What is the role of finerenone (Mineralocorticoid receptor antagonist) in the treatment of Focal Segmental Glomerulosclerosis (FSGS)?

Use of Finerenone in FSGS

Finerenone is not indicated for the treatment of FSGS and should not be used for this condition. The evidence base for finerenone is exclusively in type 2 diabetes with chronic kidney disease, and there is no data supporting its use in primary glomerular diseases like FSGS 1, 2.

Why Finerenone Is Not Appropriate for FSGS

Indication Mismatch

• Finerenone is FDA-approved only for type 2 diabetes with chronic kidney disease, not for primary glomerular diseases 1, 2
• The landmark trials (FIDELIO-DKD and FIGARO-DKD) that established finerenone's efficacy enrolled exclusively patients with diabetic kidney disease, with no FSGS patients included 1, 2
• KDIGO guidelines explicitly designate finerenone for "T2D only," distinguishing it from therapies applicable to all kidney disease types 1, 2

Different Disease Pathophysiology

• FSGS is a podocyte injury disease with distinct pathogenic mechanisms involving circulating permeability factors, genetic mutations, and adaptive responses to nephron loss 1
• Finerenone's mechanism targets mineralocorticoid receptor-mediated inflammation and fibrosis in diabetic kidney disease, which differs fundamentally from FSGS pathophysiology 1, 3
• The proteinuria in FSGS results from podocyte loss and slit diaphragm dysfunction, not the aldosterone-mediated mechanisms that finerenone addresses 1

What Should Be Used Instead for FSGS

First-Line Supportive Therapy (All FSGS Patients)

• Maximize ACE inhibitor or ARB to highest tolerated dose as first-line antiproteinuric therapy 1
• Target blood pressure of 120-130 mmHg systolic 1
• Restrict dietary sodium to <2.0 g/day 1
• Consider traditional mineralocorticoid receptor antagonists (spironolactone/eplerenone) only as add-on therapy for refractory proteinuria with careful hyperkalemia monitoring 1

Immunosuppressive Therapy Algorithm (For Nephrotic-Range Proteinuria)

Initial therapy should only be started when:

• Urinary protein excretion persistently exceeds 4 g/day AND remains >50% of baseline despite 6 months of maximal supportive therapy, OR
• Severe, disabling, or life-threatening nephrotic syndrome symptoms are present, OR
• Serum creatinine has risen by ≥30% within 6-12 months with eGFR still >25-30 mL/min/1.73m² 1

First-line immunosuppression:

• High-dose corticosteroids for 16 weeks (various regimens including daily or alternate-day dosing) 1
• If no response by 16 weeks, consider the patient steroid-resistant 1

For steroid-resistant FSGS:

• Calcineurin inhibitors (cyclosporine or tacrolimus) are the preferred second-line agents with >70% response rates 1
• Treat for minimum 12 months to minimize relapse risk 1
• Monitor drug levels and kidney function closely; avoid in patients with significant vascular/interstitial disease on biopsy 1

For CNI-resistant or intolerant patients:

• Refer to specialized centers for rebiopsy, genetic testing, alternative treatments, or clinical trial enrollment 1
• Consider mycophenolate mofetil plus high-dose dexamethasone (33% response rate in trials, though modest) 1, 4, 5
• Rituximab has limited evidence in FSGS 1

Critical Pitfalls to Avoid

• Do not extrapolate diabetic kidney disease evidence to FSGS patients, even if they have similar levels of proteinuria or kidney dysfunction—the underlying pathophysiology and treatment responses are fundamentally different 1, 2
• Do not delay immunosuppression in appropriate candidates while attempting prolonged trials of supportive therapy alone if criteria for treatment initiation are met 1
• Do not use CNIs in patients with advanced interstitial fibrosis or vascular disease on biopsy, as these patients are at higher risk for CNI-induced nephrotoxicity 1
• Do not stop immunosuppression prematurely in responders—CNIs require at least 12 months of therapy to minimize relapse risk, which occurs in >50% with shorter courses 1