Primary, nonsyndromic vesicoureteric reflux and nephropathy in sibling pairs: a United Kingdom cohort for a DNA bank.

BACKGROUND AND OBJECTIVES: Primary vesicoureteric reflux (VUR) can coexist with reflux nephropathy (RN) and impaired renal function. VUR appears to be an inherited condition and is reported in approximately one third of siblings of index cases. The objective was to establish a DNA collection and clinical database from U.K. families containing affected sibling pairs for future VUR genetics studies. The cohort's clinical characteristics have been described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Most patients were identified from tertiary pediatric nephrology centers; each family had an index case with cystography-proven primary, nonsyndromic VUR. Affected siblings had radiologically proven VUR and/or radiographically proven RN. RESULTS: One hundred eighty-nine index cases identified families with an additional 218 affected siblings. More than 90% were <20 years at the study's end. Blood was collected and leukocyte DNA extracted from all 407 patients and from 189 mothers and 183 fathers. Clinical presentation was established in 122; 92 had urinary tract infections and 16 had abnormal antenatal renal scans. RN was radiologically proven in 223 patients. Four patients had been transplanted; none were on dialysis. In 174 others aged >1 year, estimated GFR (eGFR) was calculated. Five had eGFR 15 to 59 and 48 had eGFR 60 to 89 ml/min per 1.73 m(2). Values were lower in bilateral RN patients than in those with either unilateral or absent RN. CONCLUSIONS: The large DNA collection from families with VUR and associated RN constitutes a resource for researchers exploring the most likely complex, genetic components predisposing to VUR and RN.

Whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric 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 recessive gene for primary vesicoureteral reflux maps to chromosome 12p11-q13.

Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans.

Incidence and severity of vesicoureteral reflux in children related to age, gender, race and diagnosis.

PURPOSE: We determine if the incidence and grade of vesicoureteral reflux (VUR) differs in children based on age, race and gender, and if the incidence and severity of VUR are related to race in girls younger than 7 years presenting for evaluation after urinary tract infection (UTI). MATERIALS AND METHODS: The records of all children who underwent a voiding cystourethrogram or radionuclide cystogram between 1993 and 2001 were retrospectively reviewed. Age, gender, race, clinical indication and highest grade of VUR were recorded for the first voiding cystourethrogram or radionuclide cystogram. Frequency tables and logistic regression were conducted to correlate demographics to incidence and severity of VUR. RESULTS: A total of 15,504 patients were included in the analysis. Overall, black children were a third as likely as white children (p <0.0001) and females were twice as likely as males (p <0.0001) to have VUR. Compared to children 0 to 2 years old, the occurrence of reflux was 0.5 times as likely in those 3 to 6 years old (p <0.0001), 0.3 times as likely in those 7 to 11 years old (p <0.0001) and 0.15 times as likely in those 12 to 21 years old (p <0.0001). When analyzing children with UTI, results were similar. Of the patients with VUR 65% were younger than 7 years. The incidence of VUR in black girls younger than 7 years with a diagnosis of UTI was less than 10% compared to white girls, and no black girl had high grade reflux. In young children referred for UTI the incidence and severity of VUR in black patients were significantly lower than those of white girls. CONCLUSIONS: This study validates previous observations regarding the low incidence of VUR in black children.

Ethnic factors in the variability of primary vesico-ureteral reflux with age.

OBJECTIVE: To determine any ethnic difference in the rate of spontaneous decrease in the incidence of primary vesico-ureteral reflux (VUR). MATERIALS AND METHODS: Voiding cystourethrograms on 738 patients with urinary tract infection were reviewed, and the incidence of primary vesico-urethral reflux was correlated with age, gender and ethnic origin. RESULTS: There was a gradual decrease in the incidence of primary VUR in whites between 0-10 years, while the incidence of primary VUR in blacks was very low and remained the same. After 10 years of age, no difference was present. CONCLUSION: The possibility of delayed maturation of the antireflux mechanism in whites is considered as a possible explanation, and the possibility of an ethnic basis for this is suggested.

Primary vesicoureteral reflux in blacks with posterior urethral valves: does it occur?

Primary vesicoureteral reflux (VUR) is thought to be largely independent of obstruction. Therefore, in patients with urethral obstruction due to posterior urethral valves (PUV) the occurrence of VUR is coincidental. In addition, primary VUR is reported to be uncommon in black children. If these two premises are correct, then primary VUR should be rare in black males with PUV. To test this hypothesis, we reviewed the medical records and radiographs of 43 males with PUV. Twenty-one of the 37 non-black males with PUV had VUR, of which 67% was primary and 33% was secondary. Three of the six blacks with PUV had VUR of which all was secondary. Thus, blacks with PUV lend credence to the theory that primary VUR is not caused by obstruction and support the observation that primary VUR is rare in black children, even those with PUV.