An Unusual Nodular Glomerular Lesion

 The micrographs show nodular glomerulosclerosis, a finding that is not surprising in a patient with long standing diabetes mellitus and CKD.  PAS micrograph reveals weakly staining amorphous material in the aforementioned nodular glomerular lesion. A Congo-red stain is also positive....

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The micrographs show nodular glomerulosclerosis, a finding that is not surprising in a patient with long standing diabetes mellitus and CKD.  PAS micrograph reveals weakly staining amorphous material in the aforementioned nodular glomerular lesion. A Congo-red stain is also positive. Under polarized light, the Congo-red positive regions would show apple-green birefringence. The electron micrograph shows fibrils consistent with amyloidosis. 

These findings are consistent with significant diabetic nephropathy with superimposed amyloidosis. Immunoperoxidase staining in this patient (not shown) would be positive for serum amyloid A. 

The amyloidoses are a spectrum of diseases that may cause various types of end organ damage. The pathologic mechanism involves normally soluble protein precursors aggregating in an insoluble, anti-parallel beta pleated sheet orientation. With renal involvement there is usually nephrotic range proteinuria.  Serum or urine protein electrophoresis or immunofixation will often reveal a kappa or lambda light chain spike.  Definitive renal diagnosis is made with representative glomerular lesions that stain positive for the particular abnormal protein aggregate by immunofluorescence or immunohistochemistry. In addition to glomerular disease, amyloid fibrils can also be deposited in the vascular lumen and tubulointerstitium.

AL, or primary, amyloidosis is the most common variant of the disease.  AL amyloidosis often leads to multi-organ dysfunction. Organs commonly affected include the heart, kidneys, gastrointestinal tract, and soft tissues. Soft tissue or abdominal fat pad biopsy are often used less invasive means to make a diagnosis. Treatment for AL amyloidosis involves chemotherapy to lower the light chain burden.  AA, or secondary, amyloid usually involves proliferation of serum amyloid protein A and is seen in states of chronic inflammation. Rheumatoid arthritis is probably the most common cause of AA amyloidosis. Other chronic inflammatory states implicated include, chronic osteomyelitis, intravenous drug abuse-associated infections, inflammatory bowel disease, chronic rheumatic conditions, and Familial Mediterranean fever. In such cases, control of the underlying inflammatory state may lead to renal improvement.  However, there is high rate of progression to end-stage renal disease.

Hereditary amyloidosis including those related to transthyretin, fibrinogen Aa, apolipoprotein A1 and AII, and lysozyme, may cause various types and severity of renal disease.

Dialysis associated amyloidosis is less common thanks to high flux dialyzers in use nowadays.  In the past B2 microglobulin amyloid deposition in soft tissues and arthropathy would result in some hemodialysis patients due to poor middle and larger molecular weight molecule clearance. 

Our patient received aggressive treatment of osteomyelitis. Unfortunately, given his baseline CKD and comorbidities, renal function did not improve and he began chronic hemodialysis.

References:

Dember LM. Amyloidosis-associated kidney disease. J Am Soc Nephrol 2006;17:3458-3471

Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med 2003;349:583-596.

 

This case was prepared by Kevin T. Harley, MD, Assistant Clinical Professor of Medicine, Division of Nephrology & Hypertension, at the University of California in Irvine.