Introduction
Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome in adults and a major contributor to end-stage renal disease (ESRD) worldwide.1 Kidney transplantation is the definitive treatment for ESRD; however, recurrent FSGS occurs in 30–40% of patients with primary disease and is strongly linked to early graft loss.2,3 The pathogenesis is thought to involve circulating permeability factors such as soluble urokinase-type plasminogen activator receptor (suPAR), anti-CD40 antibodies, and cardiotrophin-like cytokine factor-1 (CLCF-1), which injure podocytes, resulting in proteinuria and progressive glomerular scarring.4,5
Recurrent FSGS poses a significant therapeutic challenge as conventional immunosuppressants, including corticosteroids and calcineurin inhibitors, often fail to prevent relapse or adequately reduce proteinuria.6 Emerging evidence suggests that B-cell–targeted therapy, particularly rituximab, can stabilize podocytes and improve outcomes in recurrent FSGS, though most data are derived from case series and small cohort studies.7,8 Early detection of recurrence through laboratory monitoring and timely renal biopsy is critical to preserve graft function.9 This case demonstrates successful reversal of recurrent FSGS with an early, intensified immunosuppression protocol and highlights the importance of prompt recognition, biopsy, and individualized therapy to prevent graft loss.
Case Presentation
A 35-year-old male with end-stage renal disease (ESRD) secondary to biopsy-confirmed primary focal segmental glomerulosclerosis (FSGS) underwent a deceased-donor kidney transplant. His medical history included steroid-responsive nephrotic syndrome during adolescence, which slowly progressed to ESRD over the course of 10 years. He had not experienced any complications from immunosuppressive treatment in the past. For induction, he was given intravenous methylprednisolone and basiliximab, and his maintenance regimen consisted of tacrolimus (with a target trough of 8–10 ng/mL) and mycophenolate mofetil (1 g/day). The immediate postoperative course went smoothly, with the graft showing prompt function, urine output reached 3.2 L/day, and his serum creatinine dropped from 8.5 mg/dL before the transplant to 1.1 mg/dL by the fifth postoperative day.
On postoperative day 14, the patient developed generalized edema, most noticeable as periorbital puffiness, along with a weight gain of 3.5 kg and mild exertional dyspnea. His blood pressure was 140/92 mmHg, heart rate 88 bpm, respiratory rate 18/min, and temperature 36.8°C. Laboratory studies showed nephrotic-range proteinuria, with a urine protein-to-creatinine ratio of 6.8 g/g, accompanied by hypoalbuminemia (2.3 g/dL) and hypercholesterolemia (total cholesterol 310 mg/dL). Despite these findings, the transplanted kidney function remained stable, and his serum creatinine remained steady at 1.5 mg/dL. Urinalysis revealed heavy proteinuria (4+), but there was no blood in the urine and the sediments were otherwise unremarkable (Table 1).A comprehensive serologic evaluation for secondary causes of FSGS, including viral hepatitis, HIV, antinuclear antibodies, complement levels, and serum protein electrophoresis, was negative.
To clarify the cause of his proteinuria, a percutaneous biopsy of the renal allograft was performed on postoperative day 14. The biopsy revealed segmental sclerosis affecting 3 of the 12 glomeruli, with associated moderate mesangial expansion. On electron microscopy, there was diffuse effacement of the podocyte foot processes, findings characteristic of recurrent FSGS (Figure 1). Importantly, there were no features to suggest acute cellular or antibody-mediated rejection, thrombotic microangiopathy, or calcineurin inhibitor toxicity. Immunofluorescence staining was negative for immune complex deposition.
Given early biopsy-confirmed recurrence, the patient was started on low-dose tacrolimus (target trough 4–6 ng/mL), continued mycophenolate mofetil (1 g/day), and received rituximab (375 mg/m² weekly for 2 doses). Supportive therapy included ramipril 5 mg once daily (an angiotensin-converting enzyme inhibitor), along with dietary salt and protein restriction and loop diuretics for edema control. Laboratory monitoring was performed weekly for the first month and then monthly.
Within four weeks, proteinuria decreased to 4.2 g/g, serum albumin rose to 2.9 g/dL, and serum creatinine remained stable at 1.4 mg/dL. At three months, proteinuria further declined to 2.1 g/g with normalization of serum albumin (3.4 g/dL). By 12 months, proteinuria was 0.9 g/g, serum albumin 3.8 g/dL, and creatinine 1.2 mg/dL. No infectious complications, hematologic abnormalities, or adverse events related to rituximab or tacrolimus were observed (Table 2).
Discussion
Recurrent FSGS is an uncommon but clinically significant complication following renal transplantation. It occurs in approximately one-third of patients with primary FSGS, and typically presents within the initial post-operative weeks.10 Early recurrence is linked to circulating permeability factors, such as suPAR, anti-CD40 antibodies, and CLCF-1, which enhance podocyte motility and disrupt slit-diaphragm integrity, leading to foot process effacement and segmental sclerosis.11,12 These mechanisms result in podocyte injury, resulting in nephrotic-range proteinuria and progressive glomerular sclerosis.11 Although circulating permeability factors were not directly measured in our patient, the clinical course and biopsy findings strongly suggest permeability factor–driven pathogenesis. In our patient, onset at day 14 post-transplant is consistent with previously reported timelines, which highlights the importance of early recognition. Laboratory markers, including proteinuria and hypoalbuminemia, were critical for early detection, and renal biopsy provided definitive confirmation, aligning with the current recommendations for prompt tissue diagnosis.12
Conventional immunosuppressive strategies, including corticosteroids and calcineurin inhibitors, are often ineffective at preventing recurrent FSGS.13 B-cell-targeted therapy with rituximab has emerged as a potential adjuvant, stabilizing podocytes, reducing proteinuria, and improving graft survival.14 In our patient, the combination of rituximab, low-dose tacrolimus, and mycophenolate mofetil led to a progressive improvement of proteinuria, normalization of serum albumin over a 12-month follow-up, and minimization of nephrotoxicity while maintaining immunosuppressive efficacy, thereby demonstrating the impact of early, targeted therapy.
Strengths of this case include detailed clinical and laboratory monitoring, early biopsy confirmation, structured immunosuppressive adjustment, and longitudinal follow-up documenting stable graft function. Limitations include the single-patient design, follow-up limited to 12 months, and the absence of direct measurement of circulating permeability factors, which would have offered additional mechanistic insight. Nevertheless, this case supports the growing evidence on early, targeted immunosuppressive regimens for recurrent FSGS post-transplant.
Conclusion
Recurrence of focal segmental glomerulosclerosis post-kidney transplant is uncommon but carries a high risk of graft dysfunction. Early recognition through laboratory monitoring and biopsy, combined with tailored immunosuppressive therapy including rituximab, low-dose tacrolimus, and mycophenolate mofetil, can lead to remission of proteinuria, normalization of hypoalbuminemia, and stabilization of renal function. This case highlights the need for physicians to remain vigilant for possible FSGS recurrence post-kidney transplantation, as well as the importance of individualized management and emerging therapeutic strategies to optimize outcomes in post-transplant FSGS.
Ethical Considerations
Written informed consent was obtained from the patient for publication of this case report and accompanying images. IRB approval was not required for this single-patient case report, as per institutional policy. All procedures were conducted in accordance with the Declaration of Helsinki.