In a 56-year-old male with extrapulmonary tuberculosis, nephrotic-range proteinuria, and a normal ejection fraction of 72%, what is the most likely diagnosis?

Diagnosis: Secondary (AA) Amyloidosis

The most likely diagnosis in this 56-year-old male with extrapulmonary tuberculosis, nephrotic-range proteinuria, and preserved ejection fraction is secondary (AA) amyloidosis caused by chronic tuberculosis infection. 1, 2, 3

Clinical Reasoning

Why Amyloidosis Fits This Presentation

• Extrapulmonary tuberculosis is a well-established cause of secondary (AA) amyloidosis, with pulmonary and extrapulmonary TB accounting for approximately 20% of secondary amyloidosis cases in published series 2, 3, 4

• Nephrotic-range proteinuria (>3.5 g/day) is the hallmark renal manifestation of amyloidosis, occurring in 75% of patients with renal amyloid deposition 2, 4

• The preserved ejection fraction of 72% is characteristic of early cardiac amyloidosis, where diastolic dysfunction (heart failure with preserved ejection fraction) typically precedes systolic impairment 1

• The combination of chronic infection plus nephrotic syndrome should immediately trigger consideration of AA amyloidosis, as this pattern is pathognomonic for amyloid deposition secondary to prolonged inflammatory states 1, 2, 3

Distinguishing Features from Other Causes

• This is NOT AL (light chain) amyloidosis because the patient has an identifiable chronic inflammatory condition (TB) rather than a plasma cell dyscrasia 1

• This is NOT TTR (transthyretin) amyloidosis because TTR predominantly affects the heart in elderly patients without causing nephrotic-range proteinuria 1

• This is NOT primary FSGS or other glomerular diseases because the clinical context of chronic TB infection points specifically toward secondary amyloidosis 1

Diagnostic Confirmation Strategy

Essential First Steps

• Obtain tissue biopsy with Congo red staining and immunohistochemistry to confirm amyloid deposition and type it as AA amyloid (versus AL or other types) 1

• Renal biopsy is the gold standard with 100% sensitivity for detecting renal amyloidosis, compared to only 20% for subcutaneous fat pad biopsy and 57.6% for rectal biopsy 2

• Mass spectrometry is the current gold standard for amyloid typing to definitively distinguish AA from AL amyloidosis, which is critical because treatment differs completely 1

Additional Confirmatory Testing

• Serum and urine protein electrophoresis with immunofixation should be performed to exclude AL amyloidosis (which would show a monoclonal protein), though this is unlikely given the TB history 1

• Cardiac biomarkers (NT-proBNP and troponin) should be measured for staging, as elevated levels predict worse outcomes even with preserved ejection fraction 1

• Echocardiography should assess for diastolic dysfunction, increased wall thickness, and granular sparkling appearance of myocardium—findings that suggest cardiac amyloid involvement despite normal systolic function 1

Critical Timing Considerations

Amyloidosis Can Develop Rapidly in TB

• Contrary to traditional teaching, renal amyloidosis can occur within 2 months to 2 years of TB onset, with 93% of cases developing within 5 years of disease duration 4

• Amyloidosis may develop even in adequately treated TB patients, emphasizing that the inflammatory stimulus can persist despite antimicrobial therapy 4

• The mean duration from TB onset to amyloidosis diagnosis is approximately 2.25 years, so this complication should be suspected early in any TB patient presenting with proteinuria 4

Treatment Implications

Addressing the Underlying TB

• Complete the full course of antituberculous therapy (6-9 months for extrapulmonary TB) as recommended, since controlling the inflammatory stimulus is essential for preventing further amyloid deposition 1, 2, 3

• Extrapulmonary TB requires 6-9 months of treatment with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months, followed by isoniazid and rifampin for 4-7 additional months 1

Amyloid-Specific Management

• Initiate colchicine 1-2 mg/day as it has demonstrated efficacy in reducing proteinuria in secondary amyloidosis, though it does not reverse established amyloid deposits 2, 3

• Add ACE inhibitor or ARB therapy (e.g., candesartan 8 mg/day) to reduce proteinuria and slow progression of renal dysfunction 3

• Monitor renal function closely (serum creatinine, eGFR) every 3-6 months, as 29% of amyloidosis patients progress to end-stage renal disease requiring dialysis 2

Common Pitfalls to Avoid

Diagnostic Delays

• Do not attribute nephrotic-range proteinuria solely to "TB-related kidney injury" without tissue confirmation, as this delays amyloidosis diagnosis and appropriate treatment 5

• Do not rely on subcutaneous fat pad biopsy alone (only 20% sensitive), as a negative result does not exclude amyloidosis—proceed directly to renal biopsy if clinical suspicion is high 2

• Do not assume preserved ejection fraction excludes cardiac amyloidosis, as diastolic dysfunction and restrictive physiology occur early while systolic function remains normal 1

Treatment Errors

• Do not stop TB treatment prematurely even after amyloidosis is diagnosed, as incomplete treatment allows ongoing inflammation and continued amyloid deposition 4

• Do not delay nephrology referral for patients with nephrotic-range proteinuria, as early intervention with colchicine and RAAS blockade may slow progression to ESRD 2, 3

• Do not overlook cardiac staging with biomarkers and echocardiography, as cardiac involvement significantly impacts prognosis and may require specific management 1