Dataset Information

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

ABSTRACT:

Background

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.

Methods

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.

Results

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; P<0.001, P<0.001, and P=0.002, respectively) but do not predict disease outcome independently of total anti-PLA₂R1 antibody levels.

Conclusions

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.

SUBMITTER: Reinhard L

PROVIDER: S-EPMC6935013 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Clinical Relevance of Domain-Specific Phospholipase A<sub>2</sub> Receptor 1 Antibody Levels in Patients with Membranous Nephropathy.

Reinhard Linda L Zahner Gunther G Menzel Stephan S Koch-Nolte Friedrich F Stahl Rolf A K RAK Hoxha Elion E

Journal of the American Society of Nephrology : JASN 20191216 1

<h4>Background</h4>Antibodies against phospholipase A<sub>2</sub> receptor 1 (PLA<sub>2</sub>R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA<sub>2</sub>R1 epitope regions. Although anti-PLA<sub>2</sub>R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear.<h4>Methods</h4>In a prospective cohort of 150 patients wi ...[more]

PMID: 31843985

Similar Datasets

Project description:BACKGROUND:Membranous nephropathy (MN) is an autoimmune disease induced by circulating antibodies against the podocyte protein phospholipase A2 receptor 1 (PLA2R1-ab) in 80% of patients and represents the leading cause of nephrotic syndrome in adults. PLA2R1-ab levels correlate with disease activity and treatment response. However, their predictive role for long-term renal outcome is not clear. METHODS:The aim of this prospective observational multicenter study was to investigate the predictive role of PLA2R1-ab levels at the time of diagnosis for long-term outcome in a cohort of 243 patients with newly diagnosed biopsy-proven PLA2R1-associated MN. Statistical analyses included Cox proportional hazard models. The primary study endpoint was defined prior to data collection as doubling of serum creatinine or development of end-stage renal disease. RESULTS:During the median follow-up time of 48 months, 36 (15%) patients reached the study endpoint. Independent predictors for reaching the study endpoint were baseline PLA2R1-ab levels (HR = 1.36, 95%CI 1.11-1.66, p = 0.01), percentage of tubular atrophy and interstitial fibrosis (HR = 1.32, 95%CI 1.03-1.68, p = 0.03), PLA2R1-ab relapse during follow-up (HR = 3.22, 95%CI 1.36-7.60, p = 0.01), and relapse of proteinuria (HR = 2.60, 95%CI 1.17-5.79, p = 0.02). Fifty-four (22%) patients received no immunosuppressive treatment during the study, in 41 (76%) of them PLA2R1-ab spontaneously disappeared during follow-up, 29 (54%) patients had a complete remission of proteinuria, and 19 (35%) had a partial remission. Patients not treated with immunosuppression were more often females and had lower PLA2R1-ab levels, proteinuria, and serum creatinine at baseline compared to patients receiving immunosuppression. However, no conclusion on the efficacy of immunosuppressive therapies can be made, since this was not a randomized controlled study and treatment decisions were not made per-protocol. CONCLUSIONS:PLA2R1-ab levels are, in addition to pre-existing renal damage, predictive factors for long-term outcome and should therefore be considered when deciding the treatment of patients with MN.