Clinical Relevance of Domain-Specific Phospholipase A2 Receptor 1 Antibody Levels in Patients with Membranous Nephropathy
Authors: Linda Reinhard, Gunther Zahner, Stephan Menzel, Friedrich Koch-Nolte, Rolf A.K. Stahl, Elion Hoxha
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Phospholipase A 2 receptor 1 (PLA 2 R1) is the major target of autoimmunity in membranous nephropathy. Anti-PLA 2 R1 antibody levels predict treatment response and outcome in this disease. Earlier studies identified three target epitope regions in the PLA 2 R1 and proposed that having antibodies against more than one PLA 2 R1 epitope region had prognostic relevance. In this prospective study of a cohort of 150 patients with newly diagnosed membranous nephropathy, the authors identified a fourth epitope region targeted by anti-PLA 2 R1 antibodies. They also found that all sera recognized at least two distinct PLA 2 R1 domains at the time of diagnosis. Detection of domain-specific antibodies was highly dependent on total anti-PLA 2 R1 antibody levels. Anti-PLA 2 R1 antibody levels, but not PLA 2 R1 epitope-recognition patterns or domain-specific PLA 2 R1 antibody levels, predict treatment response and outcome (remission of proteinuria) in membranous nephropathy. Background Antibodies against phospholipase A 2 receptor 1 (PLA 2 R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA 2 R1 epitope regions. Although anti-PLA 2 R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear. Methods In a prospective cohort of 150 patients with newly diagnosed PLA 2 R1-associated membranous nephropathy, we investigated the clinical role of epitope-recognition patterns and domain-specific PLA 2 R1 antibody levels by western blot and ELISA. Results We identified a fourth epitope region in the CTLD8 domain of PLA 2 R1, which was recognized by anti-PLA 2 R1 antibodies in 24 (16.0%) patients. In all study patients, anti-PLA 2 R1 antibodies bound both the N-terminal (CysR-FnII-CTLD1) region and the C-terminal (CTLD7-CTLD8) region of PLA 2 R1 at study enrollment. The total anti-PLA 2 R1 antibody levels of patients determined detection of domain-specific PLA 2 R1 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 PLA 2 R1 antibody levels targeting CysR, CTLD1, and CTLD7 strongly correlate with the total anti-PLA 2 R1 antibody level (Spearman’s rho, 0.95, 0.64, and 0.40; P &lt;0.001, P &lt;0.001, and P =0.002, respectively) but do not predict disease outcome independently of total anti-PLA 2 R1 antibody levels. Conclusions All patients with PLA 2 R1-associated membranous nephropathy recognize at least two epitope regions in the N- and C-terminals of PLA 2 R1 at diagnosis, contradicting the hypothesis that PLA 2 R1 “epitope spreading” determines the prognosis of membranous nephropathy. Total anti-PLA 2 R1 antibody levels, but not the epitope-recognition profiles at the time of diagnosis, are relevant for the clinical outcome of patients with this disease.