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 alpha-enolase) podocyte autoantigens. We studied their combined association with clinical outcomes. Design, setting, participants,& measurements Serumlevels of anti-PLA2R1, anti-THSD7A, anti-aldose reductase, anti-SOD2, and anti-alpha-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-alpha-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-alpha-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-alpha enolase(+) had lower eGFR at 12 months compared with patients who were anti-PLA2R1(+)/anti-SOD2(-) or anti-alpha-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 andmaintenance 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 12months. 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.