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www.kidney-international.org
Renal AA amyloidosis: presentation, diagnosis, and
current therapeutic options: a review
Sabine Karam1, Mohamad Haidous2, Virginie Royal3 and Nelson Leung4,5
1
Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, Minnesota, USA; 2Department of Medicine, University
Hospitals Cleveland Medical Center, Cleveland, Ohio, USA; 3Division of Pathology, Hôpital Maisonneuve-Rosemont, Université de
Montréal, Montréal, Quebec, Canada; 4Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; and 5Division
of Hematology, Mayo Clinic, Rochester, Minnesota, USA
Amyloid A amyloidosis is thought to be the second most
common form of systemic amyloidosis behind amyloidosis
secondary to monoclonal Ig. It is the result of deposition of
insoluble fibrils in the extracellular space of tissues and
organs derived from the precursor protein serum amyloid
A, an acute phase reactant synthesized excessively in the
setting of chronic inflammation. The kidney is the most
frequent organ involved. Most patients present with
proteinuria and kidney failure. The diagnosis is made
through tissue biopsy with involvement of the glomeruli in
most cases, but also often of the vessels and the
tubulointerstitial compartment. The treatment usually
targets the underlying etiology and consists increasingly of
blocking the inflammatory cascade of cytokines with
interleukin-1 inhibitors, interleukin-6 inhibitors, and tumor
necrosis factor-a inhibitors to reduce serum amyloid A
protein formation. This strategy has also shown efficacy in
cases where an underlying etiology cannot be readily
identified and has significantly improved the prognosis of
this entity. In addition, there has been increased interest at
developing effective therapies able to clear amyloid
deposits from tissues, albeit with mitigated results so far.
Kidney International (2023) 103, 473–484; https://doi.org/10.1016/
j.kint.2022.10.028
KEYWORDS: AA amyloidosis; clinical presentation; pathogenesis; treatment
Copyright ª 2022, International Society of Nephrology. Published by
Elsevier Inc. All rights reserved.
Correspondence: Sabine Karam, Division of Nephrology and Hypertension,
717 Delaware Street SE, Minneapolis, Minnesota 55414, USA. E-mail:
skaram@umn.edu
Received 12 July 2022; revised 26 October 2022; accepted 31 October
2022; published online 9 December 2022
Kidney International (2023) 103, 473–484
S
ystemic amyloidoses are a rare and heterogeneous group
of diseases that result from the ability of certain proteins
to misfold and polymerize into insoluble amyloid fibrils.
These fibrils are deposited in the extracellular space of tissues
and organs, causing tissue damage and significant morbidity
and even mortality.1 To date, 36 proteins have been associated
with amyloid formation in humans.2 Amyloid A (AA)
amyloidosis is derived from serum AA (SAA) protein, an
apolipoprotein of high-density lipoproteins that serves as an
acute phase reactant synthesized in the liver.3,4 The stimuli in
AA amyloidosis usually stem from chronic inflammatory
conditions, such as autoimmune diseases (rheumatoid
arthritis [RA], juvenile chronic polyarthritis, ankylosing
spondylitis, and inflammatory bowel diseases), chronic infections (tuberculosis and osteomyelitis), familial periodic
fever syndromes, such as familial Mediterranean fever (FMF),
neoplasms, and Castleman disease, among others.5 A fraction
of patients with AA amyloidosis have chronic skin or other
soft tissue infections related to injection-drug use (skin
poppers).6 Furthermore, monoclonal gammopathies, which
included Waldenström macroglobulinemia, Schnitzler syndrome, multiple myeloma, and monoclonal gammopathy of
undetermined significance, have been recently speculated as a
rare cause of AA amyloidosis in a French registry.7 A hereditary form of AA amyloidosis has been recently described.8
Sikora et al.8 examined a family with primary AA amyloidosis where the mutation was in the promoter of the SAA1.1
gene and not in the gene itself. The genetically affected individuals had sustained elevation in SAA levels, and all
developed proteinuria, chronic kidney disease, and systemic
deposition of amyloid composed specifically of the SAA1.1
isoform.8 Finally, the etiology is unknown in some cases,
which are labeled as idiopathic.9,10
AA amyloidosis is the second most common form of
amyloidosis behind Ig light chain (AL) amyloidosis.11
Although AA amyloidosis is a systemic disease, the clinical
picture is dominated by kidney involvement.12 AA amyloidosis causes kidney dysfunction with proteinuria in >80% of
cases that progress to kidney failure if left untreated.10 Previously, there were few treatment options for patients with AA
amyloidosis. Fortunately, the incidence of AA amyloidosis has
been decreasing as underlying inflammatory conditions and
infections are increasingly better managed.13 Moreover, the
advent of new drugs that target various processes involved in
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S Karam et al.: Renal AA amyloidosis: diagnosis and management
Table 1 | Common etiologies of AA amyloidosis
Entity
Infections
Autoimmune/connective
tissue diseases
Hereditary inflammatory
conditions
Other
Type
Mycobacteria (tuberculosis)
Bronchiectasis
Injection-drug–related infections
Osteomyelitis
Rheumatoid arthritis
Juvenile idiopathic arthritis
Psoriatic arthritis
Ankylosing spondylitis
Crohn disease
Vasculitis (polyarteritis nodosa–giant cell
arteritis–antineutrophil cytoplasmic
antibody–associated vasculitis)
Behcet disease
Celiac disease
Familial Mediterranean fever
Muckle-Wells syndrome
Cryopyrin-associated periodic fever
syndrome
Tumor necrosis factor receptor-associated
periodic syndrome
Mevalonate kinase deficiency/hyper IgD
syndrome
Cystic fibrosis
Castleman disease
Skin popping
Malignancy
Obesity
AA, amyloid A.
the pathogenesis raised new hope for patients. This article will
review the pathogenesis of renal AA amyloidosis, its clinical
and pathologic presentations, along with its treatment, with
emphasis on new targeted therapies.
EPIDEMIOLOGY
AA amyloidosis was the first type of amyloidosis ever
described and was thought to be the most prevalent form of
systemic amyloidosis for hundreds of years.14 It has now been
supplanted by AL amyloidosis, particularly in the Western
world, likely the result of better treatment of the various
underlying etiologies. Among 474 cases diagnosed by renal
biopsy at the Mayo Clinic between 2007 and 2011, AA
amyloidosis represented only 7% of the cases.15 In a review of
16,175 tissue samples of amyloidosis typed by mass spectrometry over 11 years, AA type accounted for only 2.9% of
cases.16
The incidence of AA amyloidosis is z1 to 2 cases per
million person-years.5,17,18 Two cases per million person-years
were reported from Sweden,19 whereas a separate study from
England found that number to be 1 case per million personyears.20 The incidence might be higher in low-resource settings
where rheumatology services are scarce and economic constraints are numerous, resulting in delay in diagnosis and
compromising management of the underlying disease.21 A
common theme throughout multiple studies is the current
trend of increasing age at diagnosis.5,17,22,23 One study found
the median age at diagnosis has increased from 50 to 70 years.5
A male predominance was found in 2 large series of 374 and
474
378 patients.23,24 In most epidemiologic studies, RA is the most
commonly associated disease with AA amyloidosis.10,24 In lowincome and low middle-income countries, however, chronic
infections remain a major cause, with most cases secondary to
mycobacteria, most notably untreated tuberculosis.11,25 Skin
popping leading to recurrent infections is a well-recognized
cause. In 1 autopsy study, as many as 14% of s.c. drug users
had AA amyloidosis,26 and at 1 hospital in San Francisco,
100% of cases of renal AA amyloidosis from 1998 to 2013 were
attributed to skin popping.13
There are also geogenetic patterns of AA amyloidosis.
Around the Mediterranean basin, untreated FMF is a major
culprit. For example, a study from Turkey found that untreated FMF was the leading cause of AA amyloidosis, accounting for 19.7% of cases, whereas chronic rheumatic
diseases and chronic infections resulted in 18.5% and 13.5%
of cases, respectively.11 AA amyloidosis due to familial periodic fever syndromes affects people of English and Irish
descent with tumor necrosis factor receptor-1–associated
periodic syndrome (TRAPS).27 The major causes of AA
amyloidosis are summarized in Table 1.
PATHOGENESIS
Amyloid fibrils are composed of insoluble and proteolyticresistant protofilaments. These protofilaments arrive from
aggregation of misfolded amyloid precursors that possess a
cross-b-sheet quaternary structure, a defining structural
element.10,28,29 The precursor protein in AA amyloid is SAA,
an apolipoprotein produced predominately by hepatocytes,
but also by other cells, including macrophages, endothelial
cells, and smooth muscle cells.10,24,30,31 It is an acute-phase
reactant synthesized under the influence of proinflammatory cytokines, such as tumor necrosis factor-a
(TNF-a), interleukin (IL)-1b, and IL-6.10,24,30 SAA possesses
multiple functions, including serving as opsonin, allowing
bacterial uptake by neutrophils, and inducing expression of
matrix metalloproteinase and angiogenesis, promoting tumor
metastasis in carcinoma and joint destruction in inflammatory arthritis.32–35 SAA may also play a role in maintenance of
normal body weight and protection from hepatic steatosis.36,37 Furthermore, SAA also acts as a hub in interaction
networks in lipid homeostasis and immune response.38,39
Aggregation of SAA into amyloid fibrils only occurs when a
critical concentration has been reached, and the high plasma
concentration persists for a prolonged period.14 Proteolytic
cleavage of SAA1 from a 122–amino acid peptide eventually
to a 76–amino acid residue by metalloproteases is a crucial
step for amyloid formation.40 Interactions with glycosaminoglycans (GAGs) and serum amyloid P component (SAP)
promote aggregation and lead to the formation of amyloid
(Figure 1).41–43 In addition to GAGs, apolipoprotein A1,
apolipoprotein A4, and apolipoprotein E are chaperone proteins found with all amyloid that play an essential role in
fibrillogenesis and protection of the amyloid fibrils.44
Genetic susceptibility also plays a role in the genesis of the
disease. SAA is genetically polymorphic, and its gene is
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S Karam et al.: Renal AA amyloidosis: diagnosis and management
Neoplasms
Castleman’s
disease
Hereditary
inflammatory
conditions
Skin
popping
Sustained
inflammation
Autoimmune/
connective
tissue diseases
SAA1 gene
promoter
mutation
Infections
Increased IL-1, IL-6,
TNF-α
Liver
GAG
Macrophages
SAA1
Extracellular
deposition
Amyloid
fibrils
Amyloid
(oligomer)
Precursor
protein
SAP
Endothelial and
smooth muscle cells
Amyloid
(monomer)
Figure 1 | Pathogenesis of amyloid A (AA) amyloidosis. Serum AA (SAA) 1 is synthesized under the influence of proinflammatory cytokines
as tumor necrosis factor-a (TNF-⍺), interleukin (IL)-1, and IL-6. SAA1 is mainly produced by hepatocytes but also by macrophages, endothelial
cells, and smooth muscle cells. Aggregation of SAA into amyloid fibrils occurs when a critical concentration has been reached and a high
plasma concentration persists for a long period. SAA usually undergoes a process of cleavage, misfolding, and aggregation, followed by a
series of interactions with other tissue components, such as glycosaminoglycans (GAGs) and serum amyloid P component (SAP), which
eventually leads to deposition as amyloid. AA deposits in the extracellular space of the liver, kidneys, spleen, and heart.
located on chromosome 11. The SAA gene products SAA1
and SAA2 are both elevated with acute inflammation, but
>90% of the precursor proteins of the AA protein are derived
from SAA1.45 Furthermore, in humans, 3 main SAA1 alleles
(SAA1.1, SAA1.3, and SAA1.5) are defined by 2 singlenucleotide polymorphisms located in exon 3, resulting in 2
amino acid differences at positions 52 and 57. There seems to
be differential amyloidogenicity among the different SAA1
isoforms, with homozygosity for SAA1.1 being a significant
risk factor for development of AA amyloidosis in Whites,46
whereas it is homozygosity of SAA1.3 in the Japanese population.47 Experiments with murine SAA1.1 found it binds
hyaluronic acid (a GAG) more than SAA2.2, which is
important for polymerization.48 Finally, obesity and age also
constitute susceptibility factors, especially in idiopathic AA
amyloidosis.9,49 It has been postulated that leptin and other
inflammatory parameters associated with obesity could
contribute to systemic inflammation and amyloidosis genesis.49 For instance, white fat tissue in obese mice contains 45%
to 60% of macrophages, of which most have acquired a
proinflammatory phenotype.50 Many cases considered
initially as idiopathic are in fact caused by rare genetic
autoinflammatory diseases, such as TRAPS1 or mevalonate
kinase deficiency/hyper IgD syndrome. Therefore, when an
autoinflammatory disease is suspected but no specific clinical
features are present, a next-generation sequencing panel for
genetic autoinflammatory diseases should be performed.51,52
CLINICAL PRESENTATION
AA amyloidosis causes a greater degree of kidney dysfunction
when compared with AL amyloidosis and is more likely to
affect younger individuals.18 In 80% to 90% of cases of AA
amyloidosis, the kidneys are involved and patients commonly
present with kidney dysfunction with glomerular amyloid
deposition that leads to nephrotic syndrome. Left untreated,
the renal amyloidosis progresses to end-stage kidney disease
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(ESKD).10,17,24,53,54 In several studies, >10% had already
developed ESKD at the time of diagnosis.24,55 In a series of
200 patients, aged >55 years, underlying infections and
estimated glomerular filtration rate (eGFR) <45 ml/min were
associated with a poor overall survival, whereas patients with
proteinuria of >4 g/24 h and eGFR <35 ml/min had an
inferior renal survival.55 There is also a predominantly
tubular form of AA amyloidosis.56 Patients with this variant
may present with a bland urinary sediment and little proteinuria, but they may show signs of distal tubular dysfunction, such as nephrogenic diabetes insipidus.57 Moreover,
there have been reports of Fanconi syndrome and renal
tubular acidosis, but these are usually in association with
nephrotic syndrome.58,59 Also, kidney function appears to
deteriorate less rapidly when amyloid deposits are completely
absent from the glomerulus.57 Finally, there are rare reports of
crescentic pauci-immune glomerulonephritis, perhaps related
to rupture of glomerular capillary loops due to amyloid
deposition.60 They have been notably depicted in some cases
of RA that were anti-neutrophil cytoplasmic autoantibody
negative.61,62 In addition to kidney involvement, hepatic and
splenic involvement is common along with gastrointestinal
(GI) involvement, which is found in around 30% of cases.10,63
The GI manifestations include macroglossia, a dilated and
atonic esophagus, gastric polyps, and luminal narrowing or
ulceration of the colon, whereas hepatic infiltration is mostly
revealed by hepatomegaly and an elevated alkaline phosphatase level.64 Cardiac, thyroid, adrenal, and neurologic involvements have also been reported but are rare.10,24,65–67
DIAGNOSTICS AND PATHOLOGY
No clinical or laboratory test has yet superseded histology for
the diagnosis of AA amyloidosis. In suspected patients, a
tissue biopsy is recommended as a first step to confirm the
presence of amyloid. Potential sites to be accessed include
abdominal fat and minor salivary glands. More invasive sites,
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Figure 2 | Histologic findings in amyloid A (AA) amyloidosis.
(a,b) Massive amyloid glomerular deposits characterized by the
replacement of the mesangial matrix by acellular, weakly periodic
acid–Schiff (PAS)–positive (asterisks) material (PAS stain, original
magnification 200) (a) and nonargyrophilic material (b). (b)
Subendothelial capillary wall deposits are present with segmental
duplication of the glomerular basement membrane (arrowheads)
(Jones silver stain, original magnification 400). (c) Predominant
deposition of AA amyloidosis along the tubular basement
membrane (arrows) (PAS stain, original magnification 100). (d)
Immunohistochemistry study using antibodies against serum AA
protein strongly stains the amyloid deposits. (e) Congo red stain
showing green-yellow birefringence under the polarized light
(Congo red stain, original magnification 200). (f) Randomly
arranged fibrils on electron microscopy (transmission electron
microscopy, original magnification 50,000). To optimize viewing of
this image, please see the online version of this article at www.
kidney-international.org.
like kidney, rectal tissue, or the GI tract, should be explored
when there is a high clinical suspicion of their involvement or
when more accessible sites are negative. Kidney involvement
is defined as a 24-hour urine protein >0.5 g, and the diagnosis is made by a kidney biopsy.17,18 Subcutaneous fat biopsy
with Congo red staining and polarized microscopy observation in a population with several types of systemic amyloidosis (AA, AL, and transthyretin-mediated [ATTR]) has a
sensitivity of 80% with thorough assessment increasing it to
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S Karam et al.: Renal AA amyloidosis: diagnosis and management
>90% and a specificity of 100%.68 In a study that reviewed
236 histologically confirmed cases, of which 19 were of the
AA type, rectal biopsies had a sensitivity of 84%.69 In another
study that followed 62 suspected AL or AA amyloidosis cases
with negative abdominal fat aspirates, salivary gland biopsies
had a sensitivity of 58%.70
Glomerular involvement is almost always present.
Glomeruli typically show periodic acid–Schiff stain pale and
nonargyrophilic deposits in the mesangium, which can be
segmental, not infrequently forming nodules.71 Amyloid deposits can also be found along the capillary wall, sometimes
forming amyloid spicules, and at the glomerular hilum. Some
vascular involvement is almost constant, with >95% of the
biopsies showing AA amyloid in the arterioles and arteries.71
In addition, AA amyloidosis with predominantly vascular
infiltration has been described.72 Furthermore, a predominantly tubular form of AA amyloidosis has been
described.56,72,73 Inflammation can be seen in 44% of patients
and appears as a multinucleated giant cell reaction or a
glomerular inflammatory infiltrate within the capillary
loops.71 Interstitial inflammation is also common and may be
present adjacent to vessels or tubules.12 Congo red stain performed on the formalin-fixed paraffinized tissue shows a
characteristic green-yellow birefringence on polarization.5,17
Electron microscopy shows solid, nonbranching fibrils that
are 9 to 15 nm in diameter.5 On confirmation of the presence
of amyloid, immune stains—including immunohistochemistry and immunofluorescence—are often the first-line
approach to determine the type of amyloid.17,18,74,75 In AA
amyloidosis, routine immunofluorescence examination is
typically negative for IgG, IgA, IgM, C1q, C3, fibrinogen, and
k and l antibodies (Figure 2).76 Immunostaining using
commercially available antibody against SAA can be helpful by
showing a strong staining of the amyloid deposits. However,
immune stains against SAA have several limitations, and both
false positivity, due to the lack of specificity of the SAA antibody, and false negativity, due to epitope loss by protein crosslinking after formalin fixation, have been described. Moreover,
the contamination of amyloid deposits by serum proteins,
such as Ig components, may lead to a false-positive staining for
Igs.77,78 Amyloid typing by laser microdissection and proteomic analysis by mass spectrometry, performed on formalinfixed paraffin-embedded tissue, is more sensitive and specific
than most immune methods for the identification of the
amyloid subtype.79 It has emerged as the method of choice for
amyloid typing but is currently not used as a standard diagnostic technique because of its limited accessibility due to the
few centers that have the facilities and expertise to perform
this assay. Immunoelectron microscopy is another highly
sensitive and specific method for amyloid typing, which is,
however, only available in few expert centers.80,81
An attempt was made to develop a pathologic renal amyloid prognostic score in AA amyloidosis that considered the
glomerular, vascular, and interstitial AA deposition, as well as
glomerular sclerosis, interstitial inflammatory infiltration,
and/or fibrosis and tubular atrophy. The score was divided
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S Karam et al.: Renal AA amyloidosis: diagnosis and management
into 3 grades (renal amyloid prognostic score I, II, and III).
Renal amyloid prognostic score grade and interstitial inflammatory infiltration were associated with baseline eGFR,
and glomerular amyloid deposition was associated with proteinuria, but only extensive glomerular amyloid deposition
(>50%) turned out to be an independent predictor for the
development of ESKD.82
The SAP scintigraphy is a tool that can be used to detect
and quantify amyloid deposits. This uses highly purified SAP
radiolabeled with the g emitting isotope of 123I that localizes
amyloid deposits and quantifies the amount of amyloid
deposited. It has a sensitivity of 100% in patients with systemic amyloidosis, but cannot type the amyloid and is not
available in the United States and many other countries
around the world.17 The measurement of SAA levels can be
used to estimate the amount of amyloid genesis but is also not
available in the United States and many non-European
countries. Elevated level >10 mg/L is associated with an
increased risk of developing AA amyloidosis, but by itself,
SAA level is not enough to make the diagnosis. On the other
hand, amyloid burden and kidney prognosis significantly
correlate with the SAA concentration, and the risk of death is
highest in patients with extremely elevated levels.24
Only a few reports describe the regression of AA amyloid
deposits in tissue after treatment. Okuda and Takasugi83 and
Hattori et al.84 have reported AA amyloidosis deposit
regression in the GI tract in patients treated with tocilizumab
(TCZ) for RA. In the kidney, 1 report describes the regression
of interstitial AA amyloid deposits in a patient with Castleman disease after treatment with TCZ.85 There was, however,
no effect of the treatment on the glomerular deposits. Inui
et al. reported a case of AA amyloidosis deposit regression in
all kidney compartments in a patient with FMF treated with
TCZ.86 Interestingly, most published reports describe significant clinical improvement after specific treatment—such as
the resolution of the nephrotic syndrome—despite persistent
amyloid deposits on the repeated kidney biopsy.87–89
TREATMENT
General principles
The mainstay of treatment is to address the primary cause by
treating any infection or chronic inflammation. Traditionally,
therapies targeting the underlying inflammatory disorder
using disease-modifying antirheumatic drugs (DMARDs) and
other drugs, such as colchicine, steroids, and cyclophosphamide, have had some success if administered in a timely
manner. DMARDs fall into 2 categories: nonbiologics and
biologics. Nonbiologic DMARDs include methotrexate
(MTX), hydroxychloroquine, sulfasalazine, and leflunomide.
In patients with active RA, MTX is suggested as the initial
treatment; it is usually administered with nonsteroidal antiinflammatory drugs or steroids. MTX dose is increased as
tolerated and as needed to control active symptoms and signs
of arthritis, and it is continued for at least 3 months.90 MTX
has a faster onset of action, has better tolerance in the
long-term, and is comparable or better in terms of efficacy
Kidney International (2023) 103, 473–484
when compared with other nonbiologic DMARDs. Also, when
compared with leflunomide, sulfasalazine, and hydroxychloroquine, MTX improved survival in patients with RA.91–93
MTX requires close monitoring as it is associated with bone
marrow, liver, and lung toxicity.91
Colchicine, an alkaloid with inhibitory effects on multiple
cellular functions, including microtubule assembly, cell
adhesion, and inflammasome activation, remains the standard of care for FMF as it has been proven to be a valuable
treatment when given life-long on a daily basis.94 It is useful
to prevent the recurrence and the intensity of febrile attacks
and subsequently the development of amyloidosis.95–100 More
important, it reduces the occurrence of kidney disease, such
as nephrotic syndrome, and prevents its progression.100,101
The minimal recommended dose is 1 mg daily, and the
most common reported adverse effects are GI effects, such as
nausea, vomiting, and diarrhea; these symptoms usually tend
to improve with dose reduction.102,103
The target is ultimately to reduce the amount of circulating
SAA protein by reducing its production in the liver.53 Indeed,
suppressing SAA leads to prolonged survival, decrease in
amyloid effects on organ function, and a regression of AA
amyloid deposits.53 The reduction of SAA levels to <7 mg/L
has been associated with favorable renal prognosis and should
always be monitored if feasible.24 If SAA assays are unavailable, efficacy of the treatment can be assessed through
measurement of serial C-reactive protein levels, even though
in some patients there could be a discrepancy between the 2
markers.5 As synthesis and secretion of acute-phase SAA is
mediated by cytokines (mainly IL-1, IL-6, and TNF-a 53,104),
therapies targeting these cytokines and their pathways have
recently gained interest. Examples include inhibitors of TNFa, IL-1, IL-1ß, and IL-6.89,105–109 Although they have been
shown to be effective for autoimmune-mediated AA
amyloidosis and hereditary periodic fever syndrome and at
least half of respondents in a population with RA,110 they have
also been successful in cases classified as idiopathic. Indeed, in
up to 20% to 40% of the cases, no specific cause can be found,
which creates a dilemma as to the choice of treatment.10,11,17,106 Since they have been in use, the risk of death
of patients with AA amyloidosis has been significantly
reduced.111 The one caveat is that these cytokine inhibitors
may exacerbate an occult or concomitant infection.112
Tuberculosis, in particular, seems to be an important safety
concern.110
Experimental agents for the treatment of renal AA
amyloidosis
There have also been efforts to either affect the deposition of
amyloid in target issues or target its clearance after deposition.
For instance, eprodisate is a negatively charged sulfonated
molecule structurally similar to heparan sulfate, a GAG that
can interfere with the interactions between GAGs and amyloidogenic fibrils, preventing their deposition.36,37,41,109,113 In
a double-blind, placebo-controlled trial of patients with renal
AA amyloidosis, eprodisate failed to show any effect on
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progression to ESKD, although it significantly decreased the
rate at which kidney function deteriorated.109 Unfortunately,
eprodisate failed to meet the primary endpoint of slowing
kidney function decline in a second phase 3 trial.114
It has been suspected that chaperone proteins protect the
amyloid fibrils from degradation. To enhance immunotherapeutic clearance of amyloid after deposition, miridesap
[(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]
pyrrolidine-2-carboxylic acid], also known as CPHPC, was
developed to target SAP, one of the chaperone proteins.
Miridesap depleted circulating SAP in an open-label study
and reduced, to a certain extent, SAP content in affected
organs.115 To increase the removal of AA amyloid from tissue,
dezamizumab, a fully humanized monoclonal IgG1 anti-SAP
antibody, was administered to 23 adult subjects after they
received 3 cycles of miridesap, and it triggered immunotherapeutic clearance of amyloid deposited in tissue.116 Unfortunately, several clinical trials investigating these new
therapeutic routes were recently interrupted due to futility
analysis or a change in benefit/risk profile.117 It is finally
worth mentioning the recent development of a prodrug of
miridesap with better oral bioavailability and physical stability, currently named GSK294.118 Unfortunately, after
administration for 7 days to humans, arrhythmias occurred,
the relation of which to GSK294 remains unclear, and the
study was terminated. Finally, another route partially
explored is the use of antisense oligonucleotides to lower the
expression of SAA in the liver. Although this strategy was
successful in mice, as it led to both suppressed SAA production and reduced tendency to develop AA amyloidosis, it
has yet to be tested in humans.119
Anti-cytokine therapy used in the treatment of AA
amyloidosis
IL-1 inhibition. Three IL-1 inhibitors are currently avail-
able for clinical use: anakinra, canakinumab, and rilonacept,
which is approved for clinical use in the United States only.
Anakinra is a recombinant nonglycosylated analogue of the IL1 receptor antagonist and, therefore, inhibits both Il-1a and Il1b. It is approved in the United States for the treatment of RA,
cryopyrin-associated periodic syndromes, and deficiency of
IL-1 receptor antagonist120 and for the treatment of FMF and
Still disease in Europe.121 Canakinumab is a human monoclonal antibody that specifically binds to IL-1b and blocks the
interaction between IL-1b and the IL-1 receptor and the
activation of subsequent inflammatory responses. Canakinumab is approved for the treatment of cryopyrin-associated
periodic syndromes and TRAPS and for the treatment of
FMF and Still disease.122 Rilonacept is approved for the
treatment of recurrent pericarditis, cryopyrin-associated periodic syndromes, and deficiency of IL-1 receptor antagonist.123 None of these 3 drugs is approved for renal AA
amyloidosis specifically.124 Anakinra is usually administered as
a daily s.c. injection. Canakinumab requires 1 s.c. injection
every 4 to 8 weeks and has been used in patients who developed leukopenia or injection site reaction with anakinra.
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S Karam et al.: Renal AA amyloidosis: diagnosis and management
No formal clinical trials have been conducted to evaluate
the efficacy of IL-1 inhibition in AA amyloidosis, and the data
available are limited to case reports and series. In patients
with AA amyloidosis secondary to TRAPS, anakinra induced
complete resolution of symptoms with normalization of Creactive protein and SAA levels in 7 patients.125 One of the 2
patients in this series with significant proteinuria achieved a
complete regression of the proteinuria, whereas the other had
stabilization of proteinuria. In patients with renal AA
amyloidosis secondary to FMF, canakinumab improved the
kidney function and proteinuria in 2 pediatric patients who
were colchicine resistant.126,127 In fact, both anakinra and
canakinumab have been reported to be effective for patients
with colchicine-resistant FMF-associated AA amyloidosis. In a
retrospective study, inflammatory markers, C-reactive protein
and erythrocyte sedimentation (ESR) rate, were significantly
reduced in all and normalized in 12 of 17 patients who
received IL-1 blockade with significant improvement in proteinuria.128 In another retrospective review of 20 patients with
colchicine-resistant FMF, both patients with biopsy-proven
AA amyloidosis (one who received anakinra, and the other
who received canakinumab) had significant improvement of
their proteinuria with treatment.129 A systematic review of the
literature found 18 patients with FMF with established AA
amyloidosis treated with anakinra and 1 patient who received
canakinumab. Four patients had nephrotic syndrome, and 8
had end-stage kidney disease. Five patients also received a
kidney allograft before initiation of the drug. A decrease in
proteinuria was observed in all patients with nephrotic syndrome, and no recurrence of AA amyloidosis was reported in
the 7 patients receiving a kidney transplant who were started
on the drug either before after receiving the transplant.130 On
the other hand, the largest observational cohort from Turkey,
which included 44 patients with FMF and AA amyloidosis,
reported mixed results with anakinra or canakinumab.
Among 35 patients not on kidney replacement therapy, kidney function was maintained or improved in 79.4% but
deteriorated in 20.6%. Patients with creatinine levels <1.5
mg/dl at onset benefitted more from IL-1 inhibition with
regard to their kidney functions and acute-phase reactants.131
Regarding patients with AA amyloidosis of unknown etiology,
a review of 11 patients treated with anakinra found that 9 had
complete or partial remission. A complete response in this
study was defined as normalization of SAA (#10 mg/L) and
resolution of chronic disease symptoms and flares/exacerbations, whereas a partial response was defined as improvement but not normalization of SAA and/or an improvement
in disease symptoms.106 Finally anakinra seems to be efficient
at treating nephrotic syndrome in patients with AA
amyloidosis and autoinflammatory disease associated with
CIAS1/NALP3/cryopyrin gene mutations.132
IL-6 inhibitors. TCZ, an IL-6 inhibitor, is another promising therapy for AA amyloidosis. IL-6 is a glycopeptide
produced by various, including fibroblasts, osteoblasts,
endothelial cells, T cells, and B cells.133,134 It is thought to
exert its effects via 2 different signaling pathways, classic cis
Kidney International (2023) 103, 473–484
review
S Karam et al.: Renal AA amyloidosis: diagnosis and management
signaling and trans signaling, the latter being responsible for
most proinflammatory responses.135 TCZ inhibits both
signaling pathways.136 IL-6 also plays a pivotal role in SAA
synthesis. In a study using HepG2 cells, a cell line derived
from hepatocytes, IL-6 stimulation alone was able to induce a
weak expression of SAA1 and SAA2 mRNA, whereas almost
no expression was induced by the stimulation with IL-1b or
TNF-a alone.137 Numerous case reports and case series have
reported successful outcomes with TCZ administered to patients with AA amyloidosis secondary to various underlying
disorders and that were previously refractory to conventional
treatment. TCZ was given to a series of 12 heavily pretreated
patients with FMF and concomitant AA amyloidosis, 4 of
whom also had ankylosing spondylitis and 1 had Crohn
disease.138 Of the 12 patients, 11 were treated with colchicine,
5 were treated with anakinra, 3 were treated with canakinumab, 3 were treated with infliximab, 2 were treated with
cyclophosphamide, 1 was treated with etanercept, 2 were
treated with sulfasalazine, and 1 was treated with azathioprine. At a mean follow-up of 17 months, C-reactive protein
was significantly reduced from 18 to 5.8 mg/L, whereas ESR
decreased from 48.7 to 28.7 mm/h. FMF attacks were reduced
in 91.7% of patients. In 2 patients with eGFR <50 ml/min,
proteinuria was reduced by 43% and 37%, whereas kidney
function improved from 37.5 to 45.1 ml/min and from 39.9
to 59.0 ml/min. In the patients with eGFR >50 ml/min,
kidney function and proteinuria remained stable.
TCZ was also administered to 5 patients with RA with AA
amyloidosis who were followed up for over a year. Improvement in kidney dysfunction, including proteinuria and a
significant decrease in SAA concentration, was noted in 4 of 5
patients (2 were refractory to etanercept).107 In another 5
patients with rheumatic disease and AA amyloidosis refractory to anti–TNF-a therapy and DMARDs, inflammation
decreased in all and kidney function either improved or
remained stable. Proteinuria also decreased or disappeared in
3 patients.108 In a larger series of 20 patients with chronic
inflammatory disorders and AA amyloidosis refractory to
other treatments, TCZ was effective at reducing amyloid deposits and at suppressing inflammation over a median followup of 23 months.139 Also, TCZ induced full remission over a
year in a patient with Behcet disease and nephrotic syndrome
due to AA amyloidosis140 and cleared the interstitial AA
kidney deposits in a patient with multicentric Castleman
disease.85 Others reported that TCZ improved both inflammation and proteinuria in 2 cases of ankylosing spondylitis.141 TCZ had a beneficial effect on members of the family
with genetic AA amyloidosis described by Sikora et al. when
prescribed early in the course of the disease.8 Finally, the first
nationwide survey of patients with AA amyloidosis in Japan
showed a good responses in 95.5% of the 66 patients who
received TCZ as opposed to 74.1% of good responses in the
27 patients who received TNF-a inhibitors, suggesting that
TCZ was superior, although the samples size was small and
the 2 groups were not randomized.142 Siltuximab, a chimeric
monoclonal antibody that binds with high affinity to IL-6, is
Kidney International (2023) 103, 473–484
the first drug approved for the treatment of multicentric
Castleman disease.143 It constitutes currently, with or without
steroids, the first-line therapy,144 and leads to durable clinical
response and longer disease stabilization, potentially preventing the development of AA amyloidosis.145 Its role in
established AA amyloidosis has not been studied yet. Sarilumab, a human anti–IL-6R antibody, was recently approved
for the treatment of RA, and is expected to be similarly
effective for AA amyloidosis.
TNF-a inhibitors. TNF-a inhibitors used in the treatment
of AA amyloidosis include etanercept, infliximab, certolizumab, and adalimumab. The rationale to use them would be
their ability to reduce SAA levels by inhibiting TNF-a–
induced SAA transcription in hepatocytes and by reducing
macrophage activation.146 Some retrospective studies and case
reports in patients with either inflammatory bowel disease or
rheumatic diseases have shown some clinical utility.147–153 For
instance, in a retrospective review of a series of 15 patients
with rheumatologic disease who received infliximab, etanercept, or both, 3 experienced a sustained decrease in proteinuria with an increase in eGFR.148 In another series of 14
patients with RA treated with infliximab or etanercept, the 24hour creatinine clearance improved in 4 patients and the
proteinuria decreased in 3 patients.149 In 6 patients with
Crohn disease complicated by AA amyloidosis, reduction of
the nephrotic syndrome was observed in 1 patient and stabilization of kidney function was observed in 2 patients.152 In
a retrospective study that compared the effectiveness of etanercept with cyclophosphamide in a cohort of Japanese patients with RA, there was significantly better survival and
improvement in the eGFR in the etanercept group.154 However, when compared with TCZ retrospectively in a singlecenter study, the 5-year retention rate was much lower for
TNF-a inhibitors, and they showed less clinical utility.155 The
reason might be a suboptimal propensity to normalize acutephase reactants.151 Serious adverse events observed during
long-term follow-up include sepsis and thrombotic events.
Targeted therapies in specific populations
The use of targeted therapies in patients with TRAPS-related
AA amyloidosis was recently reviewed as part of a national
case series in France, along with a systematic review of the
literature.51 The authors summarized the data for 21 regimens administered to 19 patients. Anakinra was used in 16
patients, of whom 6 improved, 7 stabilized, and 3 worsened
their kidney function. Canakinumab was given to 1 patient
and improved kidney function. Etanercept was administered
to 14 patients, of whom 7 were switched to anakinra because
of adverse events or partial remission. Of the remainding
patients, 2 improved partially and 1 recovered completely.
Interestingly, the administration of infliximab or adalimumab
in patients with TRAPS has led to enhanced anti-apoptotic
activity and oversecretion of proinflammatory cytokines,
leading to paradoxical exacerbation of the TRAPS.156,157 In a
review of 20 patients with mevalonate kinase deficiency/hyper
IgD syndrome, anakinra (n ¼ 8, 1 success, 5 partial responses,
479
review
and 2 failures), etanercept (n ¼ 7, 4 successes, 1 partial
response, and 2 failures), and TCZ (n ¼ 5, 4 successes and 1
partial response) were used as therapy.52 In this review,
complete response was defined as complete control of the
clinical manifestations and normalization of laboratory parameters, partial response was considered as persistence of
some clinical manifestations and/or abnormal laboratory
findings, and failure was the absence of any substantial impact
on disease activity or worsening. Rituximab might be an
alternative therapy in some patients with RA with established
AA amyloidosis. It has already shown some efficacy in patients with severe active RA who have exhibited an inadequate
response to $1 TNF-a inhibitors.158 Its use in established
amyloidosis has been reported by various authors for a total
of 9 cases, 8 with RA and 1 overlap syndrome with features of
polymyositis, scleroderma, and RA.159–161 Kidney function
either remained stable or improved in 7 patients, whereas
proteinuria improved in 5 cases. Notably, 7 patients had failed
TNF-a inhibitor therapy before receiving rituximab. The
exact mechanism behind rituximab’s potential efficacy remains unknown.
Adverse effects of anti-cytokine therapy
In patients with AA amyloidosis, treatment with anakinra is
in general well tolerated, with the main adverse event reported being the known transient injection site reactions,
which sometimes mandate switching to a different
agent.106,128,131,132 Neutrophil counts also need to be monitored with reports of leukopenia.128,162 Patients are usually
switched to canakinumab, with infections reported as the
main adverse event but also activation of psoriasis and lichen
planus.131,163 Infections are also the main adverse event reported with TCZ.107,139 Other minor adverse effects include
slightly elevated liver enzymes, mild thrombocytopenia,
diplopia, and an increase in blood pressure.138,164 TNF-a
inhibitors also seem to be relatively well tolerated, with herpes
zoster and venous thrombosis reported with infliximab use148
and an increased risk of infections, especially for patients on
hemodialysis165 (Supplemental Table S1).
AA amyloidosis and kidney replacement therapy
Patients with renal AA amyloidosis who progress to ESKD can
be treated with dialysis or kidney transplantation (KT).
However, survival on dialysis is poor, with cardiac involvement being a strong predictor of death within the first year of
dialysis.166 KT should, therefore, be considered in select patients, but AA amyloidosis can recur after KT. In a French
multicenter study that assessed the graft and patient survival
of 59 renal recipients, the recurrence rate of AA amyloidosis
nephropathy was estimated at 14% and there was a significantly higher incidence of infectious and cardiovascular
complications with a reduced survival compared with recipients with another underlying cause of ESRD.167 This
recurrence rate was derived from biopsies done based on
clinical and/or biological suspicion of recurrence, or “for
cause” biopsies. Hence, a higher recurrence rate of AA
480
S Karam et al.: Renal AA amyloidosis: diagnosis and management
amyloidosis cannot be excluded, and sequential biopsies may
play a role in early detection of recurrence of AA amyloidosis.
In a more recent study, postrenal transplant survival was
comparable to those with diabetic nephropathy.168 Colchicine
has been reported to be effective in preventing recurrence in
FMF, but data regarding treatment of established AA
amyloidosis with targeted therapies in KT are scarce. In a
series of 6 patients with FMF-related amyloidosis (1 of them
with nephrotic syndrome, 2 with chronic kidney disease, and
3 with renal transplantation) who received anakinra due to
colchicine resistance, there was partial remission of the
nephrotic syndrome. In the transplanted patients who were
having recurrent FMF attacks despite colchicine and deterioration of the renal function with each attack, the attacks
ceased completely.169 In another series of 17 patients with
FMF who received concomitantly colchicine and anakinra
post-KT, with 4 of them with recurrent AA amyloidosis,
partial response (defined as $50% decrease in proteinuria)
and complete remission (<0.3 g/d proteinuria) were achieved
in only 2 patients (Toz B, Çalışkan YK, Erer B, et al.. Efficacy
and safety of IL-1 inhibitors in amyloidosis associated with,
familial Mediterranean fever who underwent kidney transplantation [abstract 943]. Presented at 2016/ACR/ARHP
Annual Meeting. November 11–16, 2016; Washington DC).
CONCLUSION
Clinical observations stemming from the therapeutic success
achieved so far seem to indicate that the reduction of the SAA
protein is presently the most effective treatment strategy for
AA amyloidosis. This is often achieved using IL-1, IL-6, and
TNF-a inhibitors as opposed to traditional therapies, such as
colchicine used for FMF. It is, however, important to identify
the disease early to prevent advanced organ damage and to
increase the likelihood of organ response. Clinical trials are
needed to identify the most appropriate agent. Although the
few tested interventions aimed at promoting amyloid clearance did not show a clear clinical benefit, this therapeutic
approach deserves to be further pursued to complement
existing therapies to improve the outcomes of these patients.
DISCLOSURE
All the authors declared no competing interests.
SUPPLEMENTARY MATERIAL
Supplementary File (Word)
Table S1. Summary of major available and potential therapies for
renal amyloid A (AA) amyloidosis.
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