Beyond Antibodies in Post-Transplant FSGS: New Answers or Recurrent Questions?

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.

• 2. Genetic variants do not exclude recurrence. Thousands of genetic variants have been identified across more than 50 podocytopathy-associated genes implicated in FSGS, and most pathogenic variants are associated with a low risk of post-transplant recurrence. As highlighted by Mason et al., many reported cases lack confirmed pathogenicity and true recurrence in monogenic disease appears to be rare [5]. An exception is NPHS1 variants due to alloimmunization against donor nephrin, now considered a distinct entity rather than classical recurrence [5, 6]. Patient #4 carried a heterozygous missense variant in exon 13 of TRPC6 [NM_004621.6:c.2750G>C, p.(Gly917Ala)], classified as a variant of uncertain significance by ACMG guidelines. No familial segregation testing was performed, leaving inheritance undetermined. The variant is not present in databases such as ClinVar or gnomAD. This case illustrates the need for cautious interpretation of variants, ideally with the support of nephrogenetics experts, as variants of uncertain significance with unlikely causality do not rule out FSGS recurrence, and other immune or environmental mechanisms may influence disease expression. Molecular genetic testing remains thus essential in FSGS for predicting post-transplant recurrence risk. In line with this, novel agents are also being developed: a selective TRPC6 inhibitor (BI 764198) is currently undergoing phase 2 clinical trials and may represent a breakthrough in this subset of patients [7]. Gene therapy is also promising, with studies exploring adeno-associated virus-mediated gene delivery, particularly for NPHS2 variants, showing promising results for more targeted treatments [6].

• 3. There is growing evidence that complement activation plays a role in the pathogenesis of primary FSGS in the native kidney, with studies correlating worse prognosis to low plasma C3 levels, complement deposits in biopsies, and elevated urinary complement byproducts [8]. In our cohort, all patients had histologic features of FSGS in post-transplant biopsies, and C3 deposits were observed in two cases. This suggests that complement activation may reflect more than nonspecific trapping in sclerotic lesions and, despite sample size, still raises the question of whether this early deposition suggests complement-mediated injury or represents an epiphenomenon without a direct correlation to disease activity. Interestingly, Shirai et al. found no complement components colocalizing with nephrin in rFSGS biopsies, despite strong IgG-nephrin interaction [9]. This suggests that anti-nephrin antibody–mediated injury may occur via complement-independent mechanisms, possibly involving non-complement-fixing IgG subclasses. In contrast, detection of C3 deposits in anti-nephrin-negative cases raises the possibility that complement activation may play a larger role in antibody-negative or alternative pathogenic pathways. Of note, in our cohort, the patient with positive anti-nephrin antibodies had no complement deposits, while the seronegative patient did, supporting the idea of distinct pathogenic pathways. Given the growing availability of anti-complement therapies, further research is necessary to determine if complement activation contributes to disease recurrence or works alongside other pathogenic mechanisms, allowing for a more personalized mechanistic-based use of the expanding therapeutic armamentarium.