Clinical Relevance of Domain-Specific Phospholipase A₂ Receptor 1 Antibody Levels in Patients with Membranous Nephropathy.

Abstract

Antibodies against phospholipase A₂ receptor 1 (PLA₂R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA₂R1 epitope regions. Although anti-PLA₂R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear. In a prospective cohort of 150 patients with newly diagnosed PLA₂R1-associated membranous nephropathy, we investigated the clinical role of epitope-recognition patterns and domain-specific PLA₂R1 antibody levels by western blot and ELISA. We identified a fourth epitope region in the CTLD8 domain of PLA₂R1, which was recognized by anti-PLA₂R1 antibodies in 24 (16.0%) patients. In all study patients, anti-PLA₂R1 antibodies bound both the N-terminal (CysR-FnII-CTLD1) region and the C-terminal (CTLD7-CTLD8) region of PLA₂R1 at study enrollment. The total anti-PLA₂R1 antibody levels of patients determined detection of domain-specific PLA₂R1 antibodies, and thereby epitope-recognition patterns. A remission of proteinuria occurred in 133 (89%) patients and was not dependent on the domain-recognition profiles. A newly developed ELISA showed that domain-specific PLA₂R1 antibody levels targeting CysR, CTLD1, and CTLD7 strongly correlate with the total anti-PLA₂R1 antibody level (Spearman's rho, 0.95, 0.64, and 0.40; <i>P</i><0.001, <i>P</i><0.001, and <i>P</i>=0.002, respectively) but do not predict disease outcome independently of total anti-PLA₂R1 antibody levels. All patients with PLA₂R1-associated membranous nephropathy recognize at least two epitope regions in the N- and C-terminals of PLA₂R1 at diagnosis, contradicting the hypothesis that PLA₂R1 "epitope spreading" determines the prognosis of membranous nephropathy. Total anti-PLA₂R1 antibody levels, but not the epitope-recognition profiles at the time of diagnosis, are relevant for the clinical outcome of patients with this disease.