Thrombotic microangiopathy and the kidney - Dr. Mohamed Mamdouh AbdAlBary

A Beast of Many Faces
Mohammed Mamdouh Abd AlBary
Assistant Lecturer of Nephrology
Mansoura University

 In 1926, Elias Moschkowitz first reported a fatal TMA in
a 16-year-old female patient who presented with
anemia, fever, hemiparesis, and coma. This case is
recognized as the first description of a TTP. Autopsy
revealed multiple intravascular thrombi especially in
the heart, but also in the kidneys and brain.
 In 1955, Conrad Gasser coined the term hemolytic
uremic syndrome (HUS) for patients with renal failure
following bloody diarrhea.

 Group of syndromes with multiple etiologies, both hereditary and acquired
 Have characteristic microvascular pathology
(triad of MAHA = Coombs-negative hemolytic anemia with evidence of schistocytes in the blood,
thrombocytopenia) and ischemic end organ damage
 AKI is a common feature because the apparent propensity of glomerular circulation to endothelial
damage and occlusion.
 Depending on the vascular systems involved, renal failure, neurological symptoms, cardiac
complications, respiratory failure, visual disturbances,
pancreatitis, intestinal ischemia, and skin changes may occur
TMA

Historical : based on clinical findings:
 TTP : predominant neurologic involvement
 HUS : kidney dominant disease.
With understanding of the molecular basis of disease:
 TTP : severe ADAMTS13 deficiency.
 HUS caused by shiga toxin–producing Escherichia coli (STEC-HUS).
 aHUS was broadly used for all other causes of TMA.
The discovery of the role of complement with aHUS : the term complement-
mediated TMA when the cause is defined as such and use aHUS where the cause is
ill defined.
Another classifications describe primary TMAs, known as either acquired (e.g.,
factor H (FH) autoantibodies, ADAMTS13 autoantibodies) or inherited (e.g.,
complement mutations, ADAMTS13 mutations); secondary TMAs; and infection-
associated TMAs.

 mediated by ADAMTS13 deficiency:
hereditary TTP: recessive mutations in the ADAMTS13 gene,
acquired TTP, ADAMTS13 activity is inhibited by autoantibodies.
 ADAMTS13 : metalloproteinase enzyme cleave vWf; deficiency results in large
vWf and microvascular platelet aggregation.
 incidence higher in adults and females
 fever (10%)
neurological disorders (headache, confusion, neurological deficits,
and seizures; up to 80%),
hemolytic anemia (100%),
and thrombocytopenia (100%).
On the other hand,
renal impairment (≥ stage 3) is relatively rare (9%).

 patients often present with non-specific prodromes, such as flu-like symptoms or
diarrhea. variable clinical features range from general weakness to stroke or
sudden cardiac death.
 Severe hemolysis and marked thrombocytopenia with clinical symptoms usually only
appear a certain time after disease onset, when a large cross-section of vessels
have been affected by consumption of platelets and mechanical hemolysis.
 was historically fatal, but after PE treatment, mortality decreased to <10%.
 In acquired TTP “Immune-mediated” , immunosuppressive therapies reduced
relapse rate.
 In comparison to aHUS : Neurologic manifestations common , severe
thrombocytopenia, less severe AKI . These are not absolute and should not be relied
upon so the diagnosis is confirmed by ADAMTS13 activity <10%.

Consequences of complement
activation.
T. Sakari Jokiranta Blood 2017;129:2847-2856
©2017 by American Society of Hematology

 complement dysregulation
 Complement : stimulating the inflammatory response and opsonization of pathogens to
protect the host from infection (encapsulated organisms in particular); it is a
fundamental component of innate and modulates adaptive immune system.
 Three pathways.
 Alternative regulated by plasma proteins, including FH and factor I (FI), and cell surface
proteins, such as membrane cofactor protein (CD46).
 C3 and factor B.

 Defects in these regulators or in pathway components lead to complement
dysregulation, with activation of the terminal complement pathway and generation of
C5a and the membrane attack complex (C5b-9), resulting in a complement mediated
aHUS.
 Dysregulated complement activation primarily occurs on endothelial cell surfaces
 Abnormal serum levels of complement components such as C3 may be observed, normal
levels do not exclude C-TMA.
 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 A bystander phenomenon has not yet been definitively established.

 Mutations in the genes encoding alternative pathway components
 Examples : complement regulatory defects due to mutations of factor H, factor I, factor
B, C3, or membrane cofactor protein (MCP),or to autoantibodies to factor H (1).
 Genetic mutations are not causative but predisposing, need for an environmental trigger
(e.g., pregnancy or infection) to unmask a latent complement defect.
 Triggers can include for instance malignancy, pregnancy, stem cell transplantation, use
of medication, or infection. in the placenta at the fetomaternal interface in normal
pregnancy normal physiologic response to infection.

 In rare cases, mutations are present in genes involved in the coagulation system, such as
those for diacylglycerol kinase E (DGKE) and thrombomodulin, or involved in cobalamin
(B12) metabolism, leading to defects described predominantly in children (<1 year)
 Outcome was very poor, as were outcomes after kidney transplantation. In the pre-
eculizumab era >> defect in a complement protein predominantly synthesized in the
liver was combined liver and kidney transplantation.

Predisposing factors, promoters, and triggers of aHUS and secondary HUS. Under physiological conditions,
regulation of complement is always at a higher level than the activation challenge.

Schematic presentation of the main links between the complement and coagulation systems and
platelets in formation of microthrombi in aHUS.

 Autoantibodies against FH and FI was first reported in 2005.

• ST-HUS :
• more common than aHUS, - peak incidence in children aged ,5 years
• Shiga toxin translocates through the intestinal epithelium and bind to leukocytes and
circulate to the kidneys.
• cleaved to release a protease > inhibits ribosomal function and protein synthesis > cell
death. It can also activate signaling pathways, inducing an inflammatory response in
affected cells.

• The distinction between STEC-HUS and complement mediated aHUS may
not be clinically obvious:
5% of STEC-HUS do not have diarrhea - 30% of patients with complement-
mediated aHUS have concurrent diarrhea at presentation.
• Therefore, all individuals with TMA should be investigated for STEC-HUS
• Rarely, complement gene mutations detected, and in these cases
the clinical picture is unusually severe -
• There is some evidence of complement activation , the role of complement-
inhibiting therapy has not yet been defined. May be used in sever dse.
• For now, the recommendation remains supportive management.

Pneumococcal HUS :
• invasive Streptococcus pneumoniae infection
• 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
• The Coombs test is positive.
• Supportive management and treatment of the infection should be the
focus.

HIV-Associated TMA :
• more commonly in the pre-highly active antiretroviral therapy era ,
and in association with lower CD41 cell counts and higher viral RNA
levels
• supportive care and antiretroviral treatment.
• Other infections : bacterial viral
• Supportive management with appropriate treatment of the infection is
recommended and complement evaluation should be undertaken.

AKI in
Pregnancy
according
to time

 While aHUS usually occurs postpartum (80%), TTP occurs equally in both
pre- and postpartum.
 This might be explained by the physiologic increase in vWf during
pregnancy, consumes ADAMTS13, so in women with a genetic
predisposition, its activity can fall low enough for TMA to manifest.
 ADAMTS13 activity to vWF antigen ratio reaches a nadir during the second
and third trimesters, which probably potentiates the inhibitory effect of anti-
ADAMTS13 autoantibodies, leading to TMA.
 Treatment : clearance of autoantibodies using plasma exchanges or fresh
frozen plasma infusions in case of constitutional ADAMTS13 deficiency.

 Outcomes were historically poor, with 76% developing ESRD despite PE..
 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.
 Assessment of a peripheral blood smear is mandatory.
Schistocytes indicate a pregnancy-induced TMA . If schistocytes are not
present and if
other findings indicate a pregnancy-related disease, an immediate
cesarean delivery is indicated. If TMA is confirmed, PEX should not be
delayed to wait for the ADAMTS13 result.
 However, ADAMTS13 result can subsequently differentiate between TTP
and aHUS. Both diseases may be congenital; pregnancy may merely be
the trigger.

TMA LIKE DISORDER
type of hemolysis seen in HELLP is microangiopathic, as evidenced by schistocytes on the peripheral smear and a
negative Coombs test.
The pathologic lesion seen in the kidneys of patients with HELLP rarely has TMA features and more commonly will
have glomerular endotheliosis and acute tubular necrosis.However, liver biopsies done in patients withHELLP show
the classic fibrin thrombi seen also in patients with TMA.
Although the complement system is dysregulated in preeclampsia and HELLP, its contribution is still being studied
and seems to be one of many predisposing factors rather than the main triggering event.
Some patients with HELLP will have complement genetic mutations as seen in aHUS patients
BUT only a minority (8%–10%) with preeclampsia and HELLP syndrome
The treatment of severe HELLP syndrome remains controversial.
Steroids and plasma exchanges have been used in the absence of any clear rationale or established efficacy
If the link between HELLP syndrome and complement dysregulation is confirmed, complement inhibition may
represent a potential treatment for severe HELLP syndrome.
HELLP Syndrome: TMA or Not
TMA?

 two main mechanisms: immune-mediated damage and direct 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

 kidney, liver, pancreas, lung, and heart transplantation allogenic
bone marrow transplants
 multifactorial, with ischemia-reperfusion injury, antibody-mediated rejection, viral
infections such as CMV, and immunosuppressant drugs, (CNIs), contributing to an
“endothelial damaging milieu” .
 complement mutations were identified in 29% (96), providing a rationale for complement
inhibiting therapy especially
 In many cases, however, supportive treatment and addressing the precipitating factors (CNI
discontinuation or dose reduction, treatment of antibody-mediated rejection and viral
infections) may be sufficient to stop the TMA

 managed with antihypertensive and supportive ttt.
 In the majority of patients renal function and MAHA usually recover with
management of BP
 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.
• difficult to distinguish between TMA caused by chemotherapy and TMA caused
by malignancy
• Prognosis is poor because of malignancy-related mortality
• no evidence to support any treatment strategy other than
withdrawal of causative chemotherapy agents.

 TMA can manifest in (vitamin B12) deficiency - caused by recessive
mutations in the MMACHC gene, can present in adulthood as well as
childhood,
 Mortality is high if untreated or with cardiopulmonary involvement, but
metabolic therapy (hydroxocobalamin and betaine) is very effective
 encoding diacylglycerol kinase
 Recessive DGKE mutations causing TMA was first reported in 2013 complement-
independent mechanisms
 present in patients aged ,1 year and commonly results in progressive CKD and ESRD

 TMA can occur in association with IgA nephropathy, ANCA-associated vasculitis, membranous
nephropathy, FSGS, and MPGN/C3G, although it may be a histopathologic finding without
biochemical or clinical manifestation
 Mutations in CFH are observed in both complement-mediated aHUS and C3G;
 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, whereas in C3G, mutations are
more often located at the N-terminal of FH, which mediates complement regulation in the fluid
phase.

 SLE, catastrophic antiphospholipid syndrome (CAPS), and scleroderma
renal crisis (SRC);
 mechanisms remain unclear, although there is some evidence of
complement activation in SLE and CAPS
 For SLE, CAPS, and SRC with TMA,
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.

 TTP is characterized by unusually large multimers of vWf- and platelet-rich thrombi in
capillaries and arterioles
 In complement-mediated
aHUS and other TMAs The pathologic findings reflect tissue responses to endothelial injury,
including endothelial swelling and mesangiolysis in active lesions, and double contours of the
basement membrane in chronic lesions
 Overt fibrin platelet thrombosis may be absent from renal biopsies of TMA
 Evidence of TMA has also been reported in a number of glomerular diseases (7) and
autoimmune diseases
 It is not possible, on the basis of current knowledge, to establish the cause of TMA from the
histopathologic morphology, although this may change with further research ;

Light microscopy:
 In HUS, there are fibrin thrombi (often with fragmented red blood cells) within
glomeruli, in subendothelial areas, and in the mesangium. These are
accompanied by mesangiolysis, endothelial swelling, corrugation of the
glomerular basement membrane (GBM), and a bloodless appearance in segments
of glomeruli uninvolved by thrombi.
 With causes of TMA other than HUS, arterioles and arteries are more often
involved.
 Arterioles and arteries can have intimal proliferation with mucoid changes and
entrapped red blood cell fragments, or frank necrosis and/or fibrin thrombi.
 Cortical necrosis can be seen in severe cases.
 Chronic changes include duplication of GBMs resulting in a
membranoproliferative-like pattern, and focal segmental and global
glomerulosclerosis with proportional tubulointerstitial fibrosis.
 Intimal proliferation and fibrosis with narrowed lumens of arterioles/interlobular
arteries give rise to the so-called onion-skin lesions. Recanalized thrombi may be
present.

IF:
 Thrombi stain positive for fibrinogen.
 There may be nonspecific staining for IgM in glomeruli, and less
frequently C3 and IgG.
EM:
 swollen glomerular endothelial cells with loss of fenestrations,
expansion of lamina rara interna, mesangiolysis, and fibrin tactoids
with platelets and fragmented red blood cells.
Chronic findings include interposed cells with new GBM matrix
material deposition.

 Thrombotic microangiopathy has similar morphologic findings regardless of the
underlying etiology.
 HUS/TTP predominantly affect glomeruli, whereas scleroderma and malignant
hypertension predominantly affect arterioles and interlobular arteries.
 Key Diagnostic Features
 Intravascular fibrin thrombi with mucoid changes in the acute stage
 Double contours of GBMs with variable endocapillary hypercellularity in the chronic
stage, with no immune complexes
 Intimal proliferation of arterioles in the chronic stage

 (A) capillary loops
containing abundant
erythrocytes
 (silver)

Thrombus in an
artery (hematoxylin
and eosin).

Glomerular
capillary lumina
containing fibrin
thrombi (red) and
erythrocytes
(yellow) (Martius
Scarlet Blue).

 Erythrocyte
fragments
within the
arterial vessel
wall (arrow)
(HE).

Mucoid thickening
and obliteration
of the lumen of a
small artery
(hematoxylin and
eosin).

Myxoid
intimal
thickening of
small artery
(hematoxylin
and eosin,
3400).

Fibrinoid
necrosis of
arterial
wall (Martius
Scarlet Blue,
3400).

 Reduplication of
glomerular
basement membrane
(arrow) and
fibrillary mesangium
(periodic acid–
Schiff,
3400).

Glomerulus
with
endothelial
swelling and
erythrocyte
fragmentati
on (arrow)
(HE).

Figure 1
American Journal of Kidney Diseases 2016 68, e33-e34DOI: (10.1053/j.ajkd.2016.10.006)
Copyright © 2016 National Kidney Foundation, Inc. Terms and Conditions
fibrin thrombi within glomerular capillary loops (Jones silver stain).

Figure 2
fibrin thrombi within glomerular capillary loops extending
to the vascular pole (Jones silver stain).

Figure 3
chronic stage with basement membrane splitting and
segmental endocapillary hypercellularity (Jones silver
stain).

However Most cases with a TMA pattern of
injury on renal biopsy are:
Chronic
Not associated with a clear cause at diagnosis
Not associated with HUS or TTP clinical features

fibrin
tactoids
(black) in
glomerular
capillary

Figure 5
fibrin tactoids, endothelial cell swelling, and expansion of the
lamina rara interna.

Figure 6
chronic stage with new basement membrane formation and early cellular
interposition with expansion of the lamina rara interna (electron microscopy)

 should be initiated in adults as soon as the diagnosis of TMA is suspected.
 still the initial treatment of choice until ADAMTS13 activity is available to
exclude TTP as a diagnosis.
 remove ADAMTS13 autoantibodies and replacing ADAMTS13 in TTP, PE will
also replace faulty complement regulators and remove FH autoantibodies
and hyperfunctional complement components in C-TMA
 In children, associated with a high rate of complications and TTP is rare,
therefore PE is not considered as a first-line treatment when eculizumab is
available.
 In many parts of the world, the cost of eculizumab precludes its use, SO IT
The only treatment for C-TMA.
 Recognizing thrombotic microangiopathy and initiating plasmapheresis
within 4 to 8 hours is essential for successful therapy
(recommendation grade 1 B)

 Eculizumab is a recombinant humanized mAb functionally
inhibits the cleavage of C5 and thus, prevents
the generation of C5a
 was approved initially in the management of
paroxysmal nocturnal hemoglobinuria - approved by the US FDA
and the European Medicines Agency for use in aHUS in 2013
 complete response was achieved in approximately 65% after 26
weeks of eculizumab therapy
 current license for eculizumab is for lifelong treatment, but
this is not evidence based.
 The standard eculizumab regimen
includes four weekly 900-mg infusions followed by 1,200-mg
infusions every fortnight.
 Increasing data suggests that eculizumab is safe during
pregnancy

Concerns
With increased clinical use, evidence is emerging of
nonresponse to eculizumab. For those with a rare genetic
variant in the complement system or polymorphism in the C5
gene.
The primary concern with terminal complement blockade is
increased susceptibility to infection with encapsulated
organisms, particularly Neisseria For this reason,
meningococcal vaccination is considered mandatory;
hepatotoxicity in association with eculizumab has been
reported in children , and deposition of eculizumab has been
reported in individuals with C3 glomerulopathy (C3G) (but not
yet in aHUS), although the clinical significance is unclear.
The use of complement-inhibiting therapy in TMAs other than
complement-mediated aHUS is controversial; likely to be
needed before a consensus can be achieved

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.
 Withdrawal : May be appropriate in some patient, with
monitoring: liaise with specialist center ? aFor
example, if there is no renal recovery after 6 months
of

 Detection of schistocytes in a blood smear is easy to perform and is the
most important laboratory test for diagnosis, which
should always be initiated promptly, even at night, if
thrombotic microangiopathy is suspected (recommendation grade 1 A)
 Tests essential for differentiating TTP from other forms of thrombotic
microangiopathies are quantitative detection of ADAMTS13 and measurement
of the activity levels of ADAMTS13 and the ADAMTS13 inhibitor. ADAMTS13 activity is
determined in citrated blood samples prior to any treatments
with plasma therapy or blood transfusion (recommendation grade I B)
 Plasma exchange increases ADAMTS13 activity in the blood and should eliminate
ADAMTS13 neutralizing antibodies. For aTTP, a combination with steroids is recommended to
control antibody-producing B cells; however, this goal is not
usually sustainable (recommendation grade I B)

PEX may fail to induce or maintain remission, in the presence of high-titer inhibitory autoantibodies
In plasma-resistant or dependant forms, rituximab (4 × 375 mg/m2) , is most probably the optimal treatment,
improves the short-term outcome of severe ADAMTS13- deficient TMA. However, its impact on the long-term
warrants additional assessment.
Not approved for treatment of TTP (off-label use), it is currently the drug of choice for the long-term control of
immune-mediated aTTP
Corticosteroids usually used as adjunctive treatment for ADAMTS13 deficiency-related TMA or other forms of
TTP. However, there is no definitive evidence of the efficiency. Some groups recommend in all patients suspected
of having acquired TTP, although this has not been assessed in a placebo-controlled trial.
Evidence for steroids in aHUS is lacking
Asymptomatic patients with no signs of hemolysis and normal platelet counts may undergo watchful waiting.
Immuno - suppressive therapy is not useful in cTTP, as there are no autoantibodies to be targeted.

Treatment of HELLP VS TMA:
pregnant patient with preeclampsia and HELLP consists of aggressive blood
pressure control and delivery as soon as possible.
If there is no improvement in clinical status, platelets and LDH 2 to 3 days after
delivery, one must reconsider the diagnoses of TTP and aHUS and treat
accordingly.
In many of these disorders, the ADAMTS13 activity will be below “normal” or
even low (10%-20%) but not severely deficient (<10%), which typically
characterizes acquired TTP.
In a patient who responds poorly to PEX with no other clear explanation for the
TMA findings, a diagnosis of aHUS might then become more plausible

 the current definition of aHUS resistance to plasma therapy is
based mainly on the absence of PLT increase and/or LDH
decrease despite three to five daily plasma exchanges.
 This definition does not take into account the fact that platelets
count increase does not always correlate with renal function
improvement in aHUS patients.
 We believe that the absence of a significant decrease (>25%) of
serum creatinine despite three to five plasma exchanges should
also be used as a criteria for plasma resistance in the setting of
aHUS.

In all cases, plasma therapy fails to rescue renal function in
roughly 50% of patients experiencing their first Ahus episode

Thrombotic microangiopathy and the kidney - Dr. Mohamed Mamdouh AbdAlBary

Thrombotic microangiopathy and the kidney - Dr. Mohamed Mamdouh AbdAlBary

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