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Published on: January 18, 2019
Podocyte Antigen Staining to Identify Distinct Phenotypes and Outcomes in Membranous Nephropathy: A Retrospective
Nicolas Hanset1, Selda Aydin2, Nathalie Demoulin1
1Division of Nephrology, Cliniques universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.
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.
Insights
Membranous nephropathy (MN) subgroups identified by podocyte antigen staining show similar kidney failure rates. However, Thrombospondin type 1 domain-containing 7A (THSD7A)-positive MN patients have a significantly increased risk of developing cancer.
Area of Science:
- Nephrology
- Immunopathology
- Oncology
Background:
- Membranous nephropathy (MN) involves immune complex deposition in glomeruli.
- Podocyte antigens like PLA2R, THSD7A, EXT1/2, and NELL-1 are implicated in MN pathogenesis.
- Understanding antigen-specific MN subgroups is crucial for predicting clinical outcomes.
Purpose of the Study:
- To investigate the association between podocyte antigen staining in kidney biopsies and the clinical phenotype and outcomes of patients with membranous nephropathy (MN).
- To determine the prevalence of different MN subgroups based on podocyte antigen expression.
- To evaluate the impact of specific podocyte antigens on cancer incidence and kidney failure progression.
Main Methods:
- A multicenter retrospective cohort study included 177 patients with MN.
- Archived kidney biopsy samples were analyzed for positive immunostaining of podocyte antigens (PLA2R, THSD7A, EXT1/2, NELL-1).
- Kaplan-Meier estimates and Cox regression analyses assessed time to cancer and kidney failure.
Main Results:
- Prevalence: PLA2R-positive MN (66.1%), THSD7A-positive MN (3.4%), and double-negative MN (30.5%).
- Kidney failure progression was similar across all groups.
- THSD7A-positive MN, despite small numbers, showed a significantly higher incidence and risk of cancer (adjusted HR, 5.0).
- EXT1/2 and NELL-1 positivity were observed in 8% and 5% of double-negative MN cases, respectively, with EXT1/2+ cases often associated with systemic autoimmunity.
Conclusions:
- Real-world data characterize the relative prevalence of MN subgroups based on podocyte antigen staining.
- Podocyte antigen profiling in MN may offer a clinically relevant classification system.
- THSD7A-positive MN is associated with an elevated risk of cancer, warranting further investigation and monitoring.
