What are the symptoms and treatment options for a patient with nephrotic syndrome?

Nephrotic Syndrome: Clinical Presentation and Management

Core Clinical Symptoms

Nephrotic syndrome presents with the classic triad of peripheral edema, severe proteinuria (>3.5 g/24 hours in adults), and hypoalbuminemia (<3.0 g/dL in adults, ≤2.5 g/dL in children), typically accompanied by hyperlipidemia and fatigue. 1, 2

Primary Presenting Features

• Edema is the most common presenting symptom, ranging from mild periorbital swelling to severe anasarca with ascites and pleural effusions 3, 4
• Fatigue and generalized weakness occur due to hypoalbuminemia and protein loss 4, 2
• Foamy urine from severe proteinuria (lipiduria) may be noticed by patients 5
• Weight gain from fluid retention is typical at presentation 2

Laboratory Hallmarks

• Proteinuria ≥3.5 g/24 hours in adults or ≥40 mg/h/m² (or first morning UPCR ≥2 g/g) in children defines nephrotic-range proteinuria 1
• Serum albumin <3.0 g/dL in adults or ≤2.5 g/dL in children confirms hypoalbuminemia 1
• Hyperlipidemia with elevated total cholesterol, LDL-C, and triglycerides is nearly universal 1, 5

---

Serious Complications and Associated Symptoms

Thromboembolic Events

• Venous thromboembolism risk increases dramatically when serum albumin falls below 2.9 g/dL, with membranous nephropathy carrying the highest risk 1, 2
• Renal vein thrombosis occurs in up to 29% of patients with severe hypoalbuminemia 1
• Symptoms include sudden flank pain, hematuria, or acute worsening of kidney function 2

Infectious Complications

• Increased susceptibility to bacterial infections (particularly encapsulated organisms like Streptococcus pneumoniae) due to urinary immunoglobulin losses 3
• Peritonitis, cellulitis, and sepsis are common serious infections in nephrotic patients 3

Acute Kidney Injury

• Hypovolemic crisis from intravascular volume depletion despite total body fluid overload can cause prerenal AKI 3
• Symptoms include hypotension, tachycardia, poor peripheral perfusion, and oliguria 3

Cardiovascular Manifestations

• Hypertension develops in many patients from sodium retention and intravascular volume expansion 3, 1
• Accelerated coronary heart disease with four times greater risk due to severe hyperlipidemia 1

---

Treatment Approach: Algorithmic Management

Step 1: Immediate Supportive Care for Symptomatic Edema

For patients with anasarca or severe edema, initiate loop diuretics as first-line therapy while avoiding routine albumin infusions. 6

• Furosemide 0.5-2 mg/kg per dose (intravenously or orally up to six times daily; maximum 10 mg/kg per day) titrated to degree of edema 3
• Administer IV infusions over 5-30 minutes to minimize ototoxicity 3
• Restrict dietary sodium to <2.0 g/day to reduce fluid retention 7, 6
• Avoid intravenous albumin infusions unless clinical indicators of hypovolemia are present (hypotension, tachycardia, poor perfusion)—do not base decision on serum albumin levels alone 7, 6
• If albumin infusion is necessary, give furosemide 0.5-2 mg/kg at the end of each infusion unless marked hypovolemia/hyponatremia is present 3

Step 2: Antiproteinuric Therapy

• Initiate ACE inhibitors or ARBs at maximally tolerated doses for all patients to reduce proteinuria and control blood pressure 1, 7
• Target systolic blood pressure <120 mmHg using standardized office measurement 7
• Continue RAS inhibition even during immunosuppressive therapy 1

Step 3: Diagnostic Evaluation to Guide Disease-Specific Treatment

In adults, perform kidney biopsy to establish histologic diagnosis before initiating immunosuppression, except when serum anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy). 1, 8

Biopsy Indications:

• All adults with new-onset nephrotic syndrome (unless anti-PLA2R antibody positive) 1, 8
• Children ≥12 years at presentation 1
• Children <12 years with steroid resistance after 8 weeks of adequate corticosteroid therapy 1, 6

Pre-Biopsy Requirements:

• Perform within first month after onset, preferably before immunosuppression 1
• Sample must include ≥8 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stain 1
• Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains is mandatory 1
• Electron microscopy required to facilitate recognition of proliferative and membranous lesions 1

Secondary Cause Screening (Before or Concurrent with Biopsy):

• Diabetes mellitus assessment (HbA1c, fasting glucose) 7, 2
• Hepatitis B and C serologies, HIV testing 1, 7
• ANA, anti-dsDNA, complement levels (C3, C4) if systemic lupus erythematosus suspected 1, 7
• Serum and urine immunoelectrophoresis/immunofixation plus serum free light chains to exclude paraprotein-related disease 1
• Medication review to identify nephrotoxic agents 1

Step 4: Disease-Specific Immunosuppressive Therapy

For Minimal Change Disease (Most Common in Children <12 Years):

Initiate prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) for adults; 60 mg/m²/day (maximum 60 mg) for children. 1, 7, 6

• Continue high-dose therapy for minimum 4 weeks, up to 16 weeks as tolerated or until complete remission 1, 6
• After complete remission, taper slowly over 6 months 1
• Do not declare steroid resistance until at least 8 weeks of adequate therapy 6
• For children, continue initial dose for 4-6 weeks, then alternate-day dosing at 40 mg/m² for 2-5 months with gradual tapering (total duration at least 12 weeks, ideally up to 6 months) 6

Alternative First-Line Therapy (For Corticosteroid Contraindications):

Consider calcineurin inhibitors as first-line therapy for patients with uncontrolled diabetes, severe psychiatric conditions, severe osteoporosis, or morbid obesity. 1, 6

• Cyclosporine 3-5 mg/kg/day divided into 2 doses, with gradual increase to maximum 4-6 mg/kg/day based on pharmacokinetic monitoring 1, 6
• Continue for minimum 6 months, with slow tapering by 0.5 mg/kg/month after complete remission, maintaining for 1-2 years 1
• Tacrolimus 0.1-0.2 mg/kg/day divided into 2 doses (children) or 0.05-0.1 mg/kg/day (adults) 6
• Cyclosporine may be preferred over tacrolimus due to lesser tendency to precipitate diabetes 1

For Focal Segmental Glomerulosclerosis:

• Classify into primary, genetic, secondary, or undetermined cause to guide treatment 1
• Genetic testing indicated for familial kidney disease, syndromic features, steroid-resistant FSGS, or early-onset cases 1, 7
• For primary FSGS: Same corticosteroid regimen as minimal change disease 1
• For genetic FSGS: Immunosuppression is ineffective; focus on supportive care and prepare for transplantation 1

For 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 7
• Higher thromboembolism risk requires aggressive anticoagulation consideration 1, 8

Step 5: Thromboembolism Prophylaxis

Consider prophylactic full-dose anticoagulation when serum albumin is <20-25 g/L (2.0-2.5 g/dL) AND patient has additional risk factors such as proteinuria >10 g/day, BMI >35 kg/m², membranous nephropathy, heart failure, recent surgery, or prolonged immobilization. 1

• Warfarin is the anticoagulant of choice with target INR 2-3, requiring frequent monitoring due to fluctuating albumin-protein binding 1
• Do not use Factor Xa inhibitors or direct thrombin inhibitors due to unpredictable pharmacokinetics from significant albumin binding and urinary losses 1
• For documented thromboembolic events, use treatment-dose unfractionated or low-molecular-weight heparin or warfarin 1

Step 6: Infection Prevention

• Administer pneumococcal vaccination (23-valent or conjugate vaccine) before or early in immunosuppressive therapy 6
• Give annual influenza vaccination to patients and household contacts 6
• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose immunosuppression 7

Step 7: Lipid Management

• Initiate statin therapy for persistent hyperlipidemia, particularly with other cardiovascular risk factors, aligning intensity to ASCVD risk 1
• Hyperlipidemia often improves with successful treatment of underlying nephrotic syndrome 2

---

Critical Monitoring Parameters

During Initial Treatment:

• Monitor urine protein daily using dipstick or spot urine protein-to-creatinine ratio 6
• Complete remission defined as urine protein <200 mg/g (<20 mg/mmol) or trace/negative on dipstick for 3 consecutive days 6
• Assess for signs of hypovolemia (hypotension, tachycardia, poor perfusion) versus hypervolemia (hypertension, good perfusion with edema) 3
• Monitor for medication side effects, particularly with long-term immunosuppressive therapy 7

Long-Term Monitoring:

• Regular assessment of proteinuria, serum albumin, and kidney function 7
• Monitor for complications: thromboembolism, infections, hypertension, dyslipidemia, hypothyroidism, hypomagnesemia 3
• For patients on immunosuppression, monitor every 2-4 weeks for first 2-4 months, then every 3-6 months 1

---

Common Pitfalls to Avoid

Fluid Management Errors:

• Do not give intravenous saline, which worsens edema 6
• Do not use albumin infusions routinely based on serum albumin levels alone—only for clinical hypovolemia 7, 6
• Do not use diuretics in patients with intravascular hypovolemia (hypotension, poor perfusion, hyponatremia) 3

Treatment Timing Errors:

• Do not declare steroid resistance prematurely—wait at least 8 weeks of adequate therapy 6
• Do not stop therapy prematurely if partial response is occurring; continue up to 16 weeks 6
• Do not perform kidney biopsy after starting immunosuppression when possible, as it may obscure histologic changes 1

Anticoagulation Errors:

• Do not rely solely on albumin level for anticoagulation decisions—assess additional risk factors (proteinuria >10 g/day, BMI >35, membranous nephropathy, immobilization) 1
• Do not use direct oral anticoagulants (Factor Xa or thrombin inhibitors) due to unpredictable drug levels 1

Special Population Considerations:

• For congenital nephrotic syndrome (onset in utero or first 3 months of life), refer immediately to specialized pediatric nephrology units 3, 7
• For children <12 years with typical presentation, defer biopsy if response to initial steroid therapy occurs 7
• Biopsy is mandatory for steroid-resistant cases in children 7