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Mucosal immune regulation is considered a key aspect of immunopathogenesis of IgA nephropathy (IgAN). Direct experimental evidence clarifying the role of intestinal mucosa attributes in IgAN is lacking. In this study, a mouse model was established via multiple low-dose intraperitoneal injections of Lactobacillus casei cell wall extract (LCWE) emulsified with Complete Freund's Adjuvant (CFA). We found continuous and stable deposition of IgA in glomerular mesangial areas, accompanying high circulating levels of IgA and IgA-IgG complexes. Expression of the key extracellular matrix components collagen IV and fibronectin also increased in the mesangial areas of LCWE-induced mice. IgA

AIM Left ventricular hypertrophy and impaired systolic and diastolic function are commonly seen in patients with chronic kidney disease, but relationships between the disorders and cardiovascular outcomes are not well established among the patients. METHODS Totally, 2020 patients with chronic kidney disease stages 1-4 were used in the analysis. Left ventricular hypertrophy was defined by left ventricular mass index >49.2 g/m2.7 in men and >46.7 g/m2.7 in women. Incident heart failure, non-heart failure cardiovascular events, and all-cause mortality were recorded longitudinally. Cox proportional hazards regression model was used to evaluate the association between the echo parameters and the outcomes, with death treated as the competing risk event for the cardiovascular events. RESULTS After a median follow-up of 4.5 years, 53 heart failure, 76 non-heart failure cardiovascular events and 82 deaths occurred. No overall association was found between left ventricular hypertrophy and subsequent heart failure, but the relationship was significant among patients with no diabetes with the multivariable adjusted hazard ratio of 3.66 (95% confidence interval: 1.42-9.46). Ejection fraction

IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly-IgA mimic. Both uninduced rIgA (mono-rIgA) and polymeric SA-rIgA (poly-rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono-rIgA, this synthetic poly-rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long-lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly-rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer-lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Immunoglobulin A (IgA) vasculitis with nephritis (IgAVN) and IgA nephropathy (IgAN) are widely considered as related diseases. Considerable evidences support the notion of involvement of complement activation in both IgAVN and IgAN. Our previous studies identified a genetic variant in complement factor H (CFH), rs6677604, as an IgAN-susceptible variant by genome-wide association study, and further confirmed its linkage to CFHR3-1Δ and proved its influence on complement activation and thereby on IgAN susceptibility. Aim To explore the role of rs6677604 in complement activation of IgAVN. Methods In this study, we enrolled 632 patients with IgAVN, 1178 patients with IgAN and 902 healthy controls. The genotype of rs6677604 was measured by TaqMan allele discrimination assays or was extracted from genome-wide association study data. Results The frequency of the rs6677604-A allele was significantly higher in IgAVN than in IgAN. However, no significant differences were observed between IgAVN and the controls. Higher complement factor H (FH) levels were observed in IgAVN than IgAN, and positive correlation between circulating FH and C3 levels was present in IgAVN. In both IgAVN and IgAN, rs6677604-A was associated with less intensity of glomerular C3 deposits. In agreement with the higher frequency of rs6677604-A in IgAVN, the glomerular C3 deposits of patients with IgAVN were less intense than those in IgAN. Conclusion Our findings suggest that genetic variation in CFH (rs6677604) is involved in the phenotype of complement activation in both IgAVN and IgAN. Moreover, rs6677604 might contribute to the difference of complement activation intensity between IgAVN and IgAN.

AIM Studies investigating the association between blood phosphorus and renal outcomes yielded inconsistent results, and studies from Asian population are extremely limited. We initiated the present cohort study, aiming to prospectively examine the association between blood phosphorus and adverse renal outcomes in a prospective chronic kidney disease (CKD) cohort of Chinese patients majorly with glomerulonephritis. METHODS A total of 1430 patients were involved in the study. Linear regression analyses were used to assess the relationship between phosphorus and the slope of estimated glomerular filtration rate (eGFR). Cox regression analyses were used to assess the association between phosphorus and composite outcomes, which were defined as the presence of at least one of: eGFR halving, end stage renal disease, or death. RESULTS During follow-up for an average of 41.4 months, 196 patients developed composite outcomes. The time-average plasma phosphorus was independently associated with the slope of eGFR (β = -0.18, 95% CI: -4.42 to -2.19, P

Aim To validate the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines risk stratification system based on the combination of estimated glomerular filtration rate (eGFR) and proteinuria. Methods This was a cohort study. A total of 1219 study population were recruited. Estimated GFR and proteinuria measured by using 24 h urine protein excretion rate (PER) were predictors. Adverse outcomes included all-cause mortality (ACM) and end-stage renal disease (ESRD). Follow-up was done by regular visit, telephone interview and electronic medical records. Results Over a median follow-up of 4.6 years, 153 (12.6%) and 43 (3.5%) patients experienced ESRD and ACM, respectively. On multivariable analysis, the adjusted hazard ratio for ESRD and ACM (compared with patients with eGFR > 60 mL/min per 1.73 m2) was of 29.8 and 3.6 for those with eGFR of 15–29 mL/min per 1.73 m2, respectively. The adjusted hazard ratio for ESRD and ACM (compared with patients with PER 500 mg/24h. Higher KDIGO guidelines risk categories (indicating lower eGFR or higher proteinuria) were associated with a graded increase in the risk for the ESRD (P

Although the number of convincingly established genetic associations with systemic lupus erythematosus (SLE) has increased sharply over the last few years, refinement of these associations is required, and their potential roles in gene-gene interactions need to be further investigated. Recent genome-wide association studies (GWAS) in SLE have produced renewed interest in B cell/T cell responses and the NF-κB signaling pathway. The aim of this study was to search for possible gene-gene interactions based on identified single-nucleotide polymorphisms (SNPs), in using an approach based on the role of signaling pathways.The SNPs in BLK, TNFSF4, TRAF1, TNFAIP3, and REL were replicated in order to evaluate genetic associations with SLE. TaqMan genotyping was conducted in 804 Chinese patients with SLE and 722 matched control subjects. A multiple logistic regression model was used to estimate the multiplicative interaction effect of the SNPs, and additive interactions were analyzed by 2×2 factorial designs. Data from a previously published GWAS conducted by the International Consortium on the Genetics of Systemic Lupus Erythematosus were derived for comparison and validation.Single-marker analysis validated the association of BLK rs2736340 (P=4.25×10(-6)) as well as TNFSF4 rs2205960 (P=2.82×10(-5)) and TNFAIP3 rs5029939 (P=1.92×10(-3)) with SLE susceptibility in Chinese. Multiplicative interaction analysis indicated that BLK had an interactive effect with TNFSF4 in Chinese patients with SLE (P=6.57×10(-4)). Additive interaction analysis revealed interactions between TRAF1 and TNFAIP3 in both Chinese (P=2.18×10(-3)) and Caucasians (P=2.86×10(-4)). In addition, multiple tendencies toward interactions were observed, and an additive effect was observed as the number of risk genotypes increased.The results of this study provide evidence of the possible gene-gene interactions of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in SLE, which may represent a synergic effect of T cells and B cells through the NF-κB pathway in determining immunologic aberration.

Aim: Recently, several studies have provided convincing evidence that polymorphisms in the interferon regulatory factor 5 (IRF5) gene were significantly associated with systemic lupus erythematosus (SLE) in several populations. The aim of this study was to investigate the association between IRF5 and lupus nephritis in a Chinese cohort and analyze the relationship between the rs2004640 genotype and the clinical and pathological phenotypes of lupus nephritis. Methods: The IRF5 rs2004640 polymorphism in a cohort of 190 Chinese lupus nephritis patients and 182 healthy Chinese blood donors was analyzed. The polymorphism examined was genotyped using the TaqMan assay. Results: The IRF5 rs2004640 T allele was associated with the susceptibility to lupus nephritis (rs2004640 T, 41.6% in patients, 30.8% in healthy controls, odds ratio = 1.6, P = 0.002). It was also found that the Chinese population had a much lower minor allele frequency of rs2004640 than Western populations studied to date. In the present cohort, 30.8% individuals in the control group had the detrimental T allele, compared to frequencies in the range of 44–56% that exist in Western populations. No association was found between IRF5 rs2004640 and pathology, or clinical presentation of lupus nephritis in the Chinese cohort examined. Conclusion: The results suggested that the rs2004640 T allele was associated with susceptibility to lupus nephritis and that the IRF5 polymorphism analyzed did not seem to be implicated in the pathology and clinical manifestation of lupus nephritis in the Chinese population.

SUMMARY: Background: Proteinuria varies in different glomerular diseases and even the same one. Podocin, encoded by gene NPHS2, is important in maintaining the integrity of slit diaphragm structure and avoiding proteinuria. Presently, case–control association studies were performed to investigate the genetic effect of variants in NPHS2 in a mass proteinuric glomerulopathy, minimal change disease (MCD) at first, followed by further investigation in immunoglobulin A nephropathy (IgAN). Methods: At first, 214 northern Chinese patients with MCD and 493 geographically-matched healthy controls were enrolled. Variants of the NPHS2 were screened. SNP-2 (rs3829795:C>T, c.-670C>T) and SNP-5 (rs3738423:C>T, c.288C>T) were selected as tagging single nucleotide polymorphisms (SNP) and haplotypes were reconstructed. Association was analyzed in MCD patients. Then, the identified SNP site was analyzed in IgAN patients with mild histological changes (Haas subclass I and II). Results: The C allele and CC genotype frequencies at the SNP-2 site, as well as the frequency of haplotype CC, were significantly lower in MCD patients than in healthy controls. Furthermore, they were also associated with the degree of proteinuria in MCD patients. But in IgAN patients, no such association was identified. Conclusion: The study suggested the polymorphism and haplotype of NPHS2 gene were associated with the genetic susceptibility and also the degree of proteinuria to MCD. Proteinuria in MCD and IgAN might occur through different mechanisms.

SUMMARY: Aim: Immunoglobulin A nephropathy (IgAN) is a common and progressive glomerulonephritis. Histological lesions of IgAN are variable and considered as a risk factor for renal outcome. Establishing a relatively concise histological semiquantitative scoring system would be valuable in clinical practice. Methods: Renal biopsy sections of 293 patients with primary IgAN from two centres in China were reviewed. A histological scoring system was established based on multivariate survival analysis of semiquantitative histological indices, using end-stage renal disease (ESRD) as the end-point event. Results: Four indices – extracapillary glomerular activity index (exGAI), mesangial proliferation index (MsI), glomerular chronicity index (GCI) and tubulointerstitial chronicity index (TCI) – independently correlated with ESRD (relative risk (RR) = 1.16, 2.27, 1.29 and 1.80, respectively). The four indices and the sum of their scores (Total I) constituted the scoring system. Patients with exGAI of 4 or more, GCI of 4 or more, MsI of 2 or more and TCI of 2 or more were considered as having a higher risk for progression (P

SUMMARY: Aim: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. However, its natural history and risk factors are not well understood. Our aim was to identify the clinical and pathological factors that could predict disease prognosis in Chinese patients. Methods: We studied 204 biopsy-diagnosed IgAN patients, who were followed for an average of 6.1 years (range, 4–15 years). Chronic kidney disease (CKD) classified according to the Kidney Disease Outcomes Quality Initiative practice guidelines. Renal pathological lesions were graded single-blindedly according to the Haas classification. The glomerular filtration rate was estimated by the Modification of Diet in Renal Disease equation for Chinese subjects. Results: Patients with CKD were classified as stage 1 (38.10%), stage 2 (35.40%), stage 3 (13.30%), stage 4 (9.90%) and stage 5 (3.30%). During the follow up, 31 patients had progressed to end-stage renal disease. The renal survival rate following biopsy was 85.1% at the fifth year, and 77.1% at the 10th year. Univariate analysis indicated that patients who were male, had hypertension, proteinuria of more than 1 g/day, renal impairment (estimated glomerular filtration rate