2024 Update on Classification, Etiology, and Typing of Renal Amyloidosis: A Review

Key Information
Year
2024
summary/abstract
Amyloidosis is a protein folding disease that causes organ injuries and even death. In humans, 42 proteins are now known to cause amyloidosis. Some proteins become amyloidogenic as a result of a pathogenic variant as seen in hereditary amyloidoses. In acquired forms of amyloidosis, the proteins form amyloid in their wild-type state. Four types (serum amyloid A, transthyretin, apolipoprotein A-IV, and β2-macroglobulin) of amyloid can occur either as acquired or as a mutant. Iatrogenic amyloid from injected protein medications have also been reported and AIL1RAP (anakinra) has been recently found to involve the kidney. Finally, the mechanism of how leukocyte cell–derived chemotaxin 2 (ALECT2) forms amyloid remains unknown. This article reviews the amyloids that involve the kidney and how they are typed.

Introduction

Amyloid is the product of misfolded proteins that when deposited causes organ failure and eventually death. Currently, 42 proteins are recognized as amyloidogenic in humans. The most serious forms are those that involve vital organs such as heart, liver, and kidney. The pattern of organ involvement is type specific, but the kidney is the vital organ most commonly involved. The purpose of this review is to provide an update on the amyloids that involve the kidney and typing of renal amyloidosis.
Amyloidosis is named after the native protein and is often classified by whether it is wild type (acquired) or the result of a germline pathogenic variant (mutant). Currently, 6 amyloidogenic proteins can form amyloid both as a wild-type or mutant protein: transthyretin (ATTR), β2-microglobulin (AB2M), serum amyloid A (AA), and apolipoprotein A-IV (ApoAIV), Aβ protein (Aβ), and prion (APrP) (Fig 1external link, opens in a new tab); only the first 4 affect the kidney., Of the 4 iatrogenic amyloids that appear as subcutaneous nodules at the injection sites, AIL1RAP (interleukin-1 receptor antagonist [anakinra]) was recently found to have kidney involvement., Kidney involvement was reported in 1 tumor-related amyloid calcitonin (ACal). Finally, the pathogenesis of leukocyte cell–derived chemotaxin 2 amyloidosis (ALECT2) remains incompletely understood.

Pathology of Renal Amyloidosis

The diagnosis of amyloidosis requires a tissue biopsy. Common amyloid characteristics on light microscopy, immunofluorescence, electron microscopy, and Congo red staining are illustrated in Figure 2external link, opens in a new tab. In early cases, Congo red can be negative, with a very small amount of glomerular amyloid. Thioflavin T produces yellow green fluorescence on binding to amyloid and is more sensitive in detecting small amount of amyloid. However, it is less specific than Congo red and presently is rarely used in pathology practice.
Authors
Nelson Leung, Samih H. Nasr