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.     

Association of MEGSIN 2093C-2180T haplotype at the 3' untranslated region with disease severity and progression of IgA nephropathy.

BACKGROUND: MEGSIN is a gene predominantly expressed in the renal mesangium, and is upregulated in IgA nephropathy (IgAN). Our previous study has shown that the 2093C and 2180T alleles at the 3' untranslated region (3'UTR) of the gene are associated with susceptibility to IgAN, but the relationships of these genetic variants with the clinical manifestations and renal histological lesions of IgAN have not been examined previously. METHODS: 302 IgAN patients followed up for 52.8+/-22.5 months were investigated. Haplotypes at the 3'UTR were constructed using the 2093C/T and 2180C/T alleles. The genotype-phenotype relationship was studied by correlations of haplotypes and the clinical data and renal histopathological changes. RESULTS: The 2093C-2180T haplotype was present more often in patients with disease that progressed more rapidly (chi2((C-T/others)) = 8.429, P = 0.004), and was also correlated with hypertension (chi2((C-T/others)) = 6.459, P = 0.012), severe proteinuria (>or=2 g/d) (chi2((C-T/others)) = 6.332, P = 0.013), and Lee's class IV and V histological changes (chi2((C-T/others)) = 9.640, P = 0.008). CONCLUSION: In this Chinese population, the 2093C-2180T haplotype at the 3'UTR of MEGSIN gene is associated with more severe forms of IgAN, and more rapid disease progression. This provides further evidence for the involvement of genetic variations of MEGSIN in the pathogenesis of IgAN.     

Association of Megsin 2093C/T, 2180C/T and C25663G gene polymorphism with the risk of IgA nephropathy

The association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgA nephropathy (IgAN) risk remains unclear. We aimed to evaluate the association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgAN risk by performing a meta-analysis. Eligible studies were searched according to predefined criteria by using electronic databases. Six articles were identified for the analysis of the association between megsin 2093C/T, 2180C/T and C25663G gene polymorphisms and IgAN risk. 2093C/T C allele was associated with IgAN risk in overall populations and Asians (overall populations: p?=?0.014, Asians: p?=?0.037). 2093C/T CC/TT genotype was not associated with IgAN risk in overall populations, Caucasians and Asians. 2180C/T C allele was correlated with IgAN risk in Caucasians (p?=?0.024). 2180C/T CC/TT genotype was not associated with IgAN risk in overall populations, Caucasians and Asians. C25663G gene polymorphism was not associated with IgAN onset in Asians. In conclusion, megsin 2093C/T C allele may be genetic marker for IgAN susceptibility in overall populations and Asians. 2180C/T C allele may be risk factor for IgAN onset in Caucasians. However, more studies should be performed in the future.     

A family-based association study of megsin A23167G polymorphism with susceptibility and progression of IgA nephropathy in a Chinese population

AIMS: To investigate the association of megsin A23167G polymorphism with susceptibility and progression of IgA nephropathy in Chinese population. METHODS: 435 IgA nephropathy patients and their family members were recruited for a family-based association study. Genotypes of megsin A23167G were determined by direct sequencing. The results were analyzed by transmission disequilibrium test (TDT) and haplotype relative risk (HRR). Clinical data and histological scores of renal lesions were compared between patients with different genotypes. According to disease stability, IgA nephropathy patients were divided into progressive group and stable group. The distribution of genotype frequencies were compared between the 2 groups. RESULTS: TDT revealed that megsin 23167G alleles were transmitted more frequently from heterozygous parents to patients than expected (classical TDT: chi2 = 5.435, p = 0.020, extended TDT: chi2 = 5.017, p = 0.025). HRR analyses showed significant differences between transmitted and nontransmitted allele frequencies (chi2 = 7.006, p = 0.008, HRR = 1.762). The scores of glomerular index and glomerular sclerosis index were higher in GG genotype patients than those in other genotypes (F = 4.570, p = 0.033, F = 4.324, p = 0.038, respectively). The distribution frequency of GG genotype in the progressive group was higher than that of the stable group (chi2 = 4.370, p = 0.037). No statistical difference was found in tubulo-interstitial index, vascular index and clinical characteristics between the 2 groups. CONCLUSION: The polymorphism of megsin A23167G is associated with susceptibility and progression of IgA nephropathy in Chinese population. GG genotype is associated with severe histological lesions and progression of the disease.     

Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy

IgA nephropathy (IgAN) is a polygenic disorder and the precise role of genetic factors remains elusive. Increasing evidences have implicated the aberrant galactosylation of IgA1 molecules in the pathogenesis of IgAN. The galactosyltransferase, core 1 beta3-Gal-T, and its chaperone, Cosmc, play important roles in beta1,3 glycosylation of IgA1 molecule. A case-control association study was performed to investigate the association between single-nucleotide polymorphisms (SNPs) of C1GALT1 and C1GALT1C1 genes and the susceptibility to IgAN. A total of 1164 subjects were enrolled, including 670 IgAN patients and 494 geographically matched healthy controls. Five SNPs, -734C/T, -465A/G, -330G/T, -292C/-, and 1365G/A in C1GALT1 were selected as tagging SNPs. The D allele and DD genotype of -292C/- in IgAN patients were significantly lower than in the controls (P<0.01). The frequency of haplotype YATIG (Y=C or T) was significantly lower in patients than in controls (0.0719 vs 0.1168, P=2.775 x 10(-4), odds ratio (OR)=0.70). The haplotype YAGDA (0.1236 vs 0.0791, P=3.815 x 10(-3), OR=1.77) and YATDG (0.0840 vs 0.0298, P=1.258 x 10(-5), OR=3.03) were significantly higher in patients than in controls. The present study suggested that the polymorphisms of C1GALT1 gene were associated with the genetic susceptibility to IgAN in Chinese population.     

Polymorphism of the cytokine genes and IgA nephropathy

BACKGROUND: IgA nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Cytokine gene polymorphisms regulate cytokine production and play a role in immune and inflammatory responses; these immunological responses thus are possibly involved in the etiology and pathogenesis of IgAN. METHODS: We studied by polymerase chain reaction (PCR) polymorphisms of important cytokine genes of inflammation interleukin-1 (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) in 167 patients with IgAN and 400 healthy blood donor controls. IgAN patients had been followed up for 6 to 17 (median 11) years from renal biopsy. RESULTS: Carriage of the IL-1beta allele 2 (IL1beta2) or IL-1Ra allele 2 (IL1RN*2) was associated with an increased risk of IgAN. These alleles were highly linked and the odds ratio (OR) of IgAN for carriage of both alleles was 1.8 (95% confidence interval 1.2 to 2.6; P = 0.002). Carriage of the TNF-alpha allele 2 (TNF2) was associated with a decreased risk of IgAN (OR 0.5, range 0.3 to 0.7; P = 0.001). The risk of IgAN was found to be highest in those carrying IL1beta2 and IL1RN*2 but not TNF2 as compared to those who did not carry both of these IL-1 cluster genes and were carriers of TNF2 (OR 5.0 (2.4-10.3); P < 0.001). None of the polymorphisms studied was associated with poor prognosis. CONCLUSION: Carriage of IL1beta2 and IL1RN*2 together with non-carriage of TNF2 is associated with increased susceptibility, but not with a prognosis of IgAN.     

Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function.

BACKGROUND: Inflammation is implicated in cardiovascular disease (CVD) and mortality in end-stage renal failure (ESRF). Its importance in early renal disease is yet to be defined. METHODS: Serum levels of systemic and vascular inflammatory markers in early IgA nephropathy (IgAN) and control subjects were measured and related to renal function and vascular risk factors. A parallel study in type 1 diabetes mellitus subjects with (T1DM Nx) and without nephropathy (T1DM No Nx) was performed. RESULTS: Fifty-one IgAN patients aged 46+/-2 years (mean+/-SEM), calculated creatinine clearance (CrCl) 88+/-5 ml/min, were compared with 51 matched control subjects. Forty-six T1DM Nx patients aged 40+/-2 years, CrCl 84+/-5 ml/min, and 73 T1DM No Nx patients aged 38+/-2 years were also compared. High sensitivity C-reactive protein (hsCRP) was elevated in IgAN, T1DM Nx and T1DM No Nx patients compared with controls [4.2+/-0.6 (P < 0.001), 4.1+/-0.6 (P < 0.001), 2.6+/-0.4 (P < 0.05) vs 1.6+/-0.3 mg/l]. Levels in T1DM Nx patients were higher than in T1DM No Nx patients (P < 0.05). Inflammation and vascular dysfunction as measured by pulse pressure (PP) were related. HsCRP correlated with PP in IgAN and T1DM Nx (r = 0.47, P = 0.001; r = 0.40, P < 0.05). PP was the strongest independent predictor of hsCRP in IgAN (T = 2.45, P < 0.001), while body mass index (T = 7.83, P < 0.001) was the strongest predictor in T1DM Nx. Endothelial cell adhesion molecules were increased in T1DM Nx > IgAN > T1DM No Nx vs controls: soluble vascular adhesion molecule-1 (sVCAM-1) 760+/-30 (P < 0.001) > 663+/-34 (P = 0.001) > 601+/-21 (P < 0.05) vs 536+/-15 ng/ml; soluble intracellular adhesion molecule-1 (sICAM-1) 320+/-8 (P < 0.001) > 313+/-13 (P < 0.001) > 307+/-8 (P < 0.001) vs 244+/-6 ng/ml. sVCAM-1 levels were higher in T1DM Nx than in T1DM No Nx, P < 0.001. In IgAN and T1DM Nx, hsCRP correlated with sICAM-1 (r = 0.33, P = 0.017; r = 0.37; P = 0.017). sVCAM-1 was related to renal function in IgAN and T1DM Nx: serum cystatin C (r = 0.63, P < 0.001: r = 0.425, P = 0.002), and urine protein:creatinine ratio in IgAN (r = 0.48; P = 0.001). CONCLUSIONS: Systemic and vascular markers of inflammation are increased in early renal disease and relate to renal dysfunction and cardiovascular risk factors. Inflammation may be a common process in various renal diseases and may link and accelerate renal dysfunction and CVD.     

The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians.

The frequencies of the MHC class II HLA-DR and DQ alleles in 36 Caucasian patients with IgA nephropathy (IgAN) were analyzed by RFLP analysis and allele specific oligonucleotide (ASO) probing of specifically amplified genomic DNA. The class II alleles HLA-DR4 (52.7%) and DR5 (30.5%) were increased in the patient group compared to 1103 UK Caucasoid controls, but these increases were not statistically significant. However, there was a significant increase in the HLA-DQw7 allele frequency (71%) (c = 27.8%, chi 2 = 29.2, P less than 0.001, Relative Risk = 6.17). This can be explained by linkage disequilibrium between the DQw7 allele at the DQB1 locus and DRB1 genes of some DR4 and all DR5 haplotypes. The polymorphic portion of the DQ alpha chains from DR4, DQw7 and DR5, DQw7 haplotypes differ but they have identical DQ beta chains. DNA encoding DQw7 allele at the DQB1 locus was sequenced in two patients and was identical to that previously published. We conclude that the DQw7 allele at the DQB1 locus is strongly associated with susceptibility to IgAN in Caucasians.     

HLA DQ region gene polymorphism associated with primary IgA nephropathy

IgA nephropathy (IgAN) has been associated with HLA-DR4. We have recently described two non-allelic Taq I DQ beta gene-associated fragments sized 2.0 kb (T2) and 6.0 kb (T6), which strongly associate with DR4. T2 represents a polymorphism of the DQ beta gene and has been redesignated DQw8 (10th International HLA Workshop). The origin of the T6 fragment has not been determined, but probably represents a polymorphism of either the DQ beta or DX beta gene. When present together T2 and T6 define a subgroup of DR4 subjects at high risk of developing autoimmune disease. We have, therefore, studied DQ beta gene polymorphisms in IgAN. The DR antigen distribution was similar in IgAN and normal controls. The T2+/T6+ phenotype was present in 49% patients with IgAN compared to 15% of controls [P less than 0.0001, chi 2 = 32.8, Cramer's V = 0.41; relative risk = 5.5 (range, 2.8-11.0)]. Seventy-two percent of DR4+ IgAN patients and 29% of DR4+ controls were T2+/T6+ (P = 0.007, chi 2 = 17.0). These findings confirm the hypothesis that disease susceptibility genes are important in IgAN, and suggest that the putative gene(s) are located within or near to the DQ subregion. Moreover, similar DQ beta gene associations have been found in IDDM and pemphigus vulgaris, pointing to a common immunogenetic mechanism predisposing to several autoimmune diseases.     

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.     

Methylenetetrahydrofolate reductase gene C677T polymorphism,plasma homocysteine and folate in end-stage renal disease dialysis and non-dialysis patients

BACKGROUND: It has been recently suggested that the presence of the methylenetetrahydrofolate reductase gene 677TT genotype is associated with younger age at initiation of dialysis, thus raising a hypothesis that younger renal patients carrying the TT genotype are at higher risk to develop end-stage renal disease. The aim of this study was to test the association between the C677T polymorphism and the presence of end-stage renal disease using a family-based study design. MATERIAL AND METHOD: C677T polymorphism was genotyped in a group of 247 family trios (offspring affected with end-stage renal disease, dialysed or conservatively treated, and both parents). Transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected offspring. RESULTS: The TDT analysis revealed no significant deviation in the transmission of the MTHFR C677T alleles to CRF patients (51 vs. 49% for the C allele and T allele transmission, respectively). We observed a significant relationship between MTHFR genotypes and total plasma homocysteine (tHcy), as well as folate concentration. Also, plasma tHcy and folate were negatively correlated. CONCLUSION: Our results did not show any association between the MTHFR reductase C677T polymorphism and the increased risk of the development of end-stage renal disease. Whether this polymorphism contributes to the faster rate of decline of renal function in renal patients, must be evaluated further.     

Immunoglobulin heavy chain switch region gene polymorphisms in glomerulonephritis

Much evidence suggests that primary IgA nephropathy (IgAN) and idiopathic membranous nephropathy (MN) are immune complex mediated diseases. Moreover, genetic factors may play an important role in their pathogenesis. Recently, restriction fragment length polymorphisms (RFLPs) of the immunoglobulin heavy chain genes have been described which appear to associate with glomerulonephritis. We have studied RFLPs of the switch region of the IgM (S mu) and IgA1 (S alpha 1) heavy chain in MN and IgAN. DNA obtained from British Caucasoids with IgAN (N = 75), MN (N = 43), and normal controls (N = 73), was digested with the restriction enzyme Sac1, and studied using Southern blot techniques and hybridization with a 32P labelled DNA probe homologous to S mu. This probe detects RFLPs at the S mu and S alpha 1 loci. The genotypic and allelic frequencies of the S mu and S alpha 1 alleles in IgAN and MN was similar to normal controls. Caucasoid subjects with IgAN from Northern and Southern Europe (Finland and Italy, respectively) were also studied to determine whether an ethnic variation in genetic susceptibility to IgAN exists. The frequency of the S mu and S alpha 1 alleles was similar between the patient groups and their respective local healthy controls. These results do not support the recent findings of an association with RFLPs of the S mu and S alpha 1 loci in IgAN and MN, and suggest that the immunoglobulin heavy chain switch region genes are not important in conferring disease susceptibility to IgAN or MN.     

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.     

IgA synthesis by lymphocytes from patients with IgA nephropathy and their relatives

To investigate the hypothesis that a predisposition to IgA nephropathy (IgAN) is linked to the major histocompatibility complex (MHC) and associated with poorly regulated IgA synthesis, we performed HLA typing and lymphocyte cultures on patients with IgAN and their relatives. Nineteen of 22 patients had elevated culture supernatant IgA concentrations (620 vs. 154 ng/2 X 10(6) cells, P = 0.007). Supernatant IgG and IgM were normal. No HLA antigen occurred with increased frequency in patients. There was an increased incidence of homozygous null C4 alleles in patients (P less than 0.01). In families, six of 11 mothers, six of 12 fathers, and seven of 15 siblings had elevated supernatant IgA concentrations. There was no segregation of abnormal IgA production with any HLA antigen or parental haplotype. The data confirm elevated in vitro IgA production by lymphocytes from patients with IgAN, but do not support a linkage with the MHC. The increased incidence of homozygous null C4 alleles may result from functional differences in C4 A and B gene products. The familial clustering of elevated IgA production without an obvious inheritance pattern suggest that shared environmental factors may be important in the development of IgAN.     

Clinicopathological features and renal outcomes of IgA nephropathy with acute tubulointerstitial nephropathy

Objective To evaluate the clinicopathological characteristics and outcomes of IgA nephropathy (IgAN) with acute tubulointerstitial nephropathy (ATIN). Methods Patients who were diagnosed as IgAN with ATIN and IgAN without ATIN by renal biopsy in Peking University First Hospital were enrolled. There were 74 cases of IgAN with ATIN, and seventy-four cases of IgAN without ATIN were enrolled based on stratified sampling (chosen by 1∶1). The two groups were well matched with age, gender, follow-up time, mesangial hypercellularity(M), endocapillaryhypercellularity(E), segmental glomerulosclerosis(S), tubular atrophy/interstitial fibrosis(T) and cellular/fibrocellular crescent(C). The clinicopathological characteristics and outcomes of two groups were retrospectively analyzed. A composite end point, defined as 30% or 50% estimated glomerular filtration rate (eGFR) decline and end stage renal disease (ESRD) was used. Renal function and proteinuria during follow-up were observed. Renal survival was calculated by Kaplan-Meier survival analysis and risk factors of progression were analyzed by using univariate and multivariate Cox regression models. Results Seventy-four cases of IgAN with ATIN and seventy-four cases of IgAN without ATIN were enrolled. Serum creatinine [(185.6±83.2) μmol/L vs (146.3±69.2) μmol/L, P=0.010] and incidence of acute kidney disease (AKD) (31.1% vs 5.4%, P＜0.001) were higher in IgAN with ATIN group than those in IgAN without ATIN group. Patients in ATIN group received more immunosuppressive treatment (86.5% vs 58.1%, P＜0.001). During 1 year after biopsy, mean eGFR increased significantly in IgAN with ATIN group [(39.7±14.6) ml?min-1?(1.73 m2)-1 vs (47.2±19.9) ml?min-1?(1.73 m2)-1, P=0.017], but mean eGFR was not statistic different in IgAN without ATIN group [(60.0±30.5) ml?min-1?(1.73 m2)-1 vs (59.0±31.7) ml?min-1?(1.73 m2)-1, P=0.567]. Median follow-up was 23.0 months in IgAN with ATIN group, and Median follow-up was 30.0 months in IgAN without ATIN group. Incidence of composite end point had no significant differences between two groups. IgAN with ATIN was not the independent risk factor for end point. IgAN patients with ATIN were divided into two groups (with AKD and without AKD), then renal survival rate was higher (Log-rank test, χ2=5.293, P=0.021) and the risk for composite end point decreased by 79.2% (HR=0.208, 95%CI 0.046-0.939, P=0.041) in the group with AKD. Conclusions In IgAN, there is a subgroup of patients with the specific pathological phenotype combined with ATIN. Compared with those without AKD, the risk for composite end point of IgAN patients with ATIN and AKD showed a 79.2% decrease.     

Angiotensin I-converting enzyme gene insertion/deletion and angiotensinogen M235T polymorphisms: risk of chronic renal failure. End-Stage Renal Disease Study Group

BACKGROUND: Chronic renal failure (CRF) is a complex phenotype that results from an underlying kidney disease and superimposing environmental and genetic factors. The aim of our study was to evaluate the role of polymorphisms in the genes encoding for components of the renin-angiotensin system (RAS) in the development and/or progression of CRF. METHODS: Two hundred forty-seven family trios (patients with CRF and both parents; 120 with primary chronic glomerulonephritis, 80 with interstitial nephritis, and 47 with type 1 diabetes with nephropathy) were examined, and transmission/disequilibrium test (TDT) was used to evaluate allele transmission from heterozygous parents to affected offspring. RESULTS: The D allele of the angiotensin I-converting enzyme (ACE) gene insertion/deletion polymorphism was transmitted significantly more frequently than expected for no association among all examined trios and in the subgroup of patients with interstitial nephritis. The angiotensinogen 235T allele was transmitted significantly more frequently to patients with CRF than expected for no association, but the effect was seen only in patients with interstitial nephritis. The presence of the DD or ID genotype was associated with a faster rate of decline of renal function, which was not observed for the angiotensinogen M235T polymorphism. For chymase gene and angiotensin II receptor type 1 gene, allele transmission did not deviate significantly from a random proportion of 50:50%. CONCLUSIONS: The results of this study suggest that ACE gene insertion/deletion and angiotensinogen M235T polymorphisms contribute to the increased risk for the development of CRF, but the magnitude of the effect within subsets of patients with specific etiologies of CRF must be evaluated further.     

Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes

The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.     

Clinico-pathological features and renal outcomes of primary IgA nephropathy with IgM deposition

Objective To investigate the clinico-pathological features and renal outcomes of primary IgA nephropathy (IgAN) with glomerular IgM deposition. Methods Primary IgAN diagnosed with biopsy from January 2006 to December 2011 were recruited. Patients were divided into groups according to IgM deposition (Group A) and without IgM deposition (Group B). In addition, Group A was subdivided into two groups based on the position of IgM deposits as the mesangium (Group A1) and both mesangium and capillary wall (Group A2). Renal outcomes were defined as end stage renal disease (ESRD) and/or the doubling of baseline serum creatinine. Clinico-pathological features were retrospectively compared. Kaplan-Meier was conducted for renal outcomes, and Cox regression model was used to analyze the prognostic value of IgM deposition and the position of IgM deposition in the progression of nephropathy in IgAN patients. Results 939 patients were enrolled with 422 (44.9%) having IgM deposition (Group A). Of the 422 patients, 382 patients were divided as Group A1, whereas 40 patients were noted as Group A2. Compared to Group B, hemoglobin, serum protein, albumin and serum IgG levels in group A were significantly lower, and the cholesterol and serum IgM levels were significantly higher (all P＜0.05). There was no significant difference in serum creatinine, estimated glomerular filtration rate (eGFR), urinary protein, blood pressure and uric acid between group A and B. In terms of pathological manifestations, patients in Group A exhibited more severe histological lesions including glomerular sclerosis, S1, M1 and interstitial inflammatory cell infiltration (all P＜0.05). Immunofluorescence showed that the proportion of IgG, C1q and Fg deposition in group A was significantly higher than that in group B (all P＜0.05). By Kaplan-Meier, cumulative renal survival rate has no significant difference between Group A and B (Log-rank test χ2=0.019, P=0.891). Univariate and multivariable Cox regression analysis showed that IgM deposition had no significant effect on the renal progression in IgAN patients. Subgroup analysis showed that patients in Group A2 exhibited higher urine protein, creatinine and blood pressure, and lower eGFR and serum albumin, also had worse histological lesions including M1, E1 and T1-2 of Oxford classification (all P＜0.05), Immunofluorescence showed that the proportion of IgG, C1q and Fg deposition in group A2 was significantly higher than that in group A1 (all P＜0.05). By Kaplan-Meier, renal survival rates calculated from outcomes were lower in Group A2 (Log-rank test χ2=18.207, P＜0.001). In addition, IgM deposited both in the mesangium and capillary wall was a risk factor for renal progression of IgAN patients with IgM deposition by a univariate Cox hazards regression mode and multivariable-adjusted Cox models (HR=3.621, 95%CI 1.924-6.814, P＜0.001; HR=2.309, 95%CI 1.176-4.533, P=0.015 respectively). Conclusions The IgAN patients with IgM deposition relatively had more severe clinico-pathological changes, especially those with IgM deposited both in the mesangium and capillary wall. In this study, IgM deposition was not found to be an independent risk factor for the prognosis of kidney in IgAN patients. However, IgM deposited both in the mesangium and capillary wall was an independent risk factor for renal prognosis in IgAN patients with IgM deposition.