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J Am Soc Nephrol. 2016 May;27(5):1517-33. doi: 10.1681/ASN.2014111061. Epub 2015 Nov 13.

Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy.

Author information

1
Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; Service de Néphrologie, CHU de Nice, Université de Nice-Sophia Antipolis, France; Laboratoire d'Immunologie.
2
Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France;
3
Centre de Recherche Clinique, CHU de Nice, Université de Nice-Sophia Antipolis, France;
4
Service de Néphrologie Dialyse Transplantation Rénale, CHU Hôpital Nord, Saint-Etienne, and Université de Saint-Etienne PRES Université de Lyon, Saint-Etienne, France;
5
Service de Néphrologie Dialyse Transplantation Rénale, CHU de Besançon, France;
6
Service de Néphrologie et dialyse, CHU de Strasbourg, Strasbourg, France; and.
7
Laboratoire d'Immunologie.
8
Service de Néphrologie Dialyse Transplantation Rénale, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, Marseille, France et UMR S1076, Université Aix-Marseille, France.
9
Service de Néphrologie, CHU de Nice, Université de Nice-Sophia Antipolis, France;
10
Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS and Université de Nice-Sophia Antipolis, Valbonne Sophia-Antipolis, France; seitz-polski.b@chu-nice.fr lambeau@ipmc.cnrs.fr.

Abstract

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy. However, the value of anti-PLA2R1 antibody titers in predicting patient outcomes is unknown. Here, we screened serum samples from 50 patients positive for PLA2R1 for immunoreactivity against a series of PLA2R1 deletion mutants covering the extracellular domains. We identified reactive epitopes in the cysteine-rich (CysR), C-type lectin domain 1 (CTLD1), and C-type lectin domain 7 (CTLD7) domains and confirmed the reactivity with soluble forms of each domain. We then used ELISAs to stratify 69 patients positive for PLA2R1 by serum reactivity to one or more of these domains: CysR (n=23), CysRC1 (n=14), and CysRC1C7 (n=32). Median ELISA titers measured using the full-length PLA2R1 antigens were not statistically different between subgroups. Patients with anti-CysR-restricted activity were younger (P=0.008), had less nephrotic range proteinuria (P=0.02), and exhibited a higher rate of spontaneous remission (P=0.03) and lower rates of renal failure progression (P=0.002) and ESRD (P=0.01) during follow-up. Overall, 31 of 69 patients had poor renal prognosis (urinary protein/creatinine ratio >4 g/g or eGFR<45 ml/min per 1.73 m(2) at end of follow-up). High anti-PLA2R1 activity and epitope spreading beyond the CysR epitope were independent risk factors of poor renal prognosis in multivariable Cox regression analysis. Epitope spreading during follow-up associated with disease worsening (n=3), whereas reverse spreading from a CysRC1C7 profile back to a CysR profile associated with favorable outcome (n=1). We conclude that analysis of the PLA2R1 epitope profile and spreading is a powerful tool for monitoring disease severity and stratifying patients by renal prognosis.

KEYWORDS:

chronic kidney disease; epidemiology and outcomes; membranous nephropathy

PMID:
26567246
PMCID:
PMC4849812
DOI:
10.1681/ASN.2014111061
[Indexed for MEDLINE]
Free PMC Article

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