What is the treatment for a patient with nephrotic syndrome?

Treatment of Nephrotic Syndrome

Begin with conservative management using ACE inhibitors or ARBs at maximally tolerated doses, strict sodium restriction (<2 g/day), loop diuretics for edema, and statins for hyperlipidemia; reserve immunosuppressive therapy only for specific histologic subtypes (FSGS, membranous nephropathy) with persistent nephrotic-range proteinuria despite 6 months of optimal conservative therapy. 1, 2

Initial Conservative Management (All Patients)

Proteinuria and Blood Pressure Control

• Initiate ACE inhibitors or ARBs as first-line therapy, targeting blood pressure <130/80 mmHg (ideally <120 mmHg systolic) and proteinuria <1 g/day when feasible 1, 2
• Uptitrate to maximally tolerated doses rather than submaximal dosing 2
• Do not discontinue if serum creatinine rises modestly (up to 30%) and stabilizes—this is expected and acceptable 2
• Monitor electrolytes and creatinine frequently after initiation 1, 2

Edema Management

• Administer loop diuretics (furosemide 0.5-2 mg/kg per dose, up to 6 times daily) only in patients with intravascular volume overload 1, 2
• Critical pitfall: Never give diuretics to hypovolemic patients despite low serum albumin—this worsens intravascular depletion 1
• Add thiazide diuretics if loop diuretics alone are insufficient 3

Sodium Restriction

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day)—this is synergistic with pharmacologic therapy 2

Hyperlipidemia Management

• Start statin therapy for persistent hyperlipidemia, particularly with additional cardiovascular risk factors 1, 2

Thromboembolism Prevention

• Use prophylactic anticoagulation (low-molecular-weight heparin or unfractionated heparin 5000 U subcutaneously twice daily) when serum albumin <20-25 g/L plus other risk factors 1
• The risk-benefit calculation favors prophylaxis when thromboembolism risk exceeds bleeding risk 1

Immunosuppressive Therapy (Selective Use Only)

Focal Segmental Glomerulosclerosis (FSGS)

Corticosteroids should be considered only in idiopathic FSGS with nephrotic syndrome features 3

Indications for Starting Immunosuppression:

• Urinary protein excretion persistently exceeds 4 g/day AND remains >50% of baseline despite 6 months of conservative therapy 3
• OR severe, disabling, or life-threatening nephrotic symptoms 3
• OR serum creatinine risen by ≥30% within 6-12 months (with eGFR still >25-30 ml/min/1.73 m²) unexplained by other causes 3

First-Line Immunosuppression for FSGS:

• Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) 3
• Continue high-dose for minimum 4 weeks, up to maximum 16 weeks or until complete remission, whichever is earlier 3
• Taper slowly over 6 months after achieving complete remission 3

Alternative First-Line for FSGS (When Steroids Contraindicated):

• Calcineurin inhibitors (cyclosporine preferred over tacrolimus in patients with diabetes risk; starting dose 6 mg/kg/day) 3, 4
• Use CNIs for patients with uncontrolled diabetes, psychiatric conditions, severe osteoporosis, or obesity with elevated HbA1c 3
• Caution: CNIs must be used carefully in patients with significant vascular/interstitial disease on biopsy or decreased eGFR 3

Second-Line Options for Steroid-Resistant FSGS:

• Mycophenolate mofetil plus high-dose dexamethasone for 12 months induces 33% combined remission (modest benefit with prolonged exposure) 3
• Rituximab has limited evidence in FSGS 3

Membranous Nephropathy

Initial therapy consists of 6-month course of alternating monthly cycles of oral/IV corticosteroids and oral alkylating agents 3

Indications (Same as FSGS):

• Proteinuria persistently >4 g/day after 6 months conservative therapy 3
• OR severe/disabling nephrotic symptoms 3
• OR rising creatinine ≥30% within 6-12 months 3

Specific Regimen:

• Alternating monthly cycles of corticosteroids with cyclophosphamide or chlorambucil 3
• Manage conservatively for at least 6 months after completing this regimen before declaring treatment failure, unless kidney function deteriorating or severe symptoms present 3

Lupus Nephritis (Class IV)

Initial therapy with corticosteroids combined with either cyclophosphamide or mycophenolate mofetil 3

• If worsening during first 3 months (rising creatinine, worsening proteinuria), change to alternative therapy or repeat biopsy 3

Special Populations

Genetic Forms of Nephrotic Syndrome

• Do not use immunosuppressive agents—they are unlikely to respond 1
• Genetic testing not indicated with negative family history (low yield) 3

Pediatric Patients

• Prednisone 60 mg/m²/day (maximum 80 mg/day) for 4 weeks, then 40 mg/m²/alternate days for several weeks in minimal change disease 4
• Response occurs average 11 days in children (versus up to 16 weeks in adults) 4
• Monitor growth velocity—more sensitive indicator of systemic corticosteroid exposure than HPA axis testing 5

Elderly Patients

• Start at low end of dosing range given increased risk of diabetes, fluid retention, and hypertension with corticosteroids 5

Managing Hyperkalemia to Continue RAS Blockade

• Use potassium-wasting diuretics (loop or thiazide) to reduce serum potassium 2
• Consider potassium-binding agents (patiromer, sodium zirconium cyclosilicate) to allow continued ACE inhibitor/ARB use 2
• Stop ACE inhibitor/ARB only if kidney function continues worsening or refractory hyperkalemia develops 2

Critical Patient Education

• Counsel patients to hold ACE inhibitor/ARB and diuretics during intercurrent illnesses when at risk for volume depletion 2
• This prevents acute kidney injury during episodes of vomiting, diarrhea, or reduced oral intake 2

Additional Supportive Measures

• Ensure adequate nutrition to prevent malnutrition 1
• Supplement vitamin D and calcium when 25-OH-D3 is low, ionized calcium is low, or PTH is elevated 1
• Do not give albumin infusions based solely on serum albumin levels—only for clinical hypovolemia 1

Common Pitfalls to Avoid

• Never administer diuretics to hypovolemic patients despite low serum albumin—worsens intravascular depletion 1
• Do not prematurely discontinue ACE inhibitor/ARB for modest creatinine rise up to 30% if stable 2
• Do not use immunosuppression in secondary causes (diabetes, amyloidosis) or genetic forms 1
• Do not start immunosuppression without adequate trial (6 months) of conservative management first, unless severe symptoms 3