What is the most likely cause of nephrotic‑range proteinuria (urine protein‑creatinine ratio 3.8 g/g) in a 45‑year‑old man with newly diagnosed extrapulmonary tuberculosis, mild hepatomegaly, serum albumin 4.2 g/dL, and serum globulin 4.1 g/dL?

Tuberculosis-Associated Membranous Nephropathy

The most likely cause of nephrotic-range proteinuria in this patient is tuberculosis-associated membranous nephropathy or secondary amyloidosis (AA amyloidosis), both well-recognized complications of chronic extrapulmonary tuberculosis. 1

Clinical Reasoning

Why This Patient Has Nephrotic-Range Proteinuria

• The UPCR of 3.8 g/g clearly meets the threshold for nephrotic-range proteinuria (≥3.5 g/g or ≥3,500 mg/g), which corresponds to approximately 3.8 g/24 hours of protein excretion. 2, 3

• However, the serum albumin of 4.2 g/dL is notably preserved (normal range), which is atypical for classic nephrotic syndrome that typically presents with hypoalbuminemia <3.0 g/dL in adults. 1

• This discordance—nephrotic-range proteinuria with normal albumin—strongly suggests a secondary cause of proteinuria rather than primary glomerular disease, and should prompt targeted evaluation for systemic disorders. 1

Tuberculosis as the Culprit

• Extrapulmonary tuberculosis is a well-established cause of secondary glomerular disease, most commonly manifesting as membranous nephropathy or AA amyloidosis from chronic inflammation. 1

• The mild hepatomegaly further supports systemic TB involvement, as hepatic TB or reactive hepatomegaly from chronic infection is common in disseminated disease. 1

• The elevated globulin level (4.1 g/dL) with normal albumin creates a normal total protein but reflects the chronic inflammatory state characteristic of tuberculosis, which drives polyclonal hypergammaglobulinemia. 1

Diagnostic Approach

Immediate Next Steps

• Kidney biopsy is essential and should be performed within the first month, ideally before starting immunosuppressive therapy, to establish the specific histologic diagnosis (membranous nephropathy vs. amyloidosis vs. other patterns). 1

• The biopsy must include at least 8 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stains, plus immunofluorescence for IgG, C3, IgA, IgM, C1q, and κ/λ light chains. 1

• Congo red staining is mandatory to evaluate for amyloid deposits, given the chronic inflammatory context of TB. 1

• Electron microscopy should be performed to identify subepithelial immune deposits (membranous pattern) or amyloid fibrils. 1

Additional Laboratory Evaluation

• Confirm the diagnosis is not HIV-associated nephropathy (HIVAN) by testing HIV serology, as HIVAN can present with nephrotic-range proteinuria and is epidemiologically linked to TB co-infection. 4

• Check complement levels (C3, C4) to assess for immune-mediated glomerular disease, though these are typically normal in secondary membranous nephropathy. 1

• Obtain serum and urine protein electrophoresis with immunofixation to exclude paraprotein-related disease or light-chain deposition, which can mimic TB-related nephropathy. 1

Critical Pitfall to Avoid

• Do not assume this is primary (idiopathic) nephrotic syndrome simply because of the high UPCR—the preserved albumin and clinical context of TB make secondary causes far more likely. 1

• Do not delay biopsy waiting for TB treatment response, as the histologic diagnosis will guide whether adjunctive immunosuppression (for membranous nephropathy) or continued anti-TB therapy alone (for amyloidosis) is appropriate. 1

Thromboembolism Risk Assessment

• Despite the normal albumin, this patient still requires venous thromboembolism (VTE) risk stratification because nephrotic-range proteinuria itself (>10 g/day equivalent) carries thrombotic risk. 1

• Assess for additional VTE risk factors: BMI >35 kg/m², recent surgery, prolonged immobilization, or heart failure, which would warrant prophylactic anticoagulation even with albumin >2.5 g/dL. 1

• If serum albumin drops below 2.9 g/dL during follow-up, strongly consider prophylactic full-dose anticoagulation with warfarin (target INR 2-3), as this threshold marks significantly elevated VTE risk. 1

Management Strategy

Treat the Underlying Tuberculosis

• Initiate or optimize standard anti-TB therapy (rifampin, isoniazid, pyrazinamide, ethambutol) as the primary intervention, since treating the infection may lead to resolution of secondary glomerular disease. 1

• Monitor hepatic function closely given the mild hepatomegaly and hepatotoxic potential of TB medications. 1

Antiproteinuric Therapy

• Start ACE inhibitor or ARB therapy to reduce proteinuria and blood pressure (target ≤125/80 mmHg), which provides renoprotection regardless of the underlying histology. 1

• Avoid empiric immunosuppression before biopsy, as the treatment approach differs dramatically between membranous nephropathy (may benefit from immunosuppression) and amyloidosis (requires only TB treatment). 1

Monitoring

• Reassess UPCR and serum albumin every 2-4 weeks initially, then every 3-6 months, to track response to TB therapy and detect progression to full nephrotic syndrome. 1

• Serial renal function monitoring (serum creatinine, eGFR) is essential, as proteinuria >3.8 g/day carries a 35% risk of end-stage renal disease within 2 years if untreated. 2