The genetics and immunobiology of IgA nephropathy.
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ABSTRACT:
SUBMITTER: Kiryluk K
PROVIDER: S-EPMC4089454 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
Publications
The genetics and immunobiology of IgA nephropathy.
Kiryluk Krzysztof K Novak Jan J
The Journal of clinical investigation 20140602 6
IgA nephropathy (IgAN) represents the leading cause of kidney failure among East Asian populations and the most frequent form of primary glomerulonephritis among Europeans. Patients with IgAN develop characteristic IgA1-containing immune complexes that deposit in the glomerular mesangium, producing progressive kidney injury. Recent studies define IgAN as an autoimmune trait of complex architecture with a strong genetic determination. This Review summarizes new insights into the role of the O-gly ...[more]
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Project description:Immunoglobulin A (IgA) nephropathy (IgAN), the most common form of glomerulonephritis, is one of the leading causes of end-stage kidney disease (ESKD). It is widely believed that genetic factors play a significant role in the development of IgAN. Previous studies of IgAN have provided important insights to unravel the genetic architecture of IgAN and its potential pathogenic mechanisms. The genome-wide association studies (GWASs) together have identified over 30 risk loci for IgAN, which emphasizes the importance of IgA production and regulation in the pathogenesis of IgAN. Follow-up fine-mapping studies help to elucidate the candidate causal variant and the potential pathogenic molecular pathway and provide new potential therapeutic targets. With the rapid development of next-generation sequencing technologies, linkage studies based on whole-genome sequencing (WGS)/whole-exome sequencing (WES) also identify rare variants associated with IgAN, accounting for some of the missing heritability. The complexity of pathogenesis and phenotypic variability may be better understood by integrating genetics, epigenetics, and environment. We have compiled a review summarizing the latest advancements in genetic studies on IgAN. We similarly summarized relevant studies examining the involvement of epigenetics in the pathogenesis of IgAN. Future directions and challenges in this field are also proposed.
| S-EPMC10780034 | biostudies-literature
Project description:IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.
| S-EPMC5383386 | biostudies-literature
Project description:IntroductionGalactose-deficient IgA1 (Gd-IgA1) and related IgA/IgG immune complexes have been identified as the key drivers in the pathogenesis of IgA nephropathy (IgAN). However, their roles in the development of secondary IgAN are still unknown.MethodsIn this study, we measured the plasma Gd-IgA1 level, IgA/IgG complex, and Gd-IgA1 glomerular deposits in 100 patients with various kinds of secondary IgAN. Plasma Gd-IgA1 was measured using a lectin-based enzyme-linked immunosorbent assay, and Gd-IgA1 in glomerular deposits was examined by double immunofluorescent staining using its specific monoclonal antibody KM55.ResultsPatients with secondary IgAN presented with higher plasma Gd-IgA1 levels compared to healthy controls (median, 354.61 U/ml; interquartile range [IQR], 323.93, 395.57 U/ml vs. median, 303.17 U/ml; IQR, 282.24, 337.92 U/ml, P < 0.001) or patients with other kidney diseases (median, 314.61 U/ml; IQR, 278.97, 343.55 U/ml, P < 0.001). A similar trend was observed in plasma IgA/IgG immune complexes or IgA1. There were no differences between secondary and primary IgAN in plasma Gd-IgA1 levels (median, 378.54 U/ml; IQR, 315.96, 398.33 U/ml, P = 0.700) and IgA1-IgG complex levels (median, 18.76 U/ml; IQR, 14.51, 22.83 U/ml vs. median, 19.11 U/ml; IQR, 13.21, 22.37 U/ml, P = 0.888). Co-localized IgA1 and Gd-IgA1 of both secondary and primary IgAN indicated that they both share the feature of Gd-IgA1 deposits on the glomerular mesangium.ConclusionOur study strongly suggests that secondary IgAN shares a similar galactose-deficient IgA1-oriented pathogenesis with primary IgAN.
| S-EPMC7000803 | biostudies-literature
Project description:IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is considered that the pathogenesis of IgAN involves the 'multiple hit theory' and the immune-inflammatory mechanism; however, these theories have certain limitations. The gold standard for diagnosing IgAN is still renal biopsy. Although renal biopsy is accurate, it is traumatic and is associated with some risks and limitations, so there is a need for non-invasive diagnostic methods. According to recent studies, microRNAs (miRNAs) play important roles in the occurrence and development of IgAN; thus, they provide the possibility of the noninvasive diagnosis of IgAN and also have some value in predicting prognosis. This review summarizes the current research status of miRNAs in the occurrence, development, diagnosis, and prognosis of IgAN. We also highlight some interesting and challenging points that require further study.
| S-EPMC8462925 | biostudies-literature
Project description: Not available
| S-EPMC10690074 | biostudies-literature
Project description:we aimed at developing a urinary biomarker-based algorithm that predicts rapid disease progression in IgAN, thus enabling a personalized risk stratification.
2022-02-15 | PXD020288 | Pride
Project description:Background and objectivesPoly-IgA immune complex formation and glomerular deposition play a key role in IgA nephropathy. Our study sought to develop a new methodology for one-step serologic detection of poly-IgA levels.Design, setting, participants, & measurementsA novel ELISA method using recombinant CD89 as a "capturing" probe was established for detecting poly-IgA immune complex in plasma. We applied semiquantitative measurements of these poly-IgA indices in patients recruited at Peking University First Hospital who had IgA nephropathy or other kidney disease types, as compared with healthy controls. The longitudinal trend of the poly-IgA index and the association with pathologic parameters and treatment responses were evaluated. Finally, we analyzed the molecular composition of poly-IgA complexes in patients by mass spectrometry.ResultsRecombinant CD89-mounted ELISA plates specifically captured plasma poly-IgA. The levels of poly-IgA immune complex (26.7 [interquartile range (IQR) 17.1-42.6] U/ml) in IgA nephropathy were significantly higher than those in healthy controls (15.5 [IQR 10.7-20.0] U/ml; P<0.001) or in controls with non-IgA nephropathy disease (14.8 [IQR 10.5-21.9] U/ml; P<0.001). Higher levels of poly-IgA immune complex were associated with lower eGFR and worse kidney outcome. Accuracy parameters and concordant statistics showed good discrimination between IgA nephropathy and healthy controls based on poly-IgA index levels (area under the curve [AUC], 0.78; 95% confidence interval [95% CI], 0.72 to 0.83; P<0.001), significantly outperforming galactose-deficient IgA1 levels (AUC, 0.70; P=0.05). Corticosteroid and immunosuppressant treatments lowered poly-IgA indices. After a recombinant CD89-directed workflow in conjunction with mass spectrometry, we also analyzed the molecular composition of IgA immune complex in patients with IgA nephropathy.ConclusionsHigher level of recombinant CD89-bound poly-IgA immune complex was associated with the severity of the disease and with treatment response to steroids and immunosuppressants.
| S-EPMC8729420 | biostudies-literature
Project description:Background:IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB). Methods:We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB. Results:The IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23-4.38) than in controls (3.98; 3.97-3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02-4.06) than UKBB controls (3.98; 3.97-3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02-4.13) versus (3.98; 3.97-3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB. Conclusions:We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts.
| S-EPMC7572308 | biostudies-literature
Project description:BackgroundImmunoglobulin A nephropathy (IgAN) is among the commonest glomerulonephritides in Greece and an important cause of end-stage kidney disease (ESKD) with an insidious chronic course. Thus, the recently published International IgAN prediction tool could potentially provide valuable risk stratification and guide the appropriate treatment module. This study aimed to externally validate this prediction tool using a patient cohort from the IgAN registry of the Greek Society of Nephrology.MethodsWe validated the predictive performance of the two full models (with or without race) derived from the International IgAN Prediction Tool study in the Greek Society of Nephrology registry of patients with IgAN using external validation of survival prediction models (Royston and Altman). The discrimination and calibration of the models were tested using the C-statistics and stratified analysis, coefficient of determination ( RD2 ) for model fit, and the regression coefficient of the linear predictor (βPI), respectively.ResultsThe study included 264 patients with a median age of 39 (30-51) years where 65.2% are men. All patients were of Caucasian origin. The 5-year risk of the primary outcome (50% reduction in estimated glomerular filtration rate or ESKD) was 8%. The RD2 for the full models with and without race when applied to our cohort was 39 and 35%, respectively, and both were higher than the reported RD2 for the models applied to the original validation cohorts (26.3, 25.3, and 35.3%, respectively). Harrel's C statistic for the full model with race was 0.71, and for the model without race was 0.70. Renal survival curves in the subgroups (<16th, ~16 to <50th, ~50 to <84th, and >84th percentiles of linear predictor) showed adequate separation. However, the calibration proved not to be acceptable for both the models, and the risk probability was overestimated by the model.ConclusionsThe two full models with or without race were shown to accurately distinguish the highest and higher risk patients from patients with low and intermediate risk for disease progression in the Greek registry of IgAN.
| S-EPMC8885590 | biostudies-literature
Project description:The current gold-standard diagnostic technique for IgA nephropathy (IgAN), the leading form of primary glomerulonephritis, is renal biopsy. CD89 (the main IgA receptor) is expressed on the surface of monocytes and plays a role in disease pathogenesis. Immunocomplexes formed by sCD89 (soluble form) and Gd-IgA1 are related to disease prognosis. We hypothesize that reduced CD89 surface expression on monocytes may be a marker of disease severity. We aimed to analyze leukocyte subpopulations in peripheral blood and CD89 surface expression on monocytes in a prospective study of 22 patients and 12 healthy subjects (HS). Leukocyte subpopulations and CD89 expression were analyzed by flow cytometry. IgAN patients had a higher percentage of activated and effector memory CD4+ and CD8+ T lymphocytes, a lower percentage of transitional B lymphocytes and plasmablasts, and a higher percentage of CD56dimCD16+ NK cells and myeloid dendritic cells compared with HS. Correlations between reduced CD89 expression levels on nonclassical monocytes, histological findings of a poor prognosis on renal biopsy and baseline renal function were observed. IgAN patients show a characteristic immunological pattern in peripheral blood. A reduced expression level of CD89 on nonclassical monocytes identifies patients with a worse renal prognosis.
| S-EPMC7073027 | biostudies-literature