Genetic susceptibility to renal scar formation after urinary tract infection: a systematic review and meta-analysis of candidate gene polymorphisms

Abstract

Identifying patients who may develop renal scarring after urinary tract infections (UTI) remains challenging, as clinical determinants explain only a portion of individual risk. An additional factor that likely affects risk is individual genetic variability. We searched for peer-reviewed articles from 1980 to December 2009 in electronic databases that reported results showing an association between gene polymorphims and renal scaring after UTI. Two independent researchers screened articles using predetermined criteria. Studies were assessed for methodological quality using an aggregate scoring system. The 18 studies ultimately included in the review had investigated 16 polymorphisms in nine genes in association with renal scarring formation after UTI. Based on the predetermined criteria for assessing the quality of the studies, 12 studies (67%) were identified as being of poor quality design. A meta-analysis of cumulative studies showed on association between renal scarring formation after UTI and the angiotensin converting enzyme insertion/deletion polymorphism [ACE I/D; recessive model for D allele; odds ratio (OR) 1.73, 95% confidence interval (CI) 1.09-2.74, P = 0.02] or transforming growth factor (TGF)-β1 c.-509 T > C polymorphism (dominant model for T allele; OR 2.24, 95% CI 1.34-3.76, P = 0.002). However, heterogeneity among studies was large, indicating a strong difference that cannot only be explained by differences in study design. The studies reviewed in this article support a modest involvement of the vasomotor and inflammatory genes in the development of renal scarring after UTIs. This review also shows that only few possible candidate genes have been investigated for an association with renal scarring, raising the hypothesis that some gene polymorphisms may exert their effects through an interaction with as yet uninvestigated factors that may be related to geographic and/or socio-economic differences.

Functional variants in intercellular adhesion molecule‐1 and toll‐like receptor‐4 genes are more frequent in children with febrile urinary tract infection with renal parenchymal involvement

“…All VUR children were excluded from this study. Our rationale was that we needed to study the effect of the genetic predisposition on the susceptibility to renal parenchymal infection without the confounding effect of VUR, which is an established risk factor for APN .…”

“…While UTIs present clinically as asymptomatic bacteriuria, cystitis and acute pyelonephritis (APN), lower UTIs may progress to APN with the risk of developing renal parenchymal scarring (RPS), hypertension and eventually deterioration of renal function . The question about why some children develop lower UTIs and others develop APN, despite having an anatomically normal urinary tract, still poses a research dilemma and has raised the possibility of genetic predisposition . Identifying the possible role of genetic variants in APN would help the clinicians to recognise which children are at greater risk based on their genetics.…”

The impact of therapeutic delay time on acute scintigraphic lesion and ultimate scar formation in children with first febrile UTI

“…Although we have not analyzed genetic susceptibility as the risk factor for ASL and USF several reports demonstrated the role of genetic susceptibilities as clinical determinants explain only a portion of individual risk [25]. Meta-analysis by Zaffanello et al revealed association between renal scarring formation after UTI and angiotensin enzyme insertion/deletion polymorphism or transforming growth factor-beta 1 c.509 T>C polymorphism [3,9,25].…”

Vascular endothelial growth factor‐A gene polymorphism is associated with congenital renal lesions in children with urinary tract infections

“…Polymorphisms of genes regulating different stages of the inflammatory process, from the initial inflammation to fibrosis, have been associated with UTI-related renal scarring (22,23). Polymorphisms of genes regulating different stages of the inflammatory process, from the initial inflammation to fibrosis, have been associated with UTI-related renal scarring (22,23).…”