Advancing Care for AA Amyloidosis with Biomarker-Based Staging

Abstract

AA amyloidosis is the most serious kidney complication of chronic inflammation and is characterized by the deposition of fibrils derived from misfolded serum amyloid A (SAA) protein. Although more than 95% of patients present with proteinuric kidney disease and the extent of kidney damage defines prognosis, it is a systemic disorder, and gastrointestinal tract, liver, and cardiac manifestations are all recognized in more advanced disease. 1 The prevalence of AA amyloidosis is geographically dependent. In wealthier areas of the world, the reduction in most causes of chronic infection and the widespread availability of effective treatments of rheumatologic diseases have resulted in a dramatic fall in its incidence. In less economically privileged areas, AA amyloidosis remains more prevalent because of both a higher environmental risk of infection and a lower availability of effective antiinflammatory treatments. In areas with more health resources, AA amyloidosis now accounts for ,3% of amyloid diagnoses, which is thought to equate to an incidence of 1-2 per million, so that it is now rarer than immunoglobulin light chain (AL) amyloid, wild-type transthyretin (TTR), or the inherited systemic amyloidosis. 2 However, in part, this change in distribution of amyloid types undoubtedly reflects improved availability of diagnostics, such as cardiac magnetic resonance imaging, which is extremely sensitive in detecting the cardiac amyloid deposits commonly seen in AL and TTR types.There is one reported family with inherited AA amyloidosis caused by a pathogenic variant in the SAA1.1 promoter, but in all other cases, AA amyloidosis is secondary to chronic inflammation resulting in sustained overproduction of SAA. This apolipoprotein of highdensity lipoproteins is a short half-life hepatic acutephase reactant, which rises and falls in parallel with C-reactive protein (CRP), and sustained high levels are necessary but not sufficient for the development of AA amyloidosis. SAA is also produced by other cells, including macrophages and adipocytes. Its transcription is regulated by proinflammatory cytokines, and plasma concentrations can vary between ,1 and .2000 mg/L. The physiologic role for SAA and its remarkable dynamic range remains incompletely understood.