Kidney Int. 2012 Jan;81(2):201-6. doi: 10.1038/ki.2011.316. Epub 2011 Sep 7.
Medullary amyloidosis associated with apolipoprotein A-IV deposition.
Sethi S(1), Theis JD, Shiller SM, Nast CC, Harrison D, Rennke HG, Vrana JA, Dogan
A.
Author information:
(1)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
Minnesota 55905, USA. sethi.sanjeev@mayo.edu
Comment in
Kidney Int. 2012 Jul;82(1):114; author reply 114.
Amyloidosis is caused by extracellular deposition of proteins in an insoluble
manner within tissues. In hereditary forms of amyloidosis, transthyretin,
fibrinogen A-α, lysozyme, gelsolin, apolipoprotein A-I, and A-II accumulate in
the tissue plaques. Here we describe a 52-year-old man with no family history of
renal disease who presented with increased urinary frequency, gradual loss of
renal function but no significant proteinuria. Renal biopsy found large amounts
of amyloid restricted to the medulla with no involvement of glomeruli or vessels.
Immunohistochemical analysis for transthyretin or serum amyloid A and tests for
an underlying monoclonal gammopathy were negative. Although initially suspected
to be amyloid light chain amyloidosis, laser microdissection and mass
spectrometry showed that the amyloid was composed of large amounts of
apolipoprotein A-IV. This was based on mass spectrometry studies that showed 100,
96, and 73 spectra in three microdissected samples that matched to apolipoprotein
A-IV with 100% probability. DNA analyses detected three sequence variants
representing common polymorphisms of the apolipoprotein A-IV gene. Thus, in this
case, apolipoprotein A-IV deposition and renal involvement appear to be
restricted to the medulla. A high degree of suspicion is required for the
diagnosis of apolipoprotein A-IV amyloidosis as it may be missed if a renal
biopsy consists only of cortex.
PMID: 21900878 [PubMed - indexed for MEDLINE]
Clin J Am Soc Nephrol. 2010 Dec;5(12):2180-7. doi: 10.2215/CJN.02890310. Epub2010 Sep 28.
Mass spectrometry-based proteomic diagnosis of renal immunoglobulin heavy chain
amyloidosis.
Sethi S(1), Theis JD, Leung N, Dispenzieri A, Nasr SH, Fidler ME, Cornell LD,
Gamez JD, Vrana JA, Dogan A.
Author information:
(1)Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
55905, USA. sethi.sanjeev@mayo.edu
BACKGROUND AND OBJECTIVES: Amyloidosis is a group of disorders characterized by
accumulation of extracellular deposition of proteins as insoluble aggregates. The
clinical management of amyloidosis is based on identifying the underlying
etiology and accurate typing of the amyloid. Ig heavy chain amyloid involving the
kidney is poorly recognized and often poses a diagnostic dilemma. DESIGN,
SETTING, PARTICIPANTS, & MEASURES: In this study, we describe the use of laser
microdissection (LMD) and mass spectrometry (MS)-based proteomic analysis for the
accurate typing of 14 cases of amyloidosis. We also describe the
clinicopathologic findings of four problematic cases of renal Ig heavy chain
amyloidosis that required LMD/MS proteomic analysis for accurate typing of the
amyloid.
RESULTS: LMD/MS proteomic data of four cases of Ig heavy chain renal amyloidosis
showed Ig heavy chains with or without light chains. The break up of the Ig heavy
chains was as follows: one case showed Igγ1 chain constant region and λ light
chains, one case showed Igα chain constant region and κ light chains variable and
constant regions, whereas two cases showed Igγ3 chain constant region and heavy
chains variable region I and/or III without light chains. We compare the LMD/MS
proteomic data of Ig heavy chain renal amyloid with that of other types of
amyloid, including Ig light chains, serum amyloid A, fibrinogen A-α chain renal
amyloid, and transthyretin amyloid.
CONCLUSIONS: We conclude that LMD/MS is a sensitive and specific tool for
diagnosis and accurate typing of renal amyloidosis, including Ig heavy chain
amyloid.
PMCID: PMC2994078
PMID: 20876678 [PubMed - indexed for MEDLINE]
N Engl J Med. 2002 Jun 6;346(23):1786-91.
Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis.
Lachmann HJ(1), Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys
MB, Hawkins PN.
Author information:
(1)National Amyloidosis Centre, Department of Medicine, Royal Free and University
College Medical School, Royal Free Campus, London, United Kingdom.
Comment in
N Engl J Med. 2002 Jun 6;346(23):1818-9.
N Engl J Med. 2002 Oct 10;347(15):1206-7; author reply 1206-7.
N Engl J Med. 2002 Oct 10;347(15):1206-7; author reply 1206-7.
BACKGROUND: Hereditary, autosomal dominant amyloidosis, caused by mutations in
the genes encoding transthyretin, fibrinogen A alpha-chain, lysozyme, or
apolipoprotein A-I, is thought to be extremely rare and is not routinely included
in the differential diagnosis of systemic amyloidosis unless there is a family
history.
METHODS: We studied 350 patients with systemic amyloidosis, in whom a diagnosis
of the light-chain (AL) type of the disorder had been suggested by clinical and
laboratory findings and by the absence of a family history, to assess whether
they had amyloidogenic mutations.
RESULTS: Amyloidogenic mutations were present in 34 of the 350 patients (9.7
percent), most often in the genes encoding fibrinogen A alpha-chain (18 patients)
and transthyretin (13 patients). In all 34 of these patients, the diagnosis of
hereditary amyloidosis was confirmed by additional investigations. A low-grade
monoclonal gammopathy was detected in 8 of the 34 patients (24 percent).
CONCLUSIONS: A genetic cause should be sought in all patients with amyloidosis
that is not the reactive systemic amyloid A type and in whom confirmation of the
AL type cannot be obtained.
PMID: 12050338 [PubMed - indexed for MEDLINE]
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