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      “Associated” or “Secondary” IgA nephropathy? An outcome analysis

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          Abstract

          Background

          Whether differences in outcome between primary (pIgAN) and secondary IgA nephropathy (sIgAN) exist is uncertain.

          Methods

          We conducted a retrospective, observational study that included all histologically diagnosed IgAN patients between 2010–2017 (N = 306), 248 with pIgAN and 58 with sIgAN. To obtain samples with similar risk of progression, sIgAN patients were grouped as liver disease and autoimmune/viral disease and propensity score matched to corresponding pIgAN samples. Univariate (Kaplan Meier) and multivariate time-dependent (Cox modelling) analyses were performed to identify predictors of the composite end-point (doubling of serum creatinine, end-stage kidney disease or death).

          Results

          Of the whole cohort, 20% had sIgAN (6% alcoholic cirrhosis, 6% autoimmune disease and 8% viral infections). sIgAN patients were older, had more comorbidities, lower proteinuria and higher haematuria, but similar distribution in MESTC lesions and eGFR as those with pIgAN. They reached the end-point in similar proportions with those with pIgAN (43 vs. 30%; p = 0.09) but their mortality was higher (19 vs. 3%; p<0.0001). Both in unmatched (HR 0.80, 95%CI 0.42–1.52; p = 0.5) and matched samples (log-rank test: liver disease-IgAN vs. pIgAN, p = 0.1; autoimmune/viral-IgAN vs. pIgAN, p = 0.3), sIgAN was not predictive for end-point. In analyses restricted only to sIgAN, those with viral infections (HR, 10.98; 95% CI, 1.12–107.41; p = 0.03) and lower eGFR (HR, 0.94; 95%CI, 0.89–0.98; p = 0.007) had a worse prognosis. Immunosuppression did not influence outcome.

          Conclusions

          The differences in MESTC score and outcome between pIgAN and sIgAN seems to be minimal, suggesting that “associated” describes better than “secondary” the relationship among the two. Immunosuppression did not to influence outcome of sIgAN.

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          Most cited references19

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          The incidence of primary glomerulonephritis worldwide: a systematic review of the literature.

          Little is known about the worldwide variation in incidence of primary glomerulonephritis (GN). The objective of this review was to critically appraise studies of incidence published in 1980-2010 so that an overall view of trends of these diseases can be found. This would provide important information for determining changes in rates and understanding variations between countries. All relevant papers found through searches of Medline, Embase and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. This review includes 40 studies of incidence of primary GN from Europe, North and South America, Canada, Australasia and the Middle East. Rates for the individual types of disease were found to be in adults, 0.2/100,000/year for membrano-proliferative GN, 0.2/100,000/year for mesangio-proliferative GN, 0.6/100,000/year for minimal change disease, 0.8/100,000/year for focal segmental glomerulosclerosis, 1.2/100,000/year for membranous nephropathy and 2.5/100,000/year for IgA nephropathy. Rates were lower in children at around 0.1/100,000/year with the exception of minimal change disease where incidence was reported to be 2.0/100,000/year in Caucasian children with higher rates in Arabian children (9.2/100,000/year) and Asian children (6.2-15.6/100,000/year). This study found that incidence rates of primary GN vary between 0.2/100,000/year and 2.5/100,000/year. The incidence of IgA nephropathy is at least 2.5/100,000/year in adults; this disease can exist subclinically and is therefore only detected by chance in some patients. In addition, referral policies for diagnostic biopsy vary between countries. This will affect the incidence rates found.
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            New developments in the genetics, pathogenesis, and therapy of IgA nephropathy

            Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multi-hit pathogenesis model that integrates findings from studies of galactose-deficient IgA1, anti-glycan response and immune complex-induced kidney injury, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geo-ethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of inter-population allelic differentiation across all Genome Wide Association Studies (GWAS) loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multi-locus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the “Intestinal Immune Network for IgA Production” emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multi-hit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies.
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              The MEST score provides earlier risk prediction in lgA nephropathy.

              The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: SupervisionRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SupervisionRole: Writing – original draft
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Supervision
                Role: ConceptualizationRole: Data curationRole: Formal analysis
                Role: ConceptualizationRole: Data curationRole: Formal analysis
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SupervisionRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                9 August 2019
                2019
                : 14
                : 8
                : e0221014
                Affiliations
                [1 ] Nephrology Department, Fundeni Clinical Institute, Bucharest, Romania
                [2 ] Nephrology Department,”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
                [3 ] ”Dr. Carol Davila” Teaching Hospital of Nephrology, Bucharest, Romania
                [4 ] ”Victor Babes” National Institute of Pathology, Bucharest, Romania
                International University of Health and Welfare, School of Medicine, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-4796-4950
                http://orcid.org/0000-0003-3306-189X
                http://orcid.org/0000-0002-4788-7724
                Article
                PONE-D-19-14472
                10.1371/journal.pone.0221014
                6688810
                31398224
                62c92b5a-3821-4b9e-ab19-ad63c93f9687
                © 2019 Obrișcă et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 May 2019
                : 30 July 2019
                Page count
                Figures: 4, Tables: 4, Pages: 12
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Proteinuria
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Proteinuria
                Biology and Life Sciences
                Immunology
                Immune Suppression
                Medicine and Health Sciences
                Immunology
                Immune Suppression
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Immune Suppression
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Immune Suppression
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Transmission and Infection
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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