Patient has a normal complete blood count (except mildly elevated absolute lymphocyte count) and nephrotic‑range proteinuria (24‑hour urine protein 8.1 g/day, urine albumin 100 mg/dL) with negative urine immunofixation; what is the likely diagnosis and what are the appropriate next steps in management?

Diagnostic Evaluation and Management of Nephrotic-Range Proteinuria with Negative Immunofixation

This patient has nephrotic-range proteinuria (8.1 g/24 hours) with predominantly albumin excretion and requires urgent kidney biopsy to establish the specific glomerular disease diagnosis and guide immunosuppressive therapy. 1, 2

Immediate Diagnostic Priority

Kidney Biopsy is Mandatory

• Perform kidney biopsy within the first month after nephrotic syndrome onset, ideally before starting immunosuppressive treatment 2
• The biopsy is indicated because this patient has nephrotic-range proteinuria (>3.5 g/24 hours) with 100 mg/dL urine albumin, meeting criteria for nephrotic syndrome 1, 2
• The negative urine immunofixation effectively rules out monoclonal gammopathy of renal significance (MGRS), making primary glomerular disease the most likely diagnosis 3

Technical Biopsy Requirements

• Obtain at least 8-10 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stains 2
• Perform immunofluorescence for IgG, C3, IgA, IgM, C1q, and κ/λ light chains 2
• Conduct electron microscopy to detect proliferative or membranous lesions and assess podocyte foot-process effacement 2

Complete Pre-Biopsy Evaluation

Essential Laboratory Testing

• Measure serum albumin immediately – this is critical for both confirming nephrotic syndrome (expect <3.0 g/dL) and assessing thromboembolism risk 2
• Calculate estimated glomerular filtration rate (eGFR) from serum creatinine to assess kidney function 1
• Obtain fasting lipid panel (total cholesterol, LDL-C, HDL-C, triglycerides) as hyperlipidemia is expected with nephrotic syndrome 2

Screen for Secondary Causes

• Check fasting glucose and HbA1c to exclude diabetic nephropathy, the most common secondary cause in adults 2
• Obtain autoimmune serologies: ANA, anti-dsDNA, complement C3 and C4 to evaluate for lupus nephritis 3, 2
• Test hepatitis B and C serologies to rule out viral-related glomerulopathies 2
• Review all medications for potential nephrotoxic agents 1, 2
• Document family history of kidney disease and assess BMI (obesity >35 kg/m² suggests secondary FSGS) 2

Urine Sediment Analysis

• Examine urine sediment for dysmorphic red blood cells (>80% dysmorphic suggests glomerular hemorrhage) and red cell casts (pathognomonic for glomerulonephritis) 2
• The predominantly albumin composition (100 mg/dL albumin with 8.1 g/24hr total protein) indicates glomerular rather than tubular proteinuria 4

Assess Thromboembolism Risk Immediately

Critical Risk Stratification

• If serum albumin is <2.0-2.5 g/dL (20-25 g/L), strongly consider prophylactic full-dose anticoagulation, especially with additional risk factors 2
• Additional risk factors include: proteinuria >10 g/day, BMI >35 kg/m², heart failure, recent surgery, or prolonged immobilization 2
• Warfarin is the anticoagulant of choice with target INR 2-3; avoid Factor Xa inhibitors and direct thrombin inhibitors due to unpredictable pharmacokinetics from albumin binding and urinary losses 2

Common Pitfall to Avoid

• Do not wait for thrombotic symptoms to develop – nephrotic syndrome carries a 29% risk of renal vein thrombosis when albumin is severely low, and prophylaxis must be considered proactively 2

Initiate Conservative Management While Awaiting Biopsy

Antiproteinuric Therapy

• Start ACE inhibitor or ARB immediately for proteinuria >0.5-1 g/day, even if blood pressure is normal 1, 2
• Target blood pressure ≤125/80 mmHg 2

Symptomatic Management

• Use loop diuretics (furosemide) for edema control 2
• Consider statin therapy for hyperlipidemia, particularly with other cardiovascular risk factors 2

Most Likely Differential Diagnosis

Based on the clinical presentation of isolated nephrotic-range proteinuria with negative immunofixation in an adult:

• Primary focal segmental glomerulosclerosis (FSGS) – most common in adults without secondary causes 2
• Minimal change disease – less common in adults but possible 2
• Membranous nephropathy – can present with pure nephrotic syndrome; consider checking serum anti-PLA2R antibodies (if positive, biopsy may be deferred) 2
• Early lupus nephritis – must be excluded with serologies before biopsy 3

Post-Biopsy Management Algorithm

Disease-Specific Immunosuppression

• For primary FSGS: Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) as first-line therapy 2
• For minimal change disease: High-dose corticosteroids with expected response within 8-16 weeks 2
• For membranous nephropathy: Consider cyclophosphamide or calcineurin inhibitors based on risk stratification 2
• For lupus nephritis Class III/IV: Aggressive therapy with glucocorticoids plus cyclophosphamide or mycophenolate mofetil 3

Monitoring Schedule

• Assess proteinuria response, serum albumin, and kidney function every 2-4 weeks for the first 2-4 months, then every 3-6 months 2
• Continue thromboembolism risk assessment at each visit 2

Key Clinical Caveat

The mildly elevated absolute lymphocyte count (4.5 × 10⁹/L) is likely reactive and not directly related to the nephrotic syndrome, but document this finding and monitor for evolution, as lymphoproliferative disorders can rarely cause paraprotein-related kidney disease (though immunofixation was negative here) 3, 5