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Kidney non-tumor

Associated with systemic conditions

Amyloidosis


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 8 December 2014, last major update September 2012
Copyright: (c) 2003-2014, PathologyOutlines.com, Inc.

General
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● Group of conditions with extracellular deposition of fibrillar proteins having an anti-parallel, beta-pleated sheet tertiary structure, leading to Congo Red staining and apple-green birefringence under polarized light
● Amyloid is composed of a fibrillary protein (types described below) and non-fibrillary glycoproteins (amyloid P component also called serum amyloid P [SAP], glycosaminoglycans and apolipoprotein E)
● Serum amyloid P may contribute to stability of amyloid deposits; radioactive iodine-labeled SAP is used in nuclear medicine studies to assess amyloid deposition
● Irrespective of molecular composition, amyloid always has the same characteristic histologic and ultrastructural appearance
● Amyloid is resistant to digestion, accumulates within tissue, interferes with function and destroys vital organs

Clinical features
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● Renal amyloidosis causes 5% of adult cases of nephrotic syndrome
● Suggestive of renal amyloidosis (Chinese study): middle-age, nephrotic syndrome, weight loss, organ enlargement, monoclonal light chains in serum or urine (Clin Lab 2011;57:947)
● Systemic or localized
● Duodenal biopsy is sensitive for diagnosing amyloidosis in chronic kidney disease patients, and highly correlates with renal amyloidosi (Clin Nephrol 2012;77:114)
● Can determine specific type based on immunohistochemistry / immunofluoresence; also laser microdissection and mass spectrometry (Kidney Int 2012;82:226)

AL type:
● Also called primary amyloidosis
● Most common cause of renal amyloidosis in US
● Due to plasma cell dyscrasias with systemic deposition of amyloid and mild increase in bone marrow plasma cells that are monoclonal
● 20% have myeloma or other lymphoproliferative disorders
● Deposits are more likely lambda (75%) light chains or fragments than kappa type, often from amino-terminal fragment of variable region of light chain
● Either vascular-limited or diffuse patterns (Nephrol Dial Transplant 2012;27:1097)
● 40% develop nephrotic syndrome
● Urinary exosomes may be useful to identify patients with AL amyloidosis (PLoS One 2012;7:e38061)
● Poor prognosis (Intern Med 2011;50:2511); patients may develop acute leukemia after alkylating agents, secondary malignancies after autologous transplantation

AA type:
● Also called secondary amyloidosis
● Associated with chronic inflammatory conditions such as osteomyelitis, bronchiectasis, decubitus ulcers, Crohn’s disease, rheumatoid arthritis, tuberculosis (Swiss Med Wkly 2012 May 31;142:w13580)
● Main amyloid component is protein A, derived from proteolytic cleavage of serum amyloid A protein, an acute phase reactant
● 90% have renal insufficiency or nephrotic syndrome at diagnosis
● Renal function is associated with amount of amyloid deposition (Rheumatol Int 2011 Sep 27 [Epub ahead of print])>
● Treatment: treat the underlying inflammatory condition

Beta 2 microglobulin type:
● Associated with long-term hemodialysis or peritoneal dialysis; also renal failure between treatments; increases with duration of dialysis
● Amyloid protein composed of intact and modified beta 2 microglobulin, an integral part of HLA class I antigen complex, that is usually eliminated by the kidney
● Amyloid deposits occur in blood vessel walls, perineural and periarterial tissue, bone, joint, skin, subcutaneous tissue, heart, GI and lungs
● May cause carpal tunnel syndrome, joint disease and bone cysts

ATTR type:
● Amyloid fibrils consist of transthyretin (Clin J Am Soc Nephrol 2012;7:1337)
● Associated with familial amyloidosis

Familial Mediterranean fever:
● Autosomal recessive, deposits consist of AA amyloid (Yonsei Med J 2012;53:454)

AH type:
● Due to heavy chains
● Very rare (predominantly lambda)

Case reports
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● 57 year old man with amyloid fibrils 3x usual size (Hum Pathol 1990;21:868)
● 59 year old man with IgM heavy chain amyloidosis (Am J Surg Pathol 2003;27:541)
● Patient developing lambda light chain deposition disease (treated with autologous peripheral blood stem cell transplant) and later IgG heavy chain amyloidosis (Am J Surg Pathol 2003;27:1477)
● Bilateral buttock tumors of beta 2 microglobulin after long term hemodialysis (Arch Pathol Lab Med 1994;118:651)
● AA-amyloid like deposits but fibrils twice the usual size (Arch Pathol Lab Med 1992;116:261)

Gross images
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Pale amyloid deposits in enlarged kidney

Micro description
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● Salmon orange amorphous, fluffy, extracellular deposits in mesangium and subendothelium that obliterate glomeruli
● Also deposits in blood vessel walls, interstitium and around tubules
● Also mast cells that lead to interstitial fibrosis in AA type (Mod Pathol 2000;13:1020 (mast cells and interstitial fibrosis))
● Proposed histopathologic classification system: Arch Pathol Lab Med 2010;134:532
● 10% of AL patients lack glomerular deposits
● Glomerular cell proliferations are uncommon

Micro images
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Various images

   
Patient with Amyloid AA due to hidradenitis suppurativa (H&E, PAS, Congo Red)


Patient with familial Mediterranean fever

   
Congo Red and amyloid immunostains


Interstitial mast cells accumulate around amyloid deposits


Glomerulus (PAS)


Glomerulus (Silver stain)


Glomerulus (Trichrome stain)


Glomeruli and interstitium


Congo red stain with polarization


Congo red stain without polarization


Positive lambda light chain stain in glomerulus


Positive Thioflavin-T staining in glomerulus


Predominant intracapillary deposition (PAS)


Predominant intracapillary deposition (Silver stain)

Virtual slides
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Amyloidosis

Positive stains
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● Congo Red: causes apple-green birefringence on polarization microscopy; staining lost in AA amyloidosis if pretreated with potassium permanganate
● Silver stain: may show spiking along glomerular capillary loops
● PAS: weak staining
● Thioflavine T: fluoresces; may be positive for anti-AA antibodies, light chain restriction

Electron microscopy description
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● 7.5-10 nm in diameter fibrils with randomly dispersed, non-branching arrangement in mesangium and subendothelium

Electron microscopy images
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Mast cell (MC) within extracellular matrix of renal interstitial containing collagen fibers (C) and amyloid fibrils (A); inset-mast cells stained with anti-chymase


Amyloid fibrils on EM

Differential diagnosis
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Fibrillary glomerulonephritis: fibrils are 15-30 nm, negative amyloid stains
Diabetic glomerulosclerosis: no deposits, intense silver staining
Immunotactoid glomerulonephritis: microtubules, 20–50nm

End of Kidney non-tumor > Associated with systemic conditions > Amyloidosis

Ref Updated: 7/17/12


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