Angiotensin-converting enzyme genotype and outcome in pediatric IgA nephropathy

Angiotensin-converting enzyme (ACE) I/D polymorphism has been implicated as a genetic marker for progression of glomerular disease. Studies of ACE genotypes in adults with IgA nephropathy (IgAN) have yielded conflicting results. We performed ACE genotyping on 79 patients with IgAN diagnosed prior to age 18 years who had either progressed to end-stage renal disease (ESRD) or are now more than 5 years post biopsy. Mean follow-up was 14.8 years for those with normal renal function. Forty-three (54.4%) subjects had normal renal function and a normal urinalysis at last evaluation. Sixteen (20%) progressed to ESRD and 1 has chronic renal insufficiency. Kaplan-Meier survival curves for progression to ESRD did not differ significantly for the ACE DD, ID, and II genotype groups (P=0.095, log-rank test). By univariate analysis, presence of hypertension and degree of proteinuria at diagnosis, and unfavorable histology but not ACE genotype, was significantly associated with progression to ESRD. In the Cox proportional hazards model that included grade of proteinuria, the ACE D allele was a significant independent predictor of outcome with a hazard ratio of 2.37 (P=0.031). Our data, while inconclusive, suggest that the ACE D allele may associate with poor outcome in pediatric IgAN.     

Polymorphism of the ACE gene in Henoch-Schönlein purpura nephritis

Individuals with IgA nephropathy (IgAN) who are homozygous for the deletion (D) polymorphism of the gene for angiotensin converting enzyme (ACE) are reported to be at increased risk of progressive renal damage. Since IgAN and Henoch-Schönlein purpura with associated nephritis (HSPN) share a common aetiology, we have investigated this influence in 31 children with HSPN. The distribution of genotypes was as follows: II: 4, ID: 17 and DD: 10 patients. Median length of follow-up was 4.5 years (range 0.5–15.75 years). Severe onset with nephrotic oedema and crescent formation on renal biopsy was seen in 10 of 17 patients with ID genotype and 5 of 10 patients with DD genotype. In the ID group, 2 patients have undergone renal transplantation and 4 have persistent proteinuria 4, 7, 9 and 10 years after presentation. One patient in the DD group has been transplanted and 1 patient has proteinuria and a reduced glomerular filtration rate 5 years after initial presentation. All other patients have either made a complete recovery or have microscopic haematuria alone. These results do not support an association between disease severity and DD genotype in children with HSPN; however larger studies are required to confirm this.     

ACE gene polymorphism in childhood IgA nephropathy: Association with clinicopathologic findings

A deletion polymorphism in the angiotensin-converting enzyme (ACE) gene has been reported to be a risk factor for progression to chronic renal failure in immunoglobulin A nephropathy (IgAN). In this study, we investigated the association between ACE gene polymorphism and clinical findings, early biopsy findings such as the extent of mesangial proliferation, focal lesions (capsular adhesions, glomerulosclerosis, and crescents), and the glomerular area in childhood IgAN. Genomic DNA was obtained from 97 patients and control subjects. Gene polymorphisms, consisting of an insertion (I) or deletion (D) of the 287-base pair Alu sequence, were detected using the polymerase chain reaction. The extent of capsular adhesions and glomerulosclerosis was significantly higher in patients with the ID/DD genotypes than in those with the II genotype (ID/DD v II: 8.0%+/-1.4% v 2.5%+/-0.8% [P = 0.017] and 5.1%+/-1.3% v 1.4%+/-0.6% [P = 0.028], respectively). Whereas there was no difference in the extent of mesangial proliferation and crescents between the ID/DD genotypes and the II genotype. Urinary protein excretion at the time of biopsy was significantly greater in patients with the ID/DD genotypes than in those with the II genotype (1.02+/-0.15 g/d/m2 body surface area v 0.56+/-0.13 g/d/m2 body surface area; P = 0.012). These results indicate that ACE gene polymorphism may not influence the extent of mesangial proliferation and crescents that are acute lesions. However, the ID/DD genotypes are associated with chronic lesions, such as capsular adhesions or glomerulosclerosis and urinary protein excretion in childhood IgAN. (Am J Kidney Dis 1998 May;31(5):774-9)     

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.     

ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy

Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.     

Close relationship of plasminogen activator inhibitor-1 4G/5G polymorphism and progression of IgA nephropathy

BACKGROUND: The plasminogen activator inhibitor-1 (PAI-1) 4G/4G genotype influences the development of diabetic nephropathy and lupus nephritis. However, the association of the PAI-1 4G/4G genotype and IgA nephropathy (IgAN) has not been investigated. SUBJECTS AND METHODS: The PAI-1 and ACE polymorphisms were examined in 270 healthy volunteers and 202 biopsy-proven IgAN patients, including 117 untreated IgAN patients who had an annual health check, allowing an estimation of the time of onset of overt proteinuria and/or hematuria. The relationship between the gene polymorphisms and the pathogenesis of IgAN were examined in 202 IgAN patients and the relationship between the gene polymorphisms clinical and pathohistological findings were examined in 117 untreated IgAN patients cross-sectionally at the time of renal biopsy. RESULTS: 202 IgAN patients and 117 untreated IgAN patients did not have different frequencies in PAI-1 4G/5G (4G/4G : 4G/5 : 5G/5G = 82 : 90: 30, 45 : 55 : 17) and ACE I/D (DD : ID : II = 41 : 82 : 79, 21 : 54 : 42) gene polymorphisms compared with 270 healthy volunteers (4G/4G : 4G/5 : 5G/5G = 99 : 124 : 47, DD : ID : II = 53 : 106 : 111). However, IgAN with 4G/4G had significantly more advanced histological changes than IgAN with 4G/5G or 5G/5G both in glomerular and tubulointerstitial findings (p < 0.0005). The disease duration in IgAN with 4G/4G was shorter than in IgAN with 4G/5G + 5G/5G (6.22 +/- 6.38 and 8.80 +/- 9.79 years, respectively, p < 0.05). Creatinine clearance (Ccr) in IgAN with 4G/4G was significantly lower than IgAN with 4G/5G or 5G/5G (72.3 +/- 26.5 and 82.4 +/- 22.8 ml/min, respectively, p < 0.05). The mean urinary protein excretion in IgAN with 4G/4G was significantly more than in IgAN with 4G/5G or 5G/5G (1.10 +/- 1.48 and 0.70 +/- 1.01 g/day, respectively, p < 0.05). There was no difference between IgAN with the DD ACE genotype and IgAN with ID + II genotypes in either the clinical or histopathological findings. CONCLUSION: PAI-1 polymorphism is not associated with genesis of IgA nephropathy, but may be a risk factor for the progression of IgA nephropathy in Japanese.     

ACE DD genotype is more susceptible than ACE II and ID genotypes to the antiproteinuric effect of ACE inhibitors in patients with proteinuric non-insulin-dependent diabetes mellitus.

BACKGROUND: ACE polymorphism, especially genotype DD or D allele, may be involved in the progression of diabetic nephropathy. It may also have different effects on the reduction of proteinuria by ACE inhibitors in patients with proteinuria. We investigated the relationship between ACE gene polymorphism and antiproteinuric effect of ACE inhibitors (Benazepril 10 mg/day or Perindopril 4 mg/day) in 83 NIDDM patients with overt proteinuria (urinary protein excretion over 500 mg/day). METHODS: We recruited NIDDM patients with overt proteinuria from our renal clinic. Before entry, previously used ACE inhibitors were withdrawn for at least 2 weeks and baseline proteinuria and albuminuria were measured. Patients were classified into three groups in accordance with ACE genotypes (17 DD; 33 ID; 33 II) and prospectively followed up for 3 months. Various clinical parameters including age, DM duration, body mass index (BMI), 24-h urine sodium, protein and albumin, BUN, serum creatinine, creatinine clearance (Ccr), mean arterial pressure (MAP), and HbA(1c) were measured in the pre- and post-treatment periods. ACE genotypes were determined by polymerase chain reaction. RESULTS: There were no significant differences in the clinical parameters such as age, DM duration, BMI, BUN, serum creatinine, Ccr, MAP, HbA(1c), and daily urinary excretion of sodium, protein and albumin among three groups (P>0.05). After the 3-month treatment period using ACE inhibitors, there were no significant differences in the reduction of MAP and Ccr among the three groups (P>0.05). However, the percentage reductions in urinary excretion of protein and albumin for DD genotype were significantly higher than in ID and II genotypes (50.9+/-19.2% vs 19.2+/-16.0%, 20.2+/-20.4%; 52.6+/-23.6% vs. 13.5+/-51.8%, 24.8+/-23.9%, P<0.05). There were no statistically significant correlations between the levels of baseline proteinuria and albuminuria and the magnitudes of the reduction of proteinuria and albuminuria under ACE inhibition (P>0.05). CONCLUSIONS: Our results suggest that the ACE gene polymorphism might have a role in determining the responsiveness to the antiproteinuric effect of ACE inhibition in proteinuric NIDDM patients.     

Enhanced responses of blood pressure, renal function, and aldosterone to angiotensin I in the DD genotype are blunted by low sodium intake

Angiotensin-converting enzyme (ACE) activity is increased in the DD genotype, but the functional significance for renal function is unknown. Blunted responses of BP and proteinuria to ACE inhibition among DD renal patients during periods of high sodium intake were reported. It was therefore hypothesized that sodium status affects the phenotype in the ACE I/D polymorphism. The effects of angiotensin I (AngI) and AngII among 27 healthy subjects, with both low (50 mmol sodium/d) and liberal (200 mmol sodium/d) sodium intakes, were studied. Baseline mean arterial pressure (MAP) values, renal hemodynamic parameters, and renin-angiotensin system parameters were similar for all genotypes with either sodium intake level. With liberal sodium intake, the increases in MAP, renal vascular resistance, and aldosterone levels during AngI infusion (8 ng/kg per min) were significantly higher for the DD genotype, compared with the ID and II genotypes (all parameters presented as percent changes +/- 95% confidence intervals), with mean MAP increases of 22 +/- 2% (DD genotype), 13 +/- 5% (ID genotype), and 12 +/- 6% (II genotype) (P < 0.05), mean increases in renal vascular resistance of 100.1 +/- 19.7% (DD genotype), 73.0 +/- 16.3% (ID genotype), and 63.2 +/- 16.9% (II genotype) (P < 0.05), and increases in aldosterone levels of 650 +/- 189% (DD genotype), 343 +/- 71% (ID genotype), and 254 +/- 99% (II genotype) (P < 0.05). Also, the decrease in GFR was more pronounced for the DD genotype, with mean decreases of 17.9 +/- 4.7% (DD genotype), 8.8 +/- 3.4% (ID genotype), and 6.4 +/- 5.9% (II genotype) (P < 0.05). The effective renal plasma flow, plasma AngII concentration, and plasma renin activity values were similar for the genotypes. In contrast, with low sodium intake, the responses to AngI were similar for all genotypes. The responses to AngII were also similar for all genotypes, with either sodium intake level. In conclusion, the responses of MAP, renal hemodynamic parameters, and aldosterone concentrations to AngI are enhanced for the DD genotype with liberal but not low sodium intake. These results support the presence of gene-environment interactions between ACE genotypes and dietary sodium intake.     

Polymorphisms of renin-angiotensin system genes in childhood IgA nephropathy

We investigated whether polymorphisms of the renin-angiotensin system genes are involved in IgA nephropathy in Japanese children. We identified the M235T polymorphism of the angiotensinogen (AGT) gene, the I/D polymorphisms of the angiotensin-converting enzyme (ACE) gene, and the A1166C polymorphism of the angiotensin II type 1 receptor gene in 95 Japanese children with IgA nephropathy and 99 healthy Japanese adults. There were no differences in the genotype and allele frequencies of these genes between patients with IgA nephropathy and controls. Urinary protein excretion at the time of biopsy was significantly greater in patients with the TT genotype of the AGT gene than in those with the MM/MT genotypes of the AGT gene (1.32± 1.42 versus 0.75±0.78 g/day; P=0.01) and in patients with the ID/DD genotypes of the ACE gene than in those with the II genotype of the ACE gene (1.45±1.50 versus 0.63±0.56 g/day; P=0.001). Thus, the TT genotype of the AGT gene and the ID/DD genotype of the ACE gene are associated with increased severity of proteinuria, suggesting that AGT and ACE gene polymorphisms may play a significant role in the progression of IgA nephropathy in Japanese children. Received: 21 July 2000 / Revised: 8 December 2000 / Accepted: 11 December 2000     

Role of uteroglobin G38A polymorphism in the progression of IgA nephropathy in Japanese patients

BACKGROUND: Uteroglobin is a multifunctional protein and both its gene knockout and antisense transgenic mouse models develop the pathological and clinical features of IgA nephropathy. A genetic polymorphism in uteroglobin has been reported to be associated with progression of IgA nephropathy in a Caucasian population, but the findings remain controversial. METHODS: Genomic DNA was isolated from 595 individuals including 239 patients with IgAN, 160 patients with glomerulonephritis distinct from IgAN, and 196 healthy controls. The uteroglobin G38A genotype was determined by PCR-RFLP with Sau96I. To examine the possible association of uteroglobin gene polymorphism in the patients with and without IgAN, the uteroglobin genotype and allele frequency were compared between the two groups. In addition, associations between the polymorphism and blood pressure, proteinuria and prognosis of renal function were analyzed in the patients with IgAN to investigate the role of this gene polymorphism in the risk of progressive renal dysfunction in IgAN patients. RESULTS: The Cox proportional hazard regression model revealed that hypertension and proteinuria at the time of renal biopsy were independent risk factors for poor renal survival. Uteroglobin genotype was not significantly associated with the renal survival rate. However, in the patients with heavy proteinuria (more than 2 g/day) or in those with hypertension at the time of renal biopsy, the renal survival of patients with the GG genotype was significantly worse than the other genotypes. CONCLUSION: Uteroglobin GG genotype may be a genetic marker for rapid disease progression to end-stage renal failure, especially in the IgAN patients with heavy proteinuria or high blood pressure.     

Polymorphism of angiotensin converting enzyme, angiotensinogen, and angiotensin II type 1 receptor genes and end-stage renal failure in IgA nephropathy: IGARAS--a study of 274 Men

The impact of renin-angiotensin system (RAS) gene polymorphism on the prognosis of IgA nephropathy (IgAN) is still debated. A longitudinal study of renal prognosis in patients with IgAN was conducted to search retrospectively for a genotype-phenotype association between RAS polymorphisms and end-stage renal failure (ESRF). A classification based on serum creatinine (S(cr)) and 24-h proteinuria (24-P) measured at the time of renal biopsy was used to estimate the risk of ESRF in IgAN: stage 1 (S(cr) 150 micromol/L and 24-P < 1 g or S(cr) < or = 150 micromol/L and 24-P > or = 1 g), stage 3 (S(cr) > 150 micromol/L and 24-P > or = 1 g). Deletion/insertion polymorphism (D/I) of the angiotensin I converting enzyme gene, M235T polymorphism (T/M) of the angiotensinogen gene and A1166C polymorphism (C/A) of the angiotensin II type 1 receptor gene were determined in 274 Caucasian men with biopsy-proven IgAN (n = 86, 112, and 76 in stages 1, 2, and 3, respectively). Mean global follow-up was 6 +/- 5 yr after renal biopsy. For stages 1, 2, and 3, ESRF developed in 7 (8. 1%), 39 (34.8%), and 49 (64.4%) cases (P: < 0.0001), 11.7 +/- 4, 5.4 +/- 4, and 2 +/- 2 yr, respectively, after renal biopsy (P: < 0.001). The distributions of the three genotypes into the three stages were similar. Different distributions were observed when patients were grouped by stage and genotype: ID+DD: 72% in stage 1 versus 84.6% in stages 2 + 3 (P: = 0.02; kappa = 0.14); MT+TT: 66.2% in stages 1 + 2 versus 78.9% in stage 3 (P: = 0.04; kappa = 0.09); and AA+AC: 89.9% in stages 1 + 2 versus 97.4% in stage 3 (P: = 0.04; kappa = -0.1). However, with the use of the Cox proportional hazard model, none of the three genotypes was found to have predictive value for renal survival. Compared with S(cr) and 24-P, genotypes DD, TT, and AA are unlikely to serve as clinically useful predictors of ESRF in IgAN.     

Antiproteinuric effect of losartan in non-diabetic renal disease is not dependent on ACE insertion/deletion polymorphism

BACKGROUND: The antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors appears to vary depending on the ACE insertion (I)/deletion (D) genotype in non-diabetic nephropathy. This interaction may be overcome by using an angiotensin II receptor blocker. We evaluated the short-term antiproteinuric effect of losartan according to the ACE I/D genotype in patients with non-diabetic proteinuric renal diseases. METHODS: Ninety-nine (II/ID/DD: 36/52/11) non-diabetic patients with overt proteinuria were enrolled. The patients received losartan 50 mg daily followed by 100 mg in two treatment periods each lasting 12 weeks. Clinical parameters including proteinuria were measured at baseline and at the end of each period. RESULTS: At baseline each genotype (II/ID/DD) had comparable mean arterial blood pressure (mean +/- SD) 103.2 +/- 11.1/102.7 +/- 10.6/104.1 +/- 15.3; proteinuria (geometric mean, 95% CI, mg/day) 1,839 (1,518-2,227)/1,998 (1,683-2,372)/1,613 (1,072-2,427), and creatinine clearance (ml/min/1.73 m(2)) 65.7 +/- 28.4/63.2 +/- 27.8/68.8 +/- 25.3, respectively. Both doses of losartan significantly lowered blood pressure and proteinuria (p < 0.05 vs. baseline), and losartan 100 mg was more effective than 50 mg in reducing proteinuria (52.5 +/- 29.0 vs. 40.5 +/- 30.8%, respectively, p = 0.001). No differences in the antiproteinuric effect of losartan was observed among the ACE I/D genotype. Losartan 100 mg demonstrated a comparable degree of mean arterial pressure (mean +/- SD, %) (II/ID/DD, 13.3 +/- 7.6/10.8 +/- 9.8/13.0 +/- 11.6, respectively, p = NS) and proteinuria reduction (mean, 95% CI) among the three genotypes (51.4% (40.3-62.5%)/53.4% (45.5-61.4%)/51.4% (40.0-63.8%), respectively, p = NS). CONCLUSION: Our data suggest that losartan provides a similar short-term antiproteinuric response for all three genotypes of ACE I/D genotype in non-diabetic proteinuric chronic renal disease.     

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.     

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.     

ACE gene insertion/deletion polymorphism in childhood idiopathic nephrotic syndrome

The aim of this study was to determine the distribution of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, and its effects on clinical, laboratory, histological findings, treatment responses and progression to end-stage renal disease in childhood idiopathic nephrotic syndrome (NS). 227 children diagnosed with idiopathic NS were included in the study. Eighty-three of patients were steroid resistant and 77 of patients were focal segmental glomerulosclerosis. The control group was consisted of 287 unrelated healthy adult volunteers. ACE gene I/D polymorphism were analyzed by using PCR based method. In the entire group of children with NS, the frequencies of the II, ID, and DD genotypes of ACE gene were 13.7%, 38.3% and 48%, respectively. D allele frequency was higher in NS group than control group (0.67 vs. 0.56, p=0.001). Percentage of frequent relapser patients was found more frequently in ID or DD genotype (38.7%) than II genotype (15%) when only steroid sensitive patients were evaluated (p=0.045). The D-allele frequency was 0.65, 0.69 and 0.68 respectively in focal segmental glomerulosclerosis, biopsy proven minimal change and entire minimal change group (p>0.05) and 0.69 and 0.64 respectively in steroid sensitive and resistant groups (p>0.05). D allele frequency was not significantly different in patients with or without end-stage renal disease (0.64 vs. 0.67 respectively, p>0.005) when 115 patients who were at least five year follow-up were evaluated. The D allele frequency was higher in NS patients than healthy controls and DD or ID genotype was related with frequent relapses. ACE gene I/D polymorphism was not important in laboratory and histological findings and progression of the disease in children with NS.     

Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism. Gruppo Italiano di Studi Epidemologici in Nefrologia (Gisen)

In the Ramipril Efficacy in Nephropathy study, ramipril decreased the rate of GFR decline (deltaGFR) and progression to end-stage renal disease (ESRD) in 352 patients with proteinuric chronic nephropathies. This study investigated whether in these patients disease outcome and response to treatment were affected by gender or insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. deltaGFR (0.43 +/- 0.05 versus 0.48 +/- 0.08 ml/min per 1.73 m2) and incidence of ESRD (23 and 22%, respectively) were comparable in male and female patients. However, compared to conventional treatment, ramipril decreased deltaGFR (-52% versus -19%) and progression to ESRD (-74% versus -40%) more effectively in women than in men. Thus, the relative risk (95% confidence interval [CI]) of events (ESRD) between conventional and ramipril treatment was 5.52 (1.59 to 19.17, P = 0.003) in women, but only 1.80 (1.08 to 2.97, P = 0.02) in men. This gender-related effect of ramipril was associated with more reduction in proteinuria (-7.8 +/- 4.2% versus -21.9 +/- 5.7%, P = 0.05) and was still evident even after correction for potentially confounding factors such as baseline GFR, daily sodium intake, ramipril dose, BP control, and concomitant treatment with diuretics or dihydropyridinic calcium channel blockers (adjusted RR [95% CI]: women, 5.07 [1.26 to 20.38], P = 0.02; men, 1.44 [0.85 to 2.44], P = 0.17). Ramipril uniformly decreased deltaGFR and incidence of ESRD in women with either DD (-39% and - 100%) or II + ID (-71% and -82%) genotype, and in men (-25% and -50%) with the DD genotype, but had no beneficial effect in men with the II + ID genotype (+18% and +34%). Thus, the relative risk of events (ESRD) between conventional and ramipril-treated men was higher in subjects with the DD genotype (1.85; 0.69 to 4.94) and lower in those with the II +/- ID genotype (0.71; 0.28 to 1.80). Again, in parallel with deltaGFR and events, proteinuria decreased in women with DD (-23.3 +/-8.0%) or II + ID (-16.0 +/- 9.5%) genotype and in men with the DD genotype (-14.8 +/- 7.0%), but did not change in men with II + ID genotype (+ 1.0 +/- 7.8%). Of note, the ACE genotype-related effect of ramipril was still evident even after correction for the above potentially confounding factors (adjusted RR [95% CI]: DD, 2.52 [0.83 to 7.63], P = 0.10; II + ID, 0.35 [0.12 to 1.01], P = 0.05). Thus, among patients with chronic proteinuric nephropathies, men are at increased risk of progression due to their lower response to ACE inhibitor treatment. ACE inhibition is uniformly renoprotective in women regardless of the ACE polymorphism, and in men with the DD genotype, but is virtually devoid of beneficial effects in men with the II or ID genotype. This information may help to guide therapeutic interventions in clinical practice and to interpret the results of prospective trials in chronic renal disease.     

Angiotensin-converting enzyme gene polymorphism in children with idiopathic nephrotic syndrome

AIMS: To investigate the genetic polymorphism of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) in children with idiopathic nephrotic syndrome (INS), as well as its relationship with patient's clinical response to steroid therapy. METHODS: Fifty-nine patients with INS were recruited and divided into 2 groups according to their clinical response to steroids: steroid-sensitive (SS) with 19 patients and non-SS with 40 patients, which was further divided into steroid-dependent (SD) and steroid-resistant (SR) groups with 35 and 5 patients, respectively. Seventy-nine children without previous renal diseases and negative proteinuria were enrolled as a control group. The genotypes for ACE I/D polymorphism, including DD, ID, and II, were analyzed. RESULTS: The distribution of ACE DD, ID, and II genotypes in INS patients were 52.5, 10.2 and 37.3%, respectively; the corresponding numbers for the control group were 2.5, 25.3 and 72.2%, respectively. Patients with INS had a significantly higher percentage of DD genotype (p <0.001) than the control group. This higher incidence of the DD genotype was observed in both the SS and non-SS groups. A higher percentage of the DD genotype in the non-SS group and in the SD group as compared to the SS group (both p < 0.05) was also noted. CONCLUSION: Our data shows that INS is associated with a higher incidence of the DD genotype, especially in non-SS patients. This finding suggests that the DD genotype may be a risk factor for INS and play a role in the clinical response to steroids.     

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.     

The deletion polymorphism of the ACE gene is not an independent risk factor for renal scarring in children with vesico-ureteric reflux.

BACKGROUND: The deletion (D) polymorphism of the gene encoding angiotensin-I converting enzyme has been implicated as a risk factor for progressive renal disease in several conditions. This study was designed to evaluate the association between homozygosity for the D allele and susceptibility to renal scarring in children with vesico-ureteric reflux (VUR). METHODS: Two-hundred-and-six children with VUR (all grades) were recruited into the study. Patients were stratified into two groups according to the presence or absence of renal scarring. One-hundred-and-twelve patients (group 1) had evidence of renal scarring. Ninety-four children had no evidence of renal scarring (group 2). ACE genotypes were determined by polymerase chain reaction (PCR) amplification of genomic DNA samples. RESULTS: There was no association between the DD polymorphism and the presence of renal scarring. Genotype frequencies in group 1 were: II, 29; ID, 56; and DD, 27; and in group 2 were: II, 12; ID, 52; DD, 30 (P=0.21). Neither was there evidence supporting a 'dominant' D allele. There was no association between the DD genotype and the presence of proteinuria or reduced renal function (P>0.05). Hypertension was seen more frequently in those individuals with the DD genotype, compared with the other two genotypes (P=0.012). CONCLUSION: We cannot confirm previous reports that children with vesico-ureteric reflux who are homozygous for the deletion polymorphism of the ACE gene are more susceptible to renal scarring than heterozygotes and II homozygotes.