Noninvasive Diagnostic Strategies for Membranous Nephropathy in the Nephrotic Syndrome Study Network

Key Points Antiphospholipase A2 receptor antibody seropositivity by ELISA ≥2 and positive indirect immunofluorescence was optimal. Noninvasive diagnosis of phospholipase A2 receptor–associated membranous nephropathy among patients with proteinuria is feasible using both assays. Background Clinical practice guidelines recommend that a kidney biopsy is no longer required to confirm a diagnosis of membranous nephropathy (MN) in patients with nephrotic syndrome and a positive test for antiphospholipase A2 receptor antibodies (PLA2R-Ab). However, the optimal diagnostic strategy for using the PLA2R-Ab ELISA, PLA2R-Ab indirect immunofluorescence (IIF) test, and genetic risk score (GRS) for diagnosing MN, including the tests' optimal thresholds for positivity among incident patients with proteinuria, is still unknown. Methods We used serum samples at or before the first clinically indicated kidney biopsy from participants in the Nephrotic Syndrome Study Network to analyze test performance characteristics using different combinations and cutoffs of the PLA2R-Ab ELISA, IIF, and GRS for diagnosing MN. Secondary analyses included serum samples within 6 months after biopsy but before any immunosuppression use. Results There were 325 study participants with serum samples available on or before the day of kidney biopsy and an additional 143 study participants with samples within 6 months after biopsy but before any immunosuppression use. Of these participants, 26% ( n =85) had biopsy-confirmed MN. The combination of ELISA ≥2 RU/ml and positive IIF was the optimal approach, with sensitivity of 0.60, specificity of 1.00, negative predictive value of 0.92, and positive predictive value of 1.00. Using IIF to confirm only borderline ELISA titers between 2 and 20 RU/ml resulted in similar sensitivity but specificity of >0.99. In our multiethnic study sample, we did not find improved diagnostic performance with the addition of GRSs. Conclusions In the Nephrotic Syndrome Study Network cohort, combined PLA2R-Ab testing with ELISA and IIF provided optimal test characteristics in making a noninvasive diagnosis of MN before or soon after kidney biopsy, including in patients with subnephrotic proteinuria. Further studies in multiethnic populations are needed to assess whether genetic data can augment this approach.