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IgA nephropathy (IgAN) is characterized by deposition of galactose-deficient IgA1 (Gd-IgA1) in glomerular mesangium associated with mucosal immune disorders. Since environmental pollution has been associated with the progression of chronic kidney disease in the general population, we specifically investigated the influence of exposure to fine particulate matter less than 2.5 μm in diameter (PM2.5) on IgAN progression. Patients with biopsy-proven primary IgAN were recruited from seven Chinese kidney centers. PM2.5 exposure from 1998 to 2016 was derived from satellite aerosol optical depth data and a total of 1,979 patients with IgAN, including 994 males were enrolled. The PM2.5 exposure levels for patients from different provinces varied but, in general, the PM2.5 exposure levels among patients from the north were higher than those among patients from the south. The severity of PM2.5 exposure in different regions was correlated with regional kidney failure burden. In addition, each 10 μg/m

Background Immunoglobulin A nephropathy (IgAN) and IgA vasculitis with nephritis (IgAV-N) are considered related diseases and share some similar clinicopathologic phenotypes. Elevated circulating galactose-deficient IgA1 (Gd-IgA1)-containing immune complexes and mucosal immunity were associated with the pathogenesis of IgAN and IgAV-N. Recently, studies have identified that the zonulin level, as a modulator of intestinal permeability, is significantly elevated in several inflammatory and autoimmune-related diseases. However, whether zonulin also plays a role in IgAN and IgAV-N is not clear. Methods A total of 73 IgAV-N patients, 68 IgAN patients and 54 healthy controls were assessed for circulating zonulin and Gd-IgA1 levels by enzyme-linked immunosorbent assay. The diagnostic efficiency of the combination of zonulin with Gd-IgA1 was evaluated by the area under the receiver operating characteristic curve (AUC) and integrated discrimination improvement (IDI) analysis. Results Compared with healthy controls, we found that both IgAV-N and IgAN patients had elevated zonulin and Gd-IgA1 levels (P Conclusion Elevated circulating zonulin levels were detected in both patients with IgAV-N and those with IgAN. Combined detection of circulating zonulin and Gd-IgA1 is recommended as a noninvasive diagnostic biomarker for IgAV-N and IgAN.

Arteriolar microangiopathic (MA) lesions are independent risk factors for IgA nephropathy (IgAN) patient prognosis, and the underlying mechanism remains to be elucidated. The complement plays an important role in IgAN and thrombotic microangiopathy; however, its role in MA lesions in IgAN remains unclear.Immunohistochemistry was performed to detect arteriolar complement deposition. Enzyme-linked immunosorbent assay (ELISA) and whole-exome sequencing were performed to explore possible mechanism.In this study, we found that patients with IgAN with MA lesions have more complement deposition, especially C4d, on renal arterioles than those in patients with arteriolosclerosis (AS) and patients with no vascular lesions (100% vs. 53% vsOur results indicate that the complement is involved in the development of MA lesions in IgAN, which might be associated with the circulating complex containing Gd-IgA1.

IgA nephropathy (IgAN) commonly entails arteriolar microangiopathic (MA) lesions of the kidneys. The most significant reason for MA lesions is endothelial injury, although the mechanism of injury to the vascular endothelium is not clear.59 patients with IgAN and 19 healthy controls were included for measuring the blood von Willebrand factor (vWF), soluble vascular cell adhesion molecule-1 (sVCAM1), and heparin-binding EGF-like growth factor (HB-EGF) by ELISA. Circulating IgA1 (cIgA1) was isolated from 12 patients with primary IgAN and 10 healthy controls. Then, the supernatant of growth-arrested human mesangial cells (HMCs) in a medium with cIgA1 was used to prepare the cIgA1-human mesangial cell medium (cIgA1-HMCM). Human umbilical vein endothelial cells (HUVECs) were grown in this medium along with or withoutThe concentration of vWF, sVCAM-1, and HB-EGF was higher in the patients than in the healthy participants. The expressions of IL-6 and CXCL1 in HMCM were significantly higher in cIgA1 from patients with IgAN (IgAN-cIgA1) than from healthy controls. Levels of vWF, sVCAM-1, and HB-EGF induced by conditioned HMCM treated with IgAN-cIgA1 (IgAN-HMCM) were conspicuously more than those induced in healthy controls-HMCM (HC-HMCM). After culturing HUVECs in IgAN-HMCM and PNS, the vWF, sVCAM-1 and HB-EGF were remarkably low in the supernatants of cells grown in IgAN-HMCM+PNS compared to those grown in IgAN-HMCM only.Activation of mesangial cells in vitro may occur by cIgA1 and, thus, cause endothelial cell injury via inflammation factors.

Background Positive glomerular C4d staining, representative of lectin pathway activation, has been proven to be associated with unfavorable outcomes in immunoglobulin A nephropathy (IgAN). Our previous study suggested that urinary C4d correlated positively with an increase in crescents while the relationship between urinary C4d and disease severity and progression remains unelucidated. Methods In this study we enrolled 168 patients diagnosed with IgAN with varying proportions of crescent formation at the time of biopsy. An independent cohort of 107 IgAN patients was enrolled for validation. Kidney biopsy specimens were stained using immunohistochemistry. Urinary C4d levels at renal biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was end-stage kidney disease (ESKD). Results Higher urinary C4d/creatinine levels were associated with a lower estimated glomerular filtration rate (eGFR); massive proteinuria; hypertension and severe Oxford M, E, T and C scores. After a median follow-up of 19 months (interquartile range 9–27), 53 (31.5%) participants reached ESKD. High urinary C4d/creatinine levels were independently and significantly associated with a risk of developing ESKD [hazard ratio per standard deviation increment of log-transformed C4d/creatinine 7.623 (95% confidence interval 4.117–14.113)]. Conclusions The urinary C4d/creatinine level is a potential useful biomarker that was associated with disease severity and progression in patients with IgAN and crescents.

Background Fibrinoid necrosis is considered one of the active pathological lesions in IgA nephropathy. Whether patients with IgA nephropathy with fibrinoid necrosis lesions benefit from immunosuppressive therapy in terms of long-term outcomes remains uncertain. This study aimed to evaluate the response to immunosuppressive therapy in patients with fibrinoid necrosis lesions in a large cohort of patients with IgA nephropathy. Methods A total of 1325 patients with kidney biopsy-proven IgA nephropathy from 1994 to 2016 were recruited from the Peking University First Hospital IgA Nephropathy Database. The clinicopathological characteristics of patients with fibrinoid necrosis lesions and the effect of immunosuppressive therapy on patients with fibrinoid necrosis lesions alone or in those with fibrinoid necrosis together with crescents or endocapillary hypercellularity lesions were analyzed. Results In total, 107/1325 (8.1%) patients showed fibrinoid necrosis lesions, and 92/107 (86.0%) of these patients showed fibrinoid necrosis associated either with cellular/fibrocellular crescents or endocapillary hypercellularity lesions. The presence of fibrinoid necrosis together with crescents or endocapillary hypercellularity was an independent risk factor for the kidney composite endpoint (HR, 2.11; 95% CI, 1.16-3.84; P = 0.02) in patients without immunosuppression, while for those receiving immunosuppressive therapy, kidney outcome was improved (HR, 0.80; 95% CI, 0.46-1.39; P = 0.42). However, the predictive value of fibrinoid necrosis lesions alone did not change significantly between patients with and without immunosuppressive therapy. Conclusions The presence of fibrinoid necrosis with crescents or endocapillary hypercellularity lesions together, but not fibrinoid necrosis lesions alone, was a pathological indicator of patients who may benefit from immunosuppressive therapy.

Background Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established. Methods To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis. Results We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, P=1.20×10-9); the locus we identified at GALNT12 (rs7856182; β=0.73, P=2.38×10-9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10-2) and disease risk (P=6.55×10-3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. Conclusions Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.

Hydroxychloroquine (HCQ) has been used as a supportive therapy for IgA nephropathy (IgAN). We aimed to determine the long-term efficacy and safety of HCQ therapy in patients with IgAN. A total of 180 patients with IgAN who had received HCQ therapy for at least 1 year were enrolled in this study. The changes in proteinuria and the estimated glomerular filtration rate (eGFR) were analyzed during the follow-up period. The level of proteinuria decreased from 1.69 [1.24, 2.30] to 1.01 [0.59, 1.74] g/day (− 37.58 [− 57.52, 8.24] %, P

Background and objectives IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy. Design, setting, participants, & measurements We performed a two-stage exome chip–based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored. Results We identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (Pmeta Conclusions Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.

Background Similarities in clinicopathological presentations in immunoglobulin A (IgA) nephropathy and IgA vasculitis with nephritis (IgAVN) raise the question of the utility of the Oxford classification in the latter. The aim of this study was to evaluate the Oxford classification in IgAVN. Methods We conducted a retrospective cohort study and meta-analysis following systematic searching of the MEDLINE and Excerpta Medica Database (EMBASE) databases between January 2009 and September 2019. We modeled the association of 30 and 50% decline in estimated glomerular filtration rate or end-stage renal disease with pathologic lesions of the Oxford classification including mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), interstitial fibrosis/tubular atrophy (T) and crescents (C). Results were pooled using random-effects meta-analysis. Results The cohort study included 132 patients, and only T lesion was an independently risk factor in IgAVN. The meta-analysis yielded six retrospective studies with 721 patients and 139 endpoints. In multivariate model, T lesion was significantly associated with renal outcome (hazard ratio = 2.45, P = 0.007). M and C lesions could not predict renal outcome without evidence of heterogeneity. E and S lesions could not predict renal outcome with evidence of heterogeneity (I2 = 66.6%; P = 0.01, and I2 = 65.8%; P = 0.03, respectively). Subgroup analysis showed that the possible reasons to the heterogeneity were from usage of immunosuppressant, sample size and follow-up time. Conclusions The study suggests that the Oxford classification could not be fully validated in IgAVN. Higher portion of immunosuppressant especially before renal biopsy might be the main confounder for the predictive value of Oxford classification in IgAVN.

Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen-built ofWe compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants ofThe patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the

Background Rapidly progressive immunoglobulin A nephropathy (RPIgAN) is a severe clinical phenotype of IgAN associated with a poor outcome. The recently published Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Guideline for the Management of Glomerular Diseases has proposed a new definition for RPIgAN that is based simply on a ≥50% decline in the estimated glomerular filtration rate (eGFR) over ≤3 months. Methods In 1677 IgAN patients followed at a single centre in China, we evaluated the utility of this new definition to identify the highest-risk IgAN patients who might be suitable for combination immunosuppressive therapy. Results The proportion of a ≥50% decline in eGFR over ≤3 months was 5.2%. The majority of these patients had reversible causes, with only 2.3% (39/1677) meeting the KDIGO 2021 criteria for RPIgAN. These patients had a significantly higher risk for end-stage kidney disease (ESKD) than non-RPIgAN patients (logrank P < 0.001). RPIgAN was an independent risk factor for ESKD [hazard ratio 3.99 (95% confidence interval 2.25–7.09); P Conclusions These data support the validity of the KDIGO 2021 definition but require independent validation in other non-Chinese cohorts.

Previous studies have revealed abnormal lymphocyte subsets in IgA nephropathy (IgAN). Some microRNAs have been reported to influence T helper differentiation. Here, we explored the underlying mechanism regarding how miRNAs regulate lymphocyte subsets in IgAN. First, miRNA and mRNA profiles in PBMCs from IgAN patients and controls were obtained by next-generation sequencing and gene expression array. The target miRNAs and mRNAs were identified through combined analysis. Then, in an independent population, we detected the expression of target miRNA in CD3+ T cells and CD19+ B cells. Next, we detected T helper cell subgroups and plasma IgA1 levels in another independent population and analyzed the correlations between them. In total, 22 differentially expressed miRNAs were identified between IgAN patients and controls. Among them, microRNA-21-5p (miR-21) showed the highest expression, and SPRY1, SPRY2, and FASLG were chosen as miR-21 target genes. Then, we confirmed elevated miR-21 levels in CD3+ T cells of IgAN patients. Accordingly, decreased mRNA levels of SPRY1, SPRY2, and FASLG were found, and miR-21 showed a significant negative correlation with SPRY1 levels in CD3+ T cells of IgAN patients. Finally, we revealed that the proportion of Th17 cells was significantly elevated in IgAN patients and negatively correlated with SPRY1 expression. Furthermore, the proportion of Th17 cells showed a positive correlation trend with plasma IgA1 levels. Our results suggested that in IgAN, the upregulated miR-21 expression in T lymphocytes inhibited SPRY1 expression and thereby induced Th17 polarization, which might influence the characteristic feature of IgA1 overproduction in IgAN patients.

Renal arteriolar microangiopathic lesions may occur in immunoglobulin A nephropathy (IgAN), but their role in disease progression remains unclear. We sought to understand the prevalence and character of microangiopathic lesions in IgAN and their role in disease progression.A retrospective cohort study.In this study, we enrolled a Chinese cohort with 944 adult patients with IgAN who had been followed up for at least 1 year.Renal arteriolar microangiopathic lesions.Composite kidney end point event defined as a50% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death.All kidney biopsies were independently reviewed by 2 investigators. Renal arteriolar microangiopathic lesions were detected using light microscopy. Multivariable Cox regression analysis was used to test the association between microangiopathic lesions and the outcomes.Overall, 194 (20.6%) patients had renal arteriolar microangiopathic lesions. Patients with microangiopathic lesions presented with higher blood pressures, more severe proteinuria, and lower estimated glomerular filtration rates (all P0.001) than patients without microangiopathic lesions. After a median follow-up of 4.2 years, 75 (38.7%) patients with microangiopathic lesions and 83 (11.1%) patients without these lesions reached the composite kidney end point (P0.001). In a multivariable Cox regression model adjusting for clinical and pathologic variables available at the time of biopsy, the presence of microangiopathic lesions was an independent risk factor for kidney failure (HR, 1.95; 95% CI, 1.34-2.83; P0.001). Renal vascular sclerosis (arterial intimal fibrosis or arteriolar hyalinosis) was not a risk factor for kidney disease progression (P = 0.5).A single Chinese center's experience, retrospective study, most patients were not tested for hemolytic markers (for example, haptoglobin level, lactate dehydrogenase level, and schistocytes).Renal arteriolar microangiopathic lesions are frequent in IgAN and their presence is independently associated with progression to kidney failure. If confirmed in other patient cohorts, such lesions could be considered for inclusion in formal classification schemes of IgAN.

Background Both ABO blood group antigens and pathogenic immunoglobulin A1 (IgA1) in patients with IgA nephropathy (IgAN) are influenced by modifications of N-acetylgalactosamine and galactose. The purpose of this study was to assess whether ABO blood type is associated with galactose-deficient IgA1 (Gd-IgA1) in the progression of kidney disease in patients with IgAN. Methods We enrolled 1313 IgAN patients with a median of 44 months follow-up and measured the plasma Gd-IgA1 levels. Multivariate Cox regression models were used to estimate the association between all variables and adverse outcomes. Using the propensity score matching method, 718 IgAN patients with blood type either A or B were selected, and their data were used to assess the association of blood type and Gd-IgA1/serum complement 3 (sC3) with outcomes. Results We found that the risk of adverse outcomes was significantly higher in patients with blood type A than in those with type B (hazard ratio = 1.82, 95% confidence interval 1.23–2.71; P = 0.003) after multivariate adjustment. The Gd-IgA1 levels showed trends similar to the multivariate-adjusted event-free curves for the blood types. However, this higher risk of adverse outcomes in type A than in type B patients was no longer significant after the addition of Gd-IgA1/sC3 to the model. Conclusions IgAN patients with blood type A had a higher risk of adverse outcomes than those with type B, and this risk was associated with Gd-IgA1/sC3. Thus, the ABO blood type may provide a reference for the prognostic factors for individuals with IgAN.

Background and objectives Increased circulating galactose-deficient IgA1 and subsequently complement activation both play important roles in the pathophysiology of IgA nephropathy. However, their relationship to disease severity and progression remains unclear. Design, setting, participants, & measurements We assessed 1210 participants in a cohort study of biopsy-proven IgA nephropathy at Peking University First Hospital. Plasma concentrations of galactose-deficient IgA1 and complement component C3 were measured at the time of biopsy. We tested associations of galactose-deficient IgA1 and galactose-deficient IgA1/C3 ratio with CKD progression event, defined as ESKD or 50% decline in eGFR, using Cox proportional hazards models and restricted cubic splines. Results After a median follow-up of 43 months (interquartile range, 24–76 months), 172 (14%) participants reached the CKD progression event. The association of galactose-deficient IgA1 levels and CKD progression event showed a nonlinear relationship. The risk of CKD progression events was greater with higher plasma galactose-deficient IgA1 levels but reached a plateau when galactose-deficient IgA1>325 U/ml, whereas the risk of CKD progression events monotonically increased with higher galactose-deficient IgA1/C3 ratio. After adjustment for traditional risk factors (demographics, eGFR, proteinuria, hypertension, Oxford pathologic score, and corticosteroids/immunosuppressive therapy), higher levels of galactose-deficient IgA1/C3 ratio were independently associated with CKD progression event (per natural log-transformed [galactose-deficient IgA1/C3], hazard ratio, 2.03; 95% confidence interval [95% CI], 1.25 to 3.29; P=0.004). In reference to the first quartile of the galactose-deficient IgA1/C3 ratio, hazard ratios were 1.71 (95% CI, 1.01 to 2.89) for the second quartile, 1.55 (95% CI, 0.91 to 2.63) for the third quartile, and 2.17 (95% CI, 1.33 to 3.56) for the fourth quartile. Conclusions In IgA nephropathy, plasma galactose-deficient IgA1/C3 ratio was associated with CKD progression event independent of clinical and biopsy characteristics.

Rationale & Objective Despite optimization of renin-angiotensin-aldosterone system (RAAS) inhibition, patients with immunoglobulin A nephropathy (IgAN) and persistent proteinuria remain at risk for kidney failure. We evaluated the efficacy and safety of hydroxychloroquine (HCQ), an immunomodulator, when added to the treatment regimen of patients with IgAN. Study Design Double-blind, randomized, placebo-controlled, phase 2 clinical trial. Setting & Participants Participants had IgAN (proteinuria with protein excretion of 0.75-3.5g/d and estimated glomerular filtration rate>30mL/min/1.73m2) and were receiving optimized RAAS inhibitor therapy. Interventions Patients were randomly assigned 1:1 to receive daily oral HCQ or a placebo for 6 months. Outcomes The primary outcome was percentage change in proteinuria between baseline and 6 months. Results 60 participants (mean estimated glomerular filtration rate, 53.8mL/min/1.73m2; median urine protein excretion, 1.7g/d) were recruited and randomly assigned to receive HCQ (n=30) or placebo (n=30). Percentage change in proteinuria at 6 months was significantly different between the HCQ group and the placebo group (−48.4% [IQR, −64.2%, −30.5%] vs 10.0% [IQR, −38.7%, 30.6%]; P Limitations The short treatment period and lack of postwithdrawal observations limit conclusions about long-term renoprotective efficacy and safety. Conclusions HCQ in addition to optimized RAAS inhibition significantly reduced proteinuria in patients with IgAN over 6 months without evidence of adverse events. These findings require confirmation in larger treatment trials. Funding This study was supported by grants from a government entity, the Capital of Clinical Characteristics, and the Applied Research Fund. Trial Registration Registered at ClinicalTrials.gov with study number NCT02942381.

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.

Skin-limited IgAV patients usually present self-limiting disease and good prognosis, while adult IgA vasculitis with nephritis (IgAV-N) present severe phenotype and poor prognosis. Previous studies showed that neutrophil-to-lymphocyte ratio (NLR) was an inflammatory indicator for predicting systemic involvement in children IgAV patients. In this study, we focused on adult IgAV-N patients to explore the relationship of NLR with disease phenotype and long-term renal prognosis.In this study, 245 IgAV-N patients, 1151 IgAN patients and 251 healthy controls were recruited. Composite endpoint was defined as 30% eGFR declined or end stage kidney disease.IgAV-N patients presented increased white blood cells (WBC), neutrophils (NE), platelet-to-lymphocyte ratio (PLR), and NLR levels, while decreased lymphocyte (LY) than healthy controls. When compared to clinical and pathological features matched IgAN patients, IgAV-N patients still showed higher WBC, NE, and NLR levels. NLR showed the best performance for the diagnosis of IgAV-N with the highest area under the ROC curves (0.738). IgAV-N patients in high NLR group (2.41) presented with sever baseline manifestations and more acute pathological lesions than low NLR group (≤2.41). 77 patients with regular follow-up were used for survival analysis. After adjusting some well-known risk factors, NLR levels remained as an independent risk factor for poor renal outcome in adult patients with IgAV-N (HR, 1.913; 95% CI, 1.314 to 2.787, P = 0.001).NLR levels were associated with the clinical and pathological phenotypes, and NLR may serve as an independent risk factor for poor renal outcome in adult IgAV-N patients.

Background Breast cancer (BC) is one of the most common cancers and the leading cause of death in women. Previous studies have demonstrated that FAM49B is implicated in several tumor progression, however, the role and mechanism of FAM49B in BC remain to be explored. Therefore, in this study, we aimed to systematically study the role of FAM49B in the proliferation, metastasis, apoptosis, and chemoresistance of BC, as well as the corresponding molecular mechanisms and downstream target. Methods The ONCOMINE databases and Kaplan–Meier plotter databases were analyzed to find FAM49B and its prognostic values in BC. FAM49B expression in BC and adjacent non-tumor tissues was detected by western blot and IHC. Kaplan–Meier analysis was used to identify the prognosis of BC patients. After FAM49B knockdown in MCF-7 and MDA-MB-231 cells, a combination of co-immunoprecipitation, MTT, migration, and apoptosis assays, nude mouse xenograft tumor model, in addition to microarray detection and data analysis was used for further mechanistic studies. Results In BC, the results showed that the expression level of FAM49B was significantly higher than that in normal breast tissue, and highly expression of FAM49B was significantly positively correlated with tumor volume, histological grade, lymph node metastasis rate, and poor prognosis. Knockdown of FAM49B inhibited the proliferation and migration of BC cells in vitro and in vivo. Microarray analysis revealed that the Toll-like receptor signaling pathway was inhibited upon FAM49B knockdown. In addition, the gene interaction network and downstream protein validation of FAM49B revealed that FAM49B positively regulates BC cell proliferation and migration by promoting the Rab10/TLR4 pathway. Furthermore, endogenous FAM49B interacted with ELAVL1 and positively regulated Rab10 and TLR4 expression by stabilizing ELAVL1. Moreover, mechanistic studies indicated that the lack of FAM49B expression in BC cells conferred more sensitivity to anthracycline and increased cell apoptosis by downregulating the ELAVL1/Rab10/TLR4/NF-κB signaling pathway. Conclusion These results demonstrate that FAM49B functions as an oncogene in BC progression, and may provide a promising target for clinical diagnosis and therapy of BC.

Disturbance in microbiota affects the mucosal immune response, and it is gradually recognized to be associated with the Immunoglobin A nephropathy (IgAN). This study aims to explore the potential roles of oral microbiota in disease pathogenesis. Saliva samples were collected from 31 patients with IgAN and 30 controls for 16S rRNA gene sequencing. The evenness, diversity, and composition of oral microbiota were analyzed. Moreover, sub-phenotype association analysis was conducted. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to investigate microbiota functions. Compared to healthy controls, microbial diversity tended to decrease in IgAN, and the microbial profiles were remarkably distinguished. The relative abundance of Capnocytophaga and SR1_genera_incertae_sedis were enriched, whereas 17 genera, such as Rothia, were significantly reduced in IgAN. Variable importance in projection scores showed that 12 genera, including Capnocytophaga, Rothia, and Haemophilus, could discriminate between the two groups. In the sub-phenotype correlation analysis, the relative abundance of Capnocytophaga and Haemophilus was positively associated with levels of proteinuria and serum IgA, respectively. Further metabolic pathway analysis showed 7 predictive functional profiles, including glycosphingolipid biosynthesis, oxidative phosphorylation, and N-glycan biosynthesis were enriched in IgAN. In conclusion, disturbance in oral microbiota was observed to be associated with IgAN and its sub-phenotypes, which may shed novel insights into disease pathogenesis from a microbiome perspective.

Background and objectives IgA nephropathy is the most common primary GN worldwide. Previous research demonstrated that collectin11, an initiator of the complement lectin pathway, was involved in both AKI and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy. Design, setting, participants, & measurements The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. In vitro, human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by quantitative RT-PCR and immunofluorescence. The codeposition of collectin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays. Results In total, 37% of participants with IgA nephropathy (22 of 60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface via the interaction with deposited IgA1-immune complexes. In vitro, we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells. Conclusions In situ–produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.

The gut microbiota and host genetics are implicated in the pathogenesis of IgAN. Recent studies have confirmed that microbial compositions are heritable (microbiome quantitative trait loci [QTL])., The gut microbiota has been implicated in immunoglobin A nephropathy (IgAN) because the intestinal immune response is assumed to be one of the disease triggers. Since the microbial composition is heritable, we hypothesize that genetic variants controlling gut microbiota composition may be associated with susceptibility to IgAN or clinical phenotypes. A total of 175 gut-microbiome-associated genetic variants were retrieved from the Genome-Wide Association Study (GWAS) Catalog. Genetic associations were examined in 1,511 patients with IgAN and 4,469 controls. Subphenotype associations and microbiome annotations were undertaken for a better understanding of how genes shaped phenotypes. Likely candidate microbes suggested in genetic associations were validated using 16S rRNA gene sequencing in two independent data sets with 119 patients with IgAN and 45 controls in total. Nine genetic variants were associated with susceptibility to IgAN. Risk genotypes of LYZL1 were associated with higher serum levels of galactose-deficient IgA1 (Gd-IgA1). Other significant findings included the associations between the risk genotype of SIPA1L3 and early age at onset, PLTP and worse kidney function, and AL365503.1 and more severe hematuria. Besides, risk genotypes of LYZL1 and SIPA1L3 were associated with decreased abundances of Dialister and Bacilli, respectively. Risk genotypes of PLTP and AL365503.1 were associated with increased abundances of Erysipelotrichaceae and Lachnobacterium, respectively. 16S data validated a decreased tendency for Dialister and an increased tendency for Erysipelotrichaceae in IgAN. In this pilot study, our results provided preliminary evidence that the gut microbiota in IgAN was affected by host genetics and shed new light on candidate bacteria for future pathogenesis studies. IMPORTANCE The gut microbiota and host genetics are implicated in the pathogenesis of IgAN. Recent studies have confirmed that microbial compositions are heritable (microbiome quantitative trait loci [QTL]). The relationship between host genetics and the microbiota and the role of the microbiota in IgAN are unclear. We retrieved the GWAS Catalog and associated microbiome QTL in IgAN, observing that nine genetic variants were associated with IgAN susceptibility and some clinical phenotypes. In a consistent way, the decreased abundance of Dialister was associated with higher serum levels of Gd-IgA1, and 16S rRNA gene analysis confirmed the decreased abundance of Dialister in IgAN. These data provided preliminary evidence that the gut microbiota in IgAN was affected by host genetics, which is a new strategy for future pathogenesis and intervention studies.

Background Immunoglobulin A nephropathy (IgAN) is characterized by predominant IgA deposition in the glomerular mesangium. Previous studies have proved that renal-deposited IgA in IgAN came from circulating IgA1-containing complexes (CICs). Methods To explore the composition of CICs in IgAN, we isolated CICs from IgAN patients and healthy controls and then quantitatively analyzed them by mass spectrometry. Meanwhile, the isolated CICs were used to treat human mesangial cells to monitor mesangial cell injury. Using the protein content and injury effects, the key constituent in CICs was identified. Then the circulating levels of identified key constituent–IgA complex were detected in an independent population by an in-house-developed enzyme-linked immunosorbent assay. Results By comparing the proteins of CICs between IgAN patients and controls, we found that 14 proteins showed significantly different levels. Among them, α1-microglobulin content in CICs was associated with not only in vitro mesangial cell proliferation and monocyte chemoattractant protein 1 secretion, but also in vivo estimated glomerular filtration rate (eGFR) levels and tubulointerstitial lesions in IgAN patients. Moreover, we found α1-microglobulin was prone to bind aberrant glycosylated IgA1. Additionally, elevated circulating IgA-α1-microglobulin complex levels were detected in an independent IgAN population and IgA-α1-microglobulin complex levels were correlated with hypertension, eGFR levels and Oxford T- scores in these IgAN patients. Conclusions Our results suggest that the IgA-α1-microglobulin complex is an important constituent in CICs and that circulating IgA-α1-microglobulin complex detection might serve as a potential noninvasive biomarker detection method for IgAN.

Background: Renal arteriolar microangiopathic (MA) lesions were common in IgA nephropathy (IgAN) and their presence was an independent risk factor for kidney failure. Endothelial injury is regarded as the most important cause of MA lesions. The deposition of circulating IgA1 complex (cIgA1) in the glomerular mesangium has been regarded as the most important mechanism to induce the injury of podocyte and tubular epithelium. Whether cIgA1 can induce vascular endothelial injury is not clear.Methods: Blood of 59 IgAN patients and 19 healthy controls was collected, pending the measurement of Willebrand factor (vWF) and soluble vascular cell adhesion molecule 1 (sVCAM1) and Heparin-binding EGF-like growth factor (HB-EGF) by ELISA. cIgA1 was isolated from 12 primary IgAN patients who had not been treated with steroids or immunosuppressants and 10 healthy controls. Then, IgA-HMC medium (IgA-HMCM) was prepared by collecting the cell culture supernatants of growth-arrested HMCs grown in medium containing cIgA1. Human umbilical vein endothelial cells (HUVECs) were cultured with the IgA-HMCM in the presence or absence of Panax notoginseng saponins (PNS), which are anti-inflammatory bioactive components of the Chinese medicinal herb Panax notoginseng. The protein levels of interleukin-6 (IL-6) and chemokine (C-X-C motif) ligand 1 (CXCL1) in IgA-HMCM and vWF, sVCAM1 and HB-EGF in HUVEC medium were determined by ELISA. Results: IgAN patients had higher levels of vWF, sVCAM-1 and HB-EGF than that in healthy controls. cIgA1 from IgAN patients (IgAN-cIgA1) induced significantly higher expression levels of IL-6 and CXCL1 in HMCM than cIgA1 from healthy controls. vWF, sVCAM1 and HB-EGF levels induced by conditioned IgAN-cIgA1-treated HMCM (IgAN-HMCM) were significantly higher than the levels induced by conditioned cIgA1-treated HMCM from healthy controls (HC-HMCM). After HUVECs were cultured in PNS and IgAN-HMCM, the levels of vWF, sVCAM1 and HB-EGF were significantly lower in the culture supernatants of cells cultured in PNS and IgAN-HMCM than in that of cells cultured in IgAN-HMCM alone. Conclusion: cIgA1 could activate mesangial cells and, in turn, induce the injury of endothelial cells by inflammation factors in vitro.

Introduction: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. It involves both genetic and environmental factors, among which DNA methylation, the most studied epigenetic modification, was shown to play a role. Here, we assessed genome-wide DNA methylation and gene expression profiles in 2 pairs of IgAN-discordant monozygotic (MZ) twins, in order to characterize methylation changes and their potential influences on gene expression in IgAN. Methods: Genome-wide DNA methylation and gene expression profiles were evaluated in peripheral blood mononuclear cells obtained from 2 IgAN-discordant MZ twins. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were detected, and an integrated analysis was performed. Finally, functional enrichment analysis was done for DMR-associated genes and DEGs. Results: Totally 521 DMRs were detected for 2 IgAN-discordant MZ twins. Among them, 9 DMRs were found to be mapped to genes that differentially expressed in 2 MZ twins, indicating the potential regulatory mechanisms of expression for these 9 genes ( MNDA, DYSF, IL1R2, TLR6, TREML2, TREM1, IL32, S1PR5, and ADGRE3) in IgAN. Biological process analysis of them showed that they were mostly involved in the immune system process. Functional enrichment analysis of DEGs and DMR-associated genes both identified multiple pathways relevant to inflammatory and immune responses. And DMR-associated genes were significantly enriched in terms related to T-cell function. Conclusions: Our findings indicate that changes in DNA methylation patterns were involved in the pathogenesis of IgAN. Nine target genes detected in our study may provide new ideas for the exploration of molecular mechanisms of IgAN.

IgA nephropathy (IgAN) is a disease associated with activation of the complement system. But the factors influencing complement activation in IgAN are not fully understood. Complement factor H (FH) is an essential negative regulator of complement C3 activation. Complement factor H-related protein (FHR)-5 shares high sequence similarity with factor H. However, unlike factor H, on binding to activated C3 it enables further activation to proceed. Previously, we reported the contribution of rare variants of the CFHR5 gene to IgAN susceptibility. Here we compared circulating levels of FHR-5 in 1126 patients with IgAN and regular follow-up with those of 153 unrelated healthy individuals to explore the relationship of FHR-5 levels with IgAN development and progression. Circulating FHR-5 levels were significantly elevated in patients with IgAN compared to healthy individuals (median 4.55 [interquartile range 3.58 to 5.85] μg/ml vs 3.19 [interquartile range 2.55 to 3.92] μg/ml). Higher circulating FHR-5 levels were associated with a lower estimated glomerular filtration rate, hypertension, and severe Oxford-T and Oxford-C scores. High FHR-5 levels were independently and significantly associated with a risk of developing either a 30% decline in the estimated glomerular filtration rate or end-stage renal disease (hazard ratio, per standard deviation increment of natural square root transformed FHR-5 of 1.226; 95% confidence interval: 1.106-1.359). Thus, the circulating FHR-5 level is an independent risk factor for IgAN progression.