A 55-year-old man is evaluated due to worsening fatigue and exertional shortness of breath. He has no chronic medical conditions and takes no medications. Physical examination shows facial puffiness and bilateral lower extremity edema. Urinalysis shows 3+ proteinuria. Kidney biopsy findings with special staining under polarized light are shown on the image below:
Show Explanatory Sources
Which of the following tests would be most helpful for establishing a specific diagnosis in this patient?
Major types of systemic amyloidosis | ||||
Primary | Secondary | Age related | Dialysis related | |
Disease | Plasma cell dyscrasia | Chronic infection/ | Elderly men | ESRD on dialysis |
Precursor ↓ Misfolding ↓ Amyloid | Immunoglobulin ↓ Increased ↓ AL | Serum ↓ Increased ↓ AA | Transthyretin ↓ Accumulation ↓ ATTR* | β2-Microglobulin Decreased ↓ Aβ2M |
Clinical | Nephropathy, hepatosplenomegaly, cardiomyopathy (AL > AA), peripheral neuropathy, macroglossia, skin bruising | Cardiomyopathy, CTS, other peripheral neuropathy | Scapulohumeral arthritis, CTS | |
Amyloid names begin with "A" followed by the precursor protein abbreviation. *ATTR also occurs in a hereditary form that affects younger patients. CTS = carpal tunnel syndrome; ESRD = end-stage renal disease. | ||||
This patient with heavy (ie, 3+) proteinuria and peripheral edema has nephrotic syndrome. His kidney biopsy shows apple-green birefringence under polarized light (with specialized Congo red staining), which is pathognomonic for amyloidosis.
Amyloidosis is a disorder of protein folding. Misfolded proteins form insoluble fibrils, resulting in extracellular deposition that causes organ dysfunction. The parallel fibril alignment binds to Congo red in a regular manner that produces the birefringence seen on polarized microscopy. Multiple precursor proteins can lead to amyloid fibril formation and can cause differing clinical manifestations based on the location of deposition.
Renal amyloid deposits result in glomerular damage, producing proteinuria, typically in the nephrotic range. The most common precursor proteins causing kidney injury are serum amyloid A (AA amyloidosis) and immunoglobulin light chains (AL amyloidosis). Serum amyloid A is an acute phase reactant; AA amyloidosis usually occurs in patients with chronic inflammatory conditions (unlike this patient). Therefore, serum protein electrophoresis would be helpful to look for a monoclonal protein produced by an undiagnosed plasma cell dyscrasia (eg, multiple myeloma, Waldenstrom macroglobulinemia) causing AL amyloidosis.
(Choice A) 24-hour urinary copper excretion is elevated in Wilson disease, which typically presents with hepatic, neurologic, and psychiatric abnormalities. Renal involvement is less common and causes tubular (eg, Fanconi syndrome) rather than glomerular dysfunction.
(Choice B) 24-hour urinary uric acid excretion is useful for evaluating disorders with hyperuricemia (eg, gout, kidney stones). Uric acid crystals share the property of birefringence on polarized microscopy. However, nephrotic syndrome would be unexpected even with chronic urate nephropathy.
(Choice D) Serum total bilirubin concentration is elevated in multiple disorders and can result from overproduction, impaired conjugation, biliary obstruction, or hepatocyte damage. It has no role in determining the type of amyloidosis causing nephrotic syndrome.
(Choice E) Serum total body iron content is indicated for the assessment of anemia and iron overload, neither of which is associated with nephrotic syndrome. Liver biopsy is sometimes performed for iron overload, which shows intense staining with Prussian blue.
Educational objective:
Renal amyloidosis typically presents with proteinuria and nephrotic syndrome. The diagnosis is confirmed by kidney biopsy showing apple-green birefringence with Congo red stain under polarized light. Serum protein electrophoresis demonstrating a monoclonal protein helps establish the diagnosis of immunoglobulin light chain (AL) amyloidosis.