Recurrent Focal Segmental Glomerulosclerosis after Kidney Transplantation: Challenges and Evolving Strategies

The recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation remains a major concern, contributing significantly to graft loss in both adult and pediatric recipients. This condition occurs when patients who developed end-stage kidney disease (ESKD) due to primary focal segmental glomerulosclerosis (pFSGS) experience a disease recurrence in their transplanted kidney, likely driven by circulating permeability factors. The circulating permeability factor theory is supported by vast clinical and experimental evidence, most notably by a striking case in which a kidney was transplanted into a recipient with FSGS, and massive proteinuria was noted. When the kidney graft was removed and transplanted into a patient without focal segmental glomerulosclerosis (FSGS), the graft showed disappearance of foot process effacement, and proteinuria resolved.[1] Despite advancements in transplant medicine, rFSGS continues to pose diagnostic and therapeutic challenges, highlighting the need for improved prevention, early detection, and management strategies. A recently published consensus statement in kidney international Reports (March 2024) by Raina et al. offers a detailed analysis of rFSGS, providing expert recommendations based on a thorough review of available literature.[2] The diagnosis of rFSGS can be made for those who show nephrotic range proteinuria (>3.5 g/24 h) and hypoalbuminemia (serum album <2.5 mg/dl) with allograft biopsy showing FSGS pattern of injury and widespread foot process effacement on electron microscopy. Recurrence rates in pFSGS have been reported to be as high as 70% when genetic and secondary causes are rigorously excluded. However, previous studies have shown variability, with recurrence rates ranging from 10% to 55%. The transplant glomerular disease (TANGO) cohort study, an international multicenter cohort study for post-TANGO recurrence, reported FSGS recurrence in 32% of cases of idiopathic FSGS, with graft loss occurring in 39% over a median follow-up of 5 years.[3] The timing of recurrence is variable. Early recurrence manifests within the first 48 h posttransplant, while intermediate recurrence occurs within the 1st month. Late recurrence, although less common, appears beyond 1 month. Clinical and laboratory abnormalities in early recurrence may precede histological findings by several days to weeks. Hence, there may be normal-looking glomeruli on light microscopy, and the diagnosis can only made by demonstrating diffuse foot process effacement on electron microscopy in case of early recurrence.[4] Distinguishing between the true late recurrence of pFSGS and de novo FSGS due to secondary causes – such as chronic rejection or calcineurin inhibitor toxicity – is crucial. Secondary de novo FSGS presents more gradually, lacks severe hypoalbuminemia, and does not exhibit diffuse podocyte effacement on electron microscopy (examination should focus on nonsclerotic glomeruli that do not show sclerotic changes).[5] Clinical judgment is of paramount importance in such scenarios. Several factors have been associated with an increased risk of rFSGS. The mesangioproliferative variant of FSGS, although not formally recognized in the Columbia classification, has been linked to higher recurrence rates. A rapid progression to ESKD within 3 years of diagnosis (so-called “malignant FSGS”) and prior recurrence in a previous transplant are also the strong predictors of recurrence risk. Genetic forms of FSGS generally have a lower risk of recurrence, with rare exceptions. One rare and notable cause of rFSGS is in patients with NPHS1 genetic mutation (homozygous truncating variant, with total loss of nephrin) due to the formation of de novo anti-Nephrin antibody after transplant.[6] Other identified risk factors include initial steroid responsiveness (late steroid-resistant nephrotic syndrome), Caucasian ethnicity, and elderly donors, native kidney nephrectomy at or before transplant.[7] While earlier reports suggested a higher recurrence risk in living donor kidney transplants compared to deceased donor kidney transplants, large transplant registry data from United Network for Organ Sharing and the Australian and New Zealand Transplant Registry have not demonstrated a significant difference in recurrence rates between the two groups. The Mayo Clinic has reported a protocol using bilateral native ureteral ligation without nephrectomy to detect proteinuria early and facilitate the timely initiation of plasma exchange.[8] However, no high-quality evidence supports this approach and decisions are largely institution specific. Some autoantibodies that are now actively investigated in the rFSGS are anti-nephrin antibodies, anti-actin, and anti-adenosine triphosphate synthetase antibodies. The presence of punctate immunoglobulin G deposits in graft biopsies should prompt evaluation for anti-nephrin antibodies. Delville et al. reported a panel of seven antibodies (CD40, PTPRO, CGB5, FAS, P2RY11, SNRPB2, and APOL2), which could predict FSGS recurrence with 92% accuracy. Among these, elevated anti-CD40 levels pretransplant showed the strongest correlation with recurrence risk.[9] Despite these promising findings, the routine clinical utility of these biomarkers remains limited. The treatment of rFSGS lacks standardized guidelines, primarily due to the absence of well-powered randomized controlled trials. Therapeutic plasma exchange (TPE) is widely used based on the hypothesis that a circulating permeability factor drives recurrence. Early initiation of TPE has been linked to higher remission rates and better outcomes. A 2020 meta-analysis reported that 73% of patients with rFSGS achieved remission with a combination of TPE and rituximab.[10] The recommended TPE protocol for treatment consists of daily sessions for 3 days, followed by thrice weekly sessions for 2 weeks. Rituximab is considered in patients with contraindications to TPE or those who fail to respond to TPE. Low-density lipid apheresis may be considered in patients who are refractory to TPE. Some newer therapies under investigation include ofatumumab (another anti-CD20 monoclonal antibody), tumor necrosis factor-alpha inhibitors, and mesenchymal stem cell therapy. A recent French study suggests that, despite prophylactic TPE, recurrence rates remain high in patients who have already experienced graft failure due to FSGS, challenging current assumptions about its preventive role.[11] The recently published consensus statement does not support prophylactic TPE or rituximab before transplantation.[2] A recent study from SGPGI by Yachha et al., published in this issue of IJT, provided valuable insights into rFSGS in the Indian transplant population, analyzing 18 cases over a 12-year period.[12] The study reported a median recurrence time of 45 days, with 70% of cases occurring within 6 months. Electron microscopy confirmed diffuse foot process effacement in all cases. Treatment response varied, with 56% of patients achieving remission. The highest remission rate (67%) was observed with combination therapy (plasmapheresis plus Rituximab), and the 10-year graft survival in this group was 50%. While these findings highlight the potential benefit of Rituximab, the small sample size limits definitive conclusions. Despite the decades of research, rFSGS remains a formidable challenge in kidney transplantation. While advances in understanding its pathogenesis and treatment have improved outcomes, significant gaps remain. A concerted effort involving multicenter collaborations, prospective studies, and biomarker-driven approaches is essential to develop effective preventive and therapeutic strategies. Until then, individualized management based on clinical expertise and emerging evidence remains the cornerstone of care for patients at risk of FSGS recurrence after transplantation.