Beruflich Dokumente
Kultur Dokumente
http://www.kidney-international.org
& 2014 International Society of Nephrology
National Amyloidosis Centre, UCL Medical School, Royal Free Hospital, London, UK and 2UCL Centre for Nephrology, UCL Medical
School, Royal Free Hospital, London, UK
review
Figure 1 | Sections of a renal biopsy sample were stained with Congo red dye and viewed at 200 magnification. (a) Amorphous
deposits of eosinophilic material are visible within the glomerulus. (b) Pathognomonic green birefringence of amyloid deposits is visible when
viewed under cross-polarized light. (c) Immunostaining of the amyloid deposits with anti-k antibodies was strongly positive (brown stain).
Fibril precursor
Treatment
Clinical involvement
AL
Monoclonal-free
immunoglobulin light chains
AA
ATTR: wild-type
ATTR:
hereditary
Wild-type transthyretin
Variant transthyretin
b2M
b2-Microglobulin (associated
with chronic dialysis)
AFib (hereditary)
Variant fibrinogen Aa
Apolipoprotein
AI (hereditary)
Apolipoprotein
AII (hereditary)
Lysozyme (hereditary)
Variant apolipoprotein AI
Abbreviations: AA, amyloid A; AFib, fibrinogen Aa-chain; AL, immunoglobulin light chain amyloidosis; ATTR, amyoidogenic transthyretin; b2M, b2-microglobulin; GI,
gastrointestinal; TTR, transthyretin.
review
WtTTR amyloidosis is very likely to be an underdiagnosed condition that commonly presents in the older
population with symptoms predominantly of right-sided
heart failure and often a history of the carpal tunnel
syndrome.29 Supportive treatment is with diuretics, antiarrhythmics or pacemaker implantation, anticoagulation where
supraventricular arrhythmias are present, and an avoidance
of digoxin and calcium channel blockers. Antihypertensives
are usually poorly tolerated as these patients can be profoundly hypotensive.30,31
Circulating TTR protein is almost exclusively liver derived,32
and the surgical gene therapy with liver transplantation
has been undertaken in more than 2000 FAP patients since
1990.33,34 Liver transplantation, when performed early,
prolongs life, particularly in patients with the TTR Met30
variant, but neurological impairment and a poor quality of
life remain problematic.35 In other mutations, and in older
patients, outcomes are less favorable, and may reflect
postoperative amyloid cardiomyopathy.36 This is thought to
be due to the deposition of wt TTR on a template of
preexisting cardiac amyloid derived from variant proteins.37
The need for better therapies has resulted in the development
of a number of novel strategies, and some of these have been
assessed in clinical trials.
STABILIZATION OF THE TTR TETRAMER
Diflunisal
Tafamadis
Tafamadis
(2-(3,5dichlorophenyl)-benzox-azole-6-carboxylic acid) is an orally administered drug that acts to
stabilize the TTR tetramer through its affinity for the T4binding site, and it does not carry the risks associated with
nonsteroidal anti-inflammatory drug use.41 It is protein
bound, metabolically stable, and X94% is excreted
unchanged from the digestive tract. Coelho et al.42
Kidney International
Epigallocathechin-3-gallate
Recent in vitro experiments show that 50 mmol/l epigallocatechin-3-gallate, the most abundant catechin in green tea
(GT), efficiently inhibits fibril formation from amyloid
b-protein, a-synucleine, and TTR and converts existing
fibrils into nonfibril conformers.43,44 TTR tetramer stabilization is observed when epigallocathechin-3-gallate binds to
3
review
RNA
polymerase
5
Mello,47
Nucleus
Rewinding
of DNA
3
mRNA
5
3 Promoter
region
Unwinding
of DNA
.
.
siRNA
2
Antisense
oligonucleotide
Oligonucleotide-based therapies
Hepatocyte
siRNARISC
complex
TTR
5
4
Cytoplasm
review
SYSTEMIC AA AMYLOIDOSIS
Renal involvement is the most frequent and serious complication of AA amyloidosis,66 necessitating the need for renal
replacement therapy including renal transplantation. Pinney
et al.67 described 43 patients with AA amyloidosis with renal
transplants and a median follow-up of 5.1 years. Graft loss
due to recurrent amyloid occurred in only 4.6% of cases and
predicted median graft survival was 10.3 years. Lower SAA
levels were associated with an improved outcome, with graft
survival, noncensored for death, of 14.5 years in patients with
a median SAA value of o10 mg/l and 7.8 years in those with
a median SAA value of 410 mg/l. Furthermore, the median
SAA concentration was significantly higher among those with
graft amyloid recurrence. Of the patients, 37% died, with
approximately two-fifths of deaths being due to infection.
Kofman et al.68 showed that their cohort of 59 transplanted
AA patients had a 5-year patient survival of 83.1% and graft
survival (censored for death) of 83.1%. Patient survival was
less good compared with the outcome of 179 age-matched
renal transplant recipients, although graft survival was not
statistically different.68 A total of 72.3% developed at least
one infection, and 43% of patient deaths were due to severe
sepsis. They postulated that this risk arose from both preand post-transplant immunosuppression.
Current drug treatment
review
Stage I
Stage II
Stage III
o0.035 mg/l
X0.035 mg/l
or
X332 ng/l
10.5
X0.035 mg/l
o332 ng/l
26.4
X332 ng/l
3.5
clonal responses are associated with both longer treatmentfree survival and a greater chance of improvement in organ
function. In low-risk patients, autologous stem cell transplantation is widely regarded as the treatment of choice,
although this was not supported by the only randomized
study to be performed,73 and outcomes depend heavily on
patient selection and center experience.
The prognosis of untreated AL patients remains 1215
months,74 and just a few months for patients with significant
cardiac involvement, highlighting the need for novel, more
effective regimens. The pathological light chains may have a
direct cardiotoxic effect and, although renal failure clearly
adds to disease burden, it is actually cardiac damage that is
the major prognostic marker.75 This is assessed by the Mayo
staging system (Table 2) and improvement after treatment
directly affects prognosis.76 However, one should bear in
mind the effect of a diminishing renal excretory function on
the widely used prognostic markers: serum cardiac troponin
T and the NT-proBNP (N-terminal fragment of pro-brain
natriuretic peptide). Importantly, as organ response can often
be delayed, treatment efficacy is monitored through the
measurement of hematological parameters, specifically
serum-free light-chain measurements (Table 3).77
Current treatment
The agents currently used include the newer immunomodulatory drugs and the proteasome inhibitor, bortezomib, as
well as the more traditional regimes (Table 4). Current
regimes have been modified from multiple myeloma protocols,
and treatment choice depends upon the type and severity of
organ involvementfor example, cardiac involvement, peripheral neuropathy, or significant hypotension may preclude
particular agents. These drugs are commonly combined with
6
Thalidomide is most commonly combined with cyclophosphamide and dexamethasone.85,86 Of the patients, 33% have
been reported to have achieved a complete or very good
Kidney International
review
Criteria
Complete response
Very good partial response
Partial response
No response
Normalization of FLC levels and ratio, negative serum and urine immunofixation
Reduction in the dFLC to o40 mg/l
450% reduction in the dFLC
o50% response in dFLC
Abbreviations: dFLC, difference between the involved FLC and the uninvolved FLC; FLC, free light chains.66
Alkylator
Melphalandexamethasone
Immunomodulatory
Thalidomide (with
cyclophosphamide
and dexamethasone)
Immunomodulatory
(second generation)
Lenalidomide
(with dexamethasone)
Immunomudulatory
(third generation)
Pomalidomide
(with dexamethasone)
Alkylator and
purine analog
Proteasome inhibitor
Bendamustine
(and dexamethasone)
Bortezomib (and
dexamethasone
cyclophosphamide or with
dexamethasone and melphalan)
Comments
Hematological toxicity
Fatigue
Peripheral edema
GI side effects
Fluid retention
Fatigue and postural hypotension
Peripheral neuropathy
Thromboembolism
Increase in cardiac biomarkers
Skin rash
Teratogen
Fatigue
Constipation/diarrhea
Myelosuppression
Thromboembolism
Skin rashes
Increase in cardiac biomarkers
Renal dysfunction
Fluid retention
Fatigue and postural hypotension
Peripheral neuropathy
Thromboembolism
Myelosuppression
Increase in cardiac biomarkers
Skin rash
Teratogen
Cytopenias
Peripheral neuropathy
Hypotension
GI disturbance
Peripheral edema
Abbreviations: AL, immunoglobulin light chain amyloidosis; CR, complete response; GI, gastrointestinal; IV MDex, intravenous melphalan-dexamethasone.
Bortezomib induces a rapid decrease in serum-free lightchain concentration in patients with myeloma.92 Purified
7
review
review
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
review
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
10
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
Kristen AV, Lehrke S, Buss S et al. Green tea halts progression of cardiac
transthyretin amyloidosis: an observational report. Clin Res Cardiol 2012;
101: 805813.
Fire A, Xu S, Montgomery MK et al. Potent and specific genetic
interference by doublestranded RNA in Caenorhabditis elegans. Nature
1998; 391: 806811.
Goodchild J. Therapeutic oligonucleotides. Methods Mol Biol 2011; 764:
115.
Sehgal A, Vaishnaw A, Fitzgerald K. Liver as a target for oligonucleotide
therapeutics. J Hepatol 2013; 59: 13541359.
Akinc A, Querbes W, De S et al. Targeted delivery of RNAi therapeutics
with endogenous and exogenous ligand-based mechanisms. Mol Ther
2010; 18: 13571364.
Loke SL, Stein CA, Zhang XH et al. Characterization of oligonucleotide transport into living cells. Proc Natl Acad Sci USA 1989; 86:
34743478.
Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by
21- and 22-nucleotide RNAs. Genes Dev 2001; 15: 188200.
Coelho T, Maia LF, da Silva AM et al. Long-term effects of tafamidis for
the treatment of transthyretin familial amyloid polyneuropathy. J Neurol
2013; 260: 28022814.
Akshay V, Sara N, Kevin F et al. Advances in oligonucleotide clinical
development. In: 8th annual meeting of the Oligonucleotide
Therapeutics Society. Boston, MA, 2012.
Guo S, Booten S, Alvarado L et al. Targeting transthyretin for the
treatment of transthyretin-associated polyneuropathy using antisense
technology. In: 41st Society for Neuroscience Annual Meeting,
Washington, DC, 2011.
Raal FJ, Santos RD, Blom DJ et al. Mipomersen, an apolipoprotein B
synthesis inhibitor, for lowering of LDL cholesterol concentrations in
patients with homozygous familial hypercholesterolaemia: a
randomised, double-blind, placebo-controlled trial. Lancet 2010; 375:
9981006.
Chia S, Dent S, Ellard S et al. Phase II trial of OGX-011 in combination
with docetaxel in metastatic breast cancer. Clin Cancer Res 2009; 15:
708713.
Hair P, Cameron F, McKeage K. Mipomersen sodium: first global
approval. Drugs 2013; 73: 487493.
Ackermann EJ, Guo S, Booten S et al. Clinical development of an
antisense therapy for the treatment of transthyretin-associated
polyneuropathy. Amyloid 2012; 19(Suppl 1): 4344.
Kluve-Beckerman B, Hardwick, Du L et al. AA amyloidosis: potential
therapy with antisense oligonucleotides. Amyloid 2011; 18(Suppl 1):
200202.
Lachmann HJ, Goodman HJ, Gilbertson JA et al. Natural history and
outcome in systemic AA amyloidosis. N Engl J Med 2007; 356:
23612371.
Rygg M, Uhlar CM, Thorn C et al. In vitro evaluation of an enhanced
human serum amyloid A (SAA2) promoter-regulated soluble TNF
receptor fusion protein for anti-inflammatory gene therapy. Scand J
Immunol 2001; 53: 588595.
Thorn CF, Lu ZY, Whitehead AS. Regulation of the human acute phase
serum amyloid A genes by tumour necrosis factor-alpha, interleukin-6
and glucocorticoids in hepatic and epithelial cell lines. Scand J Immunol
2004; 59: 152158.
Utsunomiya I, Nagai S, Oh-ishi S. Sequential appearance of IL-1 and IL-6
activities in rat carrageenin-induced pleurisy. J Immunol 1991; 147:
18031809.
Obici L, Raimondi S, Lavatelli F et al. Susceptibility to AA amyloidosis in
rheumatic diseases: a critical overview. Arthritis Rheum 2009; 61:
14351440.
Gertz MA, Kyle RA. Secondary systemic amyloidosis: Response and
survival in 64 patients. Medicine (Baltimore) 1991; 70: 246256.
Pinney JH, Lachmann HJ, Sattianayagam PT et al. Renal transplantation in systemic amyloidosis-importance of amyloid fibril
type and precursor protein abundance. Am J Transplant 2013; 13:
433441.
Kofman T, Grimbert P, Canou-Poitrine F et al. Renal transplantation in
patients with AA amyloidosis nephropathy: results from a French
multicenter study. Am J Transplant 2011; 11: 24232431.
Gillmore JD, Lovat LB, Persey MR et al. Amyloid load and clinical
outcome in AA amyloidosis in relation to circulating concentration of
serum amyloid A protein. Lancet 2001; 358: 2429.
Dember LM, Hawkins PN, Hazenberg BP et al. Eprodisate for AA
Amyloidosis Trial Group. Eprodisate for the treatment of renal disease in
AA amyloidosis. N Engl J Med 2007; 356: 23492360.
Kidney International
review
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
Kidney International
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
11