What is the treatment approach for a patient with nephrotic syndrome, characterized by excessive proteinuria, edema, and hyperlipidemia?

Treatment of Nephrotic Syndrome

The treatment of nephrotic syndrome requires a comprehensive approach targeting both the underlying glomerular disease with immunosuppression (when appropriate) and managing the complications of proteinuria, edema, hyperlipidemia, and thromboembolism through supportive measures. 1

Initial Assessment and Risk Stratification

Before initiating therapy, determine whether the nephrotic syndrome is primary (idiopathic) or secondary to systemic disease, as this fundamentally changes management:

• Rule out secondary causes including diabetes mellitus, systemic lupus erythematosus, medications, infections (HIV, HBV, HCV), and malignancy through targeted history and laboratory testing 1, 2
• Screen for latent infections prior to immunosuppression: tuberculosis, hepatitis B and C, HIV, syphilis, and Strongyloides (in at-risk patients with eosinophilia) 1
• Assess thromboembolism risk, particularly critical when serum albumin <2.9 g/dL, as this confers highest risk for venous thrombosis 1
• Consider genetic testing in patients with early-onset disease, family history, steroid-resistant disease, or syndromic features, as 11-24% of adults with steroid-resistant FSGS have disease-causing genetic variants 3

Management of Edema and Volume Overload

Loop diuretics are the preferred agents for edema management, combined with strict dietary sodium restriction 1:

• Furosemide is FDA-approved specifically for edema associated with nephrotic syndrome 4
• Add mechanistically different diuretics (thiazides, potassium-sparing agents) if response to loop diuretics alone is insufficient 1
• Monitor closely for complications: hyponatremia, hypokalemia, volume depletion, and acute kidney injury from excessive diuresis 4
• Counsel patients on "sick day rules": hold diuretics during intercurrent illness with vomiting, diarrhea, or inadequate fluid intake to prevent hemodynamic acute kidney injury 1

Important caveat: In patients with severe hypoalbuminemia, furosemide's effect may be weakened and ototoxicity potentiated 4. Intravenous albumin may be considered in specific circumstances of diuretic resistance, though routine use is not recommended 1.

Management of Hypertension and Proteinuria

ACE inhibitors or ARBs should be up-titrated to maximally tolerated doses as first-line therapy for both blood pressure control and proteinuria reduction 1:

• Target systolic blood pressure <120 mmHg using standardized office measurement 1
• Maximize RAAS inhibition before considering additional immunosuppression 1
• Use potassium-wasting diuretics and/or potassium binders to maintain normal potassium levels, allowing continued RAAS inhibitor use 1
• Avoid dihydropyridine calcium channel blockers (amlodipine, nifedipine) as they worsen edema and may increase proteinuria 1
• Counsel patients to hold ACE inhibitors/ARBs during volume depletion risk (diarrhea, vomiting, excessive sweating) 1

Management of Hyperlipidemia

Consider statin therapy as first-line for persistent dyslipidemia, particularly in patients with additional cardiovascular risk factors 1:

• Lifestyle modifications are important in all patients with persistent dyslipidemia 1
• Initiate non-statin therapy in patients who cannot tolerate statins or fail to achieve LDL/triglyceride goals despite maximal statin dose 1
• Hyperlipidemia occurs as a compensatory mechanism for plasma protein loss and contributes to cardiovascular risk 3

Thromboembolism Prevention and Treatment

Full anticoagulation is mandatory for documented thromboembolic events 1:

• Prophylactic anticoagulation should be employed when thromboembolism risk exceeds bleeding risk, particularly in membranous nephropathy with nephrotic syndrome and albumin <2.9 g/dL 1
• Use unfractionated heparin, low-molecular-weight heparin, or warfarin as preferred agents 1
• Avoid factor Xa inhibitors and direct thrombin inhibitors in active nephrotic syndrome, as these agents have significant albumin binding, are lost in nephrotic urine, and have poorly studied pharmacokinetics in this population 1
• Risk assessment tools are available at www.med.unc.edu/gntools/bleedrisk.html 1

Critical point: Thromboembolism occurs in 29% (renal vein thrombosis), 17-28% (pulmonary embolism), and 11% (deep vein thrombosis) of nephrotic patients, most commonly within the first 6 months of diagnosis 1, 5.

Infection Prevention

Implement vaccination and prophylaxis strategies before and during immunosuppression 1:

• Administer pneumococcal vaccine to all patients with nephrotic syndrome or CKD 1
• Annual influenza vaccine for patients and household contacts 1
• Meningococcal vaccine for patients with complement deficiencies or receiving complement inhibitors 1
• Trimethoprim-sulfamethoxazole prophylaxis when using prednisone ≥20 mg daily or other potent immunosuppressants (rituximab, cyclophosphamide) 1

Disease-Specific Immunosuppressive Therapy

Minimal Change Disease

• Cyclosporin is an alternative to high-dose corticosteroids for patients who cannot tolerate or have contraindications to steroids 3
• Cyclosporin acts through calcineurin inhibition, suppressing IL-2 production and T-cell activation 1

Focal Segmental Glomerulosclerosis (Primary)

First-line therapy is high-dose corticosteroids 3:

• Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) 3
• Continue for minimum 4 weeks up to 16 weeks as tolerated or until complete remission 3
• Taper slowly over 6 months after achieving complete remission 3
• Second-line options for steroid-resistant or steroid-dependent disease include calcineurin inhibitors, rituximab, or mycophenolate 3

Critical distinction: Do not use immunosuppression in secondary FSGS (from obesity, reduced nephron mass, medications, viral infections), as this can cause harm without benefit 3.

Membranous Nephropathy

• Treatment approach varies based on proteinuria severity and risk stratification 1
• For nephrotic-range proteinuria, combined immunosuppression with glucocorticoids plus mycophenolic acid analogs, cyclophosphamide, or calcineurin inhibitors is recommended 1

Lupus Nephritis Class V

For nephrotic-range proteinuria in Class V lupus nephritis 1:

• Combined immunosuppressive treatment with glucocorticoid and mycophenolic acid analogs, cyclophosphamide, or calcineurin inhibitors 1
• Hydroxychloroquine should be included in all lupus nephritis treatment regimens 1
• Triple immunosuppression (glucocorticoids + tacrolimus + low-dose mycophenolate) achieves higher complete remission rates (33.1% vs 7.8%) compared to cyclophosphamide-based regimens 1

Adjunctive Therapy in Established CKD

For patients with eGFR ≥20 mL/min/1.73 m² and proteinuria ≥200 mg/g, add SGLT2 inhibitors for kidney protection 3:

• Use on top of maximally tolerated RAAS inhibition, not as replacement for disease-specific therapy 3
• Monitor for initial eGFR dip of 3-5 mL/min/1.73 m² in first 4 weeks (reversible, not indication to discontinue) 3
• Implement sick day rules: hold during acute illness with nausea, vomiting, or diarrhea to prevent ketoacidosis 3
• Reduce diuretic doses before initiating in patients at risk for hypovolemia 3
• Counsel on genital hygiene to prevent mycotic infections 3

Treatment Goals and Monitoring

Remission of proteinuria is the most significant predictor of renal survival 3:

• Complete response: proteinuria <0.5 g/g (50 mg/mmol) with stable/improved kidney function within 6-12 months 1
• Partial response: ≥50% reduction in proteinuria to <3 g/g (300 mg/mmol) with stable/improved kidney function 1
• Monitor serum electrolytes (particularly potassium), CO2, creatinine, and BUN frequently during initial months, then periodically 4
• 40% or greater decline in eGFR from baseline over 2-3 years is a validated surrogate outcome measure for treatment failure 1

Common Pitfalls to Avoid

• Do not use immunosuppression in secondary FSGS or genetic forms, as this provides no benefit and causes harm 3
• Do not use factor Xa inhibitors or direct thrombin inhibitors for anticoagulation in active nephrotic syndrome due to unpredictable pharmacokinetics 1
• Do not continue dihydropyridine calcium channel blockers if proteinuria worsens, as these agents increase proteinuria 1
• Do not delay genetic testing in early-onset, familial, or steroid-resistant cases, as this fundamentally changes management 3
• Do not forget to treat metabolic acidosis if serum bicarbonate <22 mmol/L 1

Prognostic consideration: Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years, emphasizing the urgency of achieving proteinuria reduction 1, 3.