Endothelial nitric oxide synthase gene polymorphism in intron 4 affects the progression of renal failure in non-diabetic renal diseases.

BACKGROUND: Nitric oxide is a very potent regulator of intrarenal haemodynamics and is thought to be an important factor in the deterioration of renal function. Our study sought to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphism in intron 4 might have some relevance to progression in chronic renal failure. METHODS: We studied the frequencies of gene polymorphism of ecNOS intron 4 in patients with end-stage renal disease (302 cases) and compared it with that of healthy subjects (248 cases). ecNOS genotypes were determined by the polymerase chain reaction, followed by agarose gel electrophoresis. RESULTS: Two alleles of ecNOS intron 4, labelled a and b could be detected; a has four and b has five tandem 27-bp repeats. The frequencies of ecNOS4b/b, ecNOS4b/a, ecNOS4a/a genotypes were 81.0% (201/248), 19. 0% (47/248), 0.0% (0/248) in the control group, and 74.8% (226/302), 23.5% (71/302), l.7% (5/302) in all the patients, 72.7% (168/231), 25.1% (58/231), 2.2% (5/231) in the group with end-stage renal diseases, excluding diabetic nephropathy (non-DM group), and 81.7% (58/71), 18.3% (13/71), 0.0% (0/71) in diabetic nephropathy (DM group) respectively. The frequency of the ecNOS4a (ecNOSb/a, and ecNOSa/a) in all the patients and in the non-DM group were significantly higher than that in the control group (P=0.021; P=0. 0096 respectively). In contrast, there was no significant difference in the frequencies of ecNOS genotypes between the DM group and the control group (P=0.81). CONCLUSION: Among the frequencies of ecNOS intron 4 gene polymorphism, a allele displayed a significantly higher frequency in cases with end-stage renal failure (ESRF) not caused by diabetic nephropathy. ecNOS gene polymorphism in intron 4 appears, therefore, to affect the progression of renal failure in non- diabetic renal diseases, but the same conclusion could not be drawn in diabetic nephropathy.     

Association of endothelial nitric oxide synthase gene intron 4 polymorphism with end-stage renal disease

BACKGROUND: Nitric oxide (NO) released from endothelial cells is related to the maintenance of physiological vascular tone. The impairment of endothelial NO generation brought about by gene polymorphism is considered one of the deterioration factors in progressive renal disease. In the endothelial nitric oxide synthase (eNOS) intron 4 polymorphism, the presence of the aa genotype has been associated with cardiovascular and renal disease. The aim of this study was to investigate the presence of eNOS gene intron 4 polymorphism in patients with end-stage renal disease (ESRD). METHODS: A total of 114 patients and 94 controls were studied. DNA specimens were extracted from blood and amplified by polymerase chain reaction. The alleles were separated by agarose gel electrophoresis. Genotype distribution and allele frequencies were compared between groups using the chi-squared test. RESULTS: Statistical analysis revealed that the frequency of the eNOS4 genotype aa was significantly different in ESRD patients and in controls (P=0.016, OR=2.07, CI 95%: 1.14-3.74). There was also a statistically significant difference between ESRD patients and controls regarding allele carriers (P=0.004; OR=2.26; CI 95%: 1.29-3.96). When the frequencies of allele carriers in the diabetic nephropathy group and in the control group were compared, a significant difference was found (P=0.034, OR=2.28; CI 95%: 1.04-5.00). CONCLUSION: This study showed a strong correlation between eNOS4a polymorphism and end-stage renal disease.     

Association of endothelial nitric oxide synthase gene polymorphisms with end-stage renal disease: a systematic review and meta-analysis

Background and objective: Endothelial nitric oxide synthase (eNOS) is one of the potent regulators of intra renal hemodynamics. Polymorphisms of eNOS gene may be involved in the progression of renal disease, and may be the causative factors that contribute to the deterioration of renal functions. During the past decades, several studies investigated the association of eNOS polymorphisms with the risk of end-stage renal disease (ESRD), but the results remain unclear and the mechanisms are not defined. Our study was designed to examine the role of different eNOS genetic polymorphisms in the progression of ESRD. Materials and methods: Relevant studies were identified through PubMed, Embase, Medline and CNKI (China National Knowledge Infrastructure) database published between January 2000 and November 2013. The association between eNOS polymorphisms and ESRD susceptibility was assessed by pooled odds ratios (ORs) and 95% confidence intervals (95% CI) in fixed or random effects models. Results: Sixteen articles were identified for the analysis of association between eNOS gene polymorphisms and ESRD risk. A total of 2729 patients and 2190 controls for 4b/a, 851 patients and 1171 controls for G894T, and 513 patients and 487 controls for T786C were included in our analysis. Overall, 4a allele of 4b/a polymorphism produced a significant association in the global population (OR?=?1.47, 95% CI?=?1.05–2.06, p?=?0.03) in a random-effect model; T allele of G894T was also significantly associated with ESRD susceptibility in overall populations (OR?=?2.12, 95% CI?=?1.44–3.12, p?=?0.0001). Furthermore, 4a and T carriers were significantly associated with ESRD risk as well. No association was found between T786C polymorphism and ESRD. Conclusion: The evidence accumulated suggested that 4b/a and G894T polymorphisms in the eNOS gene were associated with ESRD susceptibility, indicating that 4a and T allele carriers might become significant genetic molecular markers for the onset of ESRD in overall populations. However, more studies should be performed in the further studies.     

Genetic analysis of nitric oxide and endothelin in end-stage renal disease.

BACKGROUND: Genetic factors have been implicated in the development of the common aetiologies of end-stage renal disease (ESRD), including renal failure attributed to hypertension, diabetes mellitus, systemic lupus erythematosus and human immunodeficiency virus infection. Nitric oxide (NO) and endothelin are powerful vasoactive mediators involved in inflammation and regulation of vascular tone and blood pressure. We evaluated the role of the neuronal constitutive (NOS1) and endothelial constitutive (NOS3) nitric oxide synthase genes and the endothelin-1 (EDN-1) gene in predisposition to chronic renal failure in African-Americans. METHODS: The study population for the linkage and association analyses in ESRD consisted of 361 individuals from 168 multiplex African-American families. These individuals comprised 207 unweighted sibling pairs concordant for all-cause ESRD. Microsatellite markers NOS1B (NOS1), D7S636 (NOS3) and CPHD1-1/2 (EDN-1) were genotyped in the sample. In addition, a mutation, Glu298Asp, in exon 7 of NOS3 and a 27 bp variable number tandem repeat (VNTR) marker in intron 4 of NOS3 were evaluated in the sibling pairs and in an additional 92 unrelated African-Americans with type 2 diabetes mellitus-associated ESRD (singletons). Association analyses utilized the relative predispositional effect method. Model independent linkage analyses were performed using GeneHunter-plus and MapMaker/SIBS (exclusion analysis) software. RESULTS: Significant evidence for association with ESRD was detected for alleles 7 and 9 of the NOS1 gene (11.9 and 34.2%, respectively, in unrelated probands of ESRD families versus 6.5 and 27.5%, respectively, in race-matched controls, both P:<0.01). These associations were maintained when the unrelated first sibling from each family was used in a case-control comparison and was most pronounced in the non-diabetic ESRD cases. The NOS3 and EDN-1 markers failed to provide consistent evidence for association in the sibling pairs and the diabetic ESRD singletons, although we identified two novel endothelial constitutive NOS4 (ecNOS4) VNTR alleles in African-Americans. Significant evidence for linkage was not detected between the NOS genes or the EDN-1 gene in either all-cause ESRD or when the ESRD sibling pairs were stratified by aetiology (type 2 diabetic ESRD or non-diabetic aetiologies). CONCLUSION: Based upon the consistent allelic associations, we believe that further evaluation of the NOS1 gene in ESRD susceptibility in African-Americans is warranted.     

Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis.

As endothelial nitric oxide synthase (eNOS) has beneficial effects on skeletal, vascular, and thrombotic systems, the association between nontraumatic femoral head osteonecrosis (FHON) and eNOS gene polymorphisms was investigated in Korean patients with FHON. Genomic DNA from 103 patients with nontraumatic FHON (idiopathic in 50, steroid-induced in 29, and alcohol abuse in 24) and 103 control subjects matched for gender and age (3-year range) was analyzed for the 27-bp repeat polymorphism in intron 4 and Glu298Asp polymorphism in exon 7. The frequencies of alleles and genotypes were compared between patients and control subjects. The frequency of 4a allele was significantly higher in total patients than control subjects [6.8% vs. 2.4%, p = 0.0345, odds ratio (OR) 2.931]. In subgroup analysis, the 4a allele significantly increased in patients with idiopathic FHON versus control subjects (9.0% vs. 2.4%, p = 0.0297, OR 3.976). The frequency of the 4a/b genotype in total patients (13.6% vs. 4.9%, p = 0.0302, OR 3.083) as well as patients with idiopathic FHON (18.0% vs. 4.9%, p = 0.0246, OR 4.302) was higher than control subjects. The distribution of Glu298Asp polymorphisms was not significantly different between patients and control subjects. Microstellate polymorphism in intron 4 of eNOS polymorphism was significantly associated with idiopathic FHON in Korean patients. Because 4a allele is associated with lower synthesis of eNOS, these results suggest that carrier state of 4a allele in intron 4 might be a genetic risk factor of FHON and could provide insight into the protective role of nitric oxide in the pathogenesis of FHON.     

内皮型一氧化氮合成酶基因Glu298Asp多态性与糖尿病肾脏病的关系

目的探讨内皮型一氧化氮合成酶（eNOS）基因Glu298Asp多态性与糖尿病肾脏病（DIcD）的关系。方法采用聚合酶链反应（PCR）后限制性内切酶消化技术,对在我院就诊的326例中国汉族2型糖尿病（T2DM）患者和215名健康体检者进行Glu298Asp基因型分析。根据尿白蛋白排泄率（UAER）水平将T2DM患者分为3组：UAER正常组（DM组）102例,微量白蛋白尿组（MAU组）81例,临床肾病组（DKD组）143例。选择同时期本院健康体检者215名为对照组。用多因素Logistic回归分析法判定DKD的独立危险因素。结果DKD组与对照组Glu298Asp基因型频率分布存在显著性差异（GG72．72％、GT26．57％、TT0．70％比GG83．41％、GT16．10％、TT0．49％,P=0．019）,而DM组和MAU组则与对照组无差异（P〉0．05）。Logistic回归分析显示,年龄、平均动脉压、GT基因型是DKD发生的独立危险因素。结论eNOS Glu298Asp基因与中国汉族T2DM患者DKD具有相关性。     

Associations between endothelial nitric oxide synthase polymorphisms and risk of diabetic nephropathy: an updated meta-analysis

Abstract

Background: Genetic polymorphism of endothelial nitric oxide synthase (eNOS) has been implicated in the risk of diabetic nephropathy (DN), but the published findings were inconsistent. We performed a comprehensive meta-analysis to derive a more precise estimation of the association between genetic polymorphisms of eNOS and the risk of DN. Methods: Six online database were researched on the associations between polymorphisms of eNOS (T786C, G894T, 4b/4a) and DN risk. PRISMA statement and Hardy–Weinberg equilibrium assessment were used in this report. Odds ratio and 95% confidence interval were estimated based on the following genetic contrast/models: allelic model, dominant model, recessive model and co-dominant model. The publication bias and sensitivity analysis were also performed to guarantee the statistical power. Results: A total of 49 case–control studies with 11,990/9754/5131 participants for DN/DM/HC group were eligible for meta-analysis (7/25/31 studies for T786C/G984T/4b/a). For the eNOS-T786C, C allele showed a weak association between C allele and DN risk in DN/T2DM group. For eNOS-G894T, there was an association between T allele and DN risk in the global, Asian and African population in DN/T2DM group. For the eNOS-4b/4a, 4a allele was found contributing significantly to increased DN risk in the global population. Conclusion: Our comprehensive meta-analysis suggests that three polymorphisms of eNOS may be the increased risk factors of DN development, especially in Asian population and T2DM group.     

A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans

Background. Four linkage analyses have identified a region onchromosome 18q22-23 that appears to harbour a diabetic nephropathy(DN) susceptibility locus. A trinucleotide repeat sequence inexon 2 of the carnosinase gene (CNDP1) residing on 18q22.3 wassubsequently associated with DN in European Caucasians and Arabs. Methods. We evaluated the role of the CNDP1 5 leucine/5 leucine(5-5) polymorphism (CNDP1 Mannheim) in diabetic end-stage renaldisease (ESRD) susceptibility in 858 European Americans: 294with type 2 DN-associated ESRD (DN-ESRD), 258 with diabetesmellitus (DM) lacking nephropathy and 306 healthy controls. Results. Subjects with DM lacking nephropathy were significantlymore likely to be homozygous for the 5-leucine repeat CNDP1genotype (5-5), compared with those with DN–ESRD (P =0.02). Healthy controls were also more likely to be homozygousfor the 5-5 genotype, compared with those with DN–ESRD(P = 0.008). No significant difference in 5-5 genotype frequencywas observed between healthy controls and DM cases without nephropathy(P = 0.74). Conclusion. European Americans homozygous for the 5-5 leucinerepeat polymorphism in the CNDP1 gene are at significantly reducedrisk for developing diabetic ESRD. This replicates the CNDP1gene association with DN that was initially detected in EuropeanCaucasians and in Arabs, and further demonstrates that the CNDP1gene and carnosine pathway appear to play a role in susceptibilityto DN.     

Endothelial nitric oxide synthase polymorphisms are associated with hypertension and cardiovascular disease in renal transplantation

Aim: Nitric oxide (NO), produced by the polymorphic endothelial nitric oxide synthase (NOS3), plays an important role in endothelial function. The aim was to determine the effect of NOS3 polymorphisms on hypertension and cardiovascular disease (CVD) in renal allograft recipients. Methods: Three polymorphisms of NOS3 were examined in 168 renal allograft recipients. A 27 base pair repeat sequence in intron 4 (NOS3 a/b), a single G→T substitution in exon 7 at nucleotide 894 and a T‐786C substitution in the promoter region were studied. Results: Significant differences in the frequencies of the 894T and ?786C alleles between allograft recipients and controls (n = 141) were demonstrated (894T: 40.5% vs 30.1%, P < 0.01; ?786C: 45.2% vs 34.4%, P < 0.01). There was a significant excess of both the 894T and ?786C alleles in hypertensive allograft recipients compared with normotensive allograft recipients and controls (894T: 41.7%, 35.7% and 30.1%, respectively, P < 0.025; ?786C: 47.4%, 37.1% and 34.4%, respectively, P < 0.01), and in allograft recipients with CVD compared with those without CVD and controls (894T: 47.2%, 38.6% and 30.1%, respectively, P < 0.025; ?786C: 54.2%, 42.8% and 34.4%, respectively, P < 0.01). Conclusion: The 894T and ?786C alleles of the NOS3 gene were significantly associated with both hypertension and CVD in renal allograft recipients.     

Expression of nitric oxide and inducible nitric oxide synthase in acute renal allograft rejection in the rat

BACKGROUND: Recent studies have shown that nitric oxide (NO) synthases, particularly inducible nitric oxide synthase (i-NOS), are induced in acute rejection episodes following heart, liver, pancreas and kidney allotransplantation. Furthermore, tissue and cellular injury has been demonstrated to be mediated by peroxynitrite (ONOO-), a metabolite of NO as well as a potent oxidant. However, a detailed relationship between NO, i-NOS and graft injury in transplantation remains elusive. METHODS: The present study used the following models of renal transplantation in rats: allografts (n = 5, Brown-Norway to Lewis [LEW] rats), isografts (n = 5, LEW to LEW) and allografts treated with aminoguanidine (AG), an i-NOS inhibitor (n = 5). Blood urea nitrogen (BUN), serum creatinine (SCr) and urinary and serum nitrosocompounds (NOx) were measured on days 2, 4 and 7 post-transplant. Western blot analysis of i-NOS protein expression and measurement of i-NOS activity were carried out in grafts harvested on Day 7, along with immunohistochemical and histopathological examinations. RESULTS: In the allograft group, both BUN and SCr levels increased markedly on Day 7, in parallel with a sharp increase in NOx. A band stained by anti-i-NOS antibody was detected at approximately 130 kDa, along with high levels of i-NOS activity and diffusely distributed i-NOS-positive cells (macrophages). Histologically, an acute rejection episode was confirmed (Grade 3 according to Banff classifications). In the AG group, reduced renal function and graft injury were significantly less severe than in the allograft group. CONCLUSIONS: In rat renal allograft acute rejection, markedly increased levels of serum NOx were observed, along with enhanced tissue i-NOS activity, together resulting in graft injury. AG administration suppressed the increase of serum NOx levels, with concomitant mitigation of tissue injury and renal function impairment.     

Endothelial nitric oxide synthase intron 4 polymorphism influences the progression of renal disease

BACKGROUND/AIM: Nitric oxide is a potent regulator of intrarenal hemodynamics and may influence the renal function. We investigated whether polymorphism of intron 4 of the endothelial constitutive nitric oxide synthase (ecNOS) gene is related to the progression of chronic renal failure. METHODS: Polymorphism of ecNOS intron 4 was studied in 1,005 hemodialysis patients (710 with nondiabetic nephropathy and 295 with diabetic nephropathy) and was compared with the findings in 189 healthy subjects. ecNOS genotypes were determined by the polymerase chain reaction, followed by agarose gel electrophoresis. RESULTS: The frequencies of ecNOS4a/a, ecNOS4a/b, and ecNOS4b/b genotypes were, respectively, 0% (0/189), 13.8% (26/189), and 86.2% (163/189) in the control group; 1.7% (12/710), 22.1% (157/710), and 76.2% (541/710) in the nondiabetic nephropathy group, and 1.0% (3/295), 22.7% (67/295), and 76.3% (225/295) in the diabetic nephropathy group. The frequency of ecNOS4a (ecNOSa/a and ecNOSa/b) was significantly higher in both the nondiabetic group and in the diabetic group than in the controls (p = 0.0025 and p = 0.0438, respectively). CONCLUSION: There was a significantly higher frequency of the a allele of intron 4 in both nondiabetic and diabetic hemodialysis patients, so the polymorphism of intron 4 of the ecNOS gene may have a wide influence on the progression of renal disease.     

Association of apolipoprotein E gene polymorphism with end-stage renal disease and hyperlipidemia in patients on long-term hemodialysis

Background: Cardiovascular diseases (CVDs) are the leading cause of death of patients with chronic renal failure. Apolipoprotein E (apoE) plays an important role in the homeostasis of cholesterol and triglycerides. Objective: We aimed to investigate the possible link(s) between apoE gene polymorphism, inflammation and lipoproteins in hemodialysis patients. Methods: We studied 109 end-stage renal disease (ESRD) patients and 97 controls. The serum lipids, apolipoproteins, lipoprotein particles, high-sensitivity C-reactive protein (hs-CRP) and total homocysteine (t-Hcy) levels and paraoxonase (PON) activity were determined in our patients. We also analyzed apoE gene polymorphism in the patients and controls. Results: The analysis of the apoE gene demonstrated a predominance of the e3 allele in both the patients and controls, followed by the e4 and then the e2 alleles. The analysis of the apoE genotype and allele frequencies showed significantly higher e4 allele and E3E4 genotype frequencies and decreased e3 allele and E3E3 genotype frequencies in the patients compared with the controls. The e2, e4 and E3E4 carriers within the ESRD patient population presented an atherogenic lipid profile. However, there were no significant variations in the serum PON activity and the hs-CRP and t-Hcy levels between individuals with different apoE polymorphisms. Conclusions: Our findings suggest an association between the e4 allele, E3E4 genotype and ESRD. The apoE polymorphism affects the serum lipoprotein levels, and the ESRD patients who are e4 and e2 allele carriers are more likely to present an atherogenic lipoprotein profile that may be a major factor associated with increased risk of CVD.     

Endothelial nitric oxide synthase gene intron 4 a/b VNTR polymorphism in children with APSGN

The role of endothelial nitric oxide synthase gene intron 4 a/b (eNOS4a/b) variable number of tandem repeats (VNTR) polymorphism in various renal diseases was investigated. We investigated whether the eNOS4a/b VNTR polymorphism is associated with susceptibility to acute poststreptococcal glomerulonephritis (APSGN) and its clinical features. Endothelial NOS4a/b VNTR polymorphism is determined by the polymerase chain reaction in 60 children with APSGN, and 66 healthy controls. The genotype distribution of eNOS4 does not differ between the patients and the controls (X²=5.1, p=0.079). However, the frequency of eNOS4a (eNOS4a/a and eNOS4a/b) genotype is higher in the patients than in the controls (X²=4.5, p=0.046). In the APSGN group we performed renal biopsy on eight patients because of nephrotic syndrome accompanies acute nephritic syndrome or glomerular filtration rate (GFR) is lower than 50% of normal, and found that to carry a/a and a/b genotypes were a significant risk factor for this type presentation (OR=17.3, 95% CI:1.95-152.67, p=0.03). Mean serum creatinine values are found statistically significantly higher in a/a and a/b genotypes when compared with b/b genotypes (p=0.022). Children carrying the “aa” and “ab” genotype or “a” allele of eNOS4 have a greater tendency to develop and clinical presentation of APSGN.     

Trends in the incidence of renal replacement therapy for end-stage renal disease in Europe, 1990-1999.

BACKGROUND: The epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) varies considerably worldwide, but we have lacked reliable quantitative estimates of trends in the incidence by age, sex and cause in Europe over the last decade. METHODS: We analysed data from nine countries participating in the ERA-EDTA registry: Austria, Belgium, Denmark, Finland, Greece, The Netherlands, Norway, Spain and UK (Scotland). Adjusted incidence rates for age and sex were studied for 2 year periods between 1990 and 1999. Average annual changes (%) were estimated by Poisson regression. RESULTS: The adjusted incidence rate of RRT increased from 79.4 per million population (pmp) (range: 58.4-101.0) in 1990-1991 to 117.1 pmp (91.6-144.8) in 1998-1999, i.e. 4.8% (3.1-6.4%) each year. This increase did not flatten out at the end of the decade, except in The Netherlands, and was greater in men than women, 5.2 vs 4.0%/year. In most countries, the incidence rate remained stable for those younger than 45 years; it rose by 2.2%/year on average in the 45-64 year age group and by 7.0% among those 65-74 years; it tripled over the decade in those 75 years or older, and by 1998-1999 it ranged from 140.9 to 540.4 pmp between countries. The incidence of ESRD due to diabetes, hypertension and renal vascular disease nearly doubled over 10 years; in 1998-1999, it varied between countries from 10.2 to 39.3 pmp for diabetes, from 5.8 to 21.0 for hypertension, and from 1.0 to 15.5 for renal vascular disease. CONCLUSION: RRT incidence continues to rise but at various rates in the European countries studied, tending to widen the gap between them. This mainly results from enlarging differences in incidence in the elderly and, to a lesser extent, in that due to diabetes, hypertension and renal vascular disease.     

Endothelial nitric oxide synthase expression in ischemia-reperfusion injury after living related-donor renal transplantation

Ischemia-reperfusion injury during renal transplantation has been linked to early graft dysfunction and late graft failure. Nitric oxide (NO), produced by NO synthase (NOS), participates in the recovery from ischemia. We correlated the intensity of graft immunoreactivity for the endothelial NOS isoform (eNOS) during early reperfusion with graft function in 25 children receiving grafts from related donors. Renal allograft biopsy specimens were obtained before transplantation, 1 h after renal artery reperfusion, and 1 year after transplantation. Immunohistochemical staining for eNOS occurred mainly within the endothelium of glomerular capillaries and peritubular capillaries as well as in tubule cells. The mean intensity score for eNOS staining (0-9) was 3.0+/-1.4 before transplantation, 4.5+/-1.9 at 1 h, and 3.3+/-1.9 at 1 year (baseline vs 1 h, P<0.05). Creatinine clearance (ml/min) in patients with a 1-h eNOS score of below 5 and of at least 5, respectively, was 77.1+/-28.4 vs 104.3+/-25.3 at 1 month, 78.7+/-33.4 vs 105.2+/-24.4 at 3 months, 64.7+/-30.1 vs 100.1+/-25.3 at 1 year, 58.2+/-31.3 vs 84.7+/-18.8 at 3 years, and 71.2+/-19.7 vs 78.3+/-23.1 at 5 years ( P<0.05 for 1 month, 1 year, and 3 years). We concluded that elevated eNOS expression after reperfusion in living related-donor renal transplantation enhances the recovery from renal ischemia and, consequently, reduces late graft deterioration.     

Angiotensin-converting enzyme polymorphism gene and evolution of nephropathy to end-stage renal disease

Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated in the pathogenesis of nephropathy and end-stage renal disease (ESRD). The association between angiotensin-converting enzyme (ACE) gene polymorphism and nephropathy evolution was studied. A random sample of 161 subjects from the Nephrology Department (of Hospital de Sant Pau) were divided into two groups: (i) 117 with end-stage renal disease; (ii) 44 with established nephropathy; and (iii) control groups of 129 subjects. The ACE gene polymorphism was performed by using polymerase chain reaction. High DD genotype presentation was observed in the two groups of subjects with nephropathy (46.12 and 61.37%, respectively vs 35.66% in controls; P < 0.0482), and also, a decrease was observed in the II genotype (6.4 and 4.54%, respectively vs 13.17% in controls, P < 0.0404). Glomerular filtration rate (GFR) was evaluated after 44 months of follow up. An important decrease of GFR was observed in patients with DD polymorphism versus other genotypes (initial, 32.3 +/- 7.9 and at 44 months, 18.35 +/- 3.3 mL/min vs 31.4 +/- 11.9 and 11.7 +/- 3.2 mL/min; P < 0.039). In a non-longitudinal study of patients in ESRD, patients with an ACE-DD genotype had a lower period of time between diagnosis of nephropathy and ESRD than patients with other genotypes (10.45 +/- 9.32 vs 19.5 +/- 8.4 years; P < 0.034). In conclusion, the ACE gene that controls RAS response may influence the development and progression of nephropathy to ESRD. Patients who develop several types of nephropathy have a higher risk of severe evolution if they have a profile of ACE-DD genotype.