Angiotensin-Converting Enzyme and Angiotensin Type 2 Receptor Gene Genotype Distributions in Italian Children with Congenital Uropathies

Abstract

Angiotensin I-converting enzyme (ACE) and angiotensin type 2 receptor (AT2R) gene polymorphisms have been associated with an increased incidence of congenital anomalies of the kidney and urinary tract (CAKUT). We investigated the genotype distribution of these polymorphisms in Italian children with CAKUT. We also evaluated the association between the ACE insertion/deletion and the AT2R gene polymorphisms with the progression of renal damage in subgroups of CAKUT patients. We recruited 102 Italian children with CAKUT; 27 with vesicoureteral reflux; 12 with hypoplastic kidneys; 20 with multicystic dysplastic kidneys; 13 with ureteropelvic junctions stenosis/ atresia; 18 with nonobstructed, nonrefluxing primary megaureters; and 12 with posterior urethral valves and compared them with 92 healthy control subjects. ACE and AT2R gene polymorphisms were analyzed by PCR. The identification of AT2R gene polymorphisms in intron 1 and in exon 3 was revealed by enzymatic digestion. ACE genotype distribution in children with CAKUT was no different from that of the control subjects, but the subgroup of patients with radiographic renal parenchymal abnormalities showed an increased occurrence of the D/D genotype. The frequency of the G allele of AT2R gene in children with CAKUT was increased in respect to that of the control subjects. By contrast, no significant difference in the frequency of the C and A alleles of the AT2R gene was found. Our findings indicate that the ACE gene can be a risk factor in the progression of renal parenchymal damage in CAKUT patients. Moreover, a major role of the AT2R gene in the development of CAKUT has been found, at least in Italian children. Congenital anomalies of the kidney and urinary tract (CAKUT) are now considered a major cause of renal failure in children (1). Ureteropelvic junction (UPJ) stenosis/atresia is the most common cause of a palpable abdominal mass in the newborn. Other forms of CAKUT include vesicoureteral reflux (VUR); hypoplastic kidney (HK); multicystic dysplastic kidney (MCDK); nonobstructed, nonrefluxing primary megaureter (MU); and bladder outlet obstruction [e.g. posterior urethral valves (PUV)] (2). A number of well-recognized but puzzling features are associated with CAKUT. Anomalies such as UPJ stenosis/atresia and MCDK are often unilateral or highly asymmetrical.Some of these anomalies are often concurrent (3-5). It is also noteworthy to mention that these abnormalities often take a familial pattern, showing incomplete and variable genetic penetrance. For this reason, it is believed that these assorted anatomic anomalies may share a common genetic cause (6 -8).

Angiotensin II Type 2 Receptor Gene Polymorphism in Caucasian Children With a Wide Spectrum of Congenital Anomalies of the Kidney and Urinary Tract

“…The discrepancy among these studies is more likely to be the result of the limited number of included patients because the genetic background, at least among Caucasians, does not differ. The present study showed no significant difference in the frequency of the A-1332G transition between patients with VUR and controls, consistent with previous studies in Caucasian and Japanese patients (10,11,16,18). In contrast, Yim et al (17) found that this transition occurred significantly less often in Korean patients (males and females) with VUR than in normal controls.…”

“…Although most cases of CAKUT appear to be sporadic, in some of these (VUR, renal maldevelopment, UPJO, and PUV), a genetic pathogenesis is strongly suggested by a positive family history and genetic linkage studies (1,2). The relatively low incidence of positive family history in the present and previous studies (10,11) may be the result of the usually unilateral occurrence of CAKUT, which, being asymptomatic, may not be diagnosed throughout the lifetime.…”

“…However, Rigoli et al (11) reported a lower frequency (30.4%) of the G allele in Italian males and females with no urological anomalies. When only males were compared, the frequency of the G allele was higher in our control There was no significant difference in the frequency of each allele between controls and patients, either when they were categorized as CAKUT generally or as subgroups of CAKUT.…”

Genetics of vesicoureteral reflux

“…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.…”

“…these findings have been supported by two further studies, one of which also reported an association between the D allele of ACE to small congenital kidneys with refluxing ureters in patients with primary vur, and to the progression of reflux nephropathy. 116,117 Contrastingly, these data could not be reproduced in studies by Park et al 118 and Yoneda and colleagues, 119 who drew the opposite conclusions.…”