What is the management approach for a patient with nephrotic range proteinuria (excess protein in the urine), considering primary kidney disease and potential secondary causes such as diabetes?

Management of Nephrotic Range Proteinuria

All adults with nephrotic-range proteinuria require kidney biopsy to establish the underlying diagnosis, except when serum anti-phospholipase A2 receptor antibodies are positive, which is diagnostic of membranous nephropathy and can avoid unnecessary biopsy. 1, 2

Initial Diagnostic Workup

Before nephrology referral, obtain the following laboratory tests:

• Spot urine protein-to-creatinine ratio (PCR) to quantify proteinuria (PCR >300-350 mg/mmol or >3.5 g/g indicates nephrotic range) 1, 3
• Complete metabolic panel including serum creatinine, estimated GFR, electrolytes, glucose, and albumin 1
• Urinalysis with microscopic examination for hematuria, pyuria, and cellular casts to assess for glomerulonephritis 1, 2
• Serum anti-phospholipase A2 receptor antibodies as positive results can avoid kidney biopsy in membranous nephropathy 1, 2
• Hepatitis B and C serology to exclude viral-associated glomerular disease 1, 2
• HIV testing to exclude HIV-associated nephropathy 1, 2
• Antinuclear antibody (ANA) to screen for systemic lupus erythematosus 1, 2
• Complement levels (C3, C4) to evaluate for complement-mediated glomerular disease 1, 2
• Renal ultrasound to evaluate kidney size, structural abnormalities, and exclude obstruction 1, 2

Immediate Supportive Management (Start Before Biopsy)

Initiate ACE inhibitor or ARB for all patients with nephrotic-range proteinuria, regardless of blood pressure, as this is FDA-approved for diabetic nephropathy with proteinuria and reduces progression. 4, 1, 2

Blood Pressure Control

• Target blood pressure <125/75 mmHg in patients with nephrotic-range proteinuria 1, 2
• This is more aggressive than standard hypertension targets due to the cardiovascular and renal protective benefits 5

Edema Management

• Fluid and sodium restriction (typically <2 g sodium daily) 6
• Loop diuretics (furosemide) for persistent edema despite ACE inhibitor therapy 1, 6
• Thiazide diuretics can be added for synergistic effect if loop diuretics alone are insufficient 1

Lipid Management

• Statin therapy should be started for hyperlipidemia with target LDL-cholesterol <100 mg/dL 1
• Consider statins when fasting LDL cholesterol is persistently >160 mg/dL (4.1 mmol/L) or >130 mg/dL (3.4 mmol/L) in patients with additional cardiovascular risk factors such as hypertension and obesity 5

Nephrology Referral Criteria

Urgent referral to nephrology (ideally within 2 weeks) is necessary for all patients with nephrotic-range proteinuria. 3

Specific indications for nephrology referral include:

• Persistent proteinuria with protein excretion >1 g/day (ACR ≥60 mg/mmol or PCR ≥100 mg/mmol), as kidney biopsy may be indicated and immunosuppressive medications may need to be considered 5
• Nephrotic-range proteinuria (>3.5 g/day or PCR >350 mg/mmol) requires biopsy to establish diagnosis 1, 2
• Rapidly declining kidney function (eGFR decrease >20% after excluding reversible causes) 5

Disease-Specific Treatment Algorithms

Primary FSGS (Focal Segmental Glomerulosclerosis)

Do not start immunosuppression until genetic forms and secondary causes are excluded. 5, 1

Distinguishing Primary from Secondary FSGS:

• Primary FSGS: Full-blown nephrotic syndrome with sudden onset, diffuse foot process effacement on electron microscopy, serum albumin <30 g/L 5
• Secondary FSGS: Obesity, relatively normal serum albumin (>30 g/L), hilar histological variant, segmental foot process effacement 5, 1

Treatment for Primary FSGS:

High-dose glucocorticoid therapy with prednisone at 1 mg/kg daily (maximum 80 mg) or 2 mg/kg alternate-day (maximum 120 mg) for at least 4 weeks and until complete remission is achieved, maximum of 16 weeks. 5

• Continue high-dose therapy for 4 weeks after proteinuria disappears, then taper by 5 mg every 1-2 weeks to complete a total duration of 6 months 5
• If steroid-resistant or significant toxicities develop, rapidly taper glucocorticoids and consider calcineurin inhibitors (cyclosporine 3-5 mg/kg/day in 2 divided doses OR tacrolimus 0.05-0.1 mg/kg/day in 2 divided doses) 5

Treatment for Secondary FSGS:

Conservative management with aggressive blood pressure control, weight loss, and renin-angiotensin-aldosterone system inhibition should be the primary strategy. 1

• If proteinuria persists at 8-10 g/day despite 3-6 months of conservative therapy, this points toward primary disease requiring immunosuppression 1

Membranous Nephropathy

Observation for 6 months with conservative therapy (ACE inhibitor/ARB, blood pressure control, statins) is recommended before starting immunosuppression in most cases, as one-third will have spontaneous remission. 1

Indications for Earlier Immunosuppression (Before 6 Months):

• Urinary protein excretion persistently exceeds 4 g/day 1
• Severe symptoms are present 1
• Serum creatinine rises by ≥30% 1
• High thrombotic risk is identified 1

First-Line Immunosuppression:

6-month course of alternating monthly cycles of oral and IV corticosteroids plus oral alkylating agents (cyclophosphamide or chlorambucil). 1

Alternative Regimen:

Cyclosporine or tacrolimus for ≥6 months if patient has contraindications to corticosteroids or refuses alkylating agents 1

Lupus Nephritis (Class III, IV, or V with Nephrotic-Range Proteinuria)

Immunosuppressive treatment should be started immediately for active class III or IV lupus nephritis, and for pure class V lupus nephritis with nephrotic-range proteinuria. 1

• The distinction between membranous nephropathy and lupus nephritis is critical because lupus nephritis requires immediate immunosuppression while membranous nephropathy typically warrants a 6-month observation period 1
• Proteinuria >1 g/24 hours despite optimal use of renin-angiotensin-aldosterone system blockers for at least 3 months is an alternative indication for immunosuppression in class V lupus nephritis 1

Diabetic Nephropathy

Losartan (an ARB) is FDA-approved for treatment of diabetic nephropathy with elevated serum creatinine and proteinuria (urinary albumin-to-creatinine ratio ≥300 mg/g) in patients with type 2 diabetes and a history of hypertension. 4

• Losartan reduces the rate of progression of nephropathy as measured by doubling of serum creatinine or end-stage renal disease 4
• ACE inhibitors are an acceptable alternative if ARBs are not tolerated 1, 2

Special Populations: Congenital Nephrotic Syndrome (Infants)

Infants with congenital nephrotic syndrome (onset within first 3 months of life) should undergo whole-exome sequencing as first-line diagnostic. 1, 2

• Immediate referral to specialized tertiary pediatric nephrology center with multidisciplinary teams including neonatologists, pediatric nephrologists, dieticians, and surgeons 1, 2
• Genetic screening establishes etiology, informs management regarding potential Wilms tumor or neurological involvement, and enables family counseling 2
• Early introduction to transplant center is recommended to minimize dialysis time 2

Supportive Management for Congenital Nephrotic Syndrome:

• Iron supplementation for iron deficiency anemia 5
• Erythropoietin (EPO) therapy should be considered after correction of iron deficiency, with increased doses often required due to urinary losses; subcutaneous administration may be superior to IV 5
• Calcium and vitamin D supplementation to correct deficiencies 5
• Monitor reticulocyte count as a marker of erythropoiesis and response to EPO therapy 5
• Persistent anemia after 4 weeks of iron and EPO therapy requires evaluation for copper, ceruloplasmin, or vitamin B12 deficiency 5

Common Pitfalls to Avoid

• Do not start immunosuppressive therapy before establishing the diagnosis, as treatment varies dramatically by underlying pathology 1
• Do not delay kidney biopsy in adults with nephrotic-range proteinuria unless anti-phospholipase A2 receptor antibodies are positive 1, 2
• Do not use intravenous albumin, prophylactic antibiotics, or prophylactic anticoagulation routinely, as these are not currently recommended 6
• Do not exceed lifetime cyclophosphamide exposure of 12 g/m² to avoid excessive toxicity 7
• Do not change therapy prematurely (before 6 months) in lupus nephritis unless there is clear worsening, as response may take up to 12 months 7

Monitoring and Follow-Up

• Monitor proteinuria with spot urine PCR or ACR at regular intervals (typically every 3-6 months) 1
• Monitor kidney function with serum creatinine and eGFR 1
• Monitor for complications including venous thromboembolism, infections, and acute kidney injury 6, 3
• Transition to maintenance therapy (mycophenolate mofetil or azathioprine) if patient achieves at least partial response (≥50% reduction in proteinuria) by 6-12 months in lupus nephritis 7