What are the management options for a patient with nephrotic syndrome?

Management of Nephrotic Syndrome

Nephrotic syndrome management requires a systematic approach targeting proteinuria reduction, edema control, cardiovascular risk mitigation, and thromboembolism prevention, with treatment intensity guided by the underlying etiology and disease severity. 1

Initial Diagnostic Workup

Before initiating treatment, establish the diagnosis and identify secondary causes:

• Confirm nephrotic syndrome with proteinuria ≥3.5 g/day (or ≥1.0 g/m²/day in children), serum albumin <3.0 g/dL (<2.5 g/dL in children), and edema 2
• Obtain comprehensive laboratory evaluation: complete blood count, electrolytes (sodium, chloride, potassium), albumin, creatinine, urea, lipid panel (total cholesterol, LDL-C, triglycerides), glucose, and urinalysis 2, 3
• Screen for secondary causes: thyroid function (TSH, free T4), serum IgG, anti-phospholipase A2 receptor antibodies (diagnostic for membranous nephropathy), and infectious workup as indicated 3, 4
• Assess calcium-phosphate metabolism: ionized calcium, phosphate, alkaline phosphatase, PTH, and vitamin D levels 2, 3
• Perform renal ultrasound to evaluate kidney size, echogenicity, and detect ascites 2, 3

In adults, renal biopsy is typically indicated except when anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy) 5. In children younger than 12 years, empiric glucocorticoid therapy can be initiated without biopsy if minimal change disease is suspected; biopsy is reserved for steroid-resistant cases 5.

Proteinuria and Blood Pressure Management

First-Line Therapy: RAS Inhibition

• Initiate ACE inhibitors or ARBs as first-line therapy for proteinuria reduction and blood pressure control, targeting proteinuria <1 g/day when feasible 1
• Target blood pressure <130/80 mmHg in most patients with nephrotic syndrome 1
• Monitor electrolytes and creatinine frequently (every 1-2 weeks initially) after starting RAS inhibitors 1
• Counsel patients to hold ACE inhibitors/ARBs and diuretics during acute illness with volume depletion risk (sick day management) 1

Important caveat: In patients with rapidly steroid-responsive podocytopathies (minimal change disease, steroid-sensitive nephrotic syndrome, some FSGS cases), it may be reasonable to delay ACE inhibitor/ARB initiation in normotensive patients to allow immunosuppression to work first 1.

Managing Hyperkalemia to Enable RAS Blockade

• Use potassium-wasting diuretics (furosemide, thiazides) and/or potassium-binding agents to normalize serum potassium, allowing continuation of RAS inhibitors 1
• Treat metabolic acidosis (target serum bicarbonate ≥22 mmol/L) to reduce potassium levels 1
• Consider mineralocorticoid receptor antagonists (spironolactone, eplerenone) in refractory proteinuria cases, with careful hyperkalemia monitoring 1

Lifestyle Modifications

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) as synergistic therapy for hypertension and proteinuria control 1, 2
• Intensify sodium restriction further in patients failing to achieve proteinuria goals on maximal medical therapy 1
• Encourage weight normalization, smoking cessation, and regular exercise 1

Edema Management

Diuretic Therapy

Administer diuretics only in patients with intravascular volume overload (evidenced by hypertension and good peripheral perfusion), not in those with hypovolemia 1, 2.

• Start furosemide 0.5-2 mg/kg per dose intravenously or orally, up to 6 times daily (maximum 10 mg/kg/day) based on edema severity and diuresis achieved 1, 2, 3
• Administer furosemide (0.5-2 mg/kg) at the end of albumin infusions unless marked hypovolemia or hyponatremia is present 1, 2, 3
• Limit high-dose furosemide (>6 mg/kg/day) to ≤1 week and infuse over 5-30 minutes to prevent ototoxicity 1, 3
• Stop furosemide immediately if anuria develops 1

For stable outpatients:

• Combine oral furosemide (2-5 mg/kg/day) with thiazide or potassium-sparing diuretics with appropriate electrolyte monitoring 1
• Prefer amiloride over spironolactone as the potassium-sparing agent, since urinary proteases directly activate ENaC independent of mineralocorticoid receptors 1

Albumin Infusions

Albumin infusions are indicated only for clinical hypovolemia (oliguria, acute kidney injury, prolonged capillary refill, tachycardia, hypotension, abdominal discomfort) or failure to thrive—not based on serum albumin levels alone 1, 3.

• Avoid routine albumin infusions to normalize serum albumin, as this does not improve outcomes 1, 3
• Consider home albumin administration by trained caregivers in stable patients requiring regular infusions to improve quality of life and reduce hospitalizations 3

Fluid Management

• Restrict fluid intake when feasible, especially with hyponatremia and severe edema 2, 3
• Avoid intravenous saline in most cases; concentrate oral fluids if necessary 1

Hyperlipidemia Management

Statin Therapy

Consider statin therapy as first-line treatment for persistent hyperlipidemia, particularly in patients with additional cardiovascular risk factors (hypertension, diabetes, reduced eGFR <60 mL/min/1.73 m²) 1, 2.

• Assess ASCVD risk based on LDL-C, apolipoprotein B, triglycerides, lipoprotein(a), age, and ASCVD risk enhancers (chronic inflammatory conditions, CKD, South Asian ancestry) 1
• Align statin intensity to ASCVD risk rather than using a fixed approach 1
• Monitor fasting lipids and safety indicators 4-12 weeks after statin initiation/dose adjustment, then every 3-12 months 1
• In children >8 years, statins can be initiated with concerning family history or extremely elevated LDL-C/Lp(a) after shared decision-making 1

Alternative Lipid-Lowering Agents

For statin-intolerant patients or those not achieving goals on maximal statin therapy:

• Ezetimibe is used as salvage therapy in statin-intolerant patients 1
• Bile acid sequestrants and fibrates reduce cholesterol in small studies but have high gastrointestinal side effects; fibrates increase serum creatinine 1
• PCSK9 inhibitors may be beneficial; trials are ongoing 1

Dietary Modifications

• Avoid red meat and consider plant-based diet as first-line treatment in children and additive therapy in adults 1

Important note: High-quality data guiding lipid treatment in nephrotic syndrome are lacking 1.

Thromboembolism Prevention

Prophylactic Anticoagulation Indications

Prophylactic anticoagulation should be employed when thromboembolism risk exceeds bleeding risk, specifically when: 1

• Serum albumin <20-25 g/L PLUS any of the following:
  • Proteinuria >10 g/day
  • BMI >35 kg/m²
  • NYHA class III or IV heart failure
  • Recent orthopedic or abdominal surgery
  • Prolonged immobilization
• Membranous nephropathy carries particularly high thromboembolism risk 1
• Central venous access is required 1, 3, 4

Contraindications to Prophylactic Anticoagulation

Avoid prophylactic anticoagulation with: 1

• Patient inability to adhere
• Bleeding diathesis or hemorrhage risk
• CNS lesions affecting warfarin metabolism
• Frailty with fall risk
• Prior gastrointestinal bleeding

Anticoagulation Regimens

For prophylaxis during high-risk periods:

• Low-molecular-weight heparin (dose reduction with creatinine clearance <30 mL/min) or unfractionated heparin 5000 U subcutaneously twice daily 1

For thromboembolic events (venous thrombosis, arterial thrombosis, pulmonary embolism):

• Full-dose anticoagulation for 6-12 months and/or duration of nephrotic syndrome 1
• Initiate intravenous heparin followed by bridging to warfarin (preferred approach) 1
• Higher heparin doses may be required due to urinary antithrombin III loss 1
• Warfarin remains the anticoagulant of choice until pharmacokinetic studies with newer agents are completed 1
• Monitor INR frequently (target 2-3) as warfarin-protein binding fluctuates with changing serum albumin 1
• Factor Xa inhibitors have not been systematically studied in nephrotic syndrome 1

Critical caveat: These anticoagulation recommendations are not supported by randomized controlled trials 1.

Immunosuppressive Therapy

Corticosteroids

Prednisone is FDA-approved to induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or lupus-related nephrotic syndrome without uremia 6.

• In children <12 years with presumed minimal change disease, initiate glucocorticoid therapy empirically 5
• In adults, corticosteroid use depends on biopsy findings and specific glomerular disease 5, 7
• Steroid-resistant cases require alternative immunosuppressive agents (calcineurin inhibitors, mycophenolate mofetil, rituximab) 7

Alternative Immunosuppressants

• Do not use immunosuppressive agents for genetic forms of nephrotic syndrome as they are unlikely to respond 3
• Calcineurin inhibitors, mycophenolate mofetil, and rituximab are options for steroid-resistant or frequently relapsing disease 7

Additional Supportive Measures

Nutritional Support

• Ensure adequate nutrition to prevent malnutrition and support growth, particularly in children 2, 3
• Optimal dietary protein intake: 1.0-1.1 g/kg/day in minimal change disease; 0.8 g/kg/day in other nephrotic syndrome types; further restriction with renal dysfunction 8
• Energy requirements: ≥35 kcal/kg/day 8

Micronutrient Supplementation

• Supplement vitamin D (cholecalciferol or calcifediol) and calcium (250-500 mg/day) when 25-OH-D3 is low, ionized calcium is low, or PTH is elevated 2
• Monitor and treat iron deficiency; administer erythropoietin for anemia despite iron supplementation 2

Infection Prevention

• Implement infection prophylaxis measures, especially in severe cases and children with congenital nephrotic syndrome 2, 3
• Avoid prophylactic antibiotics routinely in adults 9

Renal Protection in Chronic Kidney Disease

• Consider SGLT2 inhibitors for renal protection in patients with FSGS, eGFR ≥20 mL/min/1.73 m², and urine albumin-creatinine ratio ≥200 mg/g 2

Special Considerations for Congenital Nephrotic Syndrome

• Refer rapidly to specialized pediatric nephrology centers for multidisciplinary management 1, 3, 4
• Pursue stepwise approach with prolonged conservative management; avoid routine early nephrectomies 1, 3, 4
• Consider nephrectomy only for persistent hypovolemia, thrombosis, and failure to thrive despite optimal conservative treatment 1, 3
• Transition to ambulatory management when stable to improve quality of life and reduce nosocomial infection risk 3, 4

Common Pitfalls to Avoid

• Do not administer diuretics to hypovolemic patients despite low serum albumin—this worsens intravascular depletion 1, 2
• Do not give albumin infusions based solely on serum albumin levels—only for clinical hypovolemia 1, 3
• Do not use high-dose furosemide (>6 mg/kg/day) for >1 week due to ototoxicity risk 1, 3
• Do not routinely anticoagulate all nephrotic patients—individualize based on thromboembolism versus bleeding risk 1
• Do not forget to counsel patients on sick day management (holding ACE inhibitors/ARBs and diuretics during volume depletion) 1