What is the recommended stepwise management of an adult with nephrotic syndrome, including first‑line high‑dose oral prednisone, low‑sodium diet, loop diuretic, ACE inhibitor (angiotensin‑converting enzyme inhibitor) or ARB (angiotensin II receptor blocker), prophylactic anticoagulation for severe hypoalbuminemia, statin therapy, monitoring parameters, and second‑line immunosuppressants if proteinuria does not improve after eight weeks?

Stepwise Management of Adult Nephrotic Syndrome

Begin with high-dose oral prednisone (1 mg/kg/day, maximum 80 mg, or 2 mg/kg alternate-day, maximum 120 mg) for 4–16 weeks alongside supportive measures including sodium restriction (<2 g/day), loop diuretics, ACE inhibitor or ARB therapy, and consider prophylactic anticoagulation when serum albumin falls below 2.0–2.5 g/dL with additional risk factors. 1, 2, 3

Step 1: Establish Diagnosis and Exclude Secondary Causes

• Confirm nephrotic syndrome with proteinuria >3.5 g/24 hours (or UPCR >3.5 g/g), serum albumin <3.0 g/dL, and edema. 2
• Perform kidney biopsy within the first month after onset, ideally before starting immunosuppression, to determine the underlying histologic diagnosis (minimal change disease, FSGS, membranous nephropathy). 2
• Screen for secondary causes: fasting glucose and HbA1c for diabetes, ANA/anti-dsDNA/complement levels for lupus, hepatitis B/C serologies, HIV testing, serum/urine immunoelectrophoresis with free light chains to exclude paraprotein disease, and review medications for nephrotoxic agents. 2
• Obtain baseline labs: complete blood count, comprehensive metabolic panel, lipid panel, and calculate eGFR. 2

Step 2: Initiate Supportive Therapy (All Patients)

Dietary Sodium Restriction

• Restrict sodium intake to <2.0 g/day (<90 mmol/day) to enhance diuretic effectiveness and reduce edema. 3
• Maintain protein intake at 0.8–1.0 g/kg/day; excess protein does not compensate for urinary losses. 3

Loop Diuretic Therapy

• Prescribe furosemide starting at 20–40 mg daily, titrated upward based on edema response; administer in the morning to prevent nocturia. 2, 3
• Monitor daily weights; instruct patients to report weight gain >2 kg within 3 days. 3
• Watch for volume depletion (dizziness, reduced urine output), hypokalemia (muscle cramps, weakness), and hyponatremia (confusion, nausea). 3

ACE Inhibitor or ARB Therapy

• Initiate lisinopril 10–20 mg daily or equivalent ARB at maximally tolerated doses to reduce proteinuria and target blood pressure ≤125/75 mmHg. 2, 4
• Continue therapy even if serum creatinine rises up to 30% from baseline, reflecting normal hemodynamic adaptation. 3
• Discontinue immediately if angioedema, persistent dry cough, creatinine increase >30%, or refractory hyperkalemia (K⁺ >5.5 mEq/L) occurs. 3
• Avoid NSAIDs and potassium supplements to reduce hyperkalemia risk. 3

Statin Therapy

• Initiate atorvastatin 20–40 mg daily or equivalent statin for persistent hyperlipidemia, particularly with additional cardiovascular risk factors. 2
• Nephrotic syndrome increases coronary heart disease risk approximately fourfold due to hyperlipidemia. 2, 3

Step 3: Assess Thromboembolism Risk and Consider Prophylactic Anticoagulation

• When serum albumin falls below 2.0–2.5 g/dL AND additional risk factors are present (proteinuria >10 g/day, BMI >35 kg/m², membranous nephropathy, heart failure, recent surgery, or prolonged immobilization), initiate prophylactic full-dose anticoagulation with warfarin targeting INR 2–3. 2, 3
• Serum albumin <2.5 g/dL confers a 29% risk of renal-vein thrombosis and 17–28% risk of pulmonary embolism. 3
• Warfarin is the anticoagulant of choice; avoid factor Xa inhibitors and direct thrombin inhibitors due to unpredictable pharmacokinetics from albumin binding and urinary losses. 2
• Educate patients to seek emergency care for sudden dyspnea, chest pain, hemoptysis (pulmonary embolism), unilateral leg swelling/pain (deep-vein thrombosis), or flank pain with hematuria (renal-vein thrombosis). 3

Step 4: First-Line Immunosuppressive Therapy (Primary FSGS or Minimal Change Disease)

High-Dose Prednisone Regimen

• Administer prednisone 1 mg/kg/day (maximum 80 mg) as a single morning dose, or 2 mg/kg alternate-day (maximum 120 mg). 1, 2, 4
• Continue high-dose therapy for a minimum of 4 weeks and up to 16 weeks, or until complete remission (proteinuria <0.2 g/day), whichever occurs first. 1, 2, 4
• Patients likely to respond will show proteinuria reduction within 4–8 weeks; if proteinuria remains high and unremitting after 8–12 weeks with significant steroid toxicity, consider switching to calcineurin inhibitor rather than extending to 16 weeks. 1, 4

Prednisone Tapering After Remission

• After complete remission, continue high-dose prednisone for an additional 2–4 weeks, then reduce by 5 mg every 1–2 weeks to complete a total 6-month course. 1, 2, 4
• After partial remission at 8–12 weeks, continue until week 16 to assess for further improvement, then taper by 5 mg every 1–2 weeks over 6 months. 1, 4
• Never abruptly discontinue prednisone after >4 weeks of therapy; gradual tapering prevents adrenal crisis. 3

Steroid-Related Monitoring and Prophylaxis

• Monitor fasting glucose weekly during high-dose phase; report values >126 mg/dL. 3
• Prescribe calcium 1200–1500 mg/day plus vitamin D supplementation to prevent steroid-induced bone loss. 3
• Ensure pneumococcal vaccination is current before discharge. 3
• Counsel patients to avoid live vaccines and report fever >38°C immediately due to infection risk. 3

Step 5: Monitoring Parameters (First 2–4 Months)

• Perform laboratory monitoring every 2–4 weeks including serum creatinine, BUN, electrolytes (Na⁺, K⁺, CO₂), serum albumin, UPCR or 24-hour urine protein, and fasting glucose (while on high-dose prednisone). 1, 3
• Treatment goals: ≥25% proteinuria reduction by 3 months, ≥50% reduction by 6 months, and UPCR <500–700 mg/g by 12 months (complete clinical response). 1
• Patients with nephrotic-range proteinuria at baseline may require an additional 6–12 months to reach complete remission; do not switch therapy prematurely if proteinuria is steadily improving. 1

Step 6: Second-Line Therapy for Steroid-Resistant or Steroid-Dependent Disease (After 8–16 Weeks)

Indications for Calcineurin Inhibitor (CNI) Therapy

• Steroid resistance (no response after 16 weeks of high-dose prednisone). 1, 4
• Steroid dependence (relapse when tapering steroids). 2, 4
• Unacceptable steroid toxicity or contraindications to prolonged corticosteroid use. 1, 4

Cyclosporine Dosing and Monitoring

• Start cyclosporine 3–5 mg/kg/day in two divided doses, titrating to target trough (C0) level of 100–175 ng/mL. 1, 2, 4
• Maintain target levels for at least 4–6 months before declaring treatment failure. 1, 2
• If partial or complete remission is achieved, continue cyclosporine for at least 12 months, then taper slowly by 0.5 mg/kg per month to the lowest effective dose, maintaining therapy for 1–2 years. 2, 4

Tacrolimus Dosing and Monitoring

• Start tacrolimus 0.05–0.1 mg/kg/day in two divided doses, targeting trough level of 5–10 ng/mL. 1, 2
• Cyclosporine may be preferred over tacrolimus due to lesser tendency to precipitate diabetes. 2

CNI Safety Monitoring

• Monitor serum creatinine regularly; if it rises >30% from baseline and does not plateau, reduce CNI dose. 1, 2, 4
• If creatinine rise persists despite dose reduction, discontinue CNI and perform kidney biopsy to distinguish nephrotoxicity from disease progression. 1, 2

Treatment Response Definitions

• Partial remission: ≥50% reduction in proteinuria, which confers clinical benefit and should be maintained with lowest effective CNI dose. 2, 4
• Treatment failure: <50% proteinuria reduction after 6 months of CNI therapy at target drug levels. 2, 4

Step 7: Third-Line Options for CNI-Resistant Disease

• For patients failing both corticosteroids and CNI, consider adding or switching to cyclophosphamide or mycophenolate mofetil. 2
• Accepting stable partial remission may be preferable to escalating to more toxic regimens. 2
• Refer to expert nephrology center for refractory cases. 2

Common Pitfalls to Avoid

• Premature steroid discontinuation: Stopping prednisone before completing the 6-month taper raises relapse risk to >50% within 6 months. 3
• Rapid CNI tapering after remission: Abrupt reduction triggers swift relapse; taper gradually over 6–12 months and maintain for 1–2 years. 2
• Ignoring thromboembolism risk: Failure to anticoagulate high-risk patients (albumin <2.5 g/dL with additional factors) can result in life-threatening venous thrombosis. 2, 3
• Continuing high-dose steroids beyond 16 weeks: If proteinuria is persistent and unremitting with significant side effects, switch to CNI rather than extending steroid exposure. 1, 4
• Abrupt ACE inhibitor discontinuation during acute illness: Obtain physician guidance before holding lisinopril during vomiting or diarrhea to prevent hemodynamic instability. 3

Prognosis and Long-Term Outlook

• Untreated proteinuria >3.8 g/day confers a 35% risk of end-stage renal disease within 2 years, versus 4% risk when proteinuria <2.0 g/day. 1, 3
• Achieving complete or partial remission markedly improves renal survival and reduces cardiovascular complications. 3
• The primary therapeutic goal is reduction of proteinuria; complete remission (proteinuria <0.2 g/day) predicts long-term kidney survival. 3