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 2.
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.
Figure 2
Pathology of renal amyloidosis. Amyloid deposits on LM appear as amorphous pale eosinophilic material on H&E-stained sections, negative or weakly positive on periodic acid Schiff, and nonargyrophilic on silver stain. On IF, amyloid has a distinctive appearance that appears smudgy with fuzzy borders, which is most important in early renal AL where a small amount of deposits can be overlooked by LM and EM. On EM, amyloid deposits exhibit a cottony appearance at low-power magnification. At high-power magnification, they appear as randomly arranged, straight fibrils, ranging in thickness between 7 and 14 nm, permeating the mesangium, GBM, interstitium, tubular basement membranes, and/or vessel walls. Two deviations from the random orientation of fibrils include the parallel arrangement and swirling pattern of fibrils in some cases of renal AGel, and amyloid spicules most commonly seen in AL amyloidosis, less common in AA and exceedingly rare in ALECT2 and hereditary amyloidoses. Podocytes overlying segments of GBM with amyloid deposits exhibit foot process effacement and condensation of actin cytoskeleton. When stained with Congo red, amyloid deposits appear salmon pink and produce yellow/orange/green birefringence under polarized light. This is best obtained by examining 8- to 10-micron sections in the dark using a strong light source. Amyloid can involve any of the kidney compartments, but glomerular involvement (97%) and vascular involvement (85%) predominate, whereas the interstitium (58%) and tubular basement membranes (8%) are less common. Some types of amyloidosis have predilection to certain kidney compartments, which can provide clues to the diagnosis.
(A) AL amyloidosis with glomerular, vascular (star), and focal cortical interstitial amyloid (arrowhead) deposits (Congo red stain under bright light).
(B) AL amyloidosis with well-developed amyloid spicules (silver stain) projecting from the outer surface of the glomerular capillaries (so-called cock’s combs, black arrows).
(C) ALECT2 amyloidosis with extensive cortical interstitial Congophilic amyloid deposits. The glomerular mesangium is also involved (arrows) but not to the extent of interstitial involvement (Congo red stain under bright light).
(D) AFib amyloidosis with massive, obliterative glomerular involvement, without significant involvement of vessels or tubulointerstitium (Congo red slide examined under fluorescent light). (E) AApoAIV amyloidosis with extensive medullary interstitial amyloid deposits which exhibit apple-green, orange, and yellow birefringence under polarized light.
(F) AApoCII amyloidosis with nodular pattern of glomerular involvement which shows apple-green, orange, and yellow birefringence under polarized light. Abbreviations: AA, serum amyloid A; AApoAIV, apolipoprotein A-IV; AApoCII, apolipoprotein CII; AGel, gelsolin amyloidosis; AFib, fibrinogen Aα chain; AL, light chain amyloidosis; ALECT2, leukocyte cell–derived chemotaxin 2 amyloidosis; EM, electron microscopy; GBM, glomerular basement membranes; H&E, hematoxylin and eosin; IF, immunofluorescence; LM, light microscopy.
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 1); 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.
