Impact of common functional polymorphisms in renin angiotensin system genes on the risk of renal parenchymal scarring following childhood urinary tract infection

Abstract

Pathogenesis of renal parenchymal scarring (RPS) after acute pyelonephritis (APN) is unclear. The risk of RPS varies markedly among individuals, suggesting a genetic role. To investigate a possible role of common polymorphisms in renin angiotensin system genes in APN-associated RPS in children. This study included 104 APN children and 300 controls. APN was diagnosed by urine culture and typical findings on 99Tc-DMSA scans. Voiding cystourethrogram tested the presence of vesicoureteral reflux (VUR). Follow-up DMSA scans were performed 4-6 months later to identify new RPS. Angiotensin converting enzyme gene I/D, angiotensin II receptor type-1 A1166C and angiotensinogen M235T polymorphisms were genotyped. New RPS developed in 44.2% (46/104) of children with APN. VUR was diagnosed in 35.6% (37/104) of APN cases. RPS developed in 73% of cases of VUR. The D allele of ACE gene I/D polymorphism was significantly more common in APN cases with RPS (73.91%) than non-RPS (58.6%) and controls (54.5%) (p = 0.021, p = 0.002, respectively). The AGTR-1 A1166C A allele was significantly more common in VUR than the non-reflux children (91.9% versus 76.1%; p = 0.005). VUR, in contrast to the D allele (OR 6.1, 95% CI 0.878-19.7; p = 0.05), was an independent risk factor for RPS. ACE gene D allele is associated with a twofold increase in RPS risk, which could be a result of a functional effect to increase tissue levels and activity of ACE during APN. However, D allele failed to qualify as an independent risk and its RPS association could be dependent on other co-factors, such as TGFβ1 activation, or the D-allele might link with recently discovered functional polymorphisms at the 5' end of the ACE gene. Although VUR is an independent risk for RPS, it is not clear whether this is due to exposure of the kidneys to infected urine, or VUR-associated dysplasia. In contrast with published literature, we noted higher rates of RPS and high-grade VUR, suggesting a more aggressive VUR course or local unawareness of APN. Our study has its limitations; the small number of VUR children, and the clinical and ethical difficulties of testing VCUG and DMSA in controls. ACE gene D allele is associated with, but cannot independently predict, RPS in children. VUR is an independent risk for post-pyelonephritic scarring. AGTR-1 1166A/C polymorphism is associated with occurrence, but not progression, of VUR.