CJASN ePress. Published on October 17, 2017 as doi: 10.2215/CJN.

00620117

Thrombotic Microangiopathy and the Kidney

Vicky Brocklebank,*† Katrina M. Wood,‡ and David Kavanagh*†

Abstract
Thrombotic microangiopathy can manifest in a diverse range of diseases and is characterized by thrombocytopenia,
microangiopathic hemolytic anemia, and organ injury, including AKI. It can be associated with significant
morbidity and mortality, but a systematic approach to investigation and prompt initiation of supportive
management and, in some cases, effective specific treatment can result in good outcomes. This review considers the *National Renal
classification, pathology, epidemiology, characteristics, and pathogenesis of the thrombotic microangiopathies, Complement
and outlines a pragmatic approach to diagnosis and management. Therapeutics Centre,
Newcastle upon Tyne,
Clin J Am Soc Nephrol 13: ccc–ccc, 2018. doi: https://doi.org/10.2215/CJN.00620117
Hospitals National
Health Service
Foundation Trust,
Newcastle upon Tyne,
Introduction nomenclature make interpretation difficult: aHUS UK; †Institute of
Cellular Medicine,
Thrombotic microangiopathy (TMA), a pathologic de- may refer specifically to complement mediated Newcastle University,
scription, is characterized by a clinical presentation with TMA, or be more loosely applied to any TMA that Newcastle upon Tyne,
thrombocytopenia, microangiopathic hemolytic anemia is not TTP or STEC-HUS. In this review, we adopt the UK; and ‡Department
(MAHA), and organ injury (1,2). It can manifest in a term complement-mediated aHUS when the cause is of Cellular Pathology,
diverse range of conditions and presentations, but AKI Newcastle upon Tyne
defined as such, and use aHUS where the cause is ill
Hospitals National
is a common prominent feature because of the apparent defined. Current classifications describe primary Health Service
propensity of the glomerular circulation to endothelial TMAs, known as either acquired (e.g., factor H Foundation Trust,
damage and occlusion (3). Early recognition is impor- (FH) autoantibodies, ADAMTS13 autoantibodies) or Newcastle upon Tyne,
tant: TMAs are associated with significant mortality and inherited (e.g., complement mutations, ADAMTS13 UK
morbidity, including ESRD, although prompt initiation mutations); secondary TMAs; and infection-associated
of supportive and specific management can transform Correspondence:
TMAs (2) (Figure 1). Although a useful framework
Prof. David Kavanagh,
outcome. In particular, the prognoses of thrombotic for discussion, these terms do not account for the National Renal
thrombocytopenic purpura (TTP) and atypical hemo- increasing recognition that patients with an under- Complement
lytic uremic syndrome (aHUS) have been revolutionized lying complement risk factor often require a second- Therapeutics Centre,
following the elucidation of the pathogenic mechanisms ary trigger for TMA to manifest. Additionally, with Atypical Haemolytic
Uremic Syndrome
and the introduction of effective therapy. Challenges and increasing reports of eculizumab nonresponse, a more Service, Building 26,
controversies remain, however. In this review, we will clinically orientated classification such as eculizumab- Royal Victoria
discuss the classification, pathology, epidemiology, char- responsive and eculizumab-resistant aHUS are likely to Infirmary, Queen
acteristics, and pathogenesis of the TMAs, and outline an be introduced. Victoria Road,
approach to diagnosis and management. Newcastle upon Tyne,
NE1 4LP, United
Pathology Kingdom. Email:
Classification of Thrombotic Microangiopathies TTP is characterized by unusually large multimers david.kavanagh@
The classification of the TMAs is challenging and of vWf- and platelet-rich thrombi in capillaries and newcastle.ac.uk
constantly evolving. Historical classifications were on arterioles (5), although with current practice, pathologic
the basis of clinical findings: TTP for predominant specimens are rarely available. In complement-mediated
neurologic involvement and hemolytic uremic syndrome aHUS and other TMAs with more pronounced AKI,
(HUS) for kidney dominant disease. Classifications kidney biopsy is more frequently performed, although
evolved with greater understanding of the molecular is not requisite for the diagnosis. The pathologic find-
basis of disease: TTP was defined by severe ADAMTS13 ings reflect tissue responses to endothelial injury, in-
deficiency, hemolytic uremic syndrome caused by shiga cluding endothelial swelling and mesangiolysis in active
toxin–producing Escherichia coli (STEC-HUS) was de- lesions, and double contours of the basement mem-
fined by the presence of shiga toxin–producing bacte- brane in chronic lesions (Figure 2) (reviewed by
ria, and aHUS was broadly used for all other causes Goodship et al. (6)). Overt fibrin platelet thrombosis
of TMA. The discovery of the role of complement may be absent from renal biopsies of TMA, which has
dysregulation in a proportion of patients with aHUS recently led to a suggested reclassification to micro-
subsequently led to the acceptance of the term angiopathy with or without thrombosis (6). Evidence
complement-mediated TMA to refer to this subgroup of TMA has also been reported in a number of glomer-
(2,4). It should be recognized that differences in the ular diseases (7) and autoimmune diseases; however,
historical and contemporary literature over in published clinicopathologic studies, only a small

www.cjasn.org Vol 13 March, 2018 Copyright © 2018 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology

Figure 1. | Thrombotic microangiopathies are classified into: Inherited or acquired primary; secondary; or infection associated TMAs. Current classi-
fications define primary TMAs as hereditary (mutations in ADAMTS13, MMACHC (cb1c deficiency), or genes encoding complement proteins) or acquired
(autoantibodies to ADAMTS13, or autoantibodies to complement FH, which is associated with homozygous CFHR3/1 deletion). TMA is associated with
various infections: in STEC-HUS and pneumococcal HUS, distinct mechanisms result in TMA; in other infections, the processes are not defined and in some
cases the infection may trigger manifestation of a primary TMA. Secondary TMAs occur in a spectrum of conditions, and in many cases the pathogenic
mechanismsaremultifactorialorunknown.Theclassificationpresentedhereisnotunequivocal:insomesecondaryTMAs,for examplepregnancy-associated
TMA or de novo TMA after transplantation, a significant proportion of individualswill have a genetic predisposition to a primary TMA. AAV, ANCA-associated
vasculitis; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical hemolytic uremic syndrome;
C3G, C3 glomerulopathy; CAPS, catastrophic antiphospholipid syndrome; cblC, cobalamin C type; DGKE, gene encoding diacylglycerol kinase «; FH, factor
H; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; HUS, hemolytic uremic syndrome; IgAN, IgA nephropathy; MN, membranous
nephropathy; MPGN, membranoproliferative GN; SRC, scleroderma renal crisis; STEC, shiga toxin–producing Escherichia coli; TMA, thrombotic micro-
angiopathy; TTP, thrombotic thrombocytopenic purpura.

proportion of individuals with pathologic evidence of TMA in
these contexts had concurrent clinical and laboratory evidence
(8,9). It is not possible, on the basis of current knowledge, to
establish the cause of TMA from the histopathologic mor-
phology, although this may change with further research (6).
Clinical and Laboratory Features
The clinical presentation of TMA reflects hemolysis
and ischemic organ dysfunction, and depends on the
underlying disease etiology; AKI is a common manifesta-
tion of TMAs, although rarely a severe feature of TTP (10).
Extrarenal manifestations are reported in thrombotic
microangiopathies, with the published data referring
primarily to those observed in complement-mediated aHUS
and STEC-HUS (Table 1), although it is not known whether
they are a consequence of the TMA, a direct effect of comple-
ment activation or shiga toxin, or complications of AKI, such as
severe hypertension and uremia (6).
The defining laboratory features comprise thrombocyto-
penia, resulting from platelet aggregation and consumption,
and MAHA, identified by evidence of erythrocyte fragmen-
tation on peripheral blood film microscopy, which occurs in
areas of turbulent flow in the microcirculation due to partial
occlusion by platelet aggregates (1). Raised lactate dehy-
drogenase is a result of cell lysis and tissue ischemia (1),
haptoglobin is low, and the direct antiglobulin (Coombs)
test is negative (except in pneumococcal HUS). Presen-
tation with AKI reflects the consequences of ischemia in
the kidney.
Once routine biochemical and hematologic analysis have
demonstrated a TMA, investigations are aimed at determining
the underlying disease cause and excluding other differential
diagnoses, with the most urgent test being an ADAMTS13
assay (Figure 3). The epidemiology, pathogenesis, and man-
agement of TMAs are summarized in Table 2.
Primary TMAs
Complement-Mediated aHUS
Complement-mediated aHUS is prototypical of disease
occurring as a consequence of complement dysregulation.
Clin J Am Soc Nephrol 13: ccc–ccc, March, 2018 TMA and the Kidney, Brocklebank et al. 3

Figure 2. | The pathological features of thrombotic microangiopathies reflect the tissue responses to endothelial injury. (A) Glomerular
paralysis with capillary loops containing abundant erythrocytes (silver, 3400). (B) Thrombus in an artery (hematoxylin and eosin, 3400). (C)
Glomerular capillary lumina containing fibrin thrombi (red) and erythrocytes (yellow) (Martius Scarlet Blue, 3400). (D) Erythrocyte fragments
within the arterial vessel wall (arrow) (hematoxylin and eosin, 3400). (E) Mucoid thickening and obliteration of the lumen of a small artery
(hematoxylin and eosin, 3400). (F) Myxoid intimal thickening of small artery (hematoxylin and eosin, 3400). (G) Fibrinoid necrosis of arterial
wall (Martius Scarlet Blue, 3400). (H) Reduplication of glomerular basement membrane (arrow) and fibrillary mesangium (periodic acid–Schiff,
3400). (I) Glomerulus with endothelial swelling and erythrocyte fragmentation (arrow) (hematoxylin and eosin, 3400). (J) Electron micrograph
demonstrating fibrin tactoids (black) in glomerular capillary (310,000).
4 Clinical Journal of the American Society of Nephrology
Table 1. Extrarenal manifestations reported in thrombotic
microangiopathies
* † Neurologic involvement, including seizures and
altered consciousness
* † Pancreatitis
* † Cardiac involvement/myocardial infarction
* † Gastrointestinal involvement (including diarrhea,
vomiting, abdominal pain)
* Cerebral artery thrombosis/stenosis
* Extracerebral artery stenosis
* Digital gangrene/skin
* Ocular involvement
* Hepatitis
* Pulmonary involvement
The published data refers primarily to those observed in
complement-mediated atypical hemolytic uremic syndrome (*)
and hemolytic uremic syndrome caused by shiga toxin–producing
Escherichia coli (†) (6,14,27,59).
The complement system is a regulated cascade network of
signaling and amplification that incorporates .30 plasma
and cell surface–bound proteins, and was reviewed in detail
earlier in this series (11). A key physiologic role involves
stimulating the inflammatory response and opsonization
and lysis of pathogens to protect the host from infection
(encapsulated organisms in particular); it is a fundamental
component of the innate immune system, and modulates
the adaptive immune system. In addition, it facilitates the
disposal of potentially injurious immune complexes and
damaged host cells (12).
Complement activation is initiated by three pathways:
the classical pathway is activated by immune complexes and
other molecules (e.g., C-reactive protein), and activation of
the lectin pathway results from protein interactions with
pathogens (11). The alternative pathway may also be initiated
by pattern recognition molecules, but crucially, it is a positive
feedback loop that is constitutively active due to spontaneous
hydrolysis (tickover) of C3, and is recruited by the classical
and lectin pathways; this enables a rapid response against
pathogens, but leaves the host vulnerable to bystander
damage if the amplification loop is unchecked. The system
is therefore tightly regulated by plasma proteins, including FH
and factor I (FI), and cell surface proteins, such as membrane
cofactor protein (CD46) (13). Defects in these regulators or in
the alternative pathway components can lead to complement
dysregulation, with activation of the terminal complement
pathway and generation of the anaphylatoxin C5a and the
membrane attack complex (C5b-9), resulting in a complement-
mediated aHUS (Figure 4). The relative roles of these effector
molecules in causing disease remains to be established.
In complement-mediated aHUS, dysregulated comple-
ment activation primarily occurs on endothelial cell sur-
faces, and although abnormal serum levels of complement
components such as C3 may be observed, normal levels do
not exclude complement-mediated disease (6,14). There is
evidence of complement activation (plasma levels and
tissue staining) in many other TMAs, but whether this
is a primary event, a disease modifier, or an inconsequen-
tial bystander phenomenon has not yet been definitively
established (13).
Hereditary Complement-Mediated aHUS
Molecular evidence that CFH mutations are associated
with aHUS was first described in genetic research published
in 1998 (15), and since then a multitude of studies have
determined heterozygous pathogenic activating mutations in
the genes encoding the alternative pathway components C3
and factor B, and loss-of-function mutations in the genes
encoding the regulators FH (including CFH/CFHR fusions),
FI, and CD46 (reviewed in Kavanagh et al. [14]).
These genetic mutations are not causative but are instead
predisposing, with penetrance incomplete. Penetrance of
disease is age-related and has been reported to be as high as
64% by the age of 70 years for individuals carrying a single
genetic mutation (6). This suggests that additional disease
risk modifiers are important. Around 3% of patients have
more than one mutation, with increased penetrance per
additional mutation. Haplotypes (particular combinations of
single nucleotide polymorphisms) in CFH and CD46 also
modify penetrance (14). Together, these still do not answer
the question of why some individuals do not develop dis-
ease until later in life. This is best explained by the need
for an environmental trigger (e.g., pregnancy or infection) to
unmask a latent complement defect. Complement activation
is a common factor in many of these triggering events: it
occurs in the placenta at the fetomaternal interface in normal
pregnancy and is the normal physiologic response to in-
fection. Counseling of family members and offering genetic
screening are important considerations.
Historically the outcome of complement mediated aHUS
at the initial presentation was very poor, as were outcomes
after kidney transplantation: recurrence was 68% and
5-year death-censored graft survival was 51% (16). The out-
come of kidney transplantation is predicted largely by the
underlying genetic abnormality, with the highest risk asso-
ciated with CFH, CFB, and C3 mutations and the lowest with
CD46 mutations (17). In the pre-eculizumab era, one option for
individuals with a defect in a complement protein predomi-
nantly synthesized in the liver (FH, FI, factor B, and C3) was
combined liver and kidney transplantation (14); however,
short-term risks were significant and international experience
was limited (18), and some people were therefore considered
to be untransplantable.
Acquired Complement-Mediated aHUS
aHUS associated with autoantibodies against FH was
first reported in 2005 (19), and functional analyses have
demonstrated disruption of complement regulation by mul-
tiple mechanisms (20). There is a strong association with
homozygous deletion of CFHR3 and CFHR1, which encode the
proteins FHR3 and FHR1 (21), although the mechanism is not
understood; CFHR3/1 deletion is a common polymorphism,
and it is not present in all individuals who develop FH
autoantibodies (22). It predominantly presents in childhood,
frequently with a gastrointestinal prodrome. Autoantibodies
against FI have also been reported, but they are rare and their
functional relevance remains to be established (23).
Plasma Exchange
Plasma exchange (PE) still remains the initial treat-
ment of choice until ADAMTS13 activity is available to
exclude TTP as a diagnosis. It should be initiated in adults
as soon as the diagnosis of TMA is suspected. In addition to
Clin J Am Soc Nephrol 13: ccc–ccc, March, 2018 TMA and the Kidney, Brocklebank et al. 5

Figure 3. | A diagnostic algorithm for the investigation and management of a patient presenting with thrombotic microangiopathy. Supportive
treatment is essential. This comprises fluid management and, if indicated, judicious packed red blood cell transfusion, intensive care unit admission,
and RRT. Platelet transfusion may worsen the TMA and so should be avoided if possible. The complete evaluation of a patient presenting with TMA
comprises complement analysis and investigations for all conditions in which TMA can manifest, and usually enables the disease cause to be
established. However, collating the results of the requisite investigations may take considerable time. The clinical evaluation during the acute
presentation of a TMA requires some time-critical decision-making, which should focus initially on the consideration of TTP, because immediate
management is imperative given the high mortality rate if untreated, and therefore in adults, PE should be instituted on the presumption that it is TTP
unless other evidence is available that strongly suggests an alternative cause. In children, in whom TTP is rarer, first-line treatment with eculizumab
should be considered if complement-mediated aHUS is suspected and should not be delayed while ADAMTS13 activity is determined. In the
absence of a defined cause, complement-mediated aHUS is presumed and treatment with eculizumab is recommended, pending the complete
evaluation. Eculizumab is not universally available; in these circumstances, treatment should comprise PE, and there may be a role for liver
transplantation. *Full complement evaluation is recommended (Kidney Disease: Improving Global Outcomes consensus [6]) in individuals with
pregnancy-associated aHUS and de novo transplantation-associated aHUS because of the high prevalence of rare genetic variants described in
these subgroups, and in cases of STEC-HUS that result in ESRD, as rare genetic variants have been described after HUS recurrence in a subsequent
kidney transplant. Additionally, it is recognized that infection can trigger manifestation of complement-mediated aHUS. In other secondary cases
of aHUS, insufficient evidence exists to recommend a full genetic evaluation, although rare genetic variants have been described in many of these
6 Clinical Journal of the American Society of Nephrology

removing ADAMTS13 autoantibodies and replacing
ADAMTS13 in TTP, PE will also replace faulty complement
regulators and remove FH autoantibodies and hyperfunc-
tional complement components in complement-mediated
aHUS. In children, PE is associated with a high rate of
complications (24) and TTP is rare, therefore PE is not
considered as a first-line treatment when eculizumab is avail-
able. In many parts of the world, the cost of eculizumab
precludes its use, and PE remains the only treatment for
complement-mediated aHUS (25).
Complement-Inhibiting Therapy
The evidence for the central role of primary complement
defects in pathogenesis summarized above provided the
mechanistic rationale for treating complement-mediated
aHUS with complement-inhibiting therapy. Eculizumab is a
recombinant humanized mAb that functionally blocks C5,
and trials published in 2013 demonstrated its efficacy (26).
Although these were single-arm studies rather than random-
ized, controlled trials, the historically poor outcomes (up to
77% of patients with CFH mutations had died or reached
ESRD by 3–5 years) justified such study designs (27,28). These
findings have been replicated in subsequent extension studies
(29), prospective (nonrandomized) studies (30,31), and cohort
analysis (32). In the prospective trials, complete TMA re-
sponse was achieved in approximately 65% after 26 weeks of
eculizumab therapy in both adults (26) and children (31).
Eculizumab was approved by the US Food and Drug
Administration and the European Medicines Agency for
use in aHUS in 2013 (see Table 3 for practical consider-
ations) (33). In those presenting late in the course of disease
who do not recover kidney function, the high recurrence
rate after kidney transplantation necessitates preemptive
eculizumab (Table 4) (6,16). The trials included patients in
whom no complement mutation or FH autoantibody had
been identified, and the majority responded to complement-
inhibiting therapy; therefore, negative genetic and autoan-
tibody investigations do not exclude the diagnosis of
complement-mediated aHUS.
The current license for eculizumab is for lifelong treatment,
but this is not evidence based. Withdrawal of eculizumab
has been described in a large series of patients with aHUS, with
relapse reported in around one third, exclusively in those
with complement mutations (34). That rapid reintroduction
of eculizumab returned kidney function to baseline suggests
that a disease-driven intermittent regime could replace long-
term therapy, although prospective trials are required.
With increased clinical use, evidence is emerging of
nonresponse to eculizumab. In the recent pediatric
trial, Greenbaum et al. (31) highlighted that, for those
with a rare genetic variant in the complement system or an
autoantibody to FH, all had an improvement in eGFR,
whereas 27% of individuals without an identified comple-
ment abnormality failed to show an improvement. It is not
clear whether this represents late presentation of disease or
true nonresponse. A polymorphism in the C5 gene (p.R885H)
has been demonstrated to prevent eculizumab binding to
C5 (35), and nonresponders to eculizumab should have
genetic screening for this single nucleotide polymorphism
and alternative treatment strategies considered. More re-
cently, individuals presenting with a TMA with failure to
respond to eculizumab have been demonstrated to have
genetic variants in the noncomplement genes DGKE (36) and
INF2 (37).
The primary concern with terminal complement blockade is
increased susceptibility to infection with encapsulated organ-
isms, particularly Neisseria infections (33,38). For this reason,
meningococcal vaccination is considered mandatory; how-
ever, serologic response is variable (39), and the efficacy of
vaccination in the context of complement blockade is un-
certain (6). Long-term antibiotic prophylaxis is therefore
recommended for the duration of treatment and up to 3
months after withdrawal (6), although meningococcal in-
fection can occur despite these precautions (40,41). Thus,
patient education regarding vigilance is essential. Other
concerns may become apparent as use of complement-
inhibiting therapy in clinical practice expands: hepatotox-
icity in association with eculizumab has been reported in
children (42), and deposition of eculizumab has been
reported in individuals with C3 glomerulopathy (C3G)
(but not yet in aHUS), although the clinical significance is
unclear (43).
The use of complement-inhibiting therapy in TMAs other
than complement-mediated aHUS is controversial; case
studies have reported success but the inherent publication
bias needs to be considered when interpreting these, and
given that the role of complement in the pathogenesis of
other TMAs has not yet been defined, interventional trials are
likely to be needed before a consensus can be achieved (13).
Thrombotic Thrombocytopenic Purpura
TTP is mediated by ADAMTS13 deficiency: in hereditary
TTP, this results from recessive mutations (homozygous or
compound heterozygous) in the ADAMTS13 gene, and in
acquired TTP, ADAMTS13 activity is inhibited by autoan-
tibodies (2). ADAMTS13 is a metalloproteinase enzyme
that functions to cleave vWf; deficiency results in unusu-
ally large vWf multimers and consequent occlusive micro-
vascular platelet aggregation (2). The incidence of TTP is
higher in adults than in children (2), and there is a female
predominance (44). Neurologic manifestations are common
and laboratory characteristics in comparison to aHUS are

presentations. In cases where the role of complement is as yet unclear, the clinician should decide on the evaluation on the basis of the potential
clinical consequences of a positive result (e.g., listing for renal transplantation). 1ve, positive; AAV, ANCA-associated vasculitis; Ab, antibody;
ACA, anticentromere antibody; ACEI, angiotensin-converting enzyme inhibitor; ADAMTS13, a disintegrin and metalloproteinase with a
thrombospondin type 1 motif, member 13; Ag, antigen; aHUS, atypical hemolytic uremic syndrome; ANA antinuclear antibody; anti-ds DNA,
antidouble-stranded DNA; anti–Scl70, anti-topoisomerase I antibody; BMT; bone marrow transplant; C3G, C3 glomerulopathy; CAPS, cata-
strophic antiphospholipid syndrome; DGKE, gene encoding diacylglycerol kinase «; DIC, disseminated intravascular coagulation; FH, factor H;
FI, factor I; Hb, hemoglobin; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MAHA, microangiopathic hemolytic anemia; MN,
membranous nephropathy; MPGN, membranoproliferative GN; PE, plasma exchange; SRC, scleroderma renal crisis; STEC, shiga toxin–producing
Escherichia coli; Stx, shiga toxin; T-Ag, Thomsen–Friedenreich antigen; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.
Table 2. The thrombotic microangiopathies: epidemiology, pathogenesis, and management

TMA Epidemiology Pathogenesis Management Recommendations

Complement- Incidence (UK): 0.42 per million per yr (32)
mediated aHUS Hereditary: incomplete penetrance; can
present at any age; “trigger” required
Acquired: anti-FH Ab aHUS more common
in children
Complement dysregulation caused by: Eculizumab
Hereditary: heterozygous mutations in CFH, CFI, If eculizumab is not available: PE, liver
CD46, C3, and CFB (27,28) transplantation may be considered.
Acquired: anti-FH Ab (19,21)

TTP/ADAMTS13 Incidence (US): 0.37 per 100,000 per yr (46); ADAMTS13 deficiency caused by: PE
deficiencymediated adults 2.9 per million per yr, children 0.1 Hereditary: recessive (homozygous or
TMA per million per yr (2) compound heterozygous) ADAMTS13
Female.Male (44) mutations
Adults . children (2) Acquired: autoantibody-mediated inhibition Immunosuppression (steroids/
Clin J Am Soc Nephrol 13: ccc–ccc, March, 2018

rituximab) indicated if acquired

Cobalamin C Incidence of cblC deficiency: 1:37,000– Disorder of cblC metabolism results from recessive Metabolic therapy recommended:
deficiency 1:100,000 births (50) (homozygous or compound heterozygous) efficacy of hydroxocobalamin and
mutations in the MMACHC gene betaine established (50)
Can present in adulthood as well as Pathogenic mechanisms causing TMA remain
childhood undetermined

DGKE TMA Rare Recessive (homozygous or compound Insufficient evidence to determine

heterozygous) mutations in DGKE (36) optimal management
Presents aged ,1 yr (36) Loss of DGKE results in prothrombotic state Reports of both nonresponse (36) and
independently of complement activation (51) response (31) to eculizumab

STEC-HUS E. coli O157 predominant causative
pathogen: incidence (UK): 7.1 per million
per yr; Latin America, 10–17 per 100,000
children per yr (113)
Peak incidence in children ,5 yr (115) and
approximately 15% of children with
enteric infection develop HUS (59)
E. coli O104: European outbreak in 2011
exceptional for high HUS occurrence rate
(24%), severity, and high proportion of
adults (60)
Other Stx producing pathogens e.g., Shigella
dysenteriae
Outbreaks and sporadic cases
Enteric infection with Stx-producing pathogens
Stx binds to Gb3, which is highly expressed in the
kidney, is internalized, and inhibits protein
synthesis (63)
The consequent endothelial injury results in
intravascular fibrin generation (59)
Complement activation observed (116) but role is
not defined
Supportive care is recommended; high
proportion may require dialysis. No
intervention evaluated in an RCT was
superior to supportive care for any
outcome (systematic review [114])
Antibiotics: controversy remains,
studies inconclusive, may worsen
outcome, therefore currently not
recommended; RCT of azithromycin
ongoing (NCT02336516)
PE: not recommended, no benefit
established (no RCTs) (46)
Eculizumab: not recommended; no
benefit demonstrated in retrospective
analyses (60,68,69); RCT ongoing
(NCT02205541)
TMA and the Kidney, Brocklebank et al.
7
 8

Table 2. (Continued)

TMA Epidemiology Pathogenesis Management Recommendations

Pneumococcal HUS Rare. Limited data available from published
cohorts, and incidence unknown
(117,118). 10-yr cumulative incidence rate
of 1.2 per 100,000 children reported (NZ)
(119). Associated with pneumonia and
empyema in children ,2 yr (72)
Neuraminidase cleaves sialic acid residues from Supportive management and treatment
glycoproteins on erythrocyte, platelet, and of infection recommended
endothelial cell membranes, exposing the
cryptic T antigen to which IgM in the plasma
can then bind, resulting in cell damage and
TMA (73).

HIV-associated TMA Pre-HAART era: incidence of 1.5%–7% Pathogenic mechanisms remain undetermined Supportive management and treatment
(75,120) of infection recommended
HAART era: incidence 0.3% (77)

Pregnancy- Complement-mediated aHUS: pregnancy Complement gene mutations in up to 86% (81) Eculizumab; start immediately (do not
associated TMA triggers complement-mediated TMA in wait for genetic analysis) if TTP has
approximately 20% of women with aHUS been excluded and presentation is not
Clinical Journal of the American Society of Nephrology

(81) suggestive of HELLP

A proportion are TTP: 10%–36% of women with TTP present vWf increases in normal pregnancy and PE
primary TMAs; during pregnancy (44) consumes ADAMTS13; in women with a
differential genetic predisposition, its activity can fall low
diagnosis includes enough for TTP to manifest (81)
complement-
mediated aHUS,
TTP, and HELLP
HELLP: incidence: 0.5%–0.9% of all Mechanisms are poorly understood (80) Definitive treatment is delivery (86). No
pregnancies; complicates 5%–10% of Increased levels of endoglin and sFlt-1 may play a role for PE (46)
cases of severe preeclampsia (121) role in endothelial dysfunction (79,86).

Drug-mediated TMA True incidence unknown Immune mediated: drug-dependent antibodies, Recommendation is drug
e.g., quinine (2) discontinuation
Reported incidences of TMA include: Toxicity mediated: multiple mechanisms, e.g., Ticlopidine-associated TMA: as per TTP
CNIs, IFN, chemotherapy agents, VEGF (46,92) (PE)
inhibitors (2)
Approximately 1:1000 patient-yr for high- Ticlopidine-associated TMA is mediated by
dose IFN-b (90) acquired ADAMTS13 deficiency (92)
2%–10% of patients treated with mitomycin
(122)
1%–4.7% of patients treated with tacrolimus
(122)
VEGF inhibitors: unknown (91)
Table 2. (Continued)

TMA Epidemiology Pathogenesis Management Recommendations

De novo TMA after Incidence after kidney transplantation: 0.8% Multifactorial Treatment of precipitating factors, e.g.,
solid organ in USRDS data (123); up to 14% in single- AMR, infection, drug withdrawal
transplant center studies (94)
Incidence: 4% in liver transplant and 2.3% in Complement gene mutations reported in up to Eculizumab where complement-
lung transplant recipients (93) 29% (renal transplants) (96) mediated aHUS is possible

TMA after bone Multisystem TMA complicates 10%–40% of Multifactorial No evidence-based effective
marrow transplant allogenic BMTs (97,98) management strategy
No established benefit with PE (46)
Favorable outcomes with eculizumab
compared with historical controls
reported in retrospective analysis
Clin J Am Soc Nephrol 13: ccc–ccc, March, 2018

(101), but prospective trials needed to

establish consensus

Severe hypertension- Incidence: variously reported; case series of Pathogenic mechanisms unclear No evidence supporting any strategy
associated TMA severe hypertension have identified TMA other than BP management
in 27%–44% (13,124–127)

Malignancy- Unknown Multifactorial Discontinuation of causative

associated TMA chemotherapy agents

TMA with TMA can occur in association with IgA Pathogenic mechanisms unclear Limited evidence for management of the
glomerular diseases nephropathy, ANCA-associated TMA
vasculitis, membranous nephropathy, Hereditary and acquired complement defects in Role of complement inhibition in C3G/
FSGS, and MPGN/C3G (13) MPGN/C3G aHUS crossover unclear

TMA with SLE: concurrent TMA reported in up to 8%– Pathogenic mechanisms unclear SLE: no evidence for specific TMA
autoimmune 15% of biopsies (9,128) management in addition to SLE
conditions management as recommended in
international guidelines
CAPS: TMA in 14% in international registry Some evidence of complement activation in SLE CAPS: efficacy of eculizumab suggested
(112) and CAPS (13) in case reports and series; prospective
trial (not RCT) to enable renal
transplantation ongoing (NCT01029587)
SRC: occurs in approximately 10% of people SRC: ACEIs significantly reduce
with SSc; TMA in 45%–50% (111,129) mortality (111)

aHUS, atypical hemolytic uremic syndrome; UK, United Kingdom; PE, plasma exchange; FH, factor H; Ab, antibody; TTP, thrombotic thrombocytopenic purpura; ADAMTS13, a disintegrin and
metalloproteinase with a thrombospondin type 1 motif, member 13; TMA, thrombotic microangiopathy; US, United States; cblC, cobalamin C type; STEC-HUS, hemolytic uremic syndrome
caused by shiga toxin–producing Escherichia coli; Stx, shiga toxin; RCT, randomized controlled trial; HUS, hemolytic uremic syndrome; Gb3, globotriaosylceramide; NZ, New Zealand; T antigen,
Thomsen–Friedenreich antigen; HAART, highly active antiretroviral therapy; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets; CNI, calcineurin inhibitor; VEGF,
vascular endothelial growth factor; USRDS, United States Renal Data System; AMR, antibody-mediated rejection; BMT, bone marrow transplants; MPGN, mesangioproliferative GN; C3G, C3
TMA and the Kidney, Brocklebank et al.

glomerulopathy; CAPS, catastrophic antiphospholipid syndrome; SRC, scleroderma renal crisis; SSc, systemic sclerosis; ACEI, angiotensin-converting enzyme inhibitor.
9
10 Clinical Journal of the American Society of Nephrology

Figure 4. | Unfettered complement activation ultimately results in thrombus formation, platelet consumption, vascular occlusion and
mechanical hemolysis. Complement is activated by the alternative, classic, and lectin pathways. The alternative pathway of complement is a
positive amplification loop. C3b interacts with factor B, which is then cleaved by factor D to form the C3 convertase C3bBb. Unchecked, this leads to
activation of the terminal complement pathway with generation of the effector molecules, the anaphylatoxin C5a and the membrane attack complex
(C5b-9). To protect host cells from bystander damage, the alternative pathway is downregulated by complement regulators including factor H (FH),
factor I (FI), and CD46. In complement-mediated aHUS, activating mutations in C3 and CFB and loss-of-function mutations in CFH, CFI, and CD46, in
addition to autoantibodies to FH, result in overactivation of the alternative pathway. This leads to immune cell and platelet activation and endothelial cell
damage and swelling, with consequent thrombus formation, platelet consumption, vascular occlusion, and mechanical hemolysis. There is evidence
that complement is activated in other TMAs, but whether this is a causative, disease modifier, or bystander phenomenon has not yet been elucidated.
Eculizumab is a humanized mAb that binds to C5 and prevents activation of the terminal pathway; it thereby inhibits the generation of the effector
molecules that cause TMA in individuals in whom a primary defect in complement underlies the TMA pathogenesis. Its role in the treatment of other
TMAs is undefined. aHUS, atypical hemolytic uremic syndrome; TMA, thrombotic microangiopathy.

reportedly more severe thrombocytopenia (,303109/L)
and less severe AKI (serum creatinine, 1.7–2.3 mg/dl) (45),
but these are not absolute and should not be relied upon in
clinical practice (10), where the diagnosis is confirmed by
ADAMTS13 activity ,10% (5). TTP was historically almost
universally fatal, but after the introduction of PE treatment,
mortality decreased to ,10% (46). In acquired TTP, immuno-
suppressive therapies (e.g., glucocorticoids and rituximab)
have reduced the relapse rate (47–49).
Cobalamin C Deficiency
TMA can manifest in methylmalonic aciduria and homo-
cystinuria, cobalamin C type, which is the most common in-
herited form of functional cobalamin (vitamin B12) deficiency
(50). It is caused by recessive (homozygous or compound
heterozygous) mutations in the MMACHC gene, can pre-
sent in adulthood as well as childhood, and the phenotype
may comprise developmental, ophthalmologic, neurologic,
cardiac, and kidney manifestations, although severity varies.
The pathophysiologic mechanisms that cause endothelial
damage and subsequent TMA have not yet been determined
(50). Mortality is high if untreated or if there is cardiopulmo-
nary involvement, but metabolic therapy (hydroxocobalamin
and betaine) is very effective (50).
by complement-independent mechanisms (51). Only a small
number of cases have been published, but it appears to
present in patients aged ,1 year and commonly results
in progressive CKD and ESRD (36). There is insufficient ev-
idence to determine optimal management; there are reports
of both response (31) and nonresponse (36) to eculizumab,
as well as response (52,53) and nonresponse (36) to plas-
ma therapy. Concomitant mutations in complement genes
have been reported (54). Genetic pleiotropy is seen, whereby
DGKE mutations have also been associated with mesangio-
proliferative GN (MPGN) (55).
Other Genetic Associations
Genetic variants in thrombomodulin (THBD) have been
reported in association with aHUS (56,57), although this
finding was not replicated by Fremeaux-Bacchi et al. (27).
Bu et al. (58) reported rare genetic variants in plasminogen
(PLG) in aHUS; however, replication analysis will be
required to clarify this disease association. Functionally
significant mutations in INF2 have been seen to segregate in
families with TMAs, but it remains to be seen whether this
is a primary TMA or secondary phenomenon in association
with FSGS (37).

DGKE TMA Infection-Associated TMAs

Recessive (homozygous or compound heterozygous) STEC-HUS
DGKE mutations causing TMA was first reported in 2013 STEC-HUS is more common than aHUS, with a peak
(36), and this defined a cohort of patients with aHUS caused incidence in children aged ,5 years (Table 2). The
Clin J Am Soc Nephrol 13: ccc–ccc, March, 2018
Table 3. Eculizumab: practical considerations
Eculizumab: Practical Considerations
Before administration
Meningococcal vaccination mandatory
Tetravalent ACWY conjugated vaccine 1
multicomponent serogroup B vaccine
Prophylaxis
Long-term antibiotic prophylaxis recommended
Administration
Intravenous infusion
Maintenance therapy is administered every 14 d
Monitoring
CH50 and AH50 ,10%
Eculizumab trough level 100 mg/ml
Hematologic indicators of TMA
Patient education
Vigilance regarding meningococcal infection
Counseling family members
Genetic screening
When to stop?
Continue during intercurrent illness, unless infection
with encapsulated organism, due to high risk of
TMA relapse in this context
Withdrawal
Systematic investigation in clinical trials is being
undertaken
May be appropriate in some patientsa, with
monitoring: liaise with specialist center
This guidance is based on our practice in the United Kingdom,
and the 2015 Kidney Disease: Improving Global Outcomes
Controversies Conference consensus recommendations (6).
Eculizumab (Soliris; Alexion Pharmaceuticals) is a recombinant
humanized mAb that functionally blocks C5, and is approved by
the US Food and Drug Administration and the European
Medicines Agency for use in atypical hemolytic uremic syn-
drome. ACWY, meningococcal serotypes; CH50, total comple-
ment hemolytic activity; AH50, alternative pathway hemolytic
activity; TMA, thrombotic microangiopathy; aHUS, atypical
hemolytic uremic syndrome.
a
For example, if there is no renal recovery after 6 months of
treatment.
predominant causative pathogen is E. coli O157; enteric
infection can occur sporadically or in the context of an
outbreak, and around 15% of children with enteric infection
develop HUS (59). The E. coli O104 outbreak in Europe in 2011
was exceptional because of the high STEC-HUS occurrence
rate (24%) and the high proportion of adults affected (60).
Shiga toxin translocates through the intestinal epithelium
and is thought to bind to leukocytes and circulate to
the kidneys (61). The shiga toxin is then internalized via the
Gb3 receptor and is cleaved to release a protease into the
cytoplasm. This protease inhibits ribosomal function and
protein synthesis, leading to cell death. It can also activate
signaling pathways, inducing an inflammatory response in
affected cells (62,63).
The distinction between STEC-HUS and complement-
mediated aHUS may not be clinically obvious: approxi-
mately 5% of patients with STEC-HUS do not have
diarrhea (64), and approximately 30% of patients with
complement-mediated aHUS have concurrent diarrhea at
TMA and the Kidney, Brocklebank et al. 11
presentation (6). Therefore, all individuals with TMA
should be investigated for STEC-HUS (Figure 3). Rarely,
complement gene mutations are detected, and in these cases
the clinical picture is unusually severe (13,65). In STEC-HUS
resulting in ESRD, it is recommended to screen for mutations
before transplantation. STEC-HUS is considered to be a self-
limiting illness, with good outcomes relative to other TMAs:
70% fully recover, the mortality rate is approximately 1%–4%,
ESRD occurs in 3% of patients, and CKD occurs in 9%–18% of
patients (66). There is some evidence of complement activation
(13), but the role of complement-inhibiting therapy has not yet
been defined. A case series in 2011 first reported efficacy of
eculizumab in three children with severe disease (67), and
a significant proportion of those affected in the 2011 E. coli
O104 outbreak were treated with eculizumab; no benefit over
supportive care or PE was demonstrated in retrospective
analyses (60,68,69), although a direct comparison is difficult
because of the inherent disadvantages of retrospective anal-
yses, for example there were no controls, patients received
multiple therapies administered with inconsistency, and those
treated with eculizumab had more severe disease. In this
self-limiting condition, only a randomized, controlled trial
will resolve this controversy; one is underway in France
(Clinicaltrials.gov identifier: NCT02205541) and another is
due to start recruiting in the United Kingdom. For now, the
recommendation remains supportive management.
Pneumococcal HUS
TMA may occur in adults and children in the context of
invasive Streptococcus pneumoniae infection, and the high
morbidity and mortality rate usually reflects the severity of
the infection (70,71). In a recently published North American
cohort, pneumococcal HUS was most commonly observed
in children aged ,2 years with pneumonia and empyema
who were extremely unwell and frequently required
prolonged hospitalization and intensive care unit admis-
sion; the mortality rate was 3%, and 33% developed ESRD
(72). The hypothesized mechanism is that pneumococci
produce neuraminidase, which cleaves sialic residues from
glycoproteins on erythrocyte, platelet, and endothelial cell
membranes, exposing the cryptic Thomsen–Friedenreich
antigen (T antigen), to which IgM in the plasma can then
bind, resulting in cell damage and TMA (73). The Coombs
test is positive. Additionally, it has been suggested that
cleavage of sialic acid may reduce FH binding, resulting in
impaired endothelial complement regulation, thus contrib-
uting to disease pathogenesis (74). Supportive management
and treatment of the infection should be the focus.
HIV-Associated TMA
TMA has been reported in association with HIV, more
commonly in the pre-highly active antiretroviral therapy
era (75–77), and in association with lower CD41 cell counts
and higher viral RNA levels (77). The pathogenic mecha-
nisms are poorly understood, although endothelial damage
is thought to be the primary event. Again, there is no evidence
for any treatment strategy other than supportive care and
antiretroviral treatment.
Other Infections
TMA has been reported in association with a wide range
of viral, bacterial, fungal, and parasitic infections, although
12 Clinical Journal of the American Society of Nephrology

Table 4. Approach to kidney transplantation when thrombotic microangiopathy results in established renal disease

Complete Complement Evaluation before Renal Transplant Listing Is Recommended if Thrombotic Microangiopathy
Results in ESRDa

Risk Stratification Inclusion Criteria Management Strategy

High Pathogenic complement mutations Prophylaxis with eculizumab (KDIGO global

Previous early recurrence panel suggest plasma exchange and liver
transplantation may also be considered)
Moderate No complement mutation, or variant
of unknown significance
Isolated CFI mutation
Detectable anti-factor H antibody

Low Isolated CD46 mutationb No prophylaxis

Previously positive but now consistently
negative anti-factor H antibody

Delay transplantation until at least 6 months after starting dialysis as late renal recovery with eculizumab treatment has been reported.
Living related kidney donation should only be considered if a genetic or acquired cause is identified in the recipient and is not present in
the intended donor. Recommendations are on the basis of the 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies
Conference consensus recommendations (6).
a
Complete complement evaluation should include: serum levels of C3, C4, factor H, factor I; anti-factor H antibody; CD46 FACS; and
CFH, CFI, CD46, C3, and CFB genetics.
b
Allograft cells express functional CD46.

it is frequently unclear if this is a direct effect of the pathogen,
a side effect of treatment, or a trigger that unmasks a latent
complement defect (reviewed by Nester et al. [4]). For instance,
Caprioli et al. (78) reported undefined infectious triggers in
.70% of patients with complement-mediated aHUS and
CFH, CFI, or CD46 mutations. Supportive management
with appropriate treatment of the infection is recommended,
and complement evaluation should be undertaken.
Secondary TMAs
Pregnancy-Associated TMA
The differential diagnosis of TMA in pregnancy includes
the primary TMAs complement-mediated aHUS and TTP,
as well as the TMA-like presentation occurring in the
syndrome of hemolysis, elevated liver enzymes, and low
platelets (HELLP) (79), which is part of the clinical spec-
trum of preeclampsia (80).
In around 20% of women with aHUS, the disease onset
appears to be triggered by pregnancy, occurring most often
in the postpartum period (81,82). Outcomes were histor-
ically poor, with 76% developing ESRD despite PE (81).
More recently, it has become clear that a high proportion
will have identifiable complement mutations (.50%), and
that pregnancy acts as a trigger in those with an underlying
genetic predisposition (81). In the era of eculizumab, this
high prevalence of complement mutations in pregnancy-
associated HUS provides the biologic rationale for com-
plement inhibition. Increasing data in both paroxysmal
nocturnal hemoglobinuria (83) and aHUS (84) suggests that
eculizumab is safe during pregnancy.
Similarly, a significant proportion of women with TTP
present during pregnancy (80), particularly in the second
and third trimesters (81). This might be explained by the
physiologic increase in vWf during pregnancy, which
consumes ADAMTS13, so in women with a genetic pre-
disposition, its activity can fall low enough for TMA to
manifest (81). PE is recommended on the basis of obser-
vational data and knowledge of pathogenesis (85).
The pathogenesis of preeclampsia and HELLP are poorly
understood (80), although there is some evidence to sug-
gest that increased circulating levels of the syncytiotrophoblast-
derived antiangiogenic factors, soluble endoglin and the soluble
form of the vascular endothelial growth factor receptor (sFlt-1),
may contribute to the observed endothelial dysfunction (79,86).
Although there is significant overlap in the clinical presentations
of HELLP and TMA, in HELLP, the predominant glomerular
pathology is endotheliosis (79). In contrast to pregnancy-
associated aHUS, only a minority (8%–10%) of patients with
preeclampsia and HELLP syndrome harbor complement
gene variants, mostly of unknown or nonpathogenic signif-
icance (87). There is some evidence that complement is
activated in preeclampsia and HELLP, although it is un-
clear whether it plays a role in pathogenesis; of note, pre-
eclampsia has occurred in women taking eculizumab for
paroxysmal nocturnal hemoglobinuria (83) and aHUS (84).
Management should be supportive, and the definitive
treatment of HELLP is expedited delivery, although expec-
tant management may be considered if the woman is not at
or near term (86).
In clinical practice, a pragmatic approach is usually taken
in peripartum cases of TMA: if expedited delivery does not
result in resolution of the TMA then standard management
is instituted (Figure 3).
Drug-Mediated TMA
In published reports TMA has been associated with a
large number of drugs, although definitive causality has
only been established in relatively few (reviewed by Al-
Nouri et al. [88]). Drug-mediated TMA occurs by two main
mechanisms: immune-mediated damage and direct toxicity
(Table 5). For example, quinine induces the development of
autoantibodies reactive with either platelet glycoprotein
Clin J Am Soc Nephrol 13: ccc–ccc, March, 2018 TMA and the Kidney, Brocklebank et al. 13

Ib/IX or IIb/IIIa complexes, or both (89). In contrast, IFN-b
(90) and bevacizumab (91) cause TMAs by a dose-dependent
toxicity. There are no trials to guide management, and the
recommendation is supportive care and discontinuation of
the causative drug. However, ticlopidine has been reported
to be associated with anti-ADAMTS13 antibodies with
resultant TTP, and therefore PE is recommended (92). It is
crucial that a full evaluation is undertaken (Figure 3) even
if drug-mediated TMA is suspected, including an urgent
ADAMTS13 assay.
De Novo TMA after Solid Organ Transplant
De novo TMA has been reported to occur after kidney,
liver, pancreas, lung, and heart transplantation (93,94). The
pathogenic mechanisms are not well understood, but it is
likely to be multifactorial, with ischemia-reperfusion in-
jury, antibody-mediated rejection, viral infections such as
cytomegalovirus, and immunosuppressant drugs, especially
calcineurin inhibitors (CNIs), contributing to an “endothelial
damaging milieu” (95). In one series of de novo TMA after
kidney transplantation, complement mutations were iden-
tified in 29% (96), providing a rationale for complement-
inhibiting therapy especially where the primary diagnosis
was not incompatible with complement-mediated aHUS.
In many cases, however, supportive treatment and address-
ing the precipitating factors (CNI discontinuation or dose
reduction, treatment of antibody-mediated rejection and viral
infections) may be sufficient to stop the TMA (13).
The optimal treatment strategy remains controversial;
favorable outcomes with eculizumab have been described
in uncontrolled retrospective analyses (101) and there is
some evidence to suggest that complement is activated (13),
but prospective trials are likely needed in order to establish
a consensus.
Severe Hypertension-Associated TMA
TMA can occur in association with severe hypertension,
and should be managed with antihypertensive and sup-
portive treatment. The pathogenic mechanisms that result
in endothelial damage and TMA are unclear (102,103). Con-
versely, any patient with a TMA can have severe hypertension,
thus a clinical conundrum can arise in the initial evaluation of a
patient presenting acutely with TMA. In practice, failure of BP
control and supportive management to control the TMA will
often result in the pragmatic initiating of PE or eculizumab until
complement evaluation is available. In the majority of patients
with TMA associated with severe hypertension, renal function
and MAHA usually recover with management of BP (102,104).
In a retrospective case series, genetic analysis identified rare
variants in complement genes in patients for whom TMA was
initially attributed to severe hypertension; eight out of nine
patients progressed to ESRD despite management of hyper-
tension (103). This may be particularly relevant when consid-
ering kidney transplant assessment in an individual with ESRD
attributed to severe hypertension with TMA, or if TMA occurs
again after transplantation.

TMA after Bone Marrow Transplant Malignancy-Associated TMA

A multisystem TMA complicates 10%–40% of allogenic
bone marrow transplants (97,98) and is associated with
significant mortality, variously reported as 21%–75% (13).
Again, this is likely to be multifactorial, with risk factors
including CNIs, graft versus host disease, HLA mismatch,
chemotherapy, radiation therapy, and infections (99). Rare
genetic variants in aHUS associated genes (98) and FH
autoantibodies (100) have been infrequently reported in
post bone marrow transplant TMA.
When TMA occurs in association with malignancy it can
be difficult to distinguish between TMA caused by chemo-
therapy and TMA caused by malignancy (105). It is possible
that the causative mechanism in disseminated malignancy
involves erythrocyte shearing after direct contact with
microvascular embolic tumor cells (106). Prognosis is poor
because of malignancy-related mortality (107,108), and there
is no evidence to support any treatment strategy other than
withdrawal of causative chemotherapy agents.

Table 5. Drugs with evidence supporting a causal association with thrombotic microangiopathya

Immune-Mediated TMA Direct Drug-Induced Toxicity Other

Quinine: Drug-dependent Immunosuppressive agents, Ticlopidine: ADAMTS13

antibodies e.g., calcineurin inhibitors: autoantibodyb
ciclosporin and tacrolimus Sirolimus
IFN-a, IFN-b
VEGF inhibitors, e g., bevacizumab,
sunitinib
Chemotherapeutic agents, e.g., gemcitabine,
mitomycin
Recreational drugs, e.g., cocaine

Even if drug-mediated TMA is suspected, a full evaluation should still be undertaken as shown in Figure 3, including an urgent
ADAMTS13 assay. TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor; TTP, thrombotic thrombocytopenic
purpura; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.
a
TMA has been reported in association with many drugs, but definite causality has been established in relatively few (2,88,90,91), some
examples of which are included in this table.
b
Ticlopidine association with TTP reported, with severe ADAMTS13 deficiency due to inhibitory autoantibodies. This should be
managed as for TTP, with plasma exchange (46,92).
14 Clinical Journal of the American Society of Nephrology
TMA Associated with Glomerular Diseases
TMA can occur in association with IgA nephropathy,
ANCA-associated vasculitis, membranous nephropa-
thy, FSGS, and MPGN/C3G, although it may be a his-
topathologic finding without biochemical or clinical
manifestation (13).
In MPGN/C3G, the hereditary and acquired comple-
ment defects are similar, although subtly different to those
seen in complement-mediated aHUS, and it is perhaps
unsurprising that concurrent (7) and sequential (109)
manifestation of C3G and TMA has been reported. Muta-
tions in CFH are observed in both complement-mediated
aHUS and C3G; the reason for this genetic pleiotropy is not
fully understood, but the location of the mutation within
the gene may be important. In aHUS, the majority of mutations
are located at the C-terminal of FH, which binds to C3b and
glycosaminoglycans on host cells to mediate cell surface
protection (14), whereas in C3G, mutations are more often
located at the N-terminal of FH, which mediates comple-
ment regulation in the fluid phase (110).
Genetic pleiotropy has also been reported in INF2- and
DGKE-mediated disease. In addition to the FSGS normally
seen in INF2-mediated disease (37) and the MPGN seen in
DGKE-mediated disease (55), TMAs have been reported in
both cases that seemed nonresponsive to eculizumab.
TMA Associated with Autoimmune Diseases
TMA can occur in association with autoimmune diseases
including SLE, catastrophic antiphospholipid syndrome
(CAPS), and scleroderma renal crisis (SRC); again, the
mechanisms remain unclear, although there is some evi-
dence of complement activation in SLE and CAPS (13). For
SLE, CAPS, and SRC with TMA, treatment should be of the
underlying condition. The influence of TMA on outcome of
SLE is uncertain, as case series have reported both no
difference and worse outcome (13); treatment should be
immunosuppression according to international guidelines,
and there is no evidence to suggest that any additional
treatment specifically directed at the TMA is beneficial. The
high mortality of SRC is significantly reduced with angiotensin-
converting enzyme inhibitors (111). In CAPS, the interna-
tional registry (522 episodes) reported the incidence of TMA
to be 14%, and overall mortality was 37%, with no subgroup
analysis according to treatment. The most frequent treatment
regimens used were anticoagulation plus glucocorticoids
(19%) or anticoagulation, glucocorticoids and PE with or
without intravenous Ig (18%), with only 0.2% receiving
eculizumab (112). There is some evidence from mouse
models and observational clinical data that complement
may be involved in the pathophysiology of CAPS; success-
ful use of eculizumab has been reported in case reports and
series, and a prospective trial of preemptive eculizumab to
enable renal transplantation is ongoing (Clinicaltrials.gov
identifier: NCT01029587) (13).
Diagnosis and Management
Establishing the cause of a TMA is usually possible after a
complete evaluation. However, the results of the requisite
investigations are not available immediately, and in clinical
practice, the scenario is often one of a severely ill patient
with TMA for whom immediate management decisions are
required. The acute decision-making is time-critical: the
initial priority should be the consideration of TTP, because
urgent management is imperative given the high mortality if
untreated, and therefore in adults, PE should be instituted
(after obtaining a sample for ADAMTS13 activity testing) on
the presumption that it is TTP unless other evidence is avai-
lable that strongly suggests an alternative cause. If the
ADAMTS13 result excludes TTP, then complement-mediated
aHUS is presumed and treatment with eculizumab is rec-
ommended, pending the complete evaluation. In children, in
whom PE may not be appropriate and is high risk, treatment
with eculizumab has been recommended by Kidney Disease:
Improving Global Outcomes before the availability of the
ADAMTS13 result, with the caveat that clinical deterioration
on eculizumab should necessitate immediate plasma therapy
(6). An algorithm for the real-time investigation and man-
agement of a patient presenting with TMA is illustrated in
Figure 3. Once the full evaluation has been completed, the
indication for eculizumab can be reviewed.
Summary
In summary, TMA can manifest in a diverse range of
diseases and can be associated with significant morbidity
and mortality. For some forms of TMA, such as TTP and
complement-mediated aHUS, research has now defined the
molecular mechanisms of disease leading to targeted ther-
apy and improved patient outcomes. However, the opti-
mal eculizumab treatment duration and the specific patient
populations who will benefit remain undefined.
Acknowledgment
V.B. has received funding from the Northern Counties Kidney
Research Fund and is a Medical Research Council/Kidney Research
UK Clinical Research Training Fellow. D.K. has received funding
from the Wellcome Trust, The Medical Research Council and Kidney
Research UK.
Disclosures
D.K. has received honoraria for consultancy work from Alexion
Pharmaceuticals, and is a director of and scientific advisor to Gyroscope
Therapeutics.
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