Multi-Autoantibody Signature and Clinical Outcome in Membranous Nephropathy

Clin J Am Soc Nephrol. 2020 Dec 7;15(12):1762-1776. doi: 10.2215/CJN.02500220. Epub 2020 Nov 30.


Background and objectives: Patients with membranous nephropathy can have circulating autoantibodies against membrane-bound (phospholipase A2 receptor 1 [PLA2R1] and thrombospondin type-1 domain containing 7A [THSD7A]) and intracellular (aldose reductase, SOD2, and α-enolase) podocyte autoantigens. We studied their combined association with clinical outcomes.

Design, setting, participants, & measurements: Serum levels of anti-PLA2R1, anti-THSD7A, anti-aldose reductase, anti-SOD2, and anti-α-enolase autoantibodies were determined in 285 patients at diagnosis and during follow-up using standardized and homemade assays. An eGFR>60 ml/min per 1.73 m2 and remission of proteinuria (<0.3/<3.5 g per d) after 12 months were the outcomes of interest.

Results: At diagnosis, 182 (64%), eight (3%), and 95 (33%) patients were anti-PLA2R1+, anti-THSD7A+, and double negative, respectively. The prevalence of a detectable antibody to at least one intracellular antigen was similarly distributed in patients who were anti-PLA2R1+ (n=118, 65%) and double negative (n=64, 67%). Positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase antibodies and higher titers at diagnosis were associated with poor clinical outcome independently to each other. Combined positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase was associated with highest risk of poor outcome (odds ratio, 5.5; 95% confidence interval, 1.2 to 24; P=0.01). In Kaplan-Meier analysis, patients who were anti-PLA2R1+/anti-SOD2+ or anti-PLA2R1+/anti-α-enolase+ had lower eGFR at 12 months compared with patients who were anti-PLA2R1+/anti-SOD2- or anti-α-enolase-. Predictive tests (net reclassification index and area under the curve-receiver-operating characteristic analysis) showed that combined assessment of antibodies improved classification of outcome in 22%-34% of cases for partial remission of proteinuria and maintenance of normal eGFR. For patients with nephrotic syndrome at diagnosis, anti-SOD2 positivity and high anti-PLA2R1 titer were associated with a lack of complete remission. Patients who were anti-PLA2R1-/anti-intracellular antigens- had the lowest proteinuria and the highest eGFR at diagnosis and the lowest risk of lower eGFR at 12 months. Epitope spreading was present in 81% of patients who were anti-PLA2R1+ and was associated with increased positivity for intracellular antigens and poor eGFR at diagnosis and 12 months.

Conclusions: Combined serological analysis of autoantibodies targeting membrane-bound and intracellular autoantigens identifies patients with poor clinical outcomes.

Keywords: autoantibodies; glomerular disease; glomerulonephritis; membranous nephropathy.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aldehyde Reductase / immunology*
  • Autoantibodies / blood*
  • Biomarkers / blood
  • Biomarkers, Tumor / immunology*
  • Cross-Sectional Studies
  • DNA-Binding Proteins / immunology*
  • Female
  • France
  • Glomerulonephritis, Membranous / blood
  • Glomerulonephritis, Membranous / diagnosis
  • Glomerulonephritis, Membranous / immunology*
  • Glomerulonephritis, Membranous / therapy
  • Humans
  • Italy
  • Male
  • Middle Aged
  • Phosphopyruvate Hydratase / immunology*
  • Predictive Value of Tests
  • Prognosis
  • Receptors, Phospholipase A2 / immunology*
  • Retrospective Studies
  • Serologic Tests
  • Superoxide Dismutase / immunology*
  • Thrombospondins / immunology*
  • Time Factors
  • Tumor Suppressor Proteins / immunology*


  • Autoantibodies
  • Biomarkers
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • PLA2R1 protein, human
  • Receptors, Phospholipase A2
  • THSD7A protein, human
  • Thrombospondins
  • Tumor Suppressor Proteins
  • Aldehyde Reductase
  • Superoxide Dismutase
  • superoxide dismutase 2
  • ENO1 protein, human
  • Phosphopyruvate Hydratase