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

Aim. Renin-angiotensin system (RAS) gene mutations have been implicated as a risk factor for the presence and progression of renal disease in vesicoureteral reflux (VUR). However, the results are contradictory, and the effects of RAS polymorphisms in VUR patients with end-stage renal disease (ESRD) have not been defined yet. This study was designed to evaluate the angiotensin-converting enzyme insertion/deletion (ACE-I/D), angiotensinogen (AGT) M235T, and angiotensin II receptor type 1 (ATR1) A1166C and type 2 (ATR2) C3123A gene polymorphisms as risk factors for progression to ESRD in patients with VUR. Methods. ACE-I/D, AGT-M235T, ATR1-A1166C, and ATR2-C3123A were identified in 161 ESRD patients (52 female, 109 male; 77 renal transplant, 84 dialysis; age: 34.4 ± 11.2 years). VUR was the ESRD etiology in 40 patients. Genetic polymorphisms of the ACE gene I/D, AGT gene M235T, ATR1 gene A1166C, and ATR2 gene C3123A were identified in all of the patients. Results. We detected no linkage between genetic polymorphisms of ATR1-, ATR2-, AGT-, and VUR-related ESRD. When ACE gene was considered, VUR(+) patients had 63.6% DD, 36.4% ID, and no II alleles, whereas VUR(?) patients had 48.6% DD, 43.2% ID, and 8.1% II alleles. Conclusion. A striking feature of VUR-related ESRD patients was the absence of II alleles, so the DD genotype may be accepted as a genetic susceptibility factor for progression to ESRD in VUR patients.     

Polymorphism of renin-angiotensin system genes in IgA nephropathy

BACKGROUND AND AIMS: Individuals are prone to disease because of certain disease-susceptible genes. The angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D), the angiotensinogen (AGT) gene, M235T, and the angiotensin II type 1 receptor (ATR) gene, A1166C, polymorphisms have been associated with IgA nephropathy (IgAN) and its progression. Several studies on Caucasians and Japanese patients have reported contradictory results. We determined these polymorphisms in 118 Chinese patients with IgAN and 94 healthy Chinese subjects to assess their clinical impact. METHODS: Genotyping was performed with DNA isolated from peripheral leucocytes, polymerase chain reaction amplification of the polymorphic sequence, restriction enzymes digestion, and separation and identification of DNA fragments. Clinical data at renal biopsy and final status on renal function were determined from patients' records. RESULTS: Comparing all IgAN patients with controls, AGT and ATR genotype distributions were similar, whereas there was a significant increase in the ACE DD genotype (P < 0.05). When comparing patients with end-stage renal failure (IgAN-ESRF) and those without (IgAN-nonESRF), there was no difference among the three gene polymorphisms. In contrast, there were significant differences in higher male prevalence (P < 0.05), increased serum creatinine at presentation (P < 0.05), more sclerosis (P < 0.01) and higher tubulointerstitial lesion score (P < 0.001) in the IgAN-ESRF group. CONCLUSION: Among the ACE, AGT and ATR gene polymorphisms, only the DD genotype may predispose the individual to IgAN in the Chinese population. None are significant for prognosticating ESRF.     

Angiotensin-converting enzyme and endothelial constitutive nitric oxide synthase polymorphisms in Turkish renal transplant population and possible influence on renal artery atherosclerosis and graft survival

BACKGROUND: Renal transplant recipients are prone to accelerated atherosclerosis secondary to immunosuppressants, which may decrease graft survival. We sought to analyze the effects on renal graft survival of atherosclerotic degeneration in the renal artery and the influence of angiotensin-converting enzyme (ACE) endothelial constitutive nitric oxide synthase (ecNOS) gene polymorphisms. METHODS AND PATIENTS: Thirty three renal transplant recipients (25 men) of mean age 28.4 +/- 9.6 years, received organs from 11 living related donors and were followed for at least 36 months. Genotyping was performed for the insertion/deletion ACE (I/D), angiotensin (AGT) (M-->T, 235), angiotensine 1 receptor (A-->C, 1166), angiotensin 2-receptor (A-->G, 1223), and ecNOS (b-->a, intron4) gene polymorphisms. Renal artery biopsies were performed during transplantation surgery to analyze the presence of atherosclerosis. RESULTS: Pathological examination indicated that 18 donor specimens and nine recipient specimens had atherosclerotic degeneration. Survival analysis (36 months) indicated that graft survival rates of recipients who had atherosclerosis in the renal artery and who received an organ from donors with an atherosclerotic renal artery were shorter than in their counterparts (P = .02, P = .04, respectively). Comparison of genetic variations of recipients revealed that CC/TC variation of AGT was higher in patients with atherosclerosis (81% vs 53%, P = .03). There was no significant difference between groups in means of other gene polymorphisms. CONCLUSION: Renin-angiotensin system gene polymorphism analysis of patients in renal transplantation waiting list may provide information about allograft survival and posttransplant atherosclerotic degeneration at graft vasculature of young transplant recipients.     

ACE and AT1 receptor gene polymorphisms and renal scarring in urinary bladder dysfunction

The objective of this study was to investigate whether DNA polymorphisms of the renin-angiotensin system (RAS) genes were associated with renal scar formation in pediatric patients with bladder dysfunction (BD). Although these children are born healthy, due to persistence of immature voiding habits and evolution of BD, some develop progressive renal damage. It has been suggested that the DD genotype of the angiotensin I-converting enzyme (ACE) gene might be an adverse renal prognostic factor. The insertion/deletion (I/D) polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor (ATR1) gene were identified by polymerase chain reaction amplification in 42 children with BD (aged 5–14 years) and 198 healthy adult controls. Twelve children had urgency syndrome and 30 had dysfunctional voiding. Renal scarring was found in 16 patients, while 26 patients had normal kidneys on dimercaptosuccinic acid scan. In children with renal lesions there was significant over-representation of the DD genotype compared with either controls or patients without renal damage (P<0.05). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 2.51-fold risk (odds ratio 2.51, 95% confidence interval 1.04–6.04, P=0.04). The A1166C gene polymorphism was not significantly associated with the development of parenchymal damage in children with BD. Our findings introduce ACE I/D gene polymorphism as an independent risk factor for parenchymal destruction in pediatric patients with BD.M. Kosti and A. Stankovi contributed equally to this work     

ACE gene polymorphism and renal scarring in primary vesicoureteric reflux

The objective of this study was to investigate whether mutations of the renin-angiotensin system genes are involved in primary vesicoureteric reflux (VUR) and VUR-associated renal scarring. The M235T polymorphism of the angiotensinogen ( ATG) gene, the I/D polymorphism of the angiotensin converting enzyme ( ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor ( AT1) gene were identified in 77 patients with primary VUR (aged 6.9+/-3.2 years, mean+/-SD) and 80 healthy controls (aged 33+/-7 years). Thirty-eight of the 77 VUR patients had low-grade VUR (grade I-III) and 39 had high-grade VUR (grade IV and V). Renal scarring was found in 43 VUR patients, while 34 patients had normal kidneys on dimercaptosuccinic acid scan. The ACE gene polymorphism was determined by polymerase chain reaction and the ATG and AT1 gene polymorphisms were determined by single-step LightCycler technology. We found significant over-representation of the DD genotype in patients with renal scarring (44 %) compared with normal controls (23%, P<0.05) and patients with no scar formation (21%, P<0.05). Significantly higher D and significantly lower I allele frequencies were present in VUR patients with scarred kidneys (D allele 0.64 and I allele 0.36) compared with controls (D allele 0.53 and I allele 0.47, P<0.05) and patients with unscarred kidneys (D allele 0.4 and I allele 0.6, P<0.05). No differences in the ATG and AT1 genotype distributions and allele frequencies were observed in VUR patients compared with the normal population. The DD genotype and D allele of ACE may be a genetic susceptibility factor contributing to scar formation in VUR. We detected no linkage of genetic polymorphisms of ATG and AT1 to VUR and VUR-associated renal scarring.     

The renin-angiotensin system and endothelial nitric oxide synthase gene polymorphisms and cyclosporine toxicity in renal transplant patients

Although cyclosporine has improved graft survival, the toxicity of the drug frequently causes problem for renal transplant patients. Cyclosporine displays deleterious effects due to direct toxicity to the nephrons and vasoconstriction of afferent arterioles, effects that may be due to increased angiotensin II and decreased nitric oxide activity. We sought to examine the relation between cyclosporine toxicity and the RAS (angiotensin-converting enzyme, angiotesinogen, angiotensin 1 and 2 receptors, and ecNOS) gene polymorphisms in 111 renal transplant patients. Retrospectively, we correlated the results of graft biopsies from these 111 patients, with the cumulative drug doses (mg), mean blood levels (mg/mL), mean daily doses (mg), and mean doses (mg/kg/d) of cyclosporine. Overall 125 patients (38 women, 87 men) were enrolled in the study. Their mean age was 34.47 +/- 11.04 years. Twenty patients displayed cyclosporine toxicity on graft biopsy; 91 showed no evidence of the disorder. We could not find any relation between cyclosporine toxicity and gene polymorphisms (P >.05), although the mean mg/kg/d dose was significantly high among cyclosporine toxicity group (P =.028, RR = 1.42). In recent studies angiotensin II and nitric oxide have been suggested to be related to cyclosporine toxicity; however, our results failed to reveal an association between cyclosporine toxicity and angiotensin II or nitric oxide-related gene polymorphisms.     

Association of the genetic polymorphisms of the renin-angiotensin system and endothelial nitric oxide synthase with chronic renal transplant dysfunction

BACKGROUND: Chronic allograft dysfunction (CAD) is a complex phenomenon caused by underlying kidney disease and superimposed environmental and genetic factors. We investigated the association of polymorphisms in the genes for angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II receptor type 1 (ATR1) and type 2 (ATR2), and endothelial nitric oxide synthase (ENOS) with the initiation of CAD. METHODS: Genotyping was performed in 125 patients who underwent renal transplantation during a 5-year period for the ACE I/D, AGT M235T, ATR1 A1166C, ATR2 C3123A, and ENOS intron 4a/b gene polymorphisms. The following information was collected for each case: date of transplantation, age and sex of donor and recipient, donor type, cold ischemia time, number of human leukocyte antigen mismatches, number of acute rejection episodes, and laboratory findings at discharge from hospital and annual rechecks. Blood pressure was measured at yearly intervals throughout follow-up. RESULTS: The proportions of the genotypes were ACE II/ID/DD 12%, 33.6%, 54.4%; AGT MM/MT/TT 33%, 65.2%, 1.9%; ATR1 AA/AC/CC 68.6%, 30.7%, 0.7%; ATR2 CC/CA/AA 57.9%, 27.5%, 14.4%; and ENOS aa/ab/bb 6.4%, 22%, 71.6%, respectively. Statistical analysis of the major risk factors for the initiation of CAD showed that ACE DD genotype, cadaveric donor type, and level of proteinuria at 1 year posttransplantation were associated with poorer renal function. The graft function was not affected by AGT, ATR1, ATR2, and ENOS gene polymorphisms. CONCLUSIONS: These findings suggest that the DD variant of the ACE gene polymorphism is associated with increased risk of developing CAD.     

Angiotensin converting enzyme gene polymorphisms do not predict the course of idiopathic nephrotic syndrome in Swiss children

AIM: Contradictory reports exist about a correlation of angiotensin I converting enzyme (ACE) gene polymorphisms to the outcome of idiopathic nephrotic syndrome (INS) in children. We investigated the frequency of ACE polymorphisms and their impact on the clinical course of INS in children in a Swiss hospital. METHODS: The ACE gene polymorphism (I, insertion; D, deletion) was assessed in 32 children - 22 with steroid-sensitive INS and 10 with steroid-resistant INS - with a median age at onset of INS of 2.9 years (range 1.1-15.0). Polymerase chain reaction amplification was performed on genomic DNA isolated from blood leucocytes. Results were correlated to clinical course and renal morphology. RESULTS: The ACE genotype was I/I, I/D and D/D in two, 12 and eight patients, respectively, with steroid-sensitive INS, and in one, eight and one patient, respectively, with steroid resistance. Renal morphology, available in 25 patients showed minimal change glomerulopathy in 17 patients (14 steroid-sensitive; three steroid-resistant) and focal segmental glomerulosclerosis in eight (one steroid-sensitive; seven steroid-resistant). There was no significant correlation between ACE genotype and steroid responsiveness, histology or outcome. ACE genotype was I/I, I/D and D/D in none, 12 and five patients, respectively, with minimal change glomerulopathy, and in one, five and two patients, respectively, with focal segmental glomerulosclerosis. Six patients with steroid-resistant nephrotic syndrome went into end stage renal disease; ACE genotype was I/I in one and I/D in five, but none were D/D. CONCLUSION: In contrast to previous reports, ACE gene polymorphism is irrelevant for clinical outcome, steroid responsiveness or morphology in Swiss children with INS.     

Cardiac hypertrophy and remodeling in relation to ACE and angiotensinogen genes genotypes in Chinese dialysis patients

BACKGROUND: Genetic polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes are associated with increased risk of hypertension and left ventricular hypertrophy (LVH) in hypertensive subjects. However, the extent to which these polymorphisms are related to LVH and remodeling in dialysis patients remains unknown. METHODS: Two hundred and forty-six end-stage renal disease (ESRD) patients on peritoneal dialysis and 183 control subjects, all of Chinese origin, were genotyped for the ACE insertion/deletion (I/D) and the AGT M235T gene polymorphisms. Left ventricular mass index (LVMi) and relative wall thickness were measured using echocardiography. RESULTS: Prevalence of ACE DD and AGT TT genotype was 14% and 83%, respectively, in ESRD patients and did not differ significantly from controls. A total percentage of 95% of our patients had LVH (171 with concentric and 63 with eccentric hypertrophy). Adjusting for age, gender, body mass index, duration of dialysis, diabetes, renal diagnosis, hematocrit, systolic and diastolic blood pressure, dialysis urea clearance, residual glomerular filtration rate, and use of converting enzyme inhibitors or angiotensin receptor blockers, AGT TT genotype remained independently associated with greater LVMi (coefficient = 28.73; 95% CI, 5.72 to 51.75; P = 0.015) and relative wall thickness (coefficient = 0.072; 95% CI, 0.022 to 0.122; P = 0.005) than MT/MM genotypes. LVMi and relative wall thickness did not differ significantly among patients with DD, DI, and II genotypes. No statistical significant interaction was noted between ACE and AGT gene polymorphism in relation to LVMi and relative wall thickness. CONCLUSION: Polymorphism of the AGT M235T gene but not ACE I/D gene is associated with greater LVMi and relative wall thickness, indicating more concentric LVH, in Chinese peritoneal dialysis patients. Possible synergistic effects between AGT and ACE gene polymorphism require further evaluation in a larger population.     

Polymorphisms in angiotensin-converting enzyme gene and severity of renal disease in Henoch-Schoenlein patients

Background. The influence of angiotensin converting enzyme (ACE) gene polymorphism on the progression of primary IgA nephropathy (pIgAN) is still debated. Even though the allele frequency was reported to be similar to controls, in some studies D/D patients had a faster decline of renal function and need of dialysis. Since Henoch-Schoenlein purpura (HSP) nephritis is considered a systemic vasculitis with renal lesions indistinguishable from pIgAN, we investigated the effect of the ACE polymorphism on presentation and progression of HSP IgAN. Methods. We examined the insertion (I) and deletion (D) polymorphism in intron 16 of ACE gene by PCR amplification of genomic DNA of 82 patients (37 children), with biopsy-proven IgAN associated with HSP enrolled in a collaborative study. Results. No significant association with clinical presentation at onset or with final outcome was found (functional impairment at outcome in 31.8% D/D, 27.4% I/D, and 11.1% I/I). Patients homozygous for the D allele had a greater number of extrarenal relapses (P=0.0028). No association was found between the ACE genotype and the presence of hypertension at onset and at the end of the follow-up. No difference was found between adults and children. Conclusions. In this cohort of HSP IgAN, no ACE I/D polymorphisms were found to be associated with progressive deterioration of renal function. Different genes possibly involved in vasculitis might more strictly modulate expression and evolution HSP/IgAN/     

Renin-angiotensin system polymorphisms and renal scarring

The purpose of the study was to determine whether DNA polymorphisms at the renin-angiotensin-aldosterone (RAS) genes were associated with evolution to renal scar formation and, consequently, with reflux nephropathy (RN) in patients with vesicoureteral reflux (VUR). Some authors have suggested that the DD genotype of the angiotensin-converting enzyme (ACE) gene would be an adverse renal prognosis factor. We recruited 246 patients (aged 3 months to 22 years) from four Spanish hospitals. These included 69 patients with VUR, 110 with RN (determined by absence/presence of renal scarring on dimercaptosuccinc acid scan), 27 with chronic renal failure due to RN, and 40 patients (control group) with urinary tract infection and normal findings on renal ultrasonography and voiding cystoureterogram. The ACE I/D, angiotensin II type 1 receptor AT1 A1166C, angiotensin II type 2 receptor A3123C AT2, and angiotensinogen AGT M235T polymorphisms were determined on the basis of polymerase chain reaction amplification. ACE serum levels were determined by spectrophotometric methods. We found no statistical differences in the distribution of RAS polymorphisms between the different groups. The ACE D allele was linked to higher ACE serum levels. We found no association between ACE I/D polymorphism and presence of hypertension, proteinuria, grade of VUR, or unilateral/bilateral VUR. Patients with the DD genotype had a lower incidence of febrile urinary tract infection as a first symptom of VUR/RN (P<0.05). We conclude that genetic polymorphisms of RAS components are not independent prognostic indicators of renal scarring in patients with VUR.     

Endothelial nitric oxide synthase and angiotensin II type 1 receptor gene polymorphisms can influence chronic inflammatory state in renal transplant patients

Serum C-reactive protein (CRP) is a sensitive indicator of inflammation. Because increasing evidence shows the effect of endothelial nitric oxide synthase (eNOS) and the renin-angiotensin system on inflammation, we studied the association among chronic inflammation, chronic rejection, and gene polymorphisms of angiotensin II type 1 receptor (ATR1) and eNOS in renal transplant patients. METHODS: Data from 80 male and 35 female renal transplant patients (mean follow-up, 60.6 +/- 22.2 months) were analyzed. Patients were grouped according to posttransplant CRP levels: group 1 patients (n = 46) had normal CRP levels (CRP <10 mg/L); group 2 had intermittent (n = 26), and group 3 had persistently elevated (n = 43) CRP levels. eNOS and ATR1 gene polymorphisms of the groups and the impact of posttransplant CRP response on development of chronic rejection and graft failure were analyzed. The bb allele of the eNOS gene was found in 74% of the patients, whereas 62% had AA allele of ATR1. RESULTS: Patients in group 1 had a significantly lower incidence of chronic rejection and graft failure when compared with patients in groups 2 and 3 (P = .05 and P = .02 respectively). The bb allele of the eNOS gene predominated in group 1 (P = .02); presence of non-AA allele of ATR1 1166 gene was found less frequently in group 3 (P = .01). CONCLUSIONS: The presence of the bb allele of the eNOS and non-AA allele of ATR1 1166 gene is associated with an anti-inflammatory state and may predict renal outcome in transplant patients.     

Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is a complex phenotype resulting from underlying kidney diseases of different etiologies as well as from environmental and genetic factors. The responsible genes influencing the development and rate of progression to ESRD have yet to be defined. We examined an association of the three renin-angiotensin system (RAS) gene polymorphisms with renal disease and progression to ESRD in dialyzed patients. METHODS: Genotyping was performed in 745 ESRD patients and 520 control subjects for the angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms using polymerase chain reaction and gel analysis. RESULTS: Allele and genotype frequencies of the ACE polymorphism did not differ significantly between ESRD patients and controls. The patient group showed an increased frequency of the T allele of the AGT polymorphism (P = 0.02) and the C allele and CC genotype of the AT1R polymorphism (P<0.01). There was an association of the AT1R gene polymorphism with the progression of renal disease to end-stage failure. The time from diagnosis to the onset of ESRD was significantly shorter in patients carrying the C allele than in subjects with the homozygous AA genotype (4.7 years vs 12.6 years, P<0.001). The observed effect was not associated with hypertension in studied subjects. CONCLUSION: The results of our study demonstrate the association between the AT1R A/C polymorphism and renal disease progression. The CC/AC genotype of this polymorphism might serve as a predictor for early ESRD and might be useful in planning therapeutic strategies for individual patients.     

Polymorphisms of the angiotensin converting enzyme and angiotensin II type 1 receptor genes and renal scarring in non-uropathic children with recurrent urinary tract infection

AIM: The aim of this study was to investigate whether the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (A1166C) gene polymorphisms were associated with the renal scar formation secondary to recurrent urinary tract infection in children without uropathy. METHODS: The polymorphisms were investigated by polymerase chain reaction in 97 children (81 females, 16 males; age, 2.5-13 years) with recurrent urinary tract infection and 100 healthy controls as a single centre study. Children with vesicoureteral reflux, bladder dysfunction and other uropathies were excluded. The dimercaptosuccinic acid (DMSA) scan performed at least 3 months after a proven urinary tract infection and the result of the last DMSA was taken into consideration. RESULTS: Renal scarring was found in 30 patients (30.9%) using DMSA scan. The number of urinary tract infection attacks was significantly higher in patients with renal scarring compared with children without scarring (P<0.05). The follow-up period and male/female ratio of patients with or without renal scarring was similar (P>0.05). Age at the first urinary tract infection was lower in the group with scarring. The ACE insertion/deletion genotype distribution and D allele frequency were similar between patients and controls (P>0.05), and in patients with renal scarring and those without renal scarring. Also, the angiotensin II type 1 receptor gene polymorphism was not associated with renal parenchymal damage (P>0.05). CONCLUSION: The results indicated that the ACE insertion/deletion and angiotensin II type 1 receptor gene polymorphisms were not independent risk factors for renal scar formation in recurrent urinary tract infection of paediatric patients without uropathy.     

Albuminuria and the renin-angiotensin system gene polymorphisms in type-2-diabetic and in normoglycemic hypertensive Chinese

BACKGROUND: Albuminuria predicts nephropathy-related mortality in Caucasian and Chinese populations. The involvement of renin-angiotensin system (RAS) gene polymorphisms in the pathogenesis of nephropathy has been described predominantly in Caucasian populations. We have previously suggested that the angiotensinogen 235T variant may be associated with nephropathy in diabetic Chinese. PATIENTS AND METHODS: To validate these findings and extend them to include non-diabetic nephropathy, we examined the association of albuminuria and gene polymorphisms of the angiotensinogen M235T, angiotensin-converting enzyme insertion/deletion and angiotensin II type I receptor A1166C polymorphisms in 614 Chinese subjects (66% type 2 diabetic, 16% normoglycemic hypertensives and 18% controls). RESULTS: Obesity and higher blood pressure were associated with albuminuria in both diabetes and normoglycemic hypertension. In the diabetic group, albuminuria was also associated with increased insulin resistance and glycemic indices, duration of diabetes and adverse lipid profiles. Only the ACE gene polymorphism showed evidence of association with albuminuria, with the D allele being less frequent in the normoglycemic hypertensive patients with albuminuria (25.0%) than the controls (41.4%) or normoalbuminuric group (39.6%) and in those hypertensives at increased risk (albumin-to-creatinine ratio > 5.6 mg/mmol) of end-stage renal disease than those at lower risk (all p < 0.05), but not in the diabetic group. The D allele was also less prevalent in the total (31.9%) and normoalbuminuric (32.2%) diabetic groups than in the controls (p < 0.05). CONCLUSION: In this cohort of Chinese subjects, the ACE gene polymorphism D allele was less frequent in normoglycemic hypertensive patients with albuminuria and in type 2 diabetes.     

Low renin-angiotensin system activity gene polymorphism and dysplasia associated with posterior urethral valves

PURPOSE: Obstructive uropathies, including posterior urethral valves (PUVs) and kidney hypodysplasia, are the most frequent cause of renal failure in children. The role of renin-angiotensin system genes in renal and urinary tract development has been observed in experimental models. The aim of this study was to investigate the distribution of angiotensin converting enzyme (ACE), angiotensinogen (AGT) and angiotensin receptor type 1 (ATR1) genetic polymorphisms in children affected by chronic renal failure due to renal hypodysplasia associated with posterior urethral valves or without urethral abnormalities. MATERIALS AND METHODS: The study included 50 children (21 with hypodysplasia associated with PUVs, 7 with obstructive uropathy and 22 with pure hypodysplasia) and 50 healthy subjects matched for sex and geographic origin. ACE ID, AGT TC and ATR1 AC gene polymorphisms were assayed in all patients with standard polymerase chain reaction techniques. RESULTS: ACE II was expressed more in patients with PUVs compared to those with other dysplasias and controls (43% vs 7% and 10%, respectively, chi-square test p <0.05), while ATR1 AA was significantly less represented in patients with hypodysplasia compared to controls (38% vs 56%, chi-square test p <0.05). ACE DD and AGT genotypes were not distributed differently in patients with PUVs compared to those with other dysplasias and controls. CONCLUSIONS: To our knowledge this is the first report associating severe congenital uropathies and renal hypodysplasia with decreased renin-angiotensin system activity associated with the ACE II genotype and a possible functional imbalance among ATR1 receptors.     

Variance of ACE and AT1 receptor gene does not influence the risk of neonatal acute renal failure

High neonatal activity of the renin-angiotensin system (RAS) is crucial for the maintenance of glomerular filtration of the newborn. The aim of the present study was to investigate whether genetic polymorphisms leading to lower angiotensin converting enzyme activity (ACE) or impaired functionality of angiotensin II (AII) type 1 receptor (AT1R) might predispose very low birth weight newborns (VLBWs) to the development of acute renal failure (ARF). The medical records of 110 VLBW infants were analyzed. ARF developed in 42 of them during the first postnatal week, while 68 neonates exhibited normal renal function. The ACE I/D polymorphism and the A¹¹⁶⁶C variants of AT1R were determined from dried blood samples. The frequency of the ACE I allele did not differ in ARF and non-ARF groups (0.307 and 0.284); the frequency of the AT1R C¹¹⁶⁶ variant was also the same in ARF and non-ARF groups (0.250 and 0.227). Although low activity of RAS has been implicated in the development of neonatal ARF and data indicated that the functionality of RAS is influenced by the I/D variants of the ACE gene and the A¹¹⁶⁶C variant of the AT1R gene, we could not demonstrate any effect of these polymorphisms on the development of ARF in VLBW infants. Received: 7 March 2001 / Revised: 9 August 2001 / Accepted: 10 August 2001     

Impact of ACE I/D gene polymorphism on congenital renal malformations

To investigate the role of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on prevalence and progression of disease in children with chronic renal failure (CRF), we determined the ACE I/D genotype in 95 children with CRF due to renal malformations (hypo- /dysplasia, obstructive uropathy, reflux nephropathy; n=59), other congenital or hereditary diseases (n=23), or acquired glomerular disorders (n=13), who had been followed prospectively over a 2-year period. CRF progression rate was followed in each individual by linear regression analysis of estimates of glomerular filtration rate (GFR) obtained every 2 months. Actuarial renal ’survival’ analysis was performed, using a GFR loss of 10 ml/min per 1.73 m² as a cutoff point. The distribution of the ACE genotype did not differ among the disease groups. There was also no difference in ACE genotype distribution between the patients and a control group of healthy Caucasian children (n=163). Among the children with renal malformations, the 2-year renal survival was significantly lower in those with the DD genotype (61%) than in patients with ID or II genotype (89%, P<0.01). In the other disease groups, the ACE I/D genotype was not predictive of CRF progression. In a multivariate analysis of risk factors, the adverse effect of the DD genotype (risk ratio 10.2, P<0.05) was independent of and additive to those of arterial hypertension (RR 13.2, P<0.001) and gross proteinuria (RR 4.7, P<0.05). We conclude that the ACE DD genotype is a significant risk factor for children with congenital renal malformations to develop progressive CRF. The effect of the ACE polymorphism in this patient group is independent of hypertension and proteinuria. Received: 25 August 2000 / Revised: 10 December 2000 / Accepted: 15 December 2000     

Renin-angiotensin system component gene polymorphisms in Japanese maintenance haemodialysis patients

Summary: The renin-angiotension system (RAS) component gene polymorphisms was examined in 216 patients undergoing maintenance haemodialysis (HD) therapy and in 208 control subjects. the RAS polymorphisms selected for analysis were angiotensin I converting enzyme (ACE) I/D, angiotensinogen (Agt) T235/M235, angiotensin II type 1 receptor (AGT1R) A1166/C1166. the control allelic frequencies was ACE I/D (0.63/0.37), Agt T235/M235 (0.16/0.84), and AGT1R A1166/C1166 (0.94/0.06). Recently, relationships between ACE I/D and the progression of renal disease attract great attention in Japanese and Caucasian populations. ACE D allele was expected to be more frequent in HD population. However, no accumulation of ACE D allele or Agt T235 allele, AFT1R C1166 allele in Japanese end-stage renal disease (ESRD) subjects was detected. to explain the paradoxical result of positive association of ACE D allele with progression of renal disease and no bias of ACE genotype in ESRD subjects, further investigation with systematic prospective study regarding the change of ACE genotype distribution around the period of entering dialysis therapy is required.     

Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux

We studied the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in 78 patients with primary vesicoureteral reflux (VUR), and examined renal function by dimercaptosuccinate (DMSA) renoscintigraphy and diethylenetriaminepenta-acetic acid (DTPA) renogram in each genotype. Patients were classified into three genotypes according to the ACE gene I/D polymorphisms: 32 in II genotype, 36 in ID, and 10 in DD. The incidence of presumably congenital unilateral small kidneys was high in DD patients (70%). Glomerular filtration rate obtained from DTPA renogram was 120.7±35.7 ml/min (expressed as mean±SD) in II genotype, 111.7±33.3 in ID, and 88.0±18.0 in DD. The total quantitative DMSA tracer uptake of both kidneys was also low in patients with the D allele. This study shows that the D allele of ACE gene is closely related to small congenital kidneys with refluxing ureters in patients with primary VUR, and in accordance with previous reports, this allele is also related to the progression of reflux nephropathy. Received: 27 November 2000 / Revised: 10 April 2001 / Accepted: 10 April 2001