What is the initial treatment for a patient presenting with nephrotic range proteinuria?

Initial Treatment for Nephrotic Range Proteinuria

The initial treatment for nephrotic range proteinuria begins with conservative management including ACE inhibitors or ARBs for all patients regardless of blood pressure, targeting BP <125/75 mmHg, while simultaneously pursuing kidney biopsy (except when anti-PLA2R antibodies are positive) to establish the underlying diagnosis before initiating immunosuppressive therapy. 1, 2

Immediate Supportive Management (Start Before Biopsy)

• Initiate ACE inhibitor or ARB therapy immediately for all patients with nephrotic-range proteinuria, regardless of baseline blood pressure, as this reduces proteinuria and slows progression 1, 2, 3

• Target blood pressure should be <125/75 mmHg, which is more aggressive than standard hypertension targets 1, 2

• Start statin therapy for hyperlipidemia with target LDL-cholesterol <100 mg/dL 1

• Implement dietary sodium restriction to help manage edema 4

• Consider thromboembolism prophylaxis in high-risk patients, particularly those with serum albumin <2.5 g/dL or membranous nephropathy, as nephrotic syndrome carries substantial thrombotic risk 4

Diagnostic Workup (Concurrent with Supportive Care)

• Obtain kidney biopsy in all adults to establish the underlying diagnosis, as this determines specific immunosuppressive therapy 1, 2

• The only exception to mandatory biopsy: positive serum anti-phospholipase A2 receptor antibodies, which are diagnostic of membranous nephropathy and can avoid unnecessary biopsy 1, 2

• Complete metabolic panel including serum creatinine, estimated GFR, electrolytes, glucose, and albumin 1

• Quantify proteinuria with spot urine protein-to-creatinine ratio (PCR >3.5 g/g confirms nephrotic range) 1, 5

• Screen for secondary causes: hepatitis B/C serology, HIV testing, ANA for lupus, complement levels (C3, C4), and serum anti-PLA2R antibodies 1, 2

• Renal ultrasound to evaluate kidney size, structural abnormalities, and exclude obstruction 1, 2

Timing of Immunosuppressive Therapy

Critical caveat: Do not rush to immunosuppressive therapy before establishing the diagnosis, as treatment varies dramatically by underlying pathology 6.

For Membranous Nephropathy (Most Common in White Adults)

• Observe for 6 months with conservative therapy before starting immunosuppression in most cases, as one-third will have spontaneous remission 6

• Start immunosuppression earlier than 6 months if any of these conditions are met:

  • Urinary protein excretion persistently exceeds 4 g/day and remains >50% of baseline despite 6 months of conservative therapy 6
  • Severe, disabling, or life-threatening nephrotic symptoms 6
  • Serum creatinine rises by ≥30% within 6-12 months (with eGFR still >25-30 mL/min/1.73m²) 6
  • High thrombotic risk (obesity, sedentary lifestyle, very low albumin) 6

• First-line immunosuppression: 6-month course of alternating monthly cycles of oral and IV corticosteroids plus oral alkylating agents (cyclophosphamide or chlorambucil) 6

• Alternative regimen: Cyclosporine or tacrolimus for ≥6 months if patient has contraindications to corticosteroids (obesity, diabetes risk, family history of diabetes) or refuses alkylating agents 6

For Diabetic Nephropathy (Most Common Secondary Cause)

• ARB therapy is specifically indicated for diabetic nephropathy with elevated serum creatinine and proteinuria (urinary albumin-to-creatinine ratio ≥300 mg/g) in type 2 diabetes with hypertension history 3

• Losartan reduces progression by 16% for the composite endpoint of doubling serum creatinine, ESRD, or death, with 25% reduction in doubling of creatinine and 29% reduction in ESRD 3

• No immunosuppression is indicated for diabetic nephropathy—treatment focuses on glycemic control, BP control with RAAS blockade, and cardiovascular risk reduction 3

For Minimal Change Disease (Most Common in Children)

• Start glucocorticoids immediately in children <12 years without biopsy, as minimal change disease is most likely and steroid-responsive 4

• Perform kidney biopsy and genetic testing only if patient fails to respond to steroids 4

Special Population Considerations

• Infants with congenital nephrotic syndrome (onset within first 3 months of life) require whole-exome sequencing as first-line diagnostic and immediate referral to specialized tertiary pediatric nephrology centers 1, 2

• Black patients: Focal segmental glomerulosclerosis is the most common cause rather than membranous nephropathy, which affects treatment approach 4, 7

Common Pitfalls to Avoid

• Do not delay ACE inhibitor/ARB therapy while waiting for biopsy results—start immediately as it benefits all causes of nephrotic syndrome 1, 2

• Do not start immunosuppression empirically without tissue diagnosis in adults (except children with presumed minimal change disease), as treatment varies dramatically by pathology 6, 1

• Do not wait the full 6 months for membranous nephropathy if patient has high thrombotic risk, rapidly rising creatinine, or severe symptoms—these warrant earlier intervention 6

• Do not use corticosteroids in diabetic nephropathy—this is a common error as diabetes is the most common secondary cause but requires completely different management 3