Podocyte Antigen Staining to Identify Distinct Phenotypes and Outcomes in Membranous Nephropathy: A Retrospective Multicenter Cohort Study

Abstract

Rationale & objective: Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A₂ receptor (PLA₂R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes.

Study design: Multicenter retrospective cohort study.

Setting & participants: 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018.

Predictor: Positive immunostaining for podocyte antigens on archived kidney biopsy samples.

Outcomes: Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure.

Analytical approach: Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure.

Results: 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA₂R-positive (PLA₂R⁺), THSD7A⁺, and double-negative (PLA₂R^-/THSD7A^-) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A⁺MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P=0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2⁺MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits.

Limitations: Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition.

Conclusions: Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.

Keywords: Membranous nephropathy (MN); cancer; glomerular disease; immunostaining; kidney biopsy; malignancy; nephrotic syndrome; outcome; phospholipase A(2) receptor (PLA(2)R); podocyte antigen; thrombospondin type 1 domain-containing 7A (THSD7A).