What is the initial treatment approach for an elderly patient with primary Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD) and nephrotic range proteinuria?

Treatment of Primary FSGS and MCD in Elderly Patients with Nephrotic Range Proteinuria

Initial Management Strategy

In elderly patients with primary FSGS or MCD presenting with nephrotic range proteinuria, begin with aggressive conservative management for at least 3-6 months before considering immunosuppression, and when immunosuppression is warranted, strongly consider calcineurin inhibitors as first-line therapy rather than high-dose corticosteroids due to the elderly population's increased risk of steroid-related complications. 1

Step 1: Conservative Management (Mandatory First-Line for 3-6 Months)

Blood Pressure and RAAS Blockade

• Initiate ACE inhibitor or ARB at maximally tolerated dose regardless of baseline blood pressure 1
• Target systolic blood pressure ≤125/80 mmHg or <120 mmHg using standardized measurement 1, 2
• Add thiazide diuretic if blood pressure remains elevated 1

Edema Management

• Loop diuretics (furosemide) as first-line agent for severe edema and anasarca 3
• Escalate to combination diuretic therapy if edema persists (furosemide plus thiazide) 1
• Restrict dietary sodium to <2.0 g/day 3, 2
• Avoid routine intravenous albumin infusions; use only if clinical indicators of hypovolemia present (hypotension, tachycardia, poor perfusion) 3

Cardiovascular Risk Reduction

• Initiate statin therapy for cholesterol control 1, 2
• Monitor for thromboembolic complications given nephrotic state 1

Monitoring During Conservative Phase

• Measure proteinuria at baseline (at least 2-3 determinations) before starting immunosuppression 1
• Monitor urine protein daily using dipstick or spot urine protein-to-creatinine ratio 3
• Assess serum creatinine and albumin levels regularly 1

Step 2: Determining Need for Immunosuppression

KDIGO Criteria for Immunosuppression (All Must Be Met)

Immunosuppression should only be considered in idiopathic FSGS or MCD with nephrotic syndrome when: 1

• Proteinuria remains >4 g/day AND stays at >50% of baseline value despite 3-6 months of maximal conservative therapy 1
• OR severe, disabling, or life-threatening symptoms related to nephrotic syndrome are present 1
• OR serum creatinine has risen by ≥30% within 6-12 months but eGFR remains >25-30 mL/min/1.73m² 1

Critical Exclusion: Do NOT Use Immunosuppression If:

• Serum creatinine persistently ≥3.5 mg/dL or eGFR ≤30 mL/min/1.73m² 1
• Kidney size reduced on ultrasound (<8 cm in length) 1
• Secondary FSGS is identified (obesity-related, medication-induced, genetic) 1
• Severe or potentially life-threatening infections present 1

Step 3: Choice of Immunosuppressive Agent in Elderly Patients

First-Line: Calcineurin Inhibitors (PREFERRED in Elderly)

For elderly patients, calcineurin inhibitors should be considered as first-line therapy due to relative contraindications to high-dose corticosteroids including uncontrolled diabetes, psychiatric conditions, severe osteoporosis, and obesity. 1

Cyclosporine Dosing (Preferred Over Tacrolimus in Elderly)

• Initial dose: 3-5 mg/kg/day in divided doses (twice daily) 1, 3
• Target trough levels: C0 = 125-175 ng/mL; C2 = 400-600 ng/mL 1
• Continue for minimum 4-6 months to assess response 1
• If partial or complete remission achieved, continue for at least 12 months, then slow taper 1
• Cyclosporine preferred over tacrolimus due to lesser tendency to precipitate diabetes 1

Response Assessment

• If proteinuria not reduced by 50% after 6 months, discontinue cyclosporine and consider alternative therapy 1
• Target: Complete remission (urine protein <200 mg/g) or partial remission (≥50% reduction in proteinuria) 1, 3

Alternative First-Line: High-Dose Corticosteroids (If CNI Contraindicated)

Use corticosteroids only if calcineurin inhibitors are contraindicated or not tolerated, recognizing the significant toxicity risk in elderly patients. 1

Corticosteroid Dosing for FSGS

• Prednisone 1 mg/kg/day (maximum 80 mg) as single daily dose OR alternate-day 2 mg/kg (maximum 120 mg) 1, 3
• Continue high-dose for minimum 4 weeks, up to maximum 16 weeks or until complete remission, whichever is earlier 1
• Average time to complete remission: 3-4 months 1
• After complete remission, taper slowly over 6 months 1

Corticosteroid Dosing for MCD

• Same dosing as FSGS: 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) 1, 3
• MCD typically responds faster than FSGS (within 4-8 weeks) 1

Step 4: Infection Prophylaxis (MANDATORY Before Immunosuppression)

Vaccination (Complete Before Starting Therapy)

• Pneumococcal vaccination (23-valent or conjugate vaccine) 3, 2
• Annual influenza vaccination for patient and household contacts 3
• Herpes zoster vaccination 2

Infection Screening

• Screen for latent tuberculosis, hepatitis B/C, and HIV before initiating immunosuppression 2

Prophylaxis During Treatment

• Trimethoprim-sulfamethoxazole prophylaxis during immunosuppression 2

Step 5: Monitoring During Immunosuppressive Therapy

Response Definitions

• Complete remission: Urine protein <200 mg/g (<20 mg/mmol) or trace/negative on dipstick for 3 consecutive days 3
• Partial remission: ≥50% reduction in proteinuria with stable renal function 1

Monitoring Schedule

• Monthly monitoring for infections, renal function, and drug levels 2
• Do not declare steroid resistance until at least 8 weeks (preferably 16 weeks) of adequate therapy completed 3
• Do not stop therapy prematurely if partial response occurring; continue up to 16 weeks 3

Critical Pitfalls to Avoid in Elderly Patients

Age-Related Considerations

• Elderly patients have higher risk of steroid-induced diabetes, osteoporosis, psychiatric effects, and infections 1
• Obesity, family history of diabetes, and elevated HbA1c favor CNI over corticosteroids 1
• Severe osteoporosis is a relative contraindication to high-dose corticosteroids 1

Common Errors

• Do not start immunosuppression without adequate trial of conservative management (minimum 3-6 months unless severe complications present) 1
• Do not use immunosuppression in secondary FSGS or FSGS of undetermined cause (FSGS-UC) 1
• Do not declare treatment failure before 6 months of CNI therapy or 16 weeks of corticosteroid therapy 1, 3
• Do not skip infection prophylaxis and vaccination before starting immunosuppression 3, 2

Distinguishing Primary from Secondary FSGS

• Features suggesting secondary FSGS: obesity, relatively normal serum albumin, hilar histological variant, glomerulomegaly 1
• Features suggesting primary FSGS: extensive foot process effacement (>70%), lack of glomerulomegaly, failure to respond to RAAS inhibition 1
• When uncertain, start with conservative management and reassess after 3-6 months 1