Angiotensin-converting enzyme activity and the ACE Alu polymorphism in autosomal dominant polycystic kidney disease.

BACKGROUND: Previous studies concerning Alu I/D polymorphism in the ACE gene and ADPKD severity have used the Alu genotypes as a representative of the true biological variable, namely ACE activity. However, wide individual and ethnic differences in the proportion of variance in ACE activity explained by the I/D genotype may have confounded these studies. This investigation examines the association between ADPKD severity and ACE in terms of plasma enzyme activity and I/D genotypes in individuals from three different countries. METHODS: Blood samples were collected from 307 ADPKD patients (116 Australian, 124 Bulgarian and 67 Polish) for determination of ACE activity levels and I/D genotypes. Chronic renal failure (CRF) was present in 117 patients and end-stage renal failure (ESRF) in 68 patients. RESULTS: ACE activity was related to the I/D genotype, showing a dosage effect of the D allele (P=0.006). The proportion of variance due to the Alu polymorphism was 14%. No difference in ACE activity and I/D genotype distribution was found between patients with CRF versus normal renal function (P=0.494; P=0.576) or between those with ESRF versus those without ESRF (P=0.872; P=0.825). No effect of the I/D genotype on age at development and progression to renal failure (CRF; ESRF) was detected in the overall group, and in subgroups based on ethnic origin, linkage status and sex. CONCLUSION: ACE is not likely to play a role as a determinant of ADPKD phenotype severity.     

Influence of ACE (I/D) and G460W polymorphism of alpha-adducin in autosomal dominant polycystic kidney disease.

BACKGROUND: The deleterious effect of the DD genotype of ACE in autosomal dominant polycystic kidney disease (ADPKD) remains controversial. Small sample size, population admixture and lack of consideration of parameters modulating the effects of ACE genotype, such as gender or alpha-adducin (ADD) genotype, might explain the discrepancy. METHODS: We investigated the effect of ACE (I/D) polymorphism on the age at end-stage renal disease (ESRD) in a homogeneous population of 191 ADPKD patients, according to gender and genotype for the G460W polymorphism of ADD. Cumulative renal survival was assessed in 276 patients from the same families. RESULTS: Though no effect was detected in the whole population, analysis of the male subset (n = 97) showed that patients harbouring the DD genotype of ACE had a 5-year lower mean age at ESRD than DI + II patients [47.8 +/- 1.8 (n = 31) vs 52.8 +/- 1.1 (n = 66), respectively] (P = 0.02). Furthermore, cumulative renal survival was lower in the corresponding pedigrees [47 +/- 1 years, 95% confidence interval (CI) 45-49, vs 51 +/- 1 years, 95% CI 48-54]. The G460W polymorphism of ADD had no effect on the age at ESRD and cumulative renal survival, either alone or in combination with the ACE (I/D) polymorphism. CONCLUSIONS: In this large series of ADPKD patients, we found no effect of the ACE (I/D) polymorphism on the age at ESRD, either alone or in combination with the G460W polymorphism of ADD. However, a deleterious effect of the DD genotype of ACE on renal disease progression was observed in ADPKD males.     

Influence of ACE I/D gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease: a meta-analysis.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a renal disease characterized by an important variability in clinical course, which cannot be fully explained by the genetic heterogeneity of the disease. Although the role for the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) polymorphism as a modifier factor in ADPKD renal deterioration has been suggested, direct evidence from genetic association studies remain inconclusive. To provide a more robust estimate of the putative effect of the ACE I/D polymorphism on the renal progression in ADPKD, we performed a meta-analysis pooling data from all relevant studies in which the role of the ACE I/D variant in ADPKD clinical features was evaluated. METHODS: We applied a random-effects model to combine odds ratio and 95% confidence intervals. Q-statistic was used to evaluate the homogeneity, and both Egger's and Begg-Mazumdar tests were used to assess publication bias. RESULTS: Altogether, three distinct meta-analyses were generated using data from 13 studies. Despite the absence of publication bias and the presence of homogeneity among study results, the DD genotype failed to show an influence on risk of end-stage renal disease (ESRD), mean age at ESRD or risk of hypertension in ADPKD patients when compared with I-allele carriers (DD vs ID+II). Likewise, meta-analyses carried out separately for Caucasian and Asian studies showed no indication of an association between the DD genotype and a faster renal deterioration in ADPKD. CONCLUSION: These findings do not support the hypothesis that the enhanced ACE activity associated with the D allele might promote a significantly worse prognosis in patients with ADPKD.     

血管紧张素转换酶基因多态性与糖尿病及其肾脏合并症发病的关系

目的探讨血管紧张素转换酶（ＡＣＥ）基因插入／缺失（Ｉ／Ｄ）多态性与Ⅱ型糖尿病（ＮＩＤＤＭ）及其肾脏合并症发病的关系。方法应用聚合酶链反应（ＰＣＲ）扩增技术检测了１０９例ＮＩＤＤＭ患者及１５５例健康对照者的ＡＣＥ基因Ｉ／Ｄ多态性。结果位于ＡＣＥ基因第１６内含子的Ｉ／Ｄ多态性经ＰＣＲ技术扩增后分为三种基因型：纯合子缺失型（ＤＤ）,纯合子插入型（Ｉ）及杂合子插入／缺失型（ＩＤ）。１０９例ＮＩＤＤＭ患者与１５５例正常对照组之间基因型及等位基因频率差异均无显著意义;ＮＩＤＤＭ合并肾病者（ＤＮ）的基因型与未合并肾病者无显著性差异,但等位基因则有显著性差异（Ｄ、Ｉ等位基因为０４５和０５５对０３０和０７０）（Ｐ＜００２）;ＮＩＤＤＭ病程≤１年即伴有肾病者与病程≥５年仍无肾病者比较,ＤＤ型及Ｄ等位基因均显著高于无肾病组（Ｐ均＜００５）,后者以Ｉ型及Ｉ等位基因占绝对优势。结论ＡＣＥ基因多态性与ＮＩＤＤＭ发病无关,而与其肾脏合并症则明显相关,ＤＤ型是ＤＮ的易感基因,而Ｉ型则为其保护基因。     

Polymorphism of the angiotensin-converting enzyme gene in end-stage renal failure patients

The plasma levels of angiotensin-converting enzyme (ACE) are modulated by the insertion (I)/deletion (D) polymorphism within the ACE gene locus. An association between progressive renal disease, raised cardiovascular risk, and ACE plasma levels has been shown. To evaluate the genotype frequencies of the I/D polymorphism in terminal renal failure, we have enrolled 341 dialysis patients (321 on hemodialysis and 20 on peritoneal dialysis) in a district of southern Italy (Foggia). As controls, 1,307 subjects from the same area have been enrolled. Genomic DNA was obtained from leukocytes, and the ACE I/D polymorphism was determined by polymerase chain reaction. Among uremics, 151 subjects (44.3%) carried the DD genotype, 149 (43.7%) the ID, and 41 (12.0%) the II genotype. In controls, 560 subjects (42.8%) had the DD genotype, 577 (44.1%) the ID, and 170 (13.1%) the II genotype (p = n.s.). Among patients, the frequency of DD subjects was higher in men (48.3%) than in women (39. 7%, p < 0.01). A slight different frequency of the DD genotype was found according to the duration of dialysis treatment: 47.5% in patients on dialysis up to 60 months and 41.7 and 40.6% in those with a dialytic age of 60-120 and >120 months, respectively (p for trend: 0.53). Patients with or without cardiovascular diseases, such as hypertension, left ventricular hypertrophy, coronary artery disease, and chronic cardiac failure, did not exhibit any difference in ACE I/D allele and genotype frequencies (p always >0.05). In conclusion, frequencies of the ACE DD genotype were similar in uremics and in controls and did not differ between patients with and without cardiovascular diseases. A nonsignificant inverse relationship with the time spent on dialysis was observed, suggesting that ACE I/D polymorphism may influence the cardiovascular death rate.     

ACE gene polymorphism and disease progression of IgA nephropathy in Asians in Singapore

The deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been considered as a risk factor for IgA nephropathy and for its progression to end-stage renal failure. However, results from various studies are conflicting. We had genotyped the ACE gene in 100 patients with IgA nephropathy, 32 of whom were in end-stage renal failure and in 90 normal adult subjects. All DD cases were subjected to confirmation with a second PCR, performed with the insert-specific forward primer. Similar genotype frequencies were obtained for the 90 normal control subjects (II: 47%, ID: 44%, DD: 9%); for the 68 patients not in end-stage renal failure (ESRF) (II: 47%, ID: 46%, DD: 7%) and for the 32 patients with ESRF (II: 53%, ID: 38%, DD: 9%). The genotype frequencies in all 3 series are in Hardy-Weinberg equilibrium. These results suggest that ACE gene polymorphism is not a risk factor for IgA nephropathy and is not a predictor for its progression. Definitive proof of association between ACE gene polymorphism and progression in IgA nephropathy will require a prospective study, controlled for important risk factors, with adequate patient numbers and facility for confirming DD genotypes.     

Angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and survival in a cohort of chronic hemodialysis patients

BACKGROUND: There are conflicting reports regarding the relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the initiation and progression of cardiovascular disease. Moreover, there is no report regarding the relationship between the ACE I/D polymorphism and the prognosis of chronic dialysis patients. METHODS: We examined the frequency of the ACE I/D polymorphism in 727 chronic hemodialysis patients in Okinawa, Japan, and observed the prognosis over 2 years in 407 men and 320 women with mean age (SD) of 55.5 (13.9) years with a mean duration of dialysis of 84.3 (66.6) months. RESULTS: Genotype frequencies were 42.1% for II, 43.2% for ID, and 14.7% for DD. The relative risks of death were examined by Cox-proportional hazards analysis after adjusting for age, sex, age at the start of dialysis, presence of diabetes mellitus and hypertension and total cholesterol and serum albumin levels. The adjusted hazard ratio (95% confidence interval) was 1.03 (0.38 - 2.85) for DD genotype and 1.50 (0.83 - 2.70) for DD+ID genotype when compared to II genotype. CONCLUSION: ACE I/D polymorphism appears to have no relation to the short-term prognosis in chronic hemodialysis patients.     

常染色体显性遗传性多囊肾病患者与血管紧张素转换酶基因多态性的关系

目的 研究人常染色体显性遗传性多囊肾病（ADPKD）与血管紧张素转换酶（ACE）基因多态性的关系。 方法 用PCR方法对103例ADPKD患者及16个ADPKD家系（患者35例,非患病直系亲属30人）进行ACE基因多态性分析。收集患者及家系成员的临床资料,以发病年龄、肝囊肿、高血压、尿路感染、尿路结石、血尿等为主要参数,用统计学方法研究该病ACE基因多态性与ADPKD的关系。 结果 DD型患者的发病年龄比DI型患者早7.2岁[（31.90±11.41）岁比（39.10±10.08）岁];DD型患者的发病年龄比Ⅱ型患者[（46.15±14.74）岁]早14.25岁;DI型患者的发病年龄比Ⅱ型患者早7.05岁,各型间的差异均有统计学意义（均P ＜ 0.05）。3组间高血压、血尿差异有统计学意义。11个家系检查结果显示,ACE基因多态性在ADPKD家系中具有遗传连锁关系,但无统计学意义;家系中患病与非患病者ACE基因型频率差异无统计学意义;家系中患病与非患病者男女之间ACE基因型频率差异无统计学意义;家系中肾功能不全组与肾功能正常组之间DD型及D等位基因频率差异有统计学意义（P ＜ 0.05）。 结论 DD型患者的发病年龄较早,Ⅱ型患者的发病年龄较晚,DI型居中。DI型患者血尿的发生率较高,Ⅱ型患者血尿的发生率较低。DI型患者高血压的发生率较高。ACE基因多态性在ADPKD家系中不提供基因诊断信息; ACE基因多态性与人ADPKD的发病无显著相关性;ACE基因多态性与性别无明显关系。DD型基因型是ADPKD发生肾功能不全的易感因素。     

The influence of G-protein beta3-subunit gene and endothelial nitric oxide synthase gene in exon 7 polymorphisms on progression of autosomal dominant polycystic kidney disease

BACKGROUND: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. We examined the influence of G-protein beta3-subunit C825T polymorphism and endothelial nitric oxide synthase Glu298Asp polymorphism on the progression of ADPKD towards end stage renal failure (ESRF). METHODS: 306 ADPKD patients (pts) were analyzed; 261 pts (136 males, 125 females) with ESRF, with subgroup of 73 pts (44 males, 29 females) with ESRF before 45 years (rapid progressors), 46 pts (20 males, 26 females) with ESRF later than in 63 years (slow progressors) and 45 ADPKD pts (17 males, 28 females) in mean age 51 years with serum creatinine under 110 micromol/L (slow progressors) and 100 genetically unrelated healthy Czech subjects. DNA samples from collected blood were genotyped for G-protein beta3-subunit C825T genotype in exon 10 and for endothelial nitric oxide synthase Glu298Asp genotype in exon 7. RESULTS: The G-protein beta3-subunit C825T genotype exhibited no significant differences among the groups of slow progressors (6.6% (6/91) TT, 54.9% (50/91) CT, 38.8% (35/91) CC), rapid progressors (9.6% (7/73) TT, 46.6% (34/73) CT, 43.8% (32/73) CC), ADPKD group with ESRF between 40-63 years (9.2% (13/142) TT, 50% (71/142) CT, 40.8% (58/142) CC) and control group (12% TT, 44% CT, 44% CC). When comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages: males TT--51.7+/-8.8 years, CT--51.9+/-10.3 years, CC--49.7+/-10.2 years and females TT--56+/-9.9 years, CT--53.2+/-8.5 years, CC--53.9+/-8.7 years. The endothelial nitric oxide synthase Glu298Asp and Asp29Asp genotypes were significantly more frequent in rapid progressors (9.6% (7/73) Asp/Asp, 39.7% (29/73) Asp/Glu, 50.7% (37/73) Glu/Glu) and in ADPKD group with ESRF between 40-63 years (11.3% (16/142) Asp/Asp, 41.5% (59/142) Asp/Glu, 47.2% (67/142) Glu/Glu) in comparison with slow progressors (8.8% (8/91) Asp/Asp, 24.2% (22/91) Asp/Glu, 67.0% (61/91) Glu/Glu) and with control group (8% Asp/Asp, 32% Asp/Glu, 60% Glu/Glu) (Chi-square test, p<0.05). Comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages in males with Asp/Asp--54.9+/-10.4 years, Asp/Glu--50.2+/-9.4 years, Glu/Glu--51.0+/-10.4 years. We found out in homozygous Asp/Asp females significantly earlier onset of ESRF (49.2+/-5.6 years) in comparison with heterozygous females (53.3+/-7.2 years) and with Glu/Glu homozygous females (54.8+/-9.7 years) (t-test, p<0.05). CONCLUSION: We excluded the significance of G-protein beta3-subunit C825T polymorphism on the progression of ADPKD. We established the negative prognostic value of the carriers of Asp variant of eNOS polymorphism. Finding of new modifiers could have in future clinical consequences for ADPKD patients.     

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

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. Received: 3 November 1998 / Revised: 3 March 1999 / Accepted: 3 March 1999     

ACE DD genotype: a predisposing factor for abdominal aortic aneurysm.

OBJECTIVE: To examine the role of polymorphisms in angiotensin converting enzyme (ACE, I/D) and angiotensin II receptor (AT1R, A1166C) in the development of abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: We investigated 250 consecutive patients, 217 males and 33 females (median age 72, range 50-83), undergone AAA elective repair and 250 healthy controls, comparable for sex and age. ACE and AT1R polymorphisms were studied by PCR-RFLP analysis. The genotype distribution was in Hardy-Weinberg equilibrium for all polymorphisms. RESULTS: The genotype distribution and allele frequency of ACE I/D, but not AT1R A1166C polymorphism were significantly different between patients and controls (ACE I/D: p=0.0002 and p<0.0001, respectively, and AT1R A1166C: p=0.6 and p=0.4, respectively). An association between the ACE DD genotype and the predisposition to AAA was found (OR DD vs. ID+II=1.9 95% CI 1.3-2.9, p<0.0001). Multivariate analysis adjusted for age, sex, traditional vascular risk factors and other atherosclerotic localizations, showed ACE DD genotype to be independently related to the disease (OR DD vs. ID+II=2.4, 95% CI 1.3-4.2 p=0.003). CONCLUSIONS: Our findings document that ACE DD genotype represents a susceptibility factor for AAA.     

Angiotensin converting enzyme gene insertion/deletion polymorphism in idiopathic nephrotic syndrome in Kuwaiti Arab children

OBJECTIVE: Angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influence the circulating and cellular levels of ACE and has been shown to be a risk factor in a number of diseases including IgA nephropathy. We have investigated the association of ACE gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome (INS) in Kuwaiti children. MATERIALS AND METHODS: The genotypes for ACE gene I/D polymorphism were determined in 102 subjects (54 INS cases and 48 healthy controls) using a PCR method. RESULTS: The distribution of DD, ID and II genotypes was 70%, 20% and 10% in INS cases compared with 52%, 46% and 2% in the controls. The mean age of onset of the disease was significantly lower in the INS cases with DD genotype (37 months) compared with cases with II genotype (65 months, p < 0.05). The clinical manifestation of the disease was considerably severe in cases with DD genotypes compared with cases having ID and II genotypes. The INS cases with DD genotype also showed a significantly higher incidence of steroid sensitivity and steroid dependence. Seventy-three per cent of the INS cases with minimal change lesion had a DD genotype. Also 70% of the cases which needed cytotoxic drugs had DD genotype. CONCLUSION: Our data suggest an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation of INS in Kuwaiti Arab children.     

The influence of angiotensin-converting enzyme gene of donor and recipient on the function of transplanted kidney

One of the genes that is supposed to influence renal graft function is the one encoding angiotensin I-converting enzyme (ACE). It shows polymorphism in the presence (I allele) or absence (D allele) of a 287-base pair fragment. The question arises whether ACE gene polymorphism of the recipient and donor influences renal graft survival. This prospective study included 94 recipients who underwent ACE genotyping (DD, DI, II) and measured their creatinine clearance after cimetidine administration. These factors were correlated with the occurrence of acute or chronic rejection and of pharmacologic treatment of hypertension. In 27 recipients it was possible to obtain the ACE genotype of the donor. Among the recipients, 36 proved to be DD genotype, 38 ID, and 20 II. Among the donors, 10 proved to be DD genotype, 10 ID, and 7 II. The changes in creatinine clearance after cimetidine administration were not significantly different among any of the genotype subgroups. Significantly higher creatinine concentrations were found among recipients with II genotype compared to the combined group of ID and DD among patients not treated with ACE inhibitors, but not among those receiving ACE I after kidney transplantation. No differences were found in the frequency of rejection episodes among the subgroups with different ACE genotypes. No significant influence of donor ACE genotype on renal graft function was observed. In summary, the I/D genotype was not an independent prognostic factor for renal graft survival in the first 4 years after transplantation. Possibly the use of ACE I alters the influence of genotype on some parameters.     

ACE gene polymorphism in Turkish children with nephrotic syndrome

Since 1990, the role of angiotensin converting enzyme (ACE) gene polymorphism in various renal and cardiac diseases is still debated. This study comprised 71 pediatric patients with nephrotic syndrome, 47 males (66%) and 24 females (34%) with a mean age of 57.4 +/- 37.6 months, and a control group of 83 healthy males (59%) and 57 healthy females (41%) with a mean age of 505 +/- 160.5 months. The distribution of the ACE genotype in the control group was II, 11%; ID, 53%; and DD, 36%, and the nephrotic syndrome was II, 4%; ID, 78%; and DD, 18%. Angiotensin-converting enzyme genotypes were significantly different between patients and control groups (p<0.05). The study groups consisted of 52 (73%) with steroid-sensitive nephrotic syndrome (SNSS) and 19 (27%) with steroid-resistant nephrotic syndrome (SRNS). The distribution of the ACE genotype was II, 6%; ID, 75%; and DD, 19% in the SSNS population and ID, 84% and DD, 16% in the SRNS population. No statistically significant difference was found between steroid sensitivity and ACE genotypes (p=0.5). The results show that ACE I/D polymorphism does not contribute to the steroid resistance, even though this study indicates that the presence of the I/D genotype has a much higher risk--approximately 2.8 times--of having nephrotic syndrome. Further studies with a larger number of patients are needed.     

DD genotype of ACE gene in boys: may it be a risk factor for minimal change nephrotic syndrome?

It has been shown that angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism affects the circulating and cellular levels of ACE and may be a risk factor in several renal diseases. We analyzed the association of ACE gene I/D polymorphism with the clinical presentation of minimal change nephrotic syndrome (MCNS) in a Turkish child population. This study consisted of 97 children with MCNS and 144 healthy controls. Genotyping of ACE gene was performed using polymerase chain reaction (PCR). The distributions of ACE genotypes were II in 13%, ID in 49%, and DD in 38% in patient group, and 9%, 49%, and 42% in control group, respectively. The frequency of the D allele was 63% and that of the I allele was 37% in patients. There were no relevant differences in the allele frequencies and genotypes of ACE I/D polymorphism between patients and controls. However, DD genotype was higher in boys in children with MCNS (78.4%. vs. 50.0%, p = 0.004). The frequencies of DD genotype and D allele in boys were 7.25 and 2.56 times higher than II genotype and I allele in the patient group, respectively. We suggest that DD genotype in boys may be one of the risk factors for MCNS.     

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     

ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies1

ACE genotype and ACE induced renoprotection in chronic proteinuric nephropathies. BACKGROUND: Whether angiotensin-converting enzyme (ACE) gene polymorphism affects disease progression and response to ACE inhibitor therapy in nondiabetic proteinuric nephropathies is not clearly established. METHODS: The relationship between insertion/deletion (I/D) genotypes and proteinuria, rate of glomerular filtration rate decline (DeltaGFR)-centrally evaluated by repeated measures of iohexol plasma clearance-and incidence of end-stage renal disease (ESRD) was prospectively evaluated in 212 patients with nondiabetic proteinuric chronic nephropathies enrolled in the Ramipril Efficacy in Nephropathy (REIN) trial, where patients were randomly assigned to ramipril or conventional treatment. RESULTS: The DeltaGFR +/- SEM (-0.38 +/- 0.09 vs. -0.50 +/- 0.08 vs. -0.36 +/- 0.06 mL/min/1.73 m2 per month) and incidence of ESRD (19 vs. 22 vs. 25%) in the three subgroups with the II, ID, and DD genotypes, respectively, were comparable. Of note, DeltaGFR (-0.28 +/- 0.07 vs. -0.43 +/- 0.09 mL/min/1.73 m2 per month) and incidence of ESRD [14% vs. 36%, P = 0.04, RR (95% CI), 2.62 (1.02 to 6.71)] were lower in ramipril than in conventionally treated patients in the DD genotype, but not in the II and ID genotype. Either at univariate (P = 0.04) or at multivariate (P = 0.01) analysis, ramipril significantly predicted a lower incidence of events in DD, but not in II and ID patients. At three months, ramipril decreased proteinuria more effectively in DD (-38.2%) than in the II (-26.7%) or ID (-19.2%) genotype. In DD (but not in II or ID) ramipril-treated patients, a short-term reduction in proteinuria correlated with DeltaGFR over the entire follow-up period (P = 0.02, r = -0.41). CONCLUSIONS: In nondiabetic proteinuric nephropathies, the ACE I/D polymorphism does not predict disease progression, but is a strong predictor of ACE inhibition-associated renoprotection in that proteinuria, DeltaGFR, and progression to ESRD are effectively reduced in patients with the DD, but not in those with the II or ID genotype.     

The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM

BACKGROUND: The insertion-deletion (I/D) polymorphism of the angiotensin converting enzyme gene is a diallelic polymorphism that constitutes a genetic influence on the progression of renal diseases such as IgA nephropathy. Patients with the DD genotype have an accelerated progression towards end stage renal failure in these diseases. The role of the I/D polymorphism in the pathogenesis of diabetic nephropathy in IDDM is unresolved. PATIENTS AND METHODS: We therefore set out to study the contribution of the I/D polymorphism in 79 patients (age 39.5 +/- 7.6 years (mean +/- SD) with end stage renal failure due to diabetic nephropathy, who were recipients of a combined kidney-pancreas transplantation (n = 60), or who were on the waiting list for such a procedure (n = 19). The control series consisted of 82 patients (age 39.5 +/- 9.6 years) without microalbuminuria after fifteen years of IDDM. RESULTS: The ACE genotype distribution in patients was not in accordance with the Hardy-Weinberg equilibrium due to a significant overrepresentation of the DD genotype (X2 = 8.9, p = 0.01). This resulted in a significant increase of the D-allele frequency in the cases compared to controls (X2 = 4.9, p = 0.03). The presence of one D-allele did not increase the risk of end stage renal failure (odds ratio ID/II = 1.0, 95% CI 0.4-2.2). The presence of the DD genotype increased the risk of end stage renal failure twofold compared to the other genotypes (odds ratio 2.1, 95% CI 1.1-4.0). The risk estimate seemed slightly higher in patients with good metabolic control (odds ratio 2.6, 95% CI 1.0-7.1), than in patients with poor control (odds ratio 1.6, 95% CI 0.59-4.3). CONCLUSION: It is concluded that the risk of end-stage renal failure in patients with IDDM is twofold increased in patients with the DD genotype as compared to patients with other genotypes.     

Association of the DD genotype and development of Japanese type 2 diabetic nephropathy.

We determined the insertion/deletion (I/D) polymorphism of the angiotensin-coverting enzyme (ACE) gene in a multicenter trial of ethnically homogeneous Japanese type 2 diabetes mellitus (DM) patients. All patients (n = 748) were divided into 5 groups as follows: group I (normoalbuminuric patients), group II (microalbuminuric patients), group III (overt albuminuric patients with serum creatinine (s-Cr) levels of less than 1.2 mg/dl), group IV (overt albuminuric patients with s-Cr levels of more than 1.3 mg/dl but excluding hemodialysis patients), and group V (hemodialysis patients). We selected patients with a diabetic duration of more than 15 years in the mild stage (groups I and II), but placed no limits on those in the advanced and end-stages (groups III, IV and V). The frequency of the DD genotype was slightly higher in the advanced and end stages. The frequency of the DD genotype in the mild stage differed from that in the end stage (II/ID/DD 47.8%/41.0%/11.2% vs. 37.0 %/43.3%/19.7% p = 0.07, II + ID/DD 88.8%/11.2% vs. 80.3%/19.7%, p < 0.05). D allele frequency in the mild stage also differed from that in the end stage (I/D 68.3%/31.7% vs. 58.7%/41.3%, p < 0.02). The presence of the DD genotype increased the risk of end-stage renal disease (ESRD) more than that of the other genotypes (odds ratio ID/II = 1.37, 95% CI 0.82-2.27; DD/II = 2.27, 95% CI 1.12-4.61). It appears that the DD genotype is associated with progression of Japanese type 2 diabetic nephropathy.     

Angiotensin-converting enzyme insertion/deletion polymorphism and prognosis of IgA nephropathy

BACKGROUND/AIM: Well-known factors for a poor prognosis in IgA nephropathy (IgAN) are hypertension, proteinuria, and renal insufficiency at the time of diagnosis. Also hypertriglyceridemia and hyperuricemia seem to play a role in the progression of IgAN. Angiotensin-converting enzyme (ACE) gene I/D polymorphism has been associated with cardiovascular diseases and with progression of IgAN. We, therefore, investigated the contribution of ACE gene I/D polymorphism in the prognosis of IgAN and its association with the other risk factors affecting the prognosis. METHODS: A total of 168 patients with IgAN were followed up for 6-17 (median 11) years from renal biopsy with respect to progression of renal disease defined as elevation of serum creatinine above 125 microM (1.4 mg/dl) in men or 105 microM (1.2 mg/dl) in women and over 20% from the baseline level. In addition to serum creatinine, the urinary protein excretion was evaluated at the time of renal biopsy and at the assessment visit at the end of the follow-up period. RESULTS: During the follow-up period, 26 (15%) patients showed progression of renal disease. Patients with ACE genotype II had a more favorable course than those with genotypes ID or DD. Although there were no significant differences among the ACE genotypes with respect to proteinuria > or =1 g/24 h at the time of renal biopsy, proteinuria > or =1 g/24 h was more frequent in patients with genotypes ID or DD than in those with genotype II at the end of the follow-up period. No associations were found between hypertension, serum lipids or serum urate, and ACE genotypes. CONCLUSIONS: Our results show that patients with ACE genotype II have a more favorable prognosis than those with genotypes ID/DD. Secondly, proteinuria (> or =1 g/24 h) found in patients with genotype II at diagnosis may improve, while in patients with genotypes ID/DD it is a more constant feature.