Angiotensinogen gene variation and renoprotective efficacy of renin-angiotensin system blockade in IgA nephropathy

BACKGROUND: Blockade of the renin-angiotensin system (RAS) is well documented to be renoprotective; however, not all patients with glomerulonephritis respond well to this therapy. The interindividual variation in response to the RAS blockade may be in part genetically determined, whereas the results have been controversial. METHODS: We investigated whether the therapeutic efficacy of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blocker on renal prognosis is modified by the angiotensinogen gene (AGT) polymorphism in immunoglobulin A nephropathy (IgAN). In total, 259 patients with histologically proven IgAN were analyzed for clinical manifestations, renal survival, and their associations with AGT A(-20)C and M235T. RESULTS: The renal prognosis of 110 patients, who received ACE inhibitors/angiotensin receptor blocker during their clinical course, was significantly better than those without ACE inhibitors/angiotensin receptor blockers despite higher blood pressures and heavier proteinuria. The Cox proportional hazards regression model showed an increased hazard ratio (HR) for urinary protein (more than 1.0 g/day) of 3.346 (P = 0.0001), hypertension of 1.949 (P = 0.01), deteriorated renal function of 3.040 (P < 0.0001), no ACE inhibitor/angiotensin receptor blocker administration of 2.725 (P = 0.0004), and the T235 and C(-20) haplotype of 1.608 (P = 0.0322). Only in patients carrying at least one M235 and A(-20) haplotype did the administration of ACE inhibitors/angiotensin receptor blockers have no significant effect on the prognosis of renal function (Kaplan-Meier, log rank test, chi2 = 0.700; P = 0.4028), whereas it was significant in patients who had other haplotypes of AGT (chi2 = 11.805; P = 0.0006). CONCLUSION: This study provides evidence that the M235T and A(-20)C genotype of AGT can influence the therapeutic efficacy of a RAS blockade on the renal survival in IgAN.     

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.     

Cardiac hypertrophy and remodeling in relation to ACE and angiotensinogen genes genotypes in Chinese dialysis patients

BACKGROUND: Genetic polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes are associated with increased risk of hypertension and left ventricular hypertrophy (LVH) in hypertensive subjects. However, the extent to which these polymorphisms are related to LVH and remodeling in dialysis patients remains unknown. METHODS: Two hundred and forty-six end-stage renal disease (ESRD) patients on peritoneal dialysis and 183 control subjects, all of Chinese origin, were genotyped for the ACE insertion/deletion (I/D) and the AGT M235T gene polymorphisms. Left ventricular mass index (LVMi) and relative wall thickness were measured using echocardiography. RESULTS: Prevalence of ACE DD and AGT TT genotype was 14% and 83%, respectively, in ESRD patients and did not differ significantly from controls. A total percentage of 95% of our patients had LVH (171 with concentric and 63 with eccentric hypertrophy). Adjusting for age, gender, body mass index, duration of dialysis, diabetes, renal diagnosis, hematocrit, systolic and diastolic blood pressure, dialysis urea clearance, residual glomerular filtration rate, and use of converting enzyme inhibitors or angiotensin receptor blockers, AGT TT genotype remained independently associated with greater LVMi (coefficient = 28.73; 95% CI, 5.72 to 51.75; P = 0.015) and relative wall thickness (coefficient = 0.072; 95% CI, 0.022 to 0.122; P = 0.005) than MT/MM genotypes. LVMi and relative wall thickness did not differ significantly among patients with DD, DI, and II genotypes. No statistical significant interaction was noted between ACE and AGT gene polymorphism in relation to LVMi and relative wall thickness. CONCLUSION: Polymorphism of the AGT M235T gene but not ACE I/D gene is associated with greater LVMi and relative wall thickness, indicating more concentric LVH, in Chinese peritoneal dialysis patients. Possible synergistic effects between AGT and ACE gene polymorphism require further evaluation in a larger population.     

Megsin 2093T-2180C haplotype at the 3' untranslated region is associated with poor renal survival in Korean IgA nephropathy patients

AIMS: Megsin is a mesangial cell-predominant gene which belongs to the serpin superfamily. The expression of megsin was upregulated and coincided with mesangial proliferation and extracellular matrix expansion in IgA nephropathy (IgAN). In the present study, we evaluated the influence of the C2093T and C2180T polymorphism within the 3' untranslated region (3'UTR) of megsin gene and its haplotypes on the development and progression of Korean IgAN patients. METHODS: Korean IgAN patients (n = 260) with a minimal follow-up of 4 years were recruited. Healthy subjects with normal renal function, normal urinalysis and normotension (n = 315) were included as controls. The polymorphisms were determined by the 5' nuclease allelic discrimination assay, and the haplotypes were constructed using the Phase program. RESULTS: The C2093T and C2180T genotype and allele frequencies were not different significantly between IgAN patients and controls. In C2093T polymorphism, patients with CC genotype showed a better renal survival than those with CT or TT genotypes by Kaplan-Meier analysis (p = 0.027). The megsin C2093T polymorphism remained an independent risk factor for progression (Cox regression model, HR for TT genotype: 3.52, 95% CI 1.69 - 7.34; HR for CT genotype: 2.15, 95% CI 1.30 - 3.57). In C2180T polymorphism, patients with TT genotype showed a better outcome than those with CC or CT genotypes (p = 0.025). The C2180T polymorphism was also an independent risk factor for progression (HR for CC genotype: 4.05, 95% CI 1.93 - 8.51; HR for CT genotype: 2.35, 95% CI 1.40 - 3.94). The two alleles showed linkage disequilibrium in phased haplotype. The patients with 2093T-2180C haplotype showed a poor renal survival compared to those with 2093C-2180T haplotype (p = 0.028). The haplotype remained an independent risk factor for progression (HR for 2093T-2180C haplotype: 2.01, 95% CI 1.44 - 2.81). CONCLUSIONS: Our results suggest that the 2093T-2180C haplotype at the 3'UTR of megsin gene is associated with rapid disease progression in Korean IgAN patients. This is the reverse of the results from the Chinese IgAN patients. Further studies are strongly needed to elucidate the reasons of disparity.     

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.     

Clinicopathological and prognostic analysis of IgA nephropathy patients with anemia

Objective To analyze the clinicopathological features of IgA nephropathy (IgAN) patients with anemia and the influencing factors of prognosis. Methods The clinical and pathological data of patients diagnosed with primary IgAN at the First Affiliated Hospital of Fujian Medical University from January 1, 2006 to December 31, 2016 were retrospectively analyzed. The patients were divided into anemia group and non-anemia group according to whether the patient was anemia or not. The clinical and pathological data of the two groups were collected. All of them were followed up from the date of renal biopsy to January 1, 2018. Survival curves of the two groups were drawn by Kaplan-Meier method, and compared by Log-rank test. Multivariate Cox proportional hazards regression model was adopted to explore the influencing factors of prognosis in IgAN patients. Results A total of 231 subjects were enrolled, including 122 males (52.8%), and the male-female ratio was 1.12∶1. Their age was (34.8±10.1) years (15-68 years). There were 70 patients (30.3%) in anemia group, 161 cases (69.7%) in non-anemic group. Compared with non-anemia group, anemia group had higher proportion of females, lower serum albumin, higher proportion of tubular atrophy/interstitial fibrosis (T1/2), endothelial cell proliferation (E1) and crescent formation (C1/2), which were statistically significant (all P＜0.05). The patients had a median follow-up time as 6.3 years (0.3-12.9 years). Survival analysis showed that patients in anemia group had lower cumulative renal survival rate than that in non-anemia group ( χ2=15.234, P＜0.001). Multivariate Cox hazards regression analysis revealed that anemia (HR=3.820, 95%CI 1.674-8.719, P=0.001), tubular atrophy/interstitial fibrosis (T1/2) (HR=3.770, 95%CI 1.026-13.852, P=0.046), glomerular segmental sclerosis/adhesion (S1) (HR=4.211, 95%CI 1.139-15.576, P=0.031), hypertension (HR=2.988, 95%CI 1.276-6.999, P=0.012), increased 24 h urinary protein (HR=1.103, 95%CI 1.046-1.163, P＜0.001) and estimated glomerular filtration (eGFR)＜60 ml?min-1?(1.73 m2)-1 (HR=3.725, 95%CI 1.639-8.462, P=0.002) were the independent risk factors for poor renal prognosis in patients with IgAN. Conclusions The clinicopathological features of IgAN patients with anemia are relatively serious, and the renal cumulative survival rate is lower. Anemia, tubular atrophy/interstitial fibrosis (T1/2), glomerular segmental sclerosis/adhesion (S1), hypertension, increased urinary protein and eGFR＜60 ml?min-1?(1.73 m2)-1 are the independent risk factors for poor renal prognosis in patients with IgAN.     

G protein beta3 subunit C825T polymorphism in primary IgA nephropathy

BACKGROUND: The T allele of the G protein beta3 subunit (GNB3) C825T polymorphism has been associated with increased signal transduction, increased activity of the kidney Na+/H+ exchanger, and also with late-onset essential hypertension. Hypertension is a strong independent risk factor for progression in IgA nephropathy (IgAN). METHODS: We have studied this polymorphism in a regularly followed cohort of 299 biopsy-proven incident cases of IgAN, collected from 1989 to 1999 [208 males (70%)] and compared the genotypes and alleles distributions to 303 local Caucasian controls matched for the male predominance (214 males). The technique used was a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) with BseDI as restriction enzyme and specific primers, followed by gel electrophoresis. RESULTS: The TT, CT, and CC genotype frequencies were 13.7%, 45.8%, and 40.5% in IgAN, respectively, versus 7.6%, 47.2%, and 45.2% in controls, respectively (chi(2)= 6.16; P= 0.05). The excess of TT patients versus non-TT was significant in IgAN versus controls (chi(2)= 5.94; P= 0.015). The T allele frequency was 0.366 in IgAN versus 0.312 in controls (chi(2)= 3.97; P= 0.05). This data indicated that this polymorphism had a significant but mild influence on the occurrence/initiation of IgAN (RR = 1.81; 95% CI 1.07-3.07). In contrast, we could not demonstrate any significant and sustained difference in the clinical presentation and evolution of the homozygous TT patients compared to non-TT patients (CC + CT) despite a mean and median follow-up about 10 years. The progression to arterial hypertension or to chronic renal failure or to end-stage renal failure (ESRF) was not significantly different. In addition, multivariate Cox regression analysis excluded a significant independent role of C825T polymorphism on progression. CONCLUSION: The C825T GNB3 polymorphism had a mild influence on occurrence/initiation of IgAN, but played no significant role in the progression of the disease.     

The efficacy of tonsillectomy on long-term renal survival in patients with IgA nephropathy

BACKGROUND: Little information has been available until now about the clinical efficacy of tonsillectomy on long-term renal survival of patients with idiopathic immunoglobulin A nephropathy (IgAN). METHODS: To investigate the effect of tonsillectomy on long-term renal survival, we reviewed the clinical course of 118 patients with idiopathic biopsy-diagnosed IgAN from 1973 to 1980. Of those, 48 patients received tonsillectomy and 70 patients did not. The starting point of observation was defined as the time of the diagnostic renal biopsy, and the end point as when requiring the first dialysis. Up to 2001, the mean observation time was 192.9 +/- 74.8 months (48-326 months). Renal survival and impact of covariates were evaluated by Kaplan-Meier analysis and Cox proportional hazards regression model. RESULTS: Age, gender, amount of urinary protein excretion, serum creatinine, serum IgA, blood pressure, and histopathologic findings at the time of renal biopsy and treatments during the observation period were not significantly different between patients with and without tonsillectomy. Five (10.4%) of the patients with tonsillectomy and 18 (25.7%) of the patients without tonsillectomy finally required dialysis therapy (chi-square test, P = 0.0393). By Kaplan-Meier analysis, renal survival rates were 89.6% and 63.7% at 240 months in the patients with and without tonsillectomy, respectively, and were significantly different (log-rank test, P = 0.0329). In the multivariate Cox regression model, tonsillectomy (hazard ratio, 0.22; 95% CI, 0.06 to 0.76; P = 0.0164) had a significant effect on renal outcome. CONCLUSION: These results indicate that tonsillectomy has a favorable effect on long-term renal survival in patients with IgAN.     

Genetic polymorphisms of the renin-angiotensin system and complications of insulin-dependent diabetes mellitus.

OBJECTIVE: Patients with insulin-dependent diabetes mellitus (IDDM) have a high risk of developing diabetic nephropathy, retinopathy and cardiovascular diseases. The contribution of gene polymorphisms of the renin angiotensin system to these complications is controversial and may differ among populations. METHODS: In 257 Dutch IDDM patients (188 with urinary albumin excretion (UAE) <30 mg/24 h), logistic regression analysis was used to study the relationships among, on the one hand, the insertion/deletion gene polymorphism of the angiotensin-converting enzyme gene (ACE-ID), the M235T gene polymorphism of the angiotensinogen gene (AGT-M235T), and the A1166C gene polymorphism of the angiotensin type 1 receptor gene (AT1-A1166C), and, on the other hand, UAE, retinopathy, hypertension, and coronary heart disease. RESULTS: The T-allele of the AGT-M235T polymorphism was associated with an increased risk of an elevated UAE (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.06-8.61), but only when interaction with the D-allele of the ACE-ID polymorphism was considered. A previously described positive interaction between the T-allele of the AGT-M235T polymorphism and the D-allele of the ACE-ID polymorphism could not be confirmed. The T-allele was also associated with an increased risk of retinopathy (OR 3.89, 95% CI 1.79-8.47). The CC-genotype of the AT1-A1166C polymorphism was associated with hypertension (OR 3.58; 95% CI 1. 23-10.37). CONCLUSIONS: In a Dutch IDDM population, including 69 patients with (incipient) diabetic nephropathy, the T-allele of the AGT-M235T polymorphism is associated with an elevated UAE and diabetic retinopathy and the CC-genotype of the AT1-A1166C polymorphism is associated with hypertension. A previously described interaction between the AGT-M235T and the ACE-ID polymorphisms could not be confirmed. Since the number of nephropathic patients in this study is small, these conclusions must be interpreted with caution.     

Interaction between gene polymorphisms of nitric oxide synthase and renin-angiotensin system in the progression of membranous glomerulonephritis.

BACKGROUND: The renin-angiotensin system (RAS) and nitric oxide synthase (NOS) play a key role in the progression of primary glomerulonephritis (GN). Although previous studies have examined genetic risk associated with single gene variations, experiments assessing risk conferred by multiple gene variations are still scanty. METHODS: The effect of combination of variant alleles of four genes encoding for three components of the RAS [angiotensin converting enzyme insertion/deletion (ACE I/D), angiotensin II receptor 1 (AT1R 1166A/C), angiotensinogen (AGT M235T)] and for NOS (ecNOS4b/a) on the development and progression of membranous GN (MGN) were evaluated in a longitudinal study comparing 117 patients with serum creatinine (s-Cr) <1.5 mg/dl at renal biopsy and follow-up > or = 5 years (Kaplan-Meier and Cox multivariate analysis). The control group consisted of DNA from 171 organ donors. RESULTS: We found no relationship between single or combined variations of the four gene polymorphisms and development of MGN. Among single gene variations, there were no independent genetic risk factors for the progression of renal disease, after adjustment for age, sex, hypertension, proteinuria, s-Cr, chronicity and activity index. However, double variation coincidences such as the combination of the allele a of ecNOS4b/a and both the allele D of ACE I/D (chi(2) =4.80, P = 0.028; HR = 1.97, 95% CI 0.98-3.96) and the allele T of AGT (M235T) (chi(2) = 5.09, P = 0.024; HR = 2.84, 95% CI 1.39-5.82) exerted an additional effect that was higher than that of the single gene variations. CONCLUSION: This study is the first to demonstrate a role for an interaction between simultaneous variations of genes encoding for NOS and components of RAS in the progression of MGN. Interactions between various polymorphisms may explain conflicting results obtained in previous studies that examined single gene variations, since the effect of a single locus variation may be influenced by the simultaneous presence of other variant alleles in polygenic diseases such as primary GN. However, the small sample sizes and possible multiple interactions limited the interpretation of the current findings, which may represent true biological interaction or simply statistical interactions or spurious results due to the small sample sizes.     

Association of angiotensinogen gene M235T polymorphism with the risk of IgA nephropathy: a meta-analysis

The association between angiotensinogen (AGT) M235T gene polymorphism and IgA nephropathy (IgAN) risk remains elusive. Our aim was to evaluate the association between AGT M235T gene polymorphism and IgAN susceptibility by performing a meta-analysis. Eligible studies were searched according to predefined criteria using electronic databases. Eight studies were identified for the analysis of the association between AGT M235T gene polymorphism and IgAN risk. M allele/MM genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p?=?0.448 and 0.861, Caucasians: p?=?0.618 and 0.886, Asians: p?=?0.566 and 0.652). TT/MT genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p?=?0.703 and 0.454, Caucasians: p?=?0.975 and 0.946, Asians: p?=?0.697 and 0.353). No evidence of publication bias was observed. In conclusion, AGT M235T gene polymorphism may not be correlated with IgAN susceptibility in overall populations, Caucasians and Asians. However, more studies should be performed in the future.     

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.     

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 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.     

Recipient RAS gene variants and renal allograft function

BACKGROUND: Genetic variants of the renin-angiotensin system (RAS) have been implicated in the progression of native kidney diseases. A decreased long-term renal allograft function has also been associated with increased activity of RAS, which may be genetically determined. METHODS: The effect of the angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin type 1 receptor (AGT1R), and aldosterone synthase (CYP11B2) genotypes on renal function was investigated in 223 first-allograft recipients. Graft function was estimated by yearly determinations of serum creatinine. Genotyping was performed for the M235T-AGT, the I/D-ACE, the A1166C-AGT1R, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction. RESULTS: The percentage of patients with preserved stable graft function up to 15 years after transplantation was higher when mean blood pressure was <97 mmHg, than when it was >117 mmHg (60 vs. 25% of patients). The CYP11B2 genotype predicted long-term stable graft function with more patients suffering from worsening renal function with the CYP11B2 TT than the CC genotype (P=0.002). There was a weak association between the AGT1R genotype (P=0.037), but not the AGT or ACE genotypes, and a preserved long-term graft function. Cox proportional hazards estimation showed no interactions between the observed effect of CYP11B2 genotype on renal function over time and the number of HLA class I and II matches, other RAS genotypes, graft function, or mean blood pressure at 1 year after transplantation. CONCLUSIONS: The rate of decline in renal allograft function is strongly associated with the CYP11B2 but not AGT, ACE, or AGT1R genotypes. This finding suggests that certain genetic factors related to the RAS are important determinants of long-term renal allograft function.     

Angiotensinogen M235T genotype predicts progression in chronic renal allograft dysfunction

BACKGROUND: Genotypes of the renin-angiotensin system have been implicated in essential hypertension and in progression of native kidney diseases, but gene effects on progression in chronic renal allograft dysfunction are unclear. METHODS: To examine gene effects on long-term renal allograft function, we conducted a prospective cohort study of 210 nondiabetic renal allograft recipients younger than 36 years of age who underwent transplantation between 1980 and 1993 and were followed up through 1999. All grafts survived more than 1 year and all subjects received cyclosporine-based immunosuppression. DNA was analyzed by polymerase chain reaction for the angiotensin-converting enzyme insertion/deletion and angiotensinogen (AGT) M235T polymorphisms. Linear regression multivariate modeling of the slope of the inverse creatinine-versus-time, survival analyses for time-to-sustained doubling of baseline serum creatinine, time-to-graft loss, and a composite endpoint including patient death were performed. RESULTS: Mean follow-up time was 8.4+/-3 years. Genotype frequencies for each marker system did not deviate significantly from the Hardy-Weinberg equilibrium. The slope of the inverse creatinine-versus-time for AGT 235T/T and M/T was significantly increased compared with M/M ( <0.0001). The AGT 235T/T genotype was also associated with a shorter time-to-sustained doubling of serum creatinine ( =0.001). When subjects were divided into quartiles based on slope magnitude, the frequency of the AGT 235T/T genotype was overrepresented in the fastest progressing group compared with the slowest ( =0.001). The AGT 235T/T genotype was also associated with shorter time-to-graft loss ( =0.007) and the composite endpoint ( =0.001). CONCLUSION: The AGT 235 T allele independently influences long-term decline in renal allograft function.     

血浆凝血因子VIII水平与IgA肾病患者临床病理改变及预后的关系

目的探讨血浆凝血因子VIII(factor VIII,FVIII)水平与IgA肾病(IgAN)患者临床参数及预后的关系。方法收集2016年1月至2016年12月中南大学湘雅二医院确诊的IgAN患者的临床资料。按照时间依赖的受试者工作特征曲线(ROC)得出的血浆FVIII预测IgAN预后的临界值,将患者分为高FVIII组(FVIII>140.50%)和低FVIII组(FVIII≤140.50%),比较两组患者肾活检时基线临床参数的差异。以估算肾小球滤过率(eGFR)下降≥30%或进入终末期肾脏病(ESRD)为终点事件,采用Kaplan-Meier生存曲线及Cox回归方程法分析血浆FVIII水平对IgAN患者预后的影响。结果共93例IgAN患者纳入本研究,中位随访时间为35.15(33.77,36.76)个月,12例(12.90%)患者发生终点事件。高FVIII组患者年龄、血肌酐、尿素氮、血三酰甘油、血总胆固醇、血浆纤维蛋白原、D-二聚体、24 h尿蛋白量、蛋白C、蛋白S和eGFR下降速率高于低FVIII组(均P<0.05);eGFR、血白蛋白、中位随访时间低于低FVIII组(均P<0.05)。Kaplan-Meier生存分析结果显示,与低FVIII组比较,高FVIII组患者肾脏累积生存率降低(χ2=5.635,P=0.018)。在校正收缩压、eGFR、尿蛋白、肾小管萎缩/间质纤维化程度等因素后,多因素Cox回归分析结果显示,高血浆FVIII水平是IgAN患者肾脏预后不良的独立危险因素(HR=4.147,95%CI 1.055~16.308,P=0.042)。结论血浆FVIII水平与IgAN患者临床指标及预后相关,高血浆FVIII水平是IgAN患者肾脏预后不良的独立危险因素。     

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.     

Gene polymorphisms contributing to hypertension in immunoglobulin A nephropathy

Background

Hypertension, which is affected by genetic and environmental factors, is one of the major risk factors for chronic kidney disease. Identification of the genetic factor contributing to hypertension in patients with chronic kidney disease may potentially refine a therapeutic strategy.

Methods

In the present multicenter cross-sectional study, 240 patients were eligible (aged 15?C50?years with urinary protein ??0.25?g/day) out of 429 patients who were diagnosed as having immunoglobulin (Ig) A nephropathy (IgAN) by renal biopsy between 1990 and 2005 and enrolled in our previous study, PREDICT-IgAN. The outcome was hypertension defined as ??140 and/or ??90?mmHg of systolic and diastolic blood pressure and/or use of antihypertensives at renal biopsy. We assessed associations between hypertension and 28 polymorphisms with the frequency of minor genotype ??10% among 100 atherosclerosis-related polymorphisms using the Chi-squared test in dominant and recessive models. We identified polymorphisms associated with hypertension in multivariate logistic regression models.

Results

Baseline characteristics: hypertension 36.3%. Among 28 polymorphisms, the Chi-squared test revealed that CD14 (-159CC vs CT/TT, P?=?0.03) and ACE (DD vs DI/II, P?=?0.03) were significantly associated with hypertension after Bonferroni correction. Multivariate logistic regression models revealed that CD14 -159CC [vs CT/TT, odds ratio (OR) 3.58 (95% confidence interval (CI) 1.66?C7.63)] and ACE DD [vs DI/II, OR 4.41 (95% CI 1.80?C10.8), P?=?0.001] were independently associated with hypertension.

Conclusions

CD14 C-159T and ACE I/D contributed to hypertension in patients with IgAN.