BACKGROUND: IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, has serious outcomes with end-stage renal disease developing in 30-50% of patients. The diagnosis requires renal biopsy. Due to its inherent risks, non-invasive approaches are needed. METHODS: We evaluated 91 Czech patients with biopsy-proven IgAN who were assessed at time of diagnosis for estimated glomerular filtration rate (eGFR), proteinuria, microscopic hematuria, and hypertension, and then followed prospectively. Serum samples collected at diagnosis were analyzed for galactose-deficient IgA1 (Gd-IgA1) using new native-IgA1 and established neuraminidase-treated-IgA1 tests, Gd-IgA1-specific IgG autoantibodies, discriminant analysis and logistic regression model assessed correlations with renal function and Oxford classification (MEST score). RESULTS: Serum levels of native (P <0.005) and neuraminidase-treated (P <0.005) Gd-IgA1 were associated with the rate of eGFR decline. A higher relative degree of galactose deficiency in native serum IgA1 predicted a faster eGFR decline and poor renal survival (P <0.005). However, Gd-IgA1 has not differentiated patients with low vs. high baseline eGFR. Furthermore, patients with high baseline eGFR that was maintained during follow-up were characterized by low serum levels of Gd-IgA1-specific IgG autoantibodies (P = 0.003). CONCLUSIONS: Including levels of native and neuraminidase-treated Gd-IgA1 and Gd-IgA1-specific autoantibodies at diagnosis may aid in the prognostication of disease progression in Czech patients with IgAN. Future tests will assess utility of these biomarkers in larger patients cohorts from geographically distinct areas.

Department of Medicine University of Alabama at Birmingham Birmingham Alabama United States of America

Department of Microbiology University of Alabama at Birmingham Birmingham Alabama United States of America

General Teaching Hospital 1st Faculty of Medicine Charles University Department of Nephrology Prague Czech Republic

General Teaching Hospital 1st Faculty of Medicine Charles University Institute of Medical Biochemistry and Laboratory Diagnostics Prague Czech Republic

Institute of Clinical and Experimental Medicine Department of Pathology Prague Czech Republic

Jan Evangelista Purkyne University in Ústí nad Labem Faculty of Environment Ústí nad Labem Czech Republic

Longhua Hospital Shanghai University of Traditional Medicine Shanghai China

PLoS One. 2019 Jul 12;14(7):e0219947. doi: 10.1371/journal.pone.0219947. PubMed

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Cattran DC, Coppo R, Cook HT, Feehally J, Roberts ISD, Troyanov S, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009; 76: 534–545. 10.1038/ki.2009.243 PubMed DOI

Wyatt RJ, Julian BA. IgA Nephropathy. New Engl J Med. 2013;368: 2402–2414. 10.1056/NEJMra1206793 PubMed DOI

Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007;18: 3177–3183. 10.1681/ASN.2007050526 PubMed DOI

Barbour SJ, Espino-Hernandez G, Reich HN, Coppo R, Roberts ISD, Feehally J, et al. The MEST score provides earlier risk prediction in IgA nephropathy. Kidney Int. 2016;89: 167–175. 10.1038/ki.2015.322 PubMed DOI

Haas M, Verhave JC, Liu ZH, Alpers CE, Barratt J, Becker JU, et al. J Am Soc Nephrol. 2017;28: 691–701. 10.1681/ASN.2016040433 PubMed DOI PMC

Suzuki H, Kiryluk K, Novak J, Moldoveanu Z, Herr AB, Renfrow MB, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011;22: 1795–803. 10.1681/ASN.2011050464 PubMed DOI PMC

Kiryluk K, Li YF, Sanna-Cherchi S, Rohanizadegan M, Suzuki H, Eitner F, et al. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS Genet. 2012;8: e1002765 10.1371/journal.pgen.1002765 PubMed DOI PMC

Kiryluk K, Li YF, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet. 2014;46: 1187–1196. 10.1038/ng.3118 PubMed DOI PMC

Kiryluk K, Li YF, Moldoveanu Z, Suzuki H, Reily C, Hou P, et al. GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet. 2017;13: e1006609 10.1371/journal.pgen.1006609 PubMed DOI PMC

Gale DP, Molyneux K, Wimbury D, Higgins P, Levine AP, Caplin B, et al. Galactosylation of IgA1 is associated with common variation in C1GALT1. J Am Soc Nephrol. 2017;28: 2158–2166. 10.1681/ASN.2016091043 PubMed DOI PMC

Moldoveanu Z, Wyatt RJ, Lee JY, Tomana M, Julian BA, Mestecky J, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. 2007;71: 1148–1154. 10.1038/sj.ki.5002185 PubMed DOI

Zhao N, Hou P, Lv JC, Moldoveanu Z, Li YF, Kiryluk K, et al. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int. 2012;82: 790–796. 10.1038/ki.2012.197 PubMed DOI PMC

Berthoux F, Suzuki H, Thibaudin L, Yanagawa H, Maillard N, Mariat C, et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J Am Soc Nephrol. 2012;23: 1579–1587. 10.1681/ASN.2012010053 PubMed DOI PMC

Hastings MC, Moldoveanu Z, Suzuki H, Berthoux F, Julian BA, Sanders JT, et al. Biomarkers in IgA nephropathy: relationship to pathogenetic hits. Expert Opin Med Diagn. 2013;7: 615–627. 10.1517/17530059.2013.856878 PubMed DOI PMC

Caliskan Y, Kiryluk K. Novel biomarkers in glomerular disease. Adv Chronic Kidney Dis. 2014;21: 205–216. 10.1053/j.ackd.2013.12.002 PubMed DOI PMC

Coppo R, Fonsato V, Balegno S, Ricotti E, Loiacono E, Camilla R, et al. Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating factor that mediates nephrin loss in cultured podocytes. Kidney Int. 2010; 77: 417–427. 10.1038/ki.2009.473 PubMed DOI

Suzuki H, Raska M, Yamada K, Moldoveanu Z, Julian BA, Wyatt RJ, et al. Cytokines alter IgA1 O-glycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes. J Biol Chem. 2014;289: 5330–5339. 10.1074/jbc.M113.512277 PubMed DOI PMC

Takahashi K, Raska M, Stuchlova Horynova M, Hall SD, Poulsen K, Kilian M, et al. Enzymatic sialylation of IgA1 O-glycans: implications for studies of IgA nephropathy. PLoS One. 2014;9(2): e99026 10.1371/journal.pone.0099026 PubMed DOI PMC

Suzuki H, Fan R, Zhang Z, Brown R, Hall S, Julian BA, et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest. 2009;119: 1668–1677. 10.1172/JCI38468 PubMed DOI PMC

Vandeginste BGM. Handbook of Chemometrics and Qualimetrics, part B1998, ISBN 0-444-82853-2.

Zhao N, Hou P, Lv J, Moldoveanu Z, Li Y, Kiryluk K, et al. The level of galactose-deficient IgA1 in the sera of patients with IgA nephropathy is associated with disease progression. Kidney Int. 2012;82: 790–796. 10.1038/ki.2012.197 PubMed DOI PMC

Shimozato S, Hiki Y, Odani H, Takahashi K, Yamamoto K, Sugiyama S. Serum under-galactosylated IgA1 is increased in Japanese patients with IgA nephropathy. Nephrol Dial Transplant. 2008;23(6): 1931–1939. 10.1093/ndt/gfm913 PubMed DOI

Camilla R, Suzuki H, Daprà V, Loiacono E, Peruzzi L, Amore A, et al. Oxidative stress and galactose-deficient IgA1 as markers of progression in IgA nephropathy. Clin J Am Soc Nephrol. 2011;6(8): 1903–1911. 10.2215/CJN.11571210 PubMed DOI PMC

Berthoux F, Suzuki H, Thibaudin L, Yanagawa H, Maillard N, Mariat C, et al. Autoantibodies targeting galactose-deficient IgA1 associate with progression of IgA nephropathy. J Am Soc Nephrol. 2012;23: 1579–1587. 10.1681/ASN.2012010053 PubMed DOI PMC

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