Renal Amyloidosis

Most renal amyloidosis is either the result of

primary fibrillar deposits of immunoglobulin light chains [amyloid L (AL)],
or
secondary to fibrillar deposits of serum amyloid A (AA) protein fragments .

Even though both occur for different reasons, their clinicopathophysiology is quite similar and will be discussed together. Amyloid infiltrates the liver, heart, peripheral nerves, carpal tunnel, upper pharynx, and kidney, producing restrictive cardiomyopathy, hepatomegaly, macroglossia, and heavy proteinuria sometimes associated with renal vein thrombosis.

In systemic AL amyloidosis, also called primary amyloidosis, light chains produced in excess by clonal plasma cell dyscrasias are made into fragments by macrophages so they can self-aggregate at acid pH. A disproportionate number of these light chains (75%) are of the lambda class. About 10% of these patients have overt myeloma with lytic bone lesions and infiltration of the bone marrow with >30% plasma cells; nephrotic syndrome is common, and about 20% of patients progress to dialysis.

 AA amyloidosis is sometimes called secondary amyloidosis and also affects the kidney with nephrotic syndrome. It is due to deposition of beta-pleated sheets of serum amyloid A protein, an acute phase reactant whose physiologic function is unknown. Forty percent of patients with AA amyloid have rheumatoid arthritis, and another 10% have ankylosing spondylitis or psoriatic arthritis; the rest derive from other lesser causes. Less common in Western countries but more common in Mediterranean regions, particularly in Sephardic and Iraqi Jews, is familial Mediterranean fever (FMF). FMF is caused by a mutation in the gene encoding pyrin, while Muckle-Wells syndrome, a related disorder, results from a mutation in cryropyrin; both proteins are important in the apoptosis of leukocytes early in inflammation. Receptor mutations in TNFR1–associated periodic syndrome also produce chronic inflammation and secondary amyloidosis. Fragments of serum amyloid A protein increase and self-aggregate by attaching to receptors for advanced glycation end products in the extracellular environment; nephrotic syndrome is common, and about 40–60% of patients progress to dialysis.

 AA and AL amyloid fibrils are detectable with Congo red or in more detail with electron microscopy . Biopsy of involved liver or kidney is diagnostic 90% of the time when the pretest probability is high; abdominal fat pad aspirates are positive about 70% of the time, but apparently less so when looking for AA amyloid. Amyloid deposits are distributed along blood vessels and in the mesangial regions of the kidney.

The treatment for primary amyloidosis is not particularly effective; melphalan and autologous hematopoietic stem cell transplantation can delay the course of disease in about 30% of patients. Secondary amyloidosis is also relentless unless the primary disease can be controlled. Some new drugs in development that disrupt the formation of fibrils may be available in the future.