What is the recommended initial and first‑line treatment for an adult with focal segmental glomerulosclerosis presenting with edema, nephrotic‑range proteinuria, low serum albumin and an estimated glomerular filtration rate of at least 30 mL/min/1.73 m²?

First-Line Treatment for Primary FSGS with Nephrotic Syndrome

High-dose oral corticosteroids (prednisone 1 mg/kg/day, maximum 80 mg, or 2 mg/kg on alternate days, maximum 120 mg) for a minimum of 4 weeks and up to 16 weeks—or until complete remission—followed by a slow taper over 6 months, represent the recommended initial therapy for adults with primary focal segmental glomerulosclerosis presenting with nephrotic syndrome and eGFR ≥30 mL/min/1.73 m². 1, 2

Initial Supportive Measures Before Immunosuppression

Before starting corticosteroids, you must establish that this is primary FSGS rather than secondary or genetic forms, because immunosuppression is contraindicated in secondary FSGS. 3

• Initiate ACE-inhibitor or ARB therapy immediately to reduce proteinuria and target blood pressure ≤125/75 mmHg, regardless of whether immunosuppression will follow. 1, 2
• Assess thromboembolism risk: When serum albumin falls below 2.0–2.5 g/dL (20–25 g/L) AND additional risk factors exist (proteinuria >10 g/day, BMI >35 kg/m², heart failure, recent surgery, or prolonged immobilization), consider prophylactic full-dose anticoagulation with warfarin (target INR 2–3). 1, 3
• Control edema with loop diuretics (furosemide) as needed. 1
• Manage hyperlipidemia with statin therapy, particularly when cardiovascular risk factors coexist. 1

Corticosteroid Protocol (KDIGO 2021 Standard)

Dosing and Duration

• Start prednisone 1 mg/kg/day (maximum 80 mg) or use an alternate-day regimen of 2 mg/kg (maximum 120 mg). 1, 2, 3
• Continue high-dose therapy for a minimum of 4 weeks, extending up to 16 weeks as tolerated or until complete remission is achieved. 1, 2, 3
• Monitor proteinuria closely during weeks 4–8: An early decline in proteinuria predicts steroid responsiveness and justifies continuing therapy. 1

Tapering Strategy

• After complete remission: Continue high-dose prednisone for an additional 2 weeks, then reduce by 5 mg every 1–2 weeks to complete a total 6-month course. 1
• After partial remission at 8–12 weeks: Maintain steroids until week 16, then taper by 5 mg every 1–2 weeks over the subsequent 6 months. 1

When to Switch to Calcineurin Inhibitors

If proteinuria remains high after 8–12 weeks or steroid-related toxicity (hyperglycemia, weight gain, psychiatric symptoms, infection) becomes unacceptable, transition to a calcineurin inhibitor rather than extending steroid exposure to the full 16 weeks. 1, 4

Second-Line Therapy: Calcineurin Inhibitors

Indications for CNI Use

• Steroid resistance (no response after 16 weeks of corticosteroids). 1, 3
• Steroid intolerance or contraindications (uncontrolled diabetes, severe osteoporosis, active infection). 1, 2
• Steroid dependence (relapse upon tapering). 5, 1

Cyclosporine Dosing and Monitoring

• Start cyclosporine at 2–3 mg/kg/day in two divided doses; gradually increase to 4–5 mg/kg/day based on response and tolerability. 5, 1
• Target trough (C0) level of 100–175 ng/mL (or C2 <500 ng/mL). 5, 1
• Maintain target levels for at least 4–6 months before declaring treatment failure. 1
• If remission is achieved, continue cyclosporine for a minimum of 12 months, then taper slowly by 0.5 mg/kg per month to the lowest effective dose, maintaining therapy for 1–2 years. 5, 1

Tacrolimus as an Alternative

• Start tacrolimus at 0.05–0.1 mg/kg/day in two divided doses; target trough level 5–10 ng/mL. 1
• Cyclosporine may be preferred over tacrolimus due to a lesser tendency to precipitate diabetes. 1

Safety Monitoring for CNI Therapy

• Monitor serum creatinine closely: If creatinine rises >30% from baseline and does not plateau, reduce the CNI dose. 1
• Discontinue the CNI if creatinine elevation persists despite dose reduction. 1
• Perform a repeat renal biopsy when it is unclear whether rising creatinine reflects CNI nephrotoxicity or disease progression. 1

Definitions of Treatment Response

• Complete remission: Proteinuria <0.3 g/day with stable renal function. 1
• Partial remission: ≥50% reduction in proteinuria from baseline, which still confers clinical benefit and should be maintained with the lowest effective CNI dose. 5, 1
• Treatment failure: <50% reduction in proteinuria after 6 months of CNI therapy at target levels. 5, 1

Management of Treatment-Resistant Disease

For patients who fail both corticosteroids and CNI (no partial remission after 6 months), consider adding or switching to cyclophosphamide or mycophenolic acid, or refer to an expert center. 1, 3

• Accepting a stable partial remission may be preferable to escalating to more toxic regimens, as even partial remission significantly improves long-term renal survival. 1, 6

Common Pitfalls and How to Avoid Them

• Failing to distinguish primary from secondary FSGS: Always exclude secondary causes (obesity with BMI >35, viral infections, drug toxicity, reflux nephropathy, reduced nephron mass from prematurity) before starting immunosuppression, as secondary FSGS does not respond to steroids and may worsen with treatment. 1, 3, 7
• Stopping corticosteroids too early: The minimum trial is 4 weeks, but many patients require 8–16 weeks to respond; premature discontinuation misses potential responders. 1, 4
• Ignoring thromboembolism risk: FSGS patients with albumin <2.0–2.5 g/dL have up to 29% risk of renal vein thrombosis and 17–28% risk of pulmonary embolism; prophylactic anticoagulation is warranted when additional risk factors are present. 1, 3
• Rapid CNI tapering after remission: Abrupt discontinuation can cause rapid relapse even after years of stable disease; taper slowly over 6–12 months to the minimum effective dose and maintain for 1–2 years. 5, 1
• Using direct oral anticoagulants (DOACs) in nephrotic syndrome: Factor Xa inhibitors and direct thrombin inhibitors have unpredictable pharmacokinetics due to significant albumin binding and urinary losses; warfarin is the anticoagulant of choice. 1

Adjunctive Therapy for Kidney Protection

• For FSGS patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, add an SGLT2 inhibitor (e.g., dapagliflozin) on top of maximally tolerated RAS inhibition for long-term kidney protection, not as a replacement for disease-specific immunosuppression. 3
• Monitor for an initial eGFR dip of 3–5 mL/min/1.73 m² in the first 4 weeks after starting SGLT2 inhibitors; this is reversible and not an indication to discontinue. 3
• Implement sick-day rules: Hold SGLT2 inhibitors during acute illness with nausea, vomiting, or diarrhea to prevent ketoacidosis. 3

Prognostic Considerations

• Remission of proteinuria is the single most significant predictor of renal survival in FSGS; patients who achieve remission have >80% 10-year renal survival, whereas those with persistent nephrotic syndrome have >50% risk of end-stage renal disease within 5–10 years. 1, 3, 6
• Patients with proteinuria >3.8 g/day have a 35% risk of ESRD within 2 years if untreated, underscoring the urgency of achieving remission. 3
• Spontaneous remissions are rare (<6%) in primary FSGS, making treatment essential. 6