What is the initial management for a patient presenting with nephrotic syndrome, including treatment options and lifestyle modifications?

Initial Management of Nephrotic Syndrome

Begin with aggressive sodium restriction to <2.0 g/day and loop diuretics for edema control, while simultaneously initiating ACE inhibitors or ARBs at maximally tolerated doses to reduce proteinuria, targeting systolic blood pressure <120 mmHg in adults. 1

Immediate Diagnostic Workup

Before initiating disease-specific therapy, confirm the diagnosis and exclude secondary causes:

• Confirm nephrotic-range proteinuria with 24-hour urine collection (>3.5 g/24h) or spot urine protein-to-creatinine ratio, and document hypoalbuminemia (<3.0 g/dL in adults, ≤2.5 g/dL in children) 2, 3
• Screen for secondary causes including diabetes mellitus, systemic lupus erythematosus (ANA, anti-dsDNA, complement levels), hepatitis B/C, HIV, and review medications for nephrotoxic agents 1, 2, 3
• Obtain kidney biopsy in adults to establish histologic diagnosis and guide immunosuppressive therapy, except when serum anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy) 3, 4
• In children <12 years, defer biopsy if typical presentation and initiate empiric corticosteroid therapy; biopsy is indicated only for steroid-resistant cases 2, 3

The biopsy must include at least 8 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stain, plus immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains, and electron microscopy 3

Conservative Management (All Patients)

Edema and Blood Pressure Control

• Restrict dietary sodium to <2.0 g/day (<90 mmol/d) as first-line intervention for edema and proteinuria reduction 1
• Initiate loop diuretics (furosemide) as preferred agents for edema management; if response is insufficient, add mechanistically different diuretics (thiazides or potassium-sparing agents) 1
• Monitor closely for diuretic complications including hyponatremia, hypokalemia, GFR reduction, and volume depletion 1
• Target systolic blood pressure <120 mmHg using standardized office measurement in adults; in children, target 24-hour mean arterial pressure at 50th percentile for age, sex, and height by ambulatory monitoring 1

Antiproteinuric Therapy

• Up-titrate ACE inhibitor or ARB to maximally tolerated or allowed daily dose as first-line therapy for both hypertension with proteinuria and proteinuria alone 1
• Counsel patients to hold ACE inhibitors/ARBs and diuretics during intercurrent illness or any situation with risk for volume depletion (sick day rules) 1
• Use potassium-wasting diuretics and/or potassium-binding agents if hyperkalemia develops, to allow continuation of RAS inhibition for blood pressure and proteinuria control 1
• Treat metabolic acidosis if serum bicarbonate <22 mmol/L 1

Important caveat: In patients with podocytopathy (minimal change disease, steroid-sensitive nephrotic syndrome, FSGS) expected to respond rapidly to immunosuppression, it may be reasonable to delay ACE inhibitor/ARB initiation if no hypertension is present 1

Dyslipidemia Management

• Consider statin therapy for persistent hyperlipidemia, particularly in patients with additional cardiovascular risk factors (hypertension, diabetes) 1
• Assess ASCVD risk based on LDL-C, apolipoprotein B, triglycerides, and lipoprotein(a) levels, then align statin dosage intensity to risk 1
• For statin-intolerant patients or those failing to achieve goals, consider non-statin therapy including ezetimibe, PCSK9 inhibitors, fibrates, bile acid sequestrants, or nicotinic acid 1

Lifestyle Modifications

Employ the following synergistic interventions in all patients to improve control of hypertension and proteinuria 1:

• Normalize body weight and limit central obesity
• Stop smoking
• Exercise regularly
• Maintain dietary sodium restriction <2.0 g/day

Thromboembolism Prevention

This is a critical and often underappreciated aspect of nephrotic syndrome management:

• Full anticoagulation is mandatory for documented thromboembolic events occurring in the context of nephrotic syndrome 1
• Consider prophylactic anticoagulation when thromboembolism risk exceeds bleeding risk, particularly in membranous nephropathy with nephrotic syndrome 1
• High-risk criteria include: serum albumin <2.0-2.5 g/dL (especially <2.0 g/dL), proteinuria >10 g/day, BMI >35 kg/m², heart failure, recent surgery, or prolonged immobilization 3, 4
• Warfarin is the anticoagulant of choice with target INR 2-3, requiring frequent monitoring due to fluctuating albumin-protein binding; avoid Factor Xa inhibitors and direct thrombin inhibitors due to unpredictable pharmacokinetics from albumin binding and urinary losses 3

Membranous nephropathy carries particularly high venous thromboembolism risk compared to other causes of nephrotic syndrome 3

Infection Prevention

• Administer pneumococcal vaccine to all patients with nephrotic syndrome and/or chronic kidney disease 1
• Ensure influenza vaccine for patients and household contacts 1
• Screen for tuberculosis, hepatitis B/C, HIV, and syphilis in clinically appropriate patients before initiating immunosuppression 1
• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose prednisone or other immunosuppressive agents (rituximab, cyclophosphamide) 1
• Meningococcal vaccine and prophylaxis are necessary in patients with complement deficiencies or those treated with complement inhibitors 1

Disease-Specific Immunosuppressive Therapy

Treatment must be tailored to the underlying histologic diagnosis:

Minimal Change Disease

• Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) for adults 2, 3
• In children: prednisone 60 mg/m²/day (maximum 80 mg/day) or 2 mg/kg/day for 4-6 weeks 2
• Continue high-dose corticosteroids for minimum 4 weeks, up to 16 weeks as tolerated or until complete remission, then taper slowly over 6 months 2
• For steroid-dependent or frequently relapsing disease, consider cyclosporine 3-5 mg/kg/day divided twice daily or tacrolimus 0.1-0.2 mg/kg/day divided twice daily 2, 3

Focal Segmental Glomerulosclerosis (FSGS)

• First classify into primary, genetic, secondary, or undetermined cause to guide treatment 3
• For primary FSGS: prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) as first-line therapy 3
• Consider calcineurin inhibitors (cyclosporine or tacrolimus) as alternative first-line for patients with contraindications to high-dose corticosteroids 2, 3
• Cyclosporine may be preferred over tacrolimus due to lesser tendency to precipitate diabetes 3
• Genetic testing is indicated for familial kidney disease, syndromic features, steroid-resistant FSGS, or early-onset cases 3

Membranous Nephropathy

• Initiate immunosuppressive therapy only when urinary protein persistently exceeds 4 g/day and remains >50% of baseline despite 6 months of conservative therapy, or severe disabling symptoms are present 2
• Risk-stratify patients: low risk (normal renal function despite maximum conservative therapy), medium risk (proteinuria 4-8 g/day observed up to 6 months), or high risk (deteriorating renal function over 2-3 months ± proteinuria >8 g/day) 1
• For medium/high risk: cyclosporine ± low-dose corticosteroid for at least 6 months (target trough level 125-200 ng/mL) or cytotoxic agent + corticosteroid 1
• This population has particularly high thromboembolism risk requiring aggressive prophylactic anticoagulation consideration 1

Monitoring and Follow-Up

• Assess proteinuria and kidney function regularly to evaluate treatment response; a 40% or greater decline in eGFR from baseline over 2-3 years suggests treatment failure 1
• Monitor for medication side effects, particularly with long-term immunosuppressive therapy 2
• Proteinuria goal is disease-specific, typically <1 g/day, though this varies by underlying glomerular disease 1
• Monitor labs frequently when on ACE inhibitors/ARBs for hyperkalemia and acute kidney injury 1

Common Pitfalls to Avoid

• Do not use intravenous albumin infusions routinely; they are not recommended as standard management and provide only transient benefit 5
• Do not delay kidney biopsy in adults attempting empiric corticosteroid therapy, as this obscures histologic diagnosis and may expose patients to unnecessary steroid toxicity 3
• Do not underestimate thromboembolism risk; assess beyond albumin level alone and include BMI, immobility, heart failure, and recent surgery in risk stratification 3
• Do not use Factor Xa inhibitors or direct thrombin inhibitors for anticoagulation due to unpredictable pharmacokinetics from significant albumin binding and urinary losses 3
• Do not continue ineffective immunosuppression; if no response after 3-6 months at non-toxic doses, switch to alternative therapy 1