A multicenter, prospective, observational study to determine association of mesangial C1q deposition with renal outcomes in IgA nephropathy
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ABSTRACT:
SUBMITTER: Tan L
PROVIDER: S-EPMC7943768 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
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Project description:Background and objectivesThe prognostic value of mesangial C4d deposits in IgA nephropathy has been analyzed in patients with reduced GFR but has not been analyzed in those with normal kidney function. The main objective of the study was to analyze the prognostic value of C4d deposits and association with response to treatment in patients with IgA nephropathy and normal GFR.Design, setting, participants, & measurementsThis retrospective cohort study included 190 patients with idiopathic IgA nephropathy diagnosed by kidney biopsy between 1988 and 2005. The patients had GFR≥80 ml/min per 1.73 m2 at the time of diagnosis, and they had a paraffin-embedded kidney biopsy with eight glomeruli available.ResultsIn total, 170 (89%) and 20 (11%) patients were >18 and <18 years old, respectively; median (interquartile range) follow-up was 15 (12-22) years. Mesangial C4d deposit prevalence was 20% (38 of 190). At diagnosis, C4d-positive versus -negative patients had higher protein-to-creatinine ratio (median [interquartile range]: 1.94 g/g [0.9-3.1] versus 1.45 g/g [0.9-2.2]; P=0.04). During follow-up, C4d-positive patients showed a higher number of nephritic flares (median [range]: 1.4 [0-5] versus 0.9 [0-2]; P=0.04), had a higher protein-to-creatinine ratio (median [interquartile range]: 1.32 g/g [0.7-1.7] versus 0.89 g/g [0.1-1.3]; P<0.01), were more prone to receive repeated treatment with corticosteroids (45% versus 24%; P<0.01), and showed a larger reduction in eGFR (-1.6 versus -0.8 ml/min per 1.73 m2 per year; P=0.04). Furthermore, the presence of mesangial C4d deposits was an independent predictor of long-term kidney survival.ConclusionsC4d deposits may be one of the earliest poor prognostic variables available for patients with idiopathic IgA nephropathy and normal kidney function at the time of diagnosis. However, Cd4 deposits alone are not associated with the response to angiotensin blockers or corticosteroid treatment.
| S-EPMC5967419 | biostudies-literature
Project description:IgA1 mesangial deposition is the hallmark of IgA nephropathy and Henoch-Schönlein purpura, the onset of which often follows infections. Deposited IgA has been reported as polymeric, J chain associated, and often, hypogalactosylated but with no information concerning the influence of the IgA repertoire or the link between immune stimuli and IgA structure. We explored these issues in the ?1KI mouse model, which produces polyclonal human IgA1 prone to mesangial deposition. Compared with mice challenged by a conventional environment, mice in a specific pathogen-free environment had less IgA deposition. However, serum IgA of specific pathogen-free mice showed more galactosylation and much lower polymerization. Notably, wild-type, ?1KI, and even J chain-deficient mice showed increased polymeric serum IgA on exposure to pathogens. Strict germfree conditions delayed but did not completely prevent deposition; mice housed in these conditions had very low serum IgA levels and produced essentially monomeric IgA. Finally, comparing monoclonal IgA1 that had different variable regions and mesangial deposition patterns indicated that, independently of glycosylation and polymerization, deposition might also depend on IgA carrying specific variable domains. Together with IgA quantities and constant region post-translational modifications, repertoire changes during immune responses might, thus, modulate IgA propensity to deposition. These IgA features are not associated with circulating immune complexes and C3 deposition and are more pertinent to an initial IgA deposition step preceding overt clinical symptoms in patients.
| S-EPMC5004660 | biostudies-literature
Project description: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.
| S-EPMC8324010 | biostudies-literature
Project description:The histologic diagnosis of idiopathic IgA Nephopathy (IgAN) is based o renal lesions scores. Aim of our study was to identify specific gene expression changes that characterize active renal lesions that may be more responsive to immunosuppressive therapy than chronic lesions. Total RNA was extracted from archival FFPE renal tissue samples of 55 IgAN patients, 31 non-IgAN patients. IgAN patients were accurately stratified based on the LUMPED classifications. Genome-wide gene expression profiles were generated and Oneway ANOVA with tukeyHSD post hoc testing was used to identify specific transcripts associated with active and chronic renal lesions in IgAN. RT-PCR was used to validate selected transcripts. Immunohistochemistry (IHC) was used to evaluate specific protein expression in biopsy specimens. Bioinfomatic analysis identified 183 genes with a Fold Change > 1.5 exclusively modulated in IgAN biopsies with active lesions and 162 genes with Fold Change > 1.5 exclusively modulated in IgAN biopsies with chronic lesions. These genes belonged to renal cellular damage and immune system regulatory pathways. To establish the validity of gene expression determined by microarray analysis, we performed RT-PCR on genes that were putatively involved in generating active and chronic lesions that may be involved in activating local inflammatory response and contributing to renal damage. Validated transcripts were also confirmed at protein level with IHC on kidney biopsy specimens. Transcriptomics on FFPE renal biopsies integrates histomorphologic renal lesions. Our study identifies specific gene expression changes involved in active and chronic lesions at the time of renal biopsy. This novel information may be used for personalized therapy through a system pharmacology approach to identify targeted molecules able to revert aberrant expression networks characterizing active and chronic lesions.
2020-06-02 | GSE115857 | GEO
Project description:Specific molecular biomarkers were detected in kidney biopsy of IgA nephropathy characterizing active (E and C) and chronic (T) renal lesions compared with other non-IgA glomerulonephritis and living donors
2020-09-13 | GSE116626 | GEO
Project description:BackgroundImmunoglobulin A nephropathy (IgAN) is a clinical and pathological syndrome with heterogenous manifestation and progression. Complement activation is involved in the disease. However, the clinical significance of C4 deposition in IgAN is obscure.MethodsA multicenter retrospective study was conducted in biopsy-proven IgAN patients. Based on mesangial C4 deposition, patients were divided into two groups. The baseline clinical data and immunopathological phenotypes were compared. The composite endpoint was defined as eGFR decline greater than 50%, doubling of baseline serum creatinine, the occurrence of end-stage renal disease (ESRD).ResultsA total of 642 IgAN patients were recruited, with 41 patients showing mesangial C4 deposition. The mesangial C4 positive group showed lower serum albumin, higher proteinuria, and a higher rate of IgG, IgM, and C1q mesangial deposition. After a median follow-up of 43.18 months, 81 (12.62%) patients achieved the composite endpoint. The multivariate Cox regression models identified glomerular C4 deposition (hazard ratios [HR] = 3.22, 95% confidence intervals [CI] = 1.51-6.87, p < 0.01), global sclerosis (G1 vs. G0, HR = 1.90, 95%CI = 1.02-3.52, p = 0.04; G2 vs. G0, HR = 3.72, 95%CI = 1.98-7.00, p < 0.01), male (HR = 1.80, 95%CI = 1.10-2.97, p = 0.02), serum creatinine (HR = 1.01, 95%CI = 1.00-1.01, p < 0.01), triglyceride (HR = 1.17, 95%CI = 1.01-1.35, p = 0.04), proteinuria (HR = 1.07, 95%CI = 1.01-1.13, p = 0.02), serum C3 level (HR = 0.05, 95%CI = 0.01-0.25, p < 0.01), and serum C4 level (HR = 99.59, 95%CI = 8.69-1140.89, p < 0.01) as independent risk factors for poor renal outcomes.ConclusionsGlomerular mesangial C4 deposition and global sclerosis are independent predictors for poor prognosis in IgAN patients.
| S-EPMC7470092 | biostudies-literature
Project description:BackgroundIgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits.MethodsTo explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic human IgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans.ResultsWe found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition.ConclusionsIn a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.
| S-EPMC6622418 | biostudies-literature
Project description:IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type-specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell-positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell-positive standard genes. Additionally, patient clinical parameters (serum creatinine values and eGFRs) significantly correlated with Z scores derived from the expression profile of mesangial cell-positive standard genes. Among patients grouped according to Oxford MEST score, patients with segmental glomerulosclerosis had a significantly higher mesangial cell-positive standard gene Z score than patients without segmental glomerulosclerosis. By investigating mesangial cell proteomics and glomerular transcriptomics, we identified 22 common pathways induced in mesangial cells by gd-IgA, most of which mediate inflammation. The genes, proteins, and corresponding pathways identified provide novel insights into the pathophysiologic mechanisms leading to IgAN.
| S-EPMC5619958 | biostudies-literature
Project description:Mesangial proliferation is a diagnostic feature and a prognostic predictor of immunoglobulin A nephropathy (IgAN). We aimed to investigate the gene expression profiles of IgAN glomerulus according to the presence of mesangial proliferation. We performed spatial-specific transcriptomic profiling on kidney biopsy tissues using the GeoMx Digital Spatial Profiler. Twelve cases with three glomeruli for each case were profiled using direct pathologic classification (4 M1-IgAN, 4 M0-IgAN, and 4 donor controls). The results of enriched glom-specific genes demonstrated that M1-IgAN could be distinguished from controls (77 upregulated and 55 downregulated DEGs), while some DEGs were identified between M1-IgAN and M0-IgAN cases (24 upregulated and 8 downregulated DEGs) or between M0 and controls (1 upregulated and 16 downregulated DEGs). TCF21, an early podocyte damage marker, was the only differentially expressed gene (DEG) consistently upregulated in both M1-IgAN and M0-IgAN patients, whereas ATF3, EGR1, DUSP1, FOS, JUNB, KLF2, NR4A1, RHOB, and ZFP36 were consistently downregulated in IgAN cases. Glomeruli from M1-IgAN cases were significantly enriched for cell surface/adhesion molecules and gene expressions associated with vascular development or the extracellular matrix. Spatial transcriptomic analysis may contribute to dissecting structure-specific pathophysiology and molecular changes in IgAN.
| S-EPMC10817934 | biostudies-literature
Project description:BackgroundCirculating immune complexes (CIC) containing galactose (Gal)-deficient IgA1 from adults with IgA nephropathy (IgAN) induce proliferation of cultured mesangial cells, but activities of CIC from pediatric patients with the disease have not been studied.MethodsCIC of different sizes were isolated from sera of pediatric and adult IgAN patients and their effects on cultured human mesangial cells (MC) were assessed by measuring cellular proliferation, expression of IL-6 and IL-8 and laminin and phosphotyrosine signaling.ResultsLarge CIC from pediatric IgAN patients (>800 kDa) containing Gal-deficient IgA1 stimulated cellular proliferation, whereas in some patients, smaller CIC were inhibitory. Addition of stimulatory and inhibitory CIC to MC differentially altered phosphorylation patterns of three major tyrosine-phosphorylated proteins of molecular mass 37, 60 and 115 kDa. The stimulatory CIC transiently increased tyrosine-phosphorylation of the 37-kDa protein and decreased phosphorylation of the other two proteins, whereas the inhibitory CIC increased phosphorylation of all three proteins. Furthermore, we investigated the influence of IgA1-containing CIC from sera of children with IgAN with clinically active disease (i.e., abnormal urinalysis and/or serum creatinine concentration) or inactive disease (i.e., normal urinalysis and serum creatinine concentration) on the expression of IL-6 and IL-8 genes by mesangial cells. Real-time reverse transcription-polymerase chain reaction results showed that the CIC from a patient with active disease stimulated MC to express the two cytokine genes at higher levels than did the CIC from a patient with inactive disease. Moreover, stimulatory CIC increased production of the extracellular matrix protein laminin.ConclusionThese data indicate that sera of pediatric IgAN patients contain biologically active CIC with Gal-deficient IgA1.
| S-EPMC3203630 | biostudies-literature