Leukocyte Cell-Derived Chemotaxin 2-Associated Amyloidosis: A Recently Recognized Disease with Distinct Clinicopathologic Characteristics

Abstract

Amyloidosis derived from leukocyte cell-derived chemotaxin 2 is a recently recognized form of amyloidosis, and it has already been established as a frequent form of systemic amyloidosis in the United States, with predominant involvement of kidney and liver. The disease has a strong ethnic bias, affecting mainly Hispanics (particularly Mexicans). Additional ethnic groups prone to develop amyloidosis derived from leukocyte cell-derived chemotaxin 2 include Punjabis, First Nations people in British Columbia, and Native Americans. Most patients are elderly who present with chronic renal insufficiency and bland urinary sediment. Proteinuria is variable, being absent altogether in about one third of patients. Liver involvement is frequently an incidental finding. Amyloidosis derived from leukocyte cell-derived chemotaxin 2 deposits shows a characteristic distribution: in the kidney, there is consistent involvement of cortical interstitium, whereas in the liver, there is a preferential involvement of periportal and pericentral vein regions. Concurrent renal disease is frequent, with diabetic nephropathy and IgA nephropathy being the most common. Patient survival is excellent, likely because of the rarity of cardiac involvement, whereas renal survival is guarded, with a median renal survival of 62 months in those without concurrent renal disease. There is currently no efficacious therapy for amyloidosis derived from leukocyte cell-derived chemotaxin 2 amyloidosis. Renal transplantation seems to be a reasonable treatment for patients with advanced renal failure, although the disease may recur in the allograft. The pathogenesis of amyloidosis derived from leukocyte cell-derived chemotaxin 2 amyloidosis has not yet been elucidated. It could be a result of leukocyte cell-derived chemotaxin 2 overexpression by hepatocytes either constitutively (controlled by yet-uncharacterized genetic defects) or secondary to hepatocellular damage. It is critical not to misdiagnose amyloidosis derived from leukocyte cell-derived chemotaxin 2 amyloidosis as Ig light chain-derived amyloidosis to avoid harmful chemotherapy.

Keywords: ALECT2 amyloidosis; kidney biopsy; leukocyte cell–derived chemotaxin 2; liver amyloidosis; renal amyloidosis.

Figure 1.

Proposed pathogenesis of amyloidosis derived from leukocyte cell–derived chemotaxin 2 (ALECT2) amyloidosis. The pathogenesis of ALECT2 amyloidosis is still unknown. It is likely caused by leukocyte cell–derived chemotaxin 2 (LECT2) overexpression by hepatocytes either constitutively resulting from a combination of the common G/G genotype and yet to be defined genetic mutations or compensatory to hepatocellular damage. Upregulation of LECT2 overexpression by hepatocytes potentially leads to production of misfolded LECT2 protein. The presence of unstable LECT2 protein combined with several other factors, such as increased local concentrations, interactions with components of extracellular matrix, such as laminin and type IV collagen, and bindings with serum amyloid P (SAP), apoE, and glycosaminoglycans (GAGs), particularly heparin sulfate, ultimately lead to amyloid fibril formation and stabilization. The accumulations of large amounts of ALECT2 amyloid fibrils in the interstitium can disrupt kidney or liver architecture and impede their physiologic functions.

Figure 2.

Renal pathology in amyloidosis derived from leukocyte cell–derived chemotaxin 2 (ALECT2) amyloidosis. (A) The case depicted shows extensive interstitial, glomerular, and vascular congophilic amyloid deposition. This patient had subnephrotic proteinuria (2.5 g/d) at diagnosis. Magnification, ×40. (B) Same field as in A. The congophilic amyloid deposits show anomalous colors (red, yellow, and green) under polarized light. Magnification, ×40. (C) The case depicted is from a patient who had a serum creatinine of 2.3 mg/dl at biopsy without proteinuria. There is diffuse cortical interstitial and focal arteriolar amyloid deposition with sparing of glomeruli (Congo red stain). Magnification, ×100. (D) This patient exhibits extensive involvement of cortical interstitium and glomeruli. The medullary interstitium (arrow) is spared (Congo red stain). Magnification, ×20. (E) A low-power electron microscopic image showing several interstitial collections of amyloid deposits (arrows). Magnification, ×5800. (F) A higher-magnification image reveals the fibrillar substructure of deposits. Magnification, ×49,000.

Figure 3.

Liver pathology in amyloidosis derived from leukocyte cell–derived chemotaxin 2 (ALECT2) amyloidosis. (A) There are periportal deposits of strongly congophilic amyloid deposits. Magnification, ×100. (B) In this low-power image, strongly congophilic amyloid deposits are seen surrounding the central veins. In contrast to Ig light chain–derived amyloidosis, the perisinusoidal spaces are spared. Magnification, ×40. (C) On high magnification, ALECT2 deposits form large acellular globules, which appear blue on trichrome stain. Magnification, ×200.

Figure 4.

Laser microdissection/mass spectrometry in a patient with renal amyloidosis derived from leukocyte cell–derived chemotaxin 2 (ALECT2) amyloidosis. (A) Glomerular and (B) interstitial congophilic amyloid deposits visualized under fluorescent light and marked for microdissection. Magnification, ×200. (C) Vacant spaces after microdissection of glomerular amyloid deposits. Magnification, ×200. (D) List of amyloid-associated proteins identified within the deposits by liquid chromatography/mass spectrometry (LC/MS) from a patient with ALECT2 displayed by Scaffold (proteome software). The four columns represent separate microdissected samples run in replicate. The spectra value indicates the total number of mass spectra collected on the mass spectrometer and matched to the protein using the proteomic software. A higher number of mass spectra is indicative of greater abundance of protein and greater amino acid sequence coverage. Our clinical amyloid testing requires a minimum number of four spectra with >95% probability in all samples before the protein identification will be deemed clinically valid. In this case, the presence of abundant spectra for apoE and serum amyloid P is indicative of amyloid, whereas the presence of abundant spectra for leukocyte cell–derived chemotaxin 2 (LECT2) establishes the type as ALECT2 amyloidosis.

Figure 5.

Immunohistochemical staining for leukocyte cell–derived chemotaxin 2 (LECT2). Glomerular and interstitial amyloid deposits are strongly positive for LECT2 by immunohistochemistry in this patient with renal amyloidosis derived from LECT2 amyloidosis. Magnification, ×100.

Figure 6.

Proposed algorithm for diagnosis of amyloidosis derived from leukocyte cell–derived chemotaxin 2 (ALECT2) amyloidosis. AL, Ig light chain–derived; IHC, immunohistochemistry; LECT2, leukocyte cell–derived chemotaxin 2; SAA, serum amyloid A.