Diagnosis, Differential ; Family Health ; Genetic Predisposition to Disease ; genetics ; Glomerulonephritis, IGA ; diagnosis ; genetics ; HLA Antigens ; genetics ; Humans

OBJECTIVE: To investigate the gut microbiota in newly diagnosed IgA nephropathy patients with chronic kidney disease (CKD) stages 1-2 and the association between the gut microbiota and the clinical risk factors of IgA nephropathy. METHODS: Fresh fecal samples were collected from nineteen newly diagnosed IgA nephropathy patients with CKD stages 1-2 and fifteen age- and sex-matched healthy controls. Fecal bacterial DNA was extracted and microbiota composition were characterized using 16S ribosomal RNA (16S rRNA) high-throughput sequencing for the V3-V4 region. The Illumina Miseq platform was used to analyze the results of 16S rRNA high-throughput sequencing of fecal flora. At the same time, the clinical risk factors of IgA nephropathy patients were collected to investigate the association between the gut microbiota and the clinical risk factors. RESULTS: (1) At the phylum level, the abundance of Bacteroidetes was significantly reduced (P=0.046), and the abundance of Actinobacteria was significantly increased (P=0.001). At the genus level, the abundance of Escherichia-Shigella, Bifidobacte-rium, Dorea and others were significantly increased (P < 0.05). The abundance of Lachnospira, Coprococcus_2 and Sutterella was significantly reduced (P < 0.05). (2) There was no significant difference in the abundance of gut microbiota between the newly diagnosed IgA nephropathy patients and the healthy control group (P>0.05), but there were differences in the structure of the gut microbiota between the two groups. The results of LEfSe analysis showed that there were 16 differential bacteria in the newly diagnosed IgA nephropathy patients and healthy controls. Among them, the abundance of the newly diagnosed IgA nephropathy patients was increased in Enterobacteriales, Actinobacteria, Escherichia-Shigella, etc. The healthy control group was increased in Bacteroidetes and Lachnospira. (3) The result of redundancy analysis (RDA) showed that Bifidobacterium was positively correlated with serum IgA levels, 24-hour urinary protein levels and the presence of hypertension. Lachnoclostridium was positively correlated with the presence of hypertension. Escherichia-Shigella was positively correlated with urine red blood cells account. Bifidobacterium was positively correlated with the proliferation of capillaries. Faecalibacterium was positively correlated with cell/fibrocytic crescents. Ruminococcus_2 was positively correlated with mesangial cell proliferation, glomerular segmental sclerosis and renal tubular atrophy/interstitial fibrosis. CONCLUSION The gut microbiota in the newly diagnosed IgA nephropathy patients with CKD stages 1-2 is different from that of the healthy controls. Most importantly, some gut bacteria are related to the clinical risk factors of IgA nephropathy. Further research is needed to understand the potential role of these bacteria in IgA nephropathy.
Humans ; Gastrointestinal Microbiome ; RNA, Ribosomal, 16S/genetics* ; Glomerulonephritis, IGA ; Bacteria/genetics* ; Risk Factors ; Renal Insufficiency, Chronic

Immunoglobulin A nephropathy (IgAN), which can develop into end-stage renal disease, is the most common primary glomerulonephritis. The pathogenesis of IgAN is not clear. Many studies have confirmed that genetic susceptibility is associated with IgAN, and it belongs to polygenic disease. Some studies have found that IgAN is associated with chromosome 6q22-23, 2q36 by linkage analysis, and several candidate genes have been confirmed to be associated with IgAN, such as angiotensin converting enzyme, Fc fragment of IgA receptor, human leukocyte antigen. In recent years, as the progression of molecular genetics and the Human Genome Project, more attention has been paid to the role of genetic factors in the pathogenesis of IgAN.
Animals ; Chromosomes, Human, Pair 2 ; genetics ; Chromosomes, Human, Pair 6 ; genetics ; Genetic Association Studies ; Genetic Linkage ; Genetic Predisposition to Disease ; genetics ; Glomerulonephritis ; complications ; Glomerulonephritis, IGA ; etiology ; genetics ; Humans

Adult ; Biopsy ; DNA ; genetics ; Female ; Gene Expression Profiling ; Glomerulonephritis, IGA ; genetics ; pathology ; Humans ; Kidney ; pathology ; Male ; Middle Aged ; Young Adult

BACKGROUNDIgA nephropathy (IgAN) is the most common primary glomerular disease. Transforming growth factor β1 (TGFβ1) plays an important role in pathogenesis of IgAN. Associations between the polymorphisms of TGFβ1 gene and the risk of IgAN remained inconsistent. A meta-analysis was conducted to investigate the association between polymorphisms in the TGFβ1 gene and IgAN susceptibility.

METHODSDatabases including Pubmed, EMBASE, ISI, et al. were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations.

RESULTSTen studies involving 1770 cases and 1953 controls were included. Significant association between C509T polymorphism and IgAN risk was observed (OR 1.42, 95% CI 1.12-1.81, P = 0.0004; I(2) = 0%) in Caucasians by the overdominant model (CT vs. CC + TT), but no significant association was found (P = 0.200) in Asians by the dominant model (CC + CT vs. TT). Significant association between T869C polymorphism and IgAN susceptibility was found (OR 1.21, 95% CI 1.02-1.44, P = 0.030) in overall populations by the dominant model (TT + TC vs. CC). Subgroup analysis found T allele of T869C polymorphism was associated with IgAN susceptibility in Caucasians (P = 0.030), but not in Asians (P = 0.290).

CONCLUSIONBoth heterozygotes of C509T polymorphism and T allele of T869C polymorphism in TGFβ1 were associated with the risk of IgAN in Caucasians, but not in Asians.

Asian Continental Ancestry Group ; genetics ; European Continental Ancestry Group ; genetics ; Genetic Predisposition to Disease ; genetics ; Glomerulonephritis, IGA ; epidemiology ; genetics ; Humans ; Polymorphism, Genetic ; genetics ; Transforming Growth Factor beta1 ; genetics

Animals ; Glomerulonephritis, IGA/drug therapy* ; Hydroxychloroquine/therapeutic use* ; Ki-67 Antigen ; Kidney ; Rats ; Toll-Like Receptor 4/genetics* ; Vitamin D

The enabled homolog gene (ENAH, hMena) is abundantly expressed in mesangial tissue, and might play an important role in inflammatory processes of IgA nephropathy (IgAN). The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the ENAH and childhood IgAN. We analyzed 12 SNPs of ENAH in 176 patients with childhood IgAN and 397 healthy controls. In addition, IgAN patients were dichotomized and compared with respect to several clinical and pathological parameters. Genotyping data showed significant differences between IgAN patients and controls in the frequency of rs2039620, rs12034829, and rs3795443. On comparison of patients with proteinuria to those without proteinuria (< or = or > 4 mg/m2/h), rs12043633 was significantly different between the two groups. With regard to maximum proteinuria (< or = or > 4 mg/m2/h), rs3795443, rs4653643, rs6751, rs10799319, rs7555139, rs576861, and rs487591 showed significant allele frequency differences. For patients with and without gross hematuria, rs4653643, rs6751, rs10799319, rs7555139, rs576861, and rs487591 showed significant allele frequency differences. The rs3795443 was found to be associated with progression of pathological findings. Our results suggest that ENAH polymorphisms are associated with increased susceptibility, development of proteinuria and gross hematuria, and pathological progression of childhood IgAN.
Adolescent ; Asian Continental Ancestry Group ; Child ; Female ; Genetic Predisposition to Disease/*genetics ; Genotype ; Glomerulonephritis, IGA/*genetics ; Humans ; Korea ; Male ; Microfilament Proteins/*genetics ; *Polymorphism, Single Nucleotide ; Proteinuria/genetics

OBJECTIVETo investigate the aberrance of histone H3 lysine 4 trimethylation (H3K4me3) in patients with IgA nephropathy (IgAN).

METHODSIn 15 patients with IgAN and 15 healthy volunteers, H3K4me3 variations in peripheral blood mononuclear cells (PBMCs) were analyzed using chromatin immunoprecipitation and microarray analysis (ChIP-chip). ChIP real-time PCR was used to validate the microarray results. Quantitative real-time PCR (qRT-PCR) was carried out to examine the correlations between the mRNA expression profiles and H3K4me3 levels.

RESULTSWe identified 83 genes that displayed significant H3K4me3 differences in IgAN patients compared with healthy subjects. Among them, 39 genes showed increased H3K4me3 and 44 genes had decreased H3K4me3 levels. The results of ChIP real-time PCR were well consistent with the microarray data. Quantitative RT-PCR revealed the correlations between the mRNA expressions and the methylation levels of H3K4me3.

CONCLUSIONIgAN patients have significant alterations in H3K4me3, and the genes with aberrant H3K4me3 may provide insights into the pathogenesis of IgAN.

Case-Control Studies ; CpG Islands ; genetics ; DNA Methylation ; Female ; Glomerulonephritis, IGA ; genetics ; metabolism ; Histones ; genetics ; metabolism ; Humans ; Leukocytes, Mononuclear ; metabolism ; Lysine ; genetics ; metabolism ; Male

OBJECTIVETo investigate the relationship between codon 54 gene polymorphism of the host defense molecule, mannose-binding protein (MBP), and the patterns of glomerular immune deposition in IgA nephropathy (IgAN).

METHODSIgAN patients with different patterns of glomerular immune deposition were selected and divided into two groups. Group A consisted of 77 patients with glomerular IgA and C3 deposits, and Group AGM consisted of 70 patients with glomerular IgA, IgG, IgM, C3 and Clq deposits. Clinical features and laboratory relevant data of all patients were collected. One-hundred and forty healthy adults were recruited as normal controls. The MBP gene codon 54 GGC/GAC polymorphism was investigated by using polymerase chain reaction and restriction fragment length polymorphism.

RESULTSThe genotype frequency of GGC/GAC heterozygotes was significantly higher in Group AGM as compared with that of Group A (41.4% vs 19.5%, P < 0.01) or normal subjects (41.4% vs. 26.4%, P < 0.05), while no difference was found in the distribution of MBP genotypes between Group A and normal subjects. GAC allele frequency was also higher in Group AGM than that in Group A (0.24 vs. 0.14, P < 0.05) or normal subjects (0.24 vs. 0.15, P < 0.05). The variant allele (GAC) was markedly associated with Group AGM (OR = 1.95, 95% CI: 1.06 - 3.58). In both Group A and Group AGM, more patients carrying the variant allele had episodes of upper respiratory or gastrointestinal infections prior to the onset of IgAN than those with wild homozygotes (GGC/GGC).

CONCLUSIONSGenetic variation of the host defense molecule, MBP, may be involved in the formation of the diverse patterns of glomerular immune deposition in IgAN. The variant allele of the MBP gene may partially account for abundant immune deposits in some IgAN patients.

Adult ; Alleles ; Carrier Proteins ; genetics ; Collectins ; DNA ; genetics ; Female ; Gene Frequency ; Genetic Variation ; Genotype ; Glomerulonephritis, IGA ; genetics ; immunology ; Humans ; Kidney Glomerulus ; immunology ; pathology ; Male ; Polymorphism, Restriction Fragment Length

Objective To investigate the effect of intestinal mucosal Toll-like receptor 4/nuclear factor κB (TLR4/NF-κB) signaling pathway on renal damage in pseudo-sterile IgA nephropathy (IgAN) mice. Methods C57BL/6 mice were randomly divided into experimental group (pseudosterile mouse model group), control group (IgAN mouse model group), pseudosterile mouse blank group, and normal mouse blank group. Pseudosterile mice were established by intragastric administration of quadruple antibiotics once a day for 14 days. The pseudosterile IgAN mouse model was set up by combination of oral bovine serum albumin (BSA) administration and staphylococcal enterotoxin B (SEB) injection. The pathological changes of renal tissue were observed by immunofluorescence staining and PAS staining, and the intestinal mucosa barrier damage indicators lipopolysaccharide(LPS), soluble intercellular adhesion molecule 1(sICAM-1) and D-lactate(D-LAC) were analyzed by ELISA. Biochemical analysis was used to test 24 hour urine protein, serum creatinine and blood urea nitrogen. The mRNA and protein levels of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear factor κB (NF-κB) were detected by reverse transcription PCR and Western blot analysis. Results The kidney damage of pseudosterile IgAN mice was more severe than that of IgAN mice, and the expressions of intestinal mucosal barrier damage markers (LPS, sICAM-1 and D-LAC) were significantly increased in pseudosterile IgAN mice. In addition, the expressions of TLR4, MyD88, and NF-κB level were all up-regulated in the intestinal tissues of IgAN pseudosterile mice. Conclusion Intestinal flora disturbance leads to intestinal mucosal barrier damage and induces activation of TLR4 signaling pathway to mediate renal injury in IgAN.
Animals ; Mice ; Mice, Inbred C57BL ; Glomerulonephritis, IGA ; NF-kappa B ; Toll-Like Receptor 4/genetics* ; Lipopolysaccharides ; Myeloid Differentiation Factor 88/genetics* ; Kidney ; Intestinal Mucosa ; Infertility ; Disease Models, Animal