Dear Editors,

More than fifty years have passed since Hoyer et al. first described recurrent focal segmental glomerulosclerosis (rFSGS) in kidney transplant recipients. Yet, despite significant advances in understanding this disease, graft survival remains alarmingly poor [1, 2]. Circulating permeability factors, particularly anti-nephrin antibodies, have long been implicated in primary rFSGS. A recent study by Batal et al. marked a significant breakthrough, demonstrating 100% specificity of this marker in recurrent cases. However, they also found that 62% of patients who developed rFSGS, did not have anti-nephrin antibody titers and lacked IgG deposits colocalizing with nephrin. This low sensitivity is a reminder that other, yet unidentified, pathogenic factors may contribute to recurrence, and the search for additional culprits is far from over. However, implementing large-scale studies is difficult due to the rarity of rFSGS cases. Moreover, the absence of standardized pathophysiology-based criteria leads to the grouping of different FSGS subtypes — each with distinct clinical, management, and prognostic features - contributing to methodological variability and inconsistent classification across studies. Addressing this heterogeneity rigorously is crucial for improving the accuracy of clinical assessments and the effectiveness of therapeutic interventions.

We have retrospectively reviewed primary rFSGS cases in our institution from January 2010 to December 2020. We included only native kidney biopsy-confirmed cases of FSGS or minimal change disease (MCD), that developed rapid-onset nephrotic syndrome post-transplant. Of the 1,372 kidney transplants performed, six allograft recipients (five males and one female) met these inclusion criteria (Supplementary Figure S1). The baseline and clinical characteristics of these patients are detailed in Table 1. Three had childhood-onset native kidney disease and only one was initially steroid-sensitive. Genetic testing was performed in four patients, and a TRPC6 gene variant was identified in one. Time from the initial diagnosis to the initiation of renal replacement therapy varied widely, ranging from 2 to 19 years. All six patients experienced recurrence within the first month post-KTx with a mean proteinuria of 11 g. Three patients received induction therapy with Basiliximab, three received thymoglobulin, and all were maintained on a triple regimen with steroids, tacrolimus, and anti-metabolite. Upon recurrence, plasmapheresis was promptly initiated in four patients. Three patients achieved complete remission after a median of 81 days. The remaining three patients, unresponsive to initial therapies, also showed a limited response to alternative modalities - additional dose of rituximab (N = 1) and adrenocorticotropic hormone (N = 1) - and progressed to graft loss.

We retrospectively assessed anti-nephrin antibodies in pre-transplant serum samples of two patients (supplementary methods). Patient #2 had elevated anti-nephrin antibody titers (466 UI/mL), while Patient #6 had negative titers.

It is unwise to draw broad conclusions from our small cohort, but we can reflect on the observed heterogeneity. As seen with some entities, such as membranoproliferative glomerulonephritis, we believe shifting toward a pathophysiology-based approach could improve stratification, management, and improve future clinical trials. Based on our cohort, we present the following observations:

1. Detection of anti-nephrin antibodies pre-KTx appears to be a key biomarker for predicting the risk of immediate rFSGS. While not universally present, when detected, these antibodies seem to respond well to B-cell depletion agents (and possibly plasma exchange), though the effectiveness in preventing recurrence remains unknown. This was demonstrated in three prospectively followed native-kidney FSGS patients, where rituximab appeared to deplete anti-nephrin autoantibodies and was associated with clinical remission. [3] A recent case report by Habbig et al. also documents successful pre-KTx depletion of anti-nephrin antibodies with rituximab and plasma exchange in a pediatric FSGS patient, resulting in excellent graft function without post-KTx proteinuria. [4] Although not yet confirmed in larger cohorts, in this high-risk patients, preemptive management strategies could be considered to help monitor antibody titers and guide the timing of interventions, potentially preventing or delaying recurrence. The need for standardized, commercially available assays for anti-nephrin antibodies is clear. Such assays would confirm the exact role of anti-nephrin antibodies in prognostication or as therapeutic monitoring tools.

The multifactorial nature of rFSGS appears to be clear, potentially influenced by genetic variants, circulating permeability factors, and immune-mediated mechanisms. This interaction could explain the variable recurrence rates and outcomes. Further research is necessary to decipher these factors' precise roles and interactions in disease development and progression. Future studies should aim to identify additional circulating permeability factors, explore the role of environmental factors in disease recurrence, and refine genetic testing to predict post-transplant outcomes. Moreover, targeted therapies addressing specific mechanisms—such as B-cell depletion for antibody-related cases, complement inhibition for complement-driven pathology, and genetic therapies for variant-driven cases—may revolutionize treatment and improve long-term graft survival.