Multi-Autoantibody Signature and Clinical Outcome in Membranous Nephropathy

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 m 2 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.