high intravesical pressures are the basic causes for vesicoureteral reflux in spinal cord injury patients. Therefore, it is important to manage spinal cord injury patients with neuropathic bladder by intermittent catheterisations along with antimuscarinic drug therapy in order to abolish high detrusor pressures and prevent vesicoureteral reflux. Angiotensin-converting enzyme inhibitors or angiotensin-receptor-blocking agents should be prescribed even in the absence of hypertension when a spinal cord injury patient develops vesicoureteral reflux and proteinuria.
Vesicoureteric reflux (VUR) is a common congenital defect of the urinary tract that is usually discovered after a child develops a urinary tract infection. It is associated with reflux nephropathy, a renal lesion characterized by the presence of chronic tubulointersitial inflammation and fibrosis. Most patients are diagnosed with reflux nephropathy after one or more febrile urinary tract infections, suggesting a potential role for infection in its development. We have recently shown that the C3H mouse has a 100% incidence of VUR. Here, we evaluate the roles of VUR and uropathogenic Escherichia coli infection in the development of reflux nephropathy in the C3H mouse. We find that VUR in combination with sustained kidney infection is crucial to the development of reflux nephropathy, whereas sterile reflux alone fails to induce reflux nephropathy. A single bout of kidney infection without reflux fails to induce reflux nephropathy. The host immune response to infection was examined in two refluxing C3H substrains, HeN and HeJ. HeJ mice, which have a defect in innate immunity and bacterial clearance, demonstrate more significant renal inflammation and reflux nephropathy compared with HeN mice. These studies demonstrate the crucial synergy between VUR...
Primary vesicoureteric reflux (VUR), the retrograde flow of urine from the bladder toward the kidneys, results from a developmental anomaly of the vesicoureteric valve mechanism, and is often associated with other urinary tract anomalies. It is the most common urological problem in children, with an estimated prevalence of 1–2%, and is a major cause of hypertension in childhood and of renal failure in childhood or adult life. We present the results of a genetic linkage and association scan using 900,000 markers. Our linkage results show a large number of suggestive linkage peaks, with different results in two groups of families, suggesting that VUR is even more genetically heterogeneous than previously imagined. The only marker achieving P < 0.02 for linkage in both groups of families is 270 kb from EMX2. In three sibships, we found recessive linkage to KHDRBS3, previously reported in a Somali family. In another family we discovered sex-reversal associated with VUR, implicating PRKX, for which there was weak support for dominant linkage in the overall data set. Several other candidate genes are suggested by our linkage or association results, and four of our linkage peaks are within copy-number variants recently found to be associated with renal hypodysplasia. Undoubtedly there are many genes related to VUR. Our study gives support to some loci suggested by earlier studies as well as suggesting new ones...
Children with severe vesicoureteric reflux were allocated randomly to either operative or non-operative treatment and followed up. Altogether 161 children were observed for two years, of whom 104 were followed up for five years. Reflux was abolished in 98% of ureters reimplanted, but more than half of the patients treated non-operatively continued to show severe reflux at five years. Two patients progressed to end stage renal failure, and a further four with extensive bilateral renal scarring became hypertensive. There were no significant differences between treatment groups in the incidence of breakthrough urinary infection, renal excretory function and concentrating ability, renal growth, progression of existing renal scars, or new scar formation. Progressive scarring occurred at all ages but was significantly more common during the first two years' observation. Furthermore, new scars developed exclusively during the first two years' observation, affecting 10 children aged 2-7 at allocation. Neither treatment can claim superiority or fully protect the kidneys from further damage, and efforts must continue to be directed towards identifying those at risk before scarring develops.
Sixty one patients with primary vesicoureteric reflux were treated by endoscopic injection of Mentor Polytef paste. Seventy six of the 94 treated ureters showed complete disappearance of vesicoureteric reflux after one injection. Eight refluxing ureters required a second injection, one required a third, and one a fourth. Six ureters showed improvement in the grade of reflux after the first injection. Two ureters did not show any change in the grade of reflux after endoscopic injection. The amount of paste injected to correct reflux in the 94 ureters varied from 0.1 to 1.0 ml (mean 0.33 ml). Patients were followed up for three to 25 months (mean 13.4 months). Follow up micturating cystograms in the 94 ureters showed absence of reflux in 83. Eleven ureters showed recurrence of reflux. Recurrence of reflux was attributed to early technical difficulties and to insufficient amounts of polytef paste used in some cases. Follow up urograms did not show evidence of ureteric obstruction in the treated ureters. Endoscopic injection of polytef paste is a safe, simple, and effective procedure for primary vesicoureteric reflux and averts the need for open operation.
Vesicoureteric reflux was produced in eight piglets by opening their bladders and slitting the anterior intravesical wall of the ureter. Cystography confirmed the presence of bilateral reflux in six piglets and unilateral reflux in two. Six to eight weeks later the bladder was again opened and Teflon paste injected in the space behind the intravesical ureter, thereby creating a support for the submucosal ureter. Cystography four to six weeks after injection of Teflon paste showed absence of reflux in all animals. Intravenous pyelography showed obstruction at the vesicoureteric junction in only one of the 14 treated ureters and this was later confirmed at necropsy. Animals were followed up from one to six months and then were killed. Gross examination of the vesicoureteric region showed a well circumscribed subureteric Teflon mass of firm consistency, retaining its shape and position at the site of the injection. Histological examination showed encapsulation of the implant by a thin layer of fibrous tissue and a foreign body granulomatous reaction with histiocytes and giant cells within the implant. Hence it is technically feasible to correct experimentally produced vesicoureteric reflux in the piglet by intravesical injection of Teflon paste--a relatively inert material. It may now be possible to treat vesicoureteric reflux in man by endoscopic injection of Teflon behind the intravesical ureter.
Thirteen girls with grade III-V vesicoureteric reflux were treated by endoscopic injection of Teflon paste behind the intravesical ureter. Fourteen of the 18 treated ureters showed complete absence of reflux after one injection of Teflon. Three ureters required a second injection of Teflon for successful treatment of the reflux. One ureter with grade IV reflux was converted to grade II reflux. Properly carried out, this procedure corrects reflux. It takes less than 15 minutes, may be done as a day procedure, and avoids open surgery. There have been no complications.
Renal growth was studied for periods ranging from 2 to 22 years (average 9·4) in 70 children who presented between 2 weeks and 12 years of age with urinary tract infection and who were found to have vesicoureteric reflux. They were managed on a conservative regimen of continuous prophylaxis and regular, complete voiding. Renal growth over the entire period of observation was normal in relation to the child's growth in height in 100 of the 111 kidneys originally drained by refluxing ureters. During the time that reflux was known to be still present, renal growth was within normal limits in 101 kidneys. Renal growth was impaired in 11 kidneys. Ten of them were exposed to a recurrence of urinary tract infection. The eleventh child had an unproved symptomatic infection. Seven of these kidneys were also already scarred and 4 had gross reflux. In 2 of these children a fresh scar developed, one in a previously normal kidney. Because of the tendency for reflux to disappear, the renal growth during the first 2 years of observation was also analysed. A significant association was found between impaired growth and, independently, infection and renal scarring. No independent association was found between impaired growth and the severity of reflux. Small kidneys tended to grow at the expected rate. If growth was compared in pairs of kidneys with unilateral reflux...
Seventy-five children aged 3 weeks to 12 years and found on investigation of symptomatic urinary infection to have vesicoureteric reflux were managed conservatively with continuous low-dose prophylaxis. Serial cystographic and renal growth studies were performed during seven to 15 years' follow-up. Reflux disappeared spontaneously in 53 children (71%) and from 79% of the affected ureters. This occurred at any age and not only in infancy or at puberty. The initial severity or reflux was the most important factor affecting the outcome. Reflux disappeared from 85% of ureters of normal calibre but from only 41% of dilated ureters. Gross reflux associated with existing severe renal scarring was least likely to disappear. Nevertheless, reflux stopped in 12 of the 19 initially scarred renal units (63%). Reflux was as likely to disappear in children who had a recurrence of urinary infection as in those who had no further infection. Renal growth appeared to be normal in 93% of kidneys and fresh or extending scarring was seen in only two children. Management programmes for children with vesicoureteric reflux should take into account the self-limiting nature of three-quarters of the reflux found on investigating uncomplicated urinary tract infection.
Children with severe vesicoureteric reflux were allocated at random within three age groups (less than 1, 1-5, and greater than or equal to 6 years) to either operative or non-operative treatment. In 96 children who completed two years' observation there was no significant difference between treatment groups in either the incidence of breakthrough urinary tract infection, slope clearance of 51Cr-edetic acid, renal length, new scar formation, or progression of existing scars. Ureteric reimplantation was technically successful in 97% of cases, whereas 74% of ureters managed non-operatively still showed significant reflux at two years. No short term advantage was shown for either form of treatment in this series, but the long term effects of persistent, severe vesicoureteric reflux require further study. The prevention of reflux nephropathy probably demands the identification of vesicoureteric reflux before the advent of urinary tract infection, a goal not attainable with present invasive techniques.