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     

Polymorphism in IgA nephropathy

Summary: IgA nephropathy (IgAN) is polyphormic in its clinical manifestation, course and prognosis. Patients with isolated IgA deposit in glomeruli tend to have a high incidence of macroscopic haematuria and carry a better prognosis. In contrast, patients with deposits of IgA and IgG and IgM have a higher incidence of nephrotic syndrome and hypertension. In parallel, patients with IgA and IgG and IgM tend to have more glomerulosclerosis and tubulointestitial lesions. Recently, the angiotensin converting enzyme (ACE) gene polymorphism and its association in disease risk provided interesting exploration leading us to speculate about a possible mechanism to explain the variation in the rate of progression of IgAN; although, the results are still controversial. The variability of plasma ACE concentration has been shown to be associated with an insertion/deletion polymorphism. The frequencies of ACE genotype in 177 Chinese patients with IgAN has been observed. We found that patients with IgAN showed a higher frequency of DD genotype than normal population. In contrast to the previous reports, we did not find any association between ACE genotype and the rate of progression of IgAN. As different genotypes of IL-1 receptor antagonist (IL-1 ra) are also responsible for the circulating levels of IL-1 ra, the polymorphism of IL-1 ra gene has been analyzed in 100 IgAN patients. There was no significant difference in the frequency of IL1RN*2 allele between normal subjects and IgAN. However, patients with recurrent macroscopic haematuria showed a higher carriage rate of IL1RN*2. Hereditable factors, in combination with a number of recognized environmental risk factors, are important determinants of the pathogenesis and natural history of IgAN. The notion that the gene polymorphism might be responsible for the clinical features and progression of IgAN is both intriguing and provocative. The lessons from previous multiple small size studies have produced conflicting results illustrating the need for observation of large numbers of cases in further studies to verify these observed associations.     

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.     

Polymorphism of renin-angiotensin system genes in progressive IgA nephropathy

Summary: Clinical studies revealed that angiotensin converting enzyme (ACE) inhibitor reduces proteinuria and attenuates progressive decline in renal function in IgA nephropathy. Recent studies by us and others have demonstrated that the homozygote of the D allele (DD) of the ACE insertion/deletion (I/D) polymorphism is a potential risk factor for poor prognosis in IgA nephropathy, and that this deletion polymorphism predicts the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function in patients with the nephropathy.     

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.     

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for IgA nephropathy

The lengthy course of IgA nephropathy and the possibility of good outcomes without therapy suggest nontoxic therapies such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs.) Among patients with IgA nephropathy, both ACE inhibitors and ARBs reduce the transglomerular passage of large, but not small, molecules, reducing proteinuria. The antiproteinuric effects of ACE inhibitors and ARBs are probably equivalent. Dual ACE inhibitor-ARB therapy reduces proteinuria by 54% to 73% and is more effective than either agent alone. To determine whether ACE inhibitors or ARBs preserve renal function long-term, one must rely on trials studying nondiabetic, proteinuric renal diseases rather than on trials specific to IgA nephropathy. Among this group of patients, several randomized, controlled trials, including the AIPRI trial, the REIN trial, and a metaanalysis of 11 randomized, controlled trials, have established clearly that the ACE inhibitors preserve renal function. There is no reason to believe that this information is not applicable to IgA nephropathy. The COOPERATE trial, in which 50% of the subjects had IgA nephropathy, established that ACE inhibitors and ARBs preserve renal function equally, and that dual ACE inhibitor-ARB therapy preserves renal function more effectively than either therapy alone. These data suggest that most individuals with proteinuric renal diseases, including IgA nephropathy, should be treated with ACE inhibitors and ARBs, ideally in combination. Polymorphisms of the angiotensinogen gene, the ACE gene, and the angiotensin II type I receptor gene have, so far, failed to predict either susceptibility to or progression of IgA nephropathy. However, the D allele of the ID polymorphism, particularly the DD genotype, could predict a favorable response to renin-angiotensin blockade.     

Influence of genetic polymorphisms of the renin-angiotensin system on IgA nephropathy

BACKGROUND: We evaluated the impact of the three major genetic polymorphisms of the renin-angiotensin system [angiotensinogen (AGT) gene M235T, angiotensin-converting enzyme (ACE) gene-I/D and angiotensin II-type 1 receptor (AT1R) gene A1166C polymorphisms] as risk factors in IgA nephropathy. METHODS: The clinical course of 107 patients with biopsy proven IgA nephropathy followed up for 6.6 +/- 5.8 years was examined. The genetic polymorphisms were determined by PCR amplification. RESULTS: The allele frequencies of the polymorphisms studied were similar in patients and control subjects. AGT-M235T genotype was associated with the presence of nephrotic syndrome (p < 0.05), correlated to the number of antihypertensive drugs agents taken (p < 0.01) and influenced the rate of deterioration of renal function (p < 0.05). Combined analysis of AGT-M235T and ACE-I/D polymorphisms detected an interaction on affecting progression (p < 0.05). ACE-inhibition had a more pronounced effect in certain AGT-M235T and ACE-I/D genotypes (p < 0.05) and their combined analysis showed a synergistic effect (p < 0.01). No association between AT(1)R-A1166C polymorphism and any of the parameters studied was observed. CONCLUSIONS: Our results suggest that angiotensinogen-M235T polymorphism is an important marker of progression in IgA nephropathy in Caucasian patients, especially when analyzed in combination with ACE-I/D polymorphism.     

No association of the -2518 MCP-1 A/G promoter polymorphism with incidence and clinical course of IgA nephropathy.

BACKGROUND: The clinical course of IgA nephropathy is highly variable, ranging from complete remission to progression with end-stage renal disease. Although the mechanisms involved in disease progression are not characterized in detail, loss of renal function is positively correlated with mononuclear cell infiltration. In general, chemokines play an important role in the directional recruitment of inflammatory cells. Recently, a polymorphism in the distal 5' regulatory region of the chemokine monocyte chemoattractant protein-1 (MCP-1), which affects gene expression, has been described (A/G at position -2518). The aim of our study was to evaluate a possible association of this polymorphism with disease progression in patients with IgA nephropathy, as well as susceptibility to this form of glomerulonephritis. METHODS: Blood samples from 207 patients with biopsy proven IgA nephropathy and 140 ethnically, age and sex-matched healthy controls were collected and genomic DNA was extracted. MCP-1 -2518 genotype was assessed by PCR, followed by restriction fragment length polymorphism analysis. Genotype distribution between the two groups was compared by chi(2) test. Cumulative renal survival was assessed by Kaplan-Meier plot and log-rank analysis. RESULTS: 111 (53.6%) patients had the MCP-1 -2518 wild-type A/A, 83 (40.1%) were heterozygous for the G allele and 13 (6.3%) patients showed homozygosity. The allelic distribution was not significantly different in the control group of 140 healthy blood donors (P = 0.71). Renal survival analysis of patients did not reveal statistically significant differences in cumulative survival (P = 0.32), median survival time and 5 year survival rate between the wild-type group and carriers of the G allele. Furthermore, the number of infiltrating CD68-positive monocytes/macrophages into the kidneys of patients with IgA nephropathy was not statistically different between the groups. CONCLUSION: Our data indicate that no association exists between the -2518 A/G polymorphism and susceptibility to IgA nephropathy or its clinical course.     

TNFα、β基因多态性对内蒙古汉族IgA肾病患者的预后影响

目的：研究TNFα、β基因多态性对内蒙古汉族IgA肾病患者的预后影响。方法：选100例内蒙古汉族IgA肾病患者（对其中33例患者进行1月～60月的随访）及105例正常对照组,采用聚合酶链式反应-限制性片段长度多态性分析（PCR-RFLP）技术检测TNFα、β基因多态性,分析不同基因型与IgA肾病临床特征、病理类型及预后的关系。结果：（1）IgA肾病患者TNFα、β的3种基因型与健康对照组间差异无统计学意义（P〉0.05）。（2）IgA肾病患者的TNFβ2等位基因频率（63.5%）较正常人（54.3%）升高（χ2=1.83,P〈0.01）。（3）TNFα、β的3种基因型与IgA肾病患者的年龄、血压、血尿、尿蛋白、肾功能及病理间无显著关系。（4）相对于其他基因型,TNFα1/1基因型在进展组高于非进展组,P=0.04〈0.05。结论：（1）TNFβ2等位基因频率与IgA肾病发病易患性相关。（2）TNFα1/1基因型可能是IgA肾病慢性化进展的危险因子之一。     

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.     

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.     

Increased frequency of angiotensin-converting enzyme DD genotype in patients with type 2 diabetes in Taiwan.

BACKGROUND: Diabetes is one of the major causes of end-stage renal failure in the Taiwanese population. Previous studies have shown that angiotensin-converting enzyme (ACE) inhibitor can improve glucose utilization and suppress hepatic glucose production and the renin-angiotensin system may play an important role in the initiation and progression of diabetic nephropathy. Thus, ACE gene polymorphism may be associated with type 2 diabetes and diabetic nephropathy. METHODS: To investigate the distribution of ACE-I/D genotype in type 2 diabetes and diabetic nephropathy, we examined 336 patients with type 2 diabetes (157 without nephropathy and 179 with nephropathy) and 263 age-matched normal controls. The diagnosis of nephropathy was made when daily protein loss exceeded 500 mg. ACE gene polymorphism was analysed by use of polymerase chain reaction. RESULTS: Our study revealed that the frequency of the D allele of the ACE gene was 29.3% in normal controls. The frequency of ACE DD genotype was significantly higher in type 2 diabetics compared with normal controls (18.2 vs 9.1%, P<0.01). The frequency of ACE DD genotype in patients with diabetic nephropathy was significantly higher than in patients without nephropathy (22.3 vs 13.4%, P<0.05). To determine whether ACE gene polymorphism was associated with the severity of diabetic nephropathy, we divided patients with diabetic nephropathy into dialysis and non-dialysis groups. The frequency of ACE DD genotype in the dialysis group was significantly higher than in non-dialysis group (28.7 vs 15.3%, P<0.05). CONCLUSION: Our results indicate that the frequency of ACE DD genotype is markedly higher in patients with type 2 diabetes, and the ACE DD genotype is significantly associated with diabetic nephropathy.     

ACE gene polymorphism and IgA nephropathy: an ethnically homogeneous study and a meta-analysis

BACKGROUND: Conflicting results have implicated the angiotensin-converting enzyme (ACE) D allele in the progression of renal damage in patients with IgA nephropathy (IgAN). Most of these findings have been obtained by heterogeneous studies. METHODS: We investigated the ACE insertion/deletion (I/D) gene polymorphism by polymerase chain reaction (PCR) amplification of genomic DNA in an ethnically homogeneous sample size of IgAN patients from Southern Italy. The association between ACE I/D gene polymorphism and the development of the disease was examined in 247 biopsy-proven IgAN patients and 205 healthy subjects. The association with the progression of renal damage was evaluated in 136 patients with a follow-up of > or =3 years according to the slope of the creatinine clearance against time, and in 221 patients with a follow-up of > or =1 year assessing by univariate and multivariate analyses of renal survival. These associations were further estimated in a meta-analysis of seven studies retrieved in the Medline database. The meta-analysis was performed according to the Mantel-Haenszel-Peto method when homogeneity of the studies was established using the chi(2) test by Breslow-Day. RESULTS: No difference in the ACE I/D gene distribution between patients and controls and between patients with stable and those with deteriorating renal function was found in our study. A meta-analysis performed separately for Caucasian and Asian studies showed that the ACE I/D gene polymorphism did not contribute to the genetic susceptibility of the development of IgAN (total OR 0.93, 95% CI, 0.71 to 1.23; and 0.95, 95% CI, 0.64 to 1.42, respectively) or the progression of the renal damage (total OR 1.12, 95% CI, 0.67 to 1.88; and 2.26, 95% CI, 0.75 to 6.79, respectively) in both groups. CONCLUSIONS: Our study and meta-analysis suggest caution in the interpretation of results from association studies enrolling heterogeneous populations. Further studies using new tests, which are free of the bias due to population stratification and ethnicity, are warranted.     

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.     

Excess of DD homozygotes in haemodialysed patients with type II diabetes. The Diabetic Nephropathy Study Group

The role of the insertion/deletion polymorphism of the angiotensin- converting enzyme (ACE) gene in the genesis of diabetic nephropathy has been controversial. It has recently been proposed that progression occurs more rapidly in individuals with diabetic and non-diabetic renal disease who are homozygous for the D allele. We studied 658 patients with type II diabetes, 347 without diabetic nephropathy and 311 with various stages of diabetic nephropathy, and determined the I/D polymorphism of the ACE gene. Patients at the extremes of renal risk, i.e. normotensive patients without antihypertensive treatment and without nephropathy (n = 144), vs patients on dialysis (n = 61), differed with respect to genotype (DD 36.8% vs 57.4%; P = 0.007) and allele frequencies (D 0.59 vs 0.76; P < 0.001). In contrast, patients with and without presumed nephropathy as assessed by albuminuria did not differ with respect to DD genotype. In conclusion, in this study, which was limited by sample size, patients with the highest renal risk more frequently had the DD genotype. This would be compatible with a greater risk of (or rate of) progression to end-stage renal failure.      

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/     

Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study

Angiotensin-I converting enzyme (ACE) regulates renal hemodynamics. Its insertion/deletion (I/D) polymorphism, which determines most of ACE interindividual variance, was proposed as a genetic marker for diabetic nephropathy. A substitution (M235T) polymorphism in angiotensinogen (AGT) may interact with ACE I/D polymorphism for the risk of diabetic nephropathy, but their prognostic values have to be established by follow-up studies. A total of 310 type 1 diabetes mellitus patients who attended the diabetic clinic in Angers (France) took part in a prospective, observational, follow-up study. Glycohemoglobin, BP, plasma creatinine, and urinary albumin excretion were determined periodically. Nephropathy was classified as absent, incipient (microalbuminuria), established (proteinuria), advanced (plasma creatinine > or = 150 micromol/L), and terminal (renal replacement therapy). The main end point was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal events was significantly influenced by ACE genotype (log-rank II versus ID versus DD, P < 0.03) with a dominant deleterious effect of the D allele: ID or DD versus II (adjusted hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors were high glycohemoglobin and systolic BP. In the patients who initially were free of nephropathy, baseline plasma ACE concentration was higher in patients who progressed to microalbuminuria (571 +/- 231 versus 466 +/- 181 microg/L; P = 0.0032); the D allele independently favored the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95% confidence interval, 1.1 to 19.4); other contributors were male gender, baseline systolic BP, and urinary albumin excretion. The AGT M235T polymorphism was not associated with renal events. The D allele of the ACE I/D polymorphism is an independent risk factor for both the onset and the progression of diabetic nephropathy in type 1 diabetes mellitus patients.     

Effect of a polymorphism of endothelial nitric oxide synthase gene in Japanese patients with IgA nephropathy.

BACKGROUND: Nitric oxide (NO) is synthesized by endothelial cell NO synthase (ecNOS) on vascular endothelium, and it plays a key role in the regulation of blood flow and pressure. A polymorphism of the ecNOS gene was recently shown to be associated with the development of cardiovascular disease. PATIENTS AND METHODS: We investigated the ecNOS gene polymorphism in 68 Japanese patients with IgA nephropathy (IgAN) and 134 normal controls. RESULTS: The genotype distributions were not different between the normal controls and the IgAN patients (ecNOS4b/b: ecNOS4b/a: ecNOS4a/a = 106:27:1 and 50:18:0, respectively). There was no significant difference in the renal histopathological grading between the patients with ecNOS4b/a and ecNOS4b/b. However, among the subgroup of patients whose duration of illness was two or more years, the advanced histopathological grading was more frequent in the patients with the ecNOS4b/a genotype (than in those with the ecNOS4b/b (p = 0.04)). The incidence of hypertension was also higher in the patients with the ecNOS4b/a genotype (50% in ecNOS4b/a versus 12% in ecNOS4b/b, p = 0.04). CONCLUSION: These results suggest that the ecNOS4b/a genotype (or ecNOS4a allele) of the ecNOS gene polymorphism may be involved in the progression of IgAN.