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.     

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.     

Role of the alpha-adducin genotype on renal disease progression

BACKGROUND: A genetic susceptibility to hypertension may predispose to the development of end-stage renal disease (ESRD) and promote a more rapid loss of renal function in patients with renal diseases. The alpha-adducin (ADD) gene, alone or in combination with the angiotensinogen (AGT) and the angiotensin-converting enzyme (ACE), is a candidate for abnormal blood pressure regulation and thus for increased susceptibility or faster progression to ESRD. METHODS: Genotyping for the G460W-ADD, M235T-AGT and the insertion/deletion (I/D)-ACE gene polymorphisms was performed in 260 control subjects and 260 ESRD patients using polymerase chain reaction, gel analysis and appropriate restriction digest. RESULTS: The frequencies of the ADD, AGT and ACE genotypes in ESRD patients did not differ from observed frequencies in control subjects. The average (+/-SE) time from diagnosis to the onset of ESRD tended to be shorter in the presence of the ADD-460WW (5.1 +/- 1.1 years, N = 10) than with the GW (9.9 +/- 0.7 years, N = 81) and GG (11.3 +/- 1.0 years, N = 164) genotypes (F-ratio=2.71, P = 0.068; WW vs. GW P < 0.06 and vs. GG <0.03). In the 167 patients homozygous for the ADD-G allele, a more rapid progression with the ACE-DD genotype as compared to ACE-DI and II was found (P < 0.02). CONCLUSIONS: The ADD genotype is predictive of the course of renal function loss in an unselected renal population and influences the effect of the ACE genotype to modulate the rate of progression to ESRD. Thus, the ADD genotype may play a role for the understanding of interindividual differences in the course of renal diseases.     

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.     

Clinical course and treatment of IgA nephropathy.

Impairment of renal function, severe proteinuria and arterial hypertension are the strongest clinical predictors of an unfavorable outcome in IgA nephropathy (IgAN). Glomerulosclerosis and interstitial fibrosis are the most reliable histologic prognostic markers. Metabolic syndrome and insulin resistance probably affect the clinical course of the disease. Among the known gene polymorphism it seems that there is a link between the ACE gene D allele and the progression of IgAN. Elevated blood pressure should be actively treated. The target blood pressure is 130/80 mmHg or less and the goal should also be to reduce proteinuria. Several large-scale trials are currently testing corticosteroids and other drugs in the treatment of IgAN.     

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.     

Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy.

BACKGROUND: The prognosis of IgA nephropathy (IgAN) is variable and about 10-20% of patients progress to end-stage renal disease (ESRD) in 10 years. Hypertension, proteinuria and renal insufficiency at the time of diagnosis are risk factors associated with poor prognosis. Lipid abnormalities may have a role in the progression of glomerulonephritides, and glomerulosclerosis and atherosclerosis may have similar pathophysiological mechanisms. We therefore evaluated factors associated with cardiovascular diseases, especially hypercholesterolaemia, hypertriglyceridaemia, and hyperuricaemia, as predictors of the progression of IgAN. METHODS: A total of 223 patients with IgAN (141 men, 82 women; median age 41 years, range 8-78 years) were studied. The following parameters were recorded at the time of renal biopsy: presence of hypertension or diabetes, smoking habits, body mass index (BMI), serum creatinine, total and HDL-cholesterol, triglycerides, and urate and 24-h urinary protein excretion. The patients were followed up for 0.2-17 years (median 10 years) with respect to progression of renal disease defined as elevation of serum creatinine above 125 micromol/l in men or 105 micromol/l in women, and over 20% elevation from baseline. RESULTS: Forty-one patients (18%) showed progression. Hypertriglyceridaemia and hyperuricaemia were significantly more common at the time of renal biopsy in patients with progressive than in those with stable disease. In patients with normal renal function at the time of diagnosis initial hypertriglyceridaemia, hyperuricaemia, hypertension and proteinuria were independent risk factors for progression of IgAN in the Cox regression hazard model. CONCLUSIONS: Our results show that hypertriglyceridaemia and hyperuricaemia at the time of diagnosis are important, previously underestimated predictors of poor outcome in IgAN, although causality between these factors and progression cannot be inferred from the present study.     

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/     

Angiotensin I-converting enzyme gene polymorphism in non-diabetic renal disease.

BACKGROUND: The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene determines the concentration of ACE in serum and local tissues. The role of this polymorphism in progressive chronic renal disease is still not fully clear. METHODS: We analysed the impact of the D/D polymorphism on the rate of decline in renal function in patients with non-diabetic, chronic progressive renal insufficiency. Seventy non-diabetic patients, aged 21-69 years at baseline, with moderately advanced renal insufficiency due to primary chronic renal disease were followed for an average of 3 years with repeated measurements of their glomerular filtration rate (GFR). Their mean GFR at baseline was 41 ml/min/1.73 m(2) body surface area (BSA). The polymerase chain reaction (PCR) amplification method was used to detect the I/D polymorphism of the ACE gene. GFR was measured as the clearance of (51)Cr-EDTA and the individual rate of progression was calculated using linear regression. RESULTS: The distributions of the genotypes were: D/D 30%, I/D 49%, and I/I 21%. The rates of progression in the three ACE genotype groups were an annual decline in renal function of -4.2 (SD 4.6) ml/minx1.73 m(2) BSA in the D/D group, -2.7 (SD 3. 4) in the I/D group and -1.7 (SD 3.4) in the I/I group (ANOVA P=0. 12). In patients with proteinuria below 3.5 g/24 h, the D/D group had a significantly higher rate of progression than patients with the I allele. The same was found in a separate analysis when only patients with normal apoliprotein B (below 155 mg/dl) levels were analysed. Furthermore, the D/D genotype was a significant predictor of a more rapid decline in renal function in male, but not female, patients. CONCLUSION: The results in this study in non-diabetic patients with chronic renal disease indicate that the presence of the D allele in the ACE genotype may be of particular importance as a predictor of a high rate of progression in male patients who otherwise do not have a major burden of documented and important prognostic factors for progressive renal insufficiency.     

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

BACKGROUND: Hypertension contributes to the progression to renal failure. A genetic susceptibility to hypertension may predispose to the development of end-stage renal disease (ESRD) and promote a more rapid progression to ESRD in patients with renal diseases. Genes encoding for angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and aldosterone synthase (CYP11B2) are candidates for abnormal blood pressure regulation. METHODS: Genotyping was performed in 327 control subjects and 260 ESRD patients for the M235T-AGT, the insertion/deletion (I/D)-ACE, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction, gel analysis, and appropriate restriction digest when required. RESULTS: Genotype frequencies did not differ significantly between ESRD patients and controls. When ESRD diabetic subjects were compared with diabetic patients without nephropathy, the prevalence of the AGT-MM genotype was lower (28.1 vs. 52.8%, P < 0.01), while the AGT-TT genotype was higher (15.6 vs. 2.7%, P < 0.05). The AGT-TT genotype was associated with a faster progression to ESRD in patients with glomerulonephritis (P < 0.05). In the total ESRD population, progression of renal disease was faster with the ACE-DD than with the DI and II alleles (P < 0.05). This association was particularly strong when the interaction with the AGT genotype was analyzed, with a rapid progression in ACE-DD as compared with ACE-DI and II in patients with the AGT-MM genotype (P < 0.01). CONCLUSIONS: Susceptibility for ESRD and faster progression to ESRD are linked with the AGT genotype in diabetic patients. Faster progression to ESRD is associated with the ACE genotype when the total population with ESRD and with the AGT genotype when patients with glomerulonephritis are considered. Thus, genes of the renin-angiotensin-aldosterone system are candidate genes for further understanding of the interindividual differences in the development and course of ESRD.     

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.     

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.     

Association of angiotensin I-converting enzyme gene insertion/deletion polymorphism and IgA nephropathy: a meta-analysis

BACKGROUND/AIMS: The angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been extensively examined for the association with immunoglobulin A (IgA) nephropathy (IgAN), however, conflicting results have occurred. We performed a meta-analysis to evaluate the association of ACE I/D polymorphism with IgAN in different ethnic groups. METHODS: 11 studies testing the association between ACE I/D polymorphism and IgAN susceptibility, and 9 studies testing the association of ACE I/D with IgAN progression were used in this analysis. The overall odds ratio (OR) was estimated by a fixed or random effect model. RESULTS: The overall OR for the risk of susceptibility and progression of IgAN in Asians for the DD genotype is 2.37 (95% CI 1.04-5.41) and 1.75 (95% CI 1.24-2.56). The overall OR for the D allele in Asians also showed a similar magnitude, though without statistical significance (p = 0.09, p = 0.13, respectively). In Caucasians, both the DD genotype and D allele were associated with IgAN progression (OR 1.90, 1.61, respectively), but not IgAN susceptibility (p = 0.30, p = 0.41, respectively). CONCLUSION: Our findings support the notion that ACE I/D polymorphism is associated with IgAN. Meanwhile, the role of ACE I/D polymorphism in Asians is different from that of Caucasians.     

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.     

Presentation, prognosis and outcome of IgA nephropathy in Indian adults

BACKGROUND: IgA nephropathy (IgAN) is not well characterized in India. This retrospective study of 478 patients with IgAN was performed to clarify the presenting features, prognostic factors and the renal survival rates of the disease. METHODS: Three hundred and forty-seven patients who had been followed on average for 27 months after diagnosis were divided into two groups based on renal function at diagnosis. In group 1 (229 patients), the creatinine clearance estimated by the Modification of Diet in Renal Disease formula was <85 mL/min and in group 2 (118 patients) it was >/=85 mL/min. RESULTS: The predominant modes of presentation were nephrotic syndrome, hypertension and renal failure. Twenty-nine percent of patients had more than a 20% decline in renal function at the last follow up. Multivariate analyses with stepwise logistic regression identified hypertension (odds ratio (OR) 3.5), nephrotic range proteinuria (OR 3.4) and sclerosed glomeruli on biopsy (OR 4.1) to be independently associated with progression in group 1 and hypertension (OR 2.3) in group 2. Seventeen percent of patients progressed to end-stage renal disease (ESRD). Using multivariate analysis by the Cox model, four risk factors for developing ESRD were identified: hypertension (hazard ratio (HR) 3.1); nephrotic proteinuria (HR 1.9); interstitial fibrosis (HR 2.5); and sclerosed glomeruli (HR 1.8). The renal survival rates at 1, 5 and 10 years were 84, 55 and 33%, respectively, with a median renal survival of 61 months from the time of biopsy. CONCLUSION: The relatively rapid rate of progression of IgAN in India is suggestive towards a 'malignant' nature of the disease in this country.     

Predicting the development of diabetic nephropathy and its progression

Diabetes remains the number one cause of end-stage renal disease worldwide. Only about one third of diabetic patients develop nephropathy, and the risk appears to be, in part, genetically determined. In this article, we review clinical and genetic markers for the development and progression of diabetic nephropathy. Microalbuminuria remains the best available predictor of the subsequent development of nephropathy, even though in recent years it has become clear that less than 50% of individuals with type 1 diabetes progress to overt proteinuria over a period of less than 10 years. It is of great interest for early recognition of risk of nephropathy that small elevations in nighttime blood pressure predict microalbuminuria in type 1 diabetes. Genetic markers for diabetic nephropathy have not been conclusively identified. The occurrence of renal events in diabetic patients, however, appears to be influenced by the angiotensin-converting enzyme (ACE) genotype, with a dominant deleterious effect of the D allele (D/D or I/D) versus I/I genotype. Some patients with the DD genotype also appear less susceptible to the renoprotective effects of conventional doses of ACE inhibitors, suggesting that ACE genotyping might be useful in selecting those patients that could benefit from higher doses of ACE inhibitors and more aggressive treatment to prevent or delay disease progression.     

IgA肾病治疗的思考

IgA肾病是我国最常见的原发性肾小球疾病。主要以IgA免疫球蛋白沉积于肾小球为病理特征;以血尿、蛋白尿、高血压和肾功能损害为主要临床表现。每次血尿和(或)蛋白尿发作是肾小球损伤的标志,如不有效进行干预,可逐渐出现肾功能损害。控制血尿和(或)蛋白尿,降低尿检异常发生的频率,是治疗原发性IgA肾病及防止肾脏慢性化损伤的关键。ACEI/ARB在减少IgA肾病患者的蛋白尿、保护残存肾功能、延缓其进展为终末期肾病等方面优于其他降压药。IgA肾病如有较多新月体形成、明显血尿和蛋白尿,可考虑使用糖皮质激素和(或)与免疫抑制剂。由于IgA肾病是一个慢性化过程,长期随访对改善该病的预后显得尤为重要。     

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.     

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.