What is the treatment for recurrent Focal Segmental Glomerulosclerosis (FSGS) post-kidney transplant?

Treatment of Recurrent FSGS Post-Kidney Transplant

Plasma exchange is the first-line treatment for recurrent FSGS after kidney transplantation, with consideration of rituximab for refractory cases, though emerging evidence suggests combined rituximab and daratumumab may be effective for treatment-resistant disease. 1

First-Line Treatment: Plasma Exchange

• Initiate plasma exchange immediately upon biopsy-confirmed recurrent FSGS, as recommended by KDIGO guidelines with a Grade 2D recommendation 1
• Plasma exchange remains the established standard of care and should be attempted before escalating to other therapies 1
• The timing and duration of plasma exchange should be aggressive in the early post-transplant period, as recurrence can occur rapidly 2

Supportive Care Measures

• Start or optimize renin-angiotensin-aldosterone system (RAAS) inhibitors (ACE inhibitors or ARBs) for all patients with recurrent FSGS and proteinuria, regardless of blood pressure 1
• Target blood pressure control to minimize proteinuric injury to the transplanted kidney 1

Second-Line Treatment: Rituximab

• Consider rituximab for patients who fail to respond to plasma exchange alone 2, 3
• The combination of plasma exchange with rituximab showed prolonged remission in pediatric patients in one study, though evidence quality is limited 2
• Rituximab can be combined with ongoing intermittent plasma exchange sessions for maintenance therapy in refractory cases 3

Emerging Treatment for Refractory Cases: Combined Rituximab and Daratumumab

While not yet guideline-recommended, the most recent high-quality evidence from 2024 demonstrates that combined rituximab and daratumumab induced complete response in all 5 cases of plasma exchange-resistant and rituximab-resistant recurrent FSGS 4

Key considerations for this combination:

• This approach should be reserved for cases resistant to plasma exchange and rituximab monotherapy 4
• All responding cases in the 2024 study were negative for genetic FSGS, suggesting this may be most appropriate for non-genetic forms 4
• The treatment was well-tolerated in reported cases 4
• However, this combination is currently classified as experimental by insurance criteria, with significant cost implications (approximately $16,753.50 for daratumumab and $10,335.20 for obinutuzumab per treatment) 1

Alternative Approaches for Specific Scenarios

High-dose corticosteroids with calcineurin inhibitors:

• Pulse methylprednisolone (20 mg/kg on three consecutive days at weeks 1,3, and 5, then monthly until 6 months) combined with cyclosporine-based immunosuppression achieved 70% complete remission in pediatric patients 5
• Continue monthly pulses every 3 months until 24 months if partial or complete remission is achieved 5
• Adjust cyclosporine dosing according to AUC0-4 monitoring 5

Costimulation blockade:

• Belatacept-based calcineurin inhibitor-free immunosuppression achieved sustained complete remission in one case report with >56 months follow-up after initial abatacept induction 6
• This approach may be considered for refractory cases, though evidence is limited to case reports 6

Treatment Algorithm

1. Immediate intervention: Start plasma exchange upon biopsy confirmation + optimize RAAS inhibition 1
2. If inadequate response after 2-4 weeks: Add rituximab to plasma exchange 2, 3
3. If still refractory: Consider pulse methylprednisolone with cyclosporine (especially in pediatric patients) 5
4. For treatment-resistant disease: Evaluate for combined rituximab and daratumumab, recognizing this is experimental but has shown promising results in recent case series 4

Critical Pitfalls to Avoid

• Do not delay plasma exchange while waiting for biopsy confirmation if clinical suspicion is high, as early aggressive treatment improves outcomes 2
• Do not use IVIg as first-line therapy, as it is not mentioned in KDIGO guidelines for recurrent FSGS 1
• Do not assume all FSGS recurrence will respond similarly—pediatric patients have higher recurrence rates (86% vs 35% in adults) but may respond better to aggressive treatment 2
• Ensure genetic testing has been performed to exclude genetic forms, as these may not respond to immunologic therapies and would not benefit from experimental monoclonal antibody approaches 4

Monitoring Response

• Track proteinuria levels closely (at minimum weekly initially, then as clinically indicated) to assess treatment response
• Maintain therapeutic calcineurin inhibitor levels throughout treatment to prevent rejection while treating recurrence 1
• Monitor for treatment-related complications, particularly infection risk with combined immunosuppressive and immunomodulatory therapies