ACE I/D gene polymorphism predicts renal damage in congenital uropathies

Abstract

We investigated angiotensin converting enzyme gene (ACE I/D) polymorphism as a risk for progressive renal damage in congenital uropathies. The ACE I/D genotype was determined in 196 Caucasian patients with congenital uropathies and 163 individuals with no clinical or sonographic evidence of any urological malformations. The study group included patients with ureteropelvic junction obstruction (n=49), primary obstructive megaureter (n=19), primary vesicoureteral reflux (VUR) (n=67), and posterior urethral valves (n=27). Thirty-four patients were excluded because of additional diseases or insufficient follow-up. There was no difference in the ACE I/D distribution between children with uropathies and normal controls (II 16%, ID 56%. DD 28% vs. II 26%, ID 50%, DD 24%). Renal lesions were found in 99 of 162 children by ultrasonography, intravenous pyelography, and nuclear scans. In these children there was significant over-representation of the DD genotype (II 11%, ID 53%, DD 36%) compared with normals (P<0.005, X2=14.9) or with patients with uropathies but no renal lesions (II 23%, ID 62%, DD 15%, P<0.005, X2=14.9). Because ACE I/D has been linked with progressive deterioration of renal function, we evaluated a subset of patients with initially normal kidneys who developed radiographic renal lesions (n=28). Among these patients there was an even greater over-representation of the DD genotype (II 0%, ID 43%, DD 57%, P<0.001, X2=22.6) compared with patients with uropathies but no radiographic lesions. Multivariate analysis revealed that the DD genotype is a risk factor for parenchymal destruction, which was independent of time of diagnosis, surgical intervention, or urinary tract infection. This finding was particularly relevant in patients with VUR who constituted the majority with initially normal kidneys who developed radiographic damage (22/28). Indeed, the odds ratio of developing parenchymal damage with VUR was significantly increased if the individual had the DD genotype (4.2, 95% confidence interval 1.4-13.0). In conclusion the ACE I/D gene polymorphism is a risk factor for renal parenchymal damage in patients with congenital urological abnormalities and appears particularly relevant in children with VUR, where it is an independent predisposing factor.

Renin-Angiotensin System Polymorphisms: A Risk Factor for Progression to End-Stage Renal Disease in Vesicoureteral Reflux Patients

“…The D allele was predominant in our ESRD patients (66%). This percentage seems to be higher than those reported in healthy Caucasian controls (DD: 24%) [8] and healthy Turkish controls (DD: 34%). [27] However, D allele frequency of our patients (66%) is in accord with the previous reports, giving the overall D (66.6%) and I (33.3%) allele frequencies in Turkish ESRD patients.…”

“…[28] Distribution of the renin-angiotensin system polymorphism in children with VUR is well-studied, and its effect on renal scarring is of interest. [2][3][4]8,20] However, reports about this subject are contradictory. Generally, the ACE polymorphism is the most commonly studied and accepted genetic effect in VUR.…”

“…[3] Several studies about the ACE I/D gene polymorphisms in VUR patients have revealed that the D allele might be a risk factor for renal parenchymal damage in children. [7][8][9] Also, the DD genotype has been reported to be associated with reduced renal function in patients with chronic renal diseases like Ig A nephropathy, [10][11][12] focal segmental glomerulosclerosis, [13,14] diabetic nephropathy, [15,16] polycystic kidney disease, [17] and tubulointerstitial nephritis. [18] Because tubulointerstitial damage is also common in VUR, the ACE polymorphism is of interest in this patient group, as it may give clues about the progression of the renal scarring.…”

Genetics of vesicoureteral reflux

“…115 However, the study found a significant overrepresentation of the ACE DD genotype in the uropathy group with renal lesions compared to controls and children with uro pathies but no renal lesions (P <0.005), a finding that was even more pronounced in the vur cohort. these data led the authors to conclude that the DD poly morphism is a risk factor for renal parenchymal damage in patients with congenital urological abnormalities, which is particularly relevant in children with vur.…”

“…whereas Hohenfellner et al 115 and Yoneda et al 120 concluded from their data that AGT2R is not involved in the pathogenesis of primary vur, nishimura et al 64 reported AGT2R polymorphisms in CaKut patients and concluded that the establishment of CaKut is preceded by delayed apoptosis of undifferentiated mesenchymal cells surrounding the urinary tract during key ontogenic events, from the ureteral budding to the expansive growth of the kidney and ureter. Furthermore, rigoli et al 117 found AGT2R polymorphisms in approximately 50% of vur patients in an italian cohort and concluded that the discrepancy between their and other studies could be explained by the differences in genetic and ethnic backgrounds.…”