CIRCULATING NEPHRIN ANTIBODIES AND POST-TRANSPLANT RECURRENCE OF DIFFUSE PODOCYTOPATHIES: A SYSTEMATIC REVIEW AND POOLED INDIVIDUAL PATIENT DATA ANALYSIS

Recurrence of diffuse podocytopathy (DP), mainly represented by focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD), after kidney transplantation is a major threat to graft survival. Circulating anti-nephrin antibody is reportedly associated with recurrence of both MCD and FSGS, while evidence in post-transplant setting is limited. We aimed to synthesize all published evidence focusing on recurrent DP in post-kidney transplant patients who has serum nephrin antibody tested.

We performed systematic review on October 6, 2025. Databases searched included Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science, and Scopus. Studies were included if they tested for circulating nephrin antibody in kidney transplant recipients with DP as their native disease. Extracted data included number of tested patients, type of kidney transplant, antibody status, recurrence, biopsy findings, therapies, and graft survival. Individial patient-level data of serum anti-nephrin and recurrent DP were collected from supplementary data to perform pooled individual patient data analysis of overall prevalence of circulating anti-nephrin antibody and diagnostic accuracy toward recurrence of DP. 

A total of 65 (25 pediatric and 40 adult) kidney transplant recipients with diffuse podocytopathies (55 FSGS, 8 MCD, and 2 steroid-resistant nephrotic syndrome) were identified from 5 studies. Thirty-six (55%) were male and 36 (55%) were living-donor kidney transplant. Pediatric cases were predominantly Japanese, with disease onset at 2–3 years and transplantation at 7–15 years. 96% of them received basiliximab induction. Adult cases, largely from North America and Europe, had a median age of 35 years at transplant. Fifty-two (80%) underwent plasma exchange and 11 (17%) received rituximab for antibody depletion prophylaxis. Circulating anti-nephrin antibodies were detected in 23 of 64 subjects (35.9%) before or within 1 day after transplantation; 1 adult patient had nephrin antibody detected 9 years post-transplant. Nephrin antibodies were measured commonly by indirect ELISA against recombinant nephrin (extracellular domain). Cut-offs were center-specific, not standardized. Post-transplant recurrence occurred in 35 (53.85%) patients. Among these, 21 of 34 (61.76%) were anti-nephrin positive. Twelve patients developed graft failure due to recurrent DP, of whom 5 were antibody positive. 2 patients had graft failure due to rejection. Circulating nephrin antibody was strongly associated with post-transplant recurrent DP (Crude OR = 22.6, 95% CI 4.6–111.2; p < 0.001). Positive anti-nephrin as a marker for recurrent disease yielded a sensitivity of 61.8%, specificity of 93.3%, positive predictive value of 91.3%, and negative predictive value of 68.3%. Anti-nephrin antibodies were consistently observed within 1 day post-transplant in patients with recurrent disease, often with punctate IgG–nephrin co-localization on graft biopsies and granular transformation of nephrin staining during recurrence in 19 of 23 seropositive cases (82.61%). Antibody titers appeared to correlate with disease activity and declined with remission. These findings may be influenced by selection bias from published cases, variability in assay cutoffs, and differences in immunosuppression protocols.

Anti-nephrin autoantibody is common and predictive of post-transplant recurrence in DP. Recurrent disease among seronegative patients indicates disease heterogeneity or possibly undetected antibody. The antibody titer may help guide pre-transplant intervention and post-transplant monitoring. Prospective multicenter validation is warranted to identify appropriate timing of testing, standard cut-off point to establish universal protocols for antibody-guided prevention of recurrence and to better illustrate allograft survival outcome.