Doyeun Oh
Department of Internal MedicineCHA University School of Medicine
Hemolytic uremic syndrome
Disclosures forDoyeun Oh
Research Support/P.I. No relevant conflicts of interest to declare
Employee No relevant conflicts of interest to declare
Consultant No relevant conflicts of interest to declare
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Scientific Advisory Board No relevant conflicts of interest to declare
Pathogenesis of STEC-HUS and aHUS
Differential diagnosis of TMA
Guidelines to manage STEC-HUS and aHUS
Contents
01
02
Initial recognition of HUS
Microangiopathic hemolytic anemia (MAHA)Hb <10 g/dL
shistocytes, increased reticulocyte counts, negative Coombs test
elevated LDH
low haptoglobin
Thrombocytopenia
(< 150K/mm3)
Acute kidney injury
(Cr ≥ 1.5 x normal)
A B
C D
04
Needs for correct diagnosis and treatment of HUS
Clinical features are similar or overlapped among
thrombotic microangiopathies.
Pathogenesis and clinical outcome with plasma
therapy is different.
Complement inhibitor can dramatically change the
outcome of aHUS.
05
Definition and terminology
Thrombotic microangiopathy (TMA): A pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury characterized by hemolytic anemia and thrombocytopenia
Hemolytic uremic syndrome (HUS) : a disease characterized by hemolytic anemia, acute kidney failure, and a low platelet count, without severe ADAMTS13 deficiency
Shiga toxin producing E coli- associated hemolytic uremic syndrome (STEC-HUS): HUS caused by infectious agents which produce Shiga toxin
Atypical HUS (aHUS): A heterogeneous group of diseases that have a TMA associated with some degree of acute kidney injury (AKI), not associated with other forms of TMA
Complement –mediated TMANoris M and Remuzzi G. N Engl J Med 2009;361:1676-87George JN and Nester CM. N Engl J Med 2014; 371:654-666Loirat C, et al. Pediatr Nephrol 2016;31:15-39
Classification of HUS
Loirat C, et al. Pediatr Nephrol 2016;31:15-39
STEC-HUS
S. pneumoniae-HUS, Influenza A / H1N1-HUS
Alternative complement pathway dysregulation (Genetic, Acquired)-HUS
Cobalamin C defect-HUS
DGKE mutation-HUS
Unexplained (idiopathic) HUS
HUS with coexisting disease/condition (secondary HUS)
TMA
STEC‐HUS
aHUS
Secondary TMATransplantationInfectionPregnancy, Eclampsia, preeclampsia, HELLPDrugs Autoimmune disease (SLE, scleroderma)Malignancy and chemotherapyMalignant hypertensionGlomerulopathy
TTP
USS
TTP : thrombotic thrombocytopenic purpuraUSS : Upshaw-Schulman syndrome
06
Endothelial damage Platelet activation
Hemolysis
Acute kidney injury
STEC-infection
Complement dysregulation
Coagulation activation
Microcirculatory platelet-rich thrombus formation
Pathogenesis of HUS
07
90% of HUS
3-7% of E. coli or enterotoxin producing organism (S. dysenteriae) infection
Shiga toxin or Shiga-like toxin (Stx); two types, Stx-1 and Stx-2
O157:H7, O26:H11/H-, O104:H4, O157:H-, O145:28/H-, O103:H2/H-, O111:H8/H, O121, O113. (O, lipopolysaccharide Ag; H, flagellar Ag)
Shiga-toxin binds to the globotriaosylceramide (Gb3) receptor in the cell membrane, internalizes and induces cell death by inhibiting protein synthesis. Gb3 receptors are highly expressed in kidney, brain and gut than other tissues. Children has more Gb3 than adults.
Shiga-toxin upregulates the expression of E-selectin, ICAM-1, VCAM-1 facilitates leukocyte activation and endothelial injury.
Shiga-toxin upregulates the expression of P-selectin and induce the formation of ULVWF and platelet activation and thrombosis.
Salvadori M, et al. World J Nephrol 2013;2:56-76Jokiranta TS. Blood 2017;129:2847-56
Pathogenesis of STEC‐HUS
08
Gb3
Stx-Gb3 binding
Endocytosis
Retrograde traffic
Inhibition of tRNA-ribosome bindingGolgi
ER
Valerio E, et al. Toxins 2010;2:2359-410
Cytosol
Infectious enterocolitis
Stx- induced renal damageEndothelial damageTF-induced fibrin formationComplement activation
Stx : Shiga toxinGb3 : globotriaosylceramide
StxStx
bloody diarrhea renal failure
Gb3
Stx Stx
Shiga toxin producing E. Coli infection
09
5-10% of HUS
50-60% has genetic abnormalities.
Genetic mutations (autosomal dominant or recessive) or autoantibodies against regulatory proteins in the complement system
Dysregulation of alternative complement pathway causing uncontrolled excessive activation of complement system is the major cause of aHUS. It results in endothelial injury, leukocyte activation, platelet activation followed by thrombosis, thrombocytopenia, hemolysis, and renal failure.
Noris M and Remuzzi G. N Engl J Med 2009;361:1676-87Jokiranta TS. Blood 2017;129:2847-56
Pathogenesis of atypical HUS
11
Classical and lectinpathways
Alternative pathway(C3 tick-over)
C3 convertase(C4b2a)
C3 convertase(C3bBb)
C3
C3b(C5-convertase)
C5(activation)
MAC C5-9(formation)
Factor HFactor I
MCPTHBD
MAC: Membrane attack complex
MCP: Membrane cofactor protein
THBD: thormbomodulin
12
Noris M, et al. Clin J Am Soc Nephrol 2010;5: 1844–1859
Complement gene abnormalities in patients with aHUS
13
661 2 3 4 5 7 8 9 10
3-10% of cases in children Functional deficiency of factor H Related with homozygous deletion of CFHR
Noris M and Remuzzi G. N Engl J Med 2009;361:1676‐87Jozsi M, et al. Blood. 2008;111:1512‐1514Sinha A, et al. Kidney Int. 2014;85:1151‐60
N-terminal C-terminal
Factor H autoantibody
611 12 13 14 15 17 18 19 2016
14
Noris M and Remuzzi G. Semin Nephrol. 2017 Sep;37(5):447-463Jokiranta TS. Blood 2017;129:2847-56
Gene Frequency in aHUS, %
CFH 24-28
CFHR1/3 homozygous deletion 3-10
MCP 5-9
CFI 4-8
CFB 0-4
C3 2-8
THBD 0-5
Combined mutations 3‐5
DGKE 0‐3
Plasminogen NA
Factor XII NA
15
Genetic abnormalities in patients with aHUS
The pathogenesis of STEC-HUS is infection.
The major pathogenesis of aHUS is dysregulation of
complement system caused by genetic abnormalities or
autoantibody development.
Summary
16
TMA
STEC-HUS
TTP
TMA
ADAMTS13<10%
STEC (+)
TMA
aHUS
Secondary TMASecondary TMA
Diagnosis of TTP, STEC‐HUS and aHUS
17
MAHA Thrombocytopenia Acute kidney injury Hypertension
Neurologic disturbances
Respiratory disturbances
GI disturbances
Existence of triggers
Poor response to PEX
18
Initial recognition of aHUS
Multiple hits are necessary for aHUS to manifest, including a trigger, mutations, and at-risk haplotypes in complement genes. Incomplete penetrance of mutations is a feature in the pathogenesis of aHUS. Mutations are predisposing rather than directly causal in the development of aHUS.
19Kavanagh D. and Goodship THJ, Hematology Am Soc Hematol Educ Program. 2011;2011:15-20
Multiple hits are necessary for aHUS to manifest
Infection
Drugs
Vaccination
Autoimmune disease
Pregnancy
Malignancy or cancer chemotherapy
Transplantation
Noris M and Remuzzi G. N Engl J Med 2009;361:1676-87Kavanach D, et al. Seminars Nephrol 2013;33:508-30 20
Triggers of aHUS
Fremeaux-Bacchi, et al. Clin J Am Soc Nephrol 2013;8: 554–562 21
aHUS patients’ characteristics at onset
The diagnosis of aHUS is made by
excluding other types of TMA by
(1) ADAMTS13 activity >10%
(2) no evidence of STEC-HUS
(3) no secondary TMA (coexisting disease)
22
Diagnosis of aHUS
Transplantation Infection Pregnancy, Eclampsia, preeclampsia, HELLP Drugs Autoimmune disease (SLE, scleroderma) Malignancy and chemotherapy Malignant hypertension Glomerulopathy These patients may have also aHUS-risk genetic variants.
Kabanach D, et al. Semin Nephrol 2013;33:508-30Campistol JM, et al. Nefrologia 2013;33:27-45Cataland SR, et al. Blood 2014;123:2478-84Scully M, Goodship T. Br J Haematol 2014;164:759-66
Secondary TMA (coexisting diseases)
23
ELISA, Radial immunodiffusion or Western blot assay (C3, C4, CFH, antibody against CFH, CFI, CFB),Flow cytometry (MCP) Anti-CHF antibody test is the only assay urgently required during the acute phase because a positive result raises additional treatment option. Normal activity cannot exclude aHUS.Overlapping results in both TTP, STEC-HUS and aHUS
Gavriilaki E, et al. Blood 2015;125:3637-46 Kavanach D, et al. Clin Am Soc Nephrol 2007; 2:591-6Mannucci Cataland Johnson S, et al. Pediatr Nephrol 2014;29:1967-78Loirat C, et al. Pediatr Nephrol 2016;31:15-39
Detection of complement dysregulation:Serologic diagnosis
24
RFLP and sequencing, next generation sequencing, copy number variation and multiplex ligation-dependent probe amplification.It is helpful for the correct diagnosis and predict the outcome of aHUS, especially for the assessment of the optimal duration of treatment and the risk of post-renal transplantation recurrence.DNA testing is not recommended as an upfront diagnostic test not only because it is time consuming but also because several patients have no identifiable mutation.
Gavriilaki E, et al. Blood 2015;125:3637-46 Kavanach D, et al. Clin Am Soc Nephrol 2007; 2:591-6Mannucci Cataland Johnson S, et al. Pediatr Nephrol 2014;29:1967-78
25
Detection of complement dysregulation:Genetic diagnosis
Modified HAM test
Quantitative hemolytic assay coupled with RFLP
In vitro activity assay
Skin biopsy
Investigational assay of atypical hemolytic uremic syndrome
26Gavriilaki E, et al. Blood 2015;125:3637-46 Yoshida Y, et al. PLoS One 2015;10:e124655Heinen S, et al. Mol Immunol 2013;54:84-8Magro CM, et al. Am J Dermatopathol 2015;37:349-56
Clinical suspicion is the first step to diagnosis aHUS.
TTP can be excluded by ADAMTS13 activity >10%.
STEC-HUS can be excluded by the demonstration of Shiga toxin in
stool.
The diagnosis of aHUS is made by excluding TTP, STEC-HUS and
secondary TMA (coexisting disease).
Screening for complementary abnormalities by serology is useful
for the diagnosis of aHUS but their concentrations are not
consistently abnormal.
Genetic screening for complementary abnormalities is most
informative but not mandatory for the diagnosis of aHUS.27
Summary
aHUS is often misdiagnosed as TTP or STEC-HUS, all of which show
common clinical features. However, the pathogenesis and response rate to
plasma exchange differ between syndromes . Eculizumab is a life saving
drug in many cases of aHUS. Delayed treatment of aHUS can cause death
or end-stage renal disease. Therefore, the early differential diagnosis of
aHUS from other forms of TMA is very important for its appropriate
management.
Guidelines facilitate the standardized management of aHUS and
accelerate the detection and clinical trials of patients with aHUS.
European pediatric guidelines , British guidelines, Japanese guidelines
Needs for guidelines on aHUS
28
TMA
Supportive care
PEXADAMTS13<10%
STEC (+)
aHUS
Treatment for secondary TMASecondary TMA
steroid
PEX
PEX
KT/LT
Eculizumab
TTP
STEC-HUS
Medical Emergency, Multidisciplinary approach
Management of HUS and aHUS
29PEX : plasma exchange KT : kidney transplantation LT : liver transplantation
Supportive care is the mainstay of therapy.
Fluid and electrolyte control, blood pressure control, red blood cell transfusion, hemodialysis..
Antibiotics: controversial effects Quinolone and trimehoprim induced Stx production, but azithromycin was effective..
Plasma exchange (PEX): controversial effects Because Stx is detectable in the circulation only very early in illness and because Stx- induced
endothelial injury are preceded the development of HUS, the pathogenetic rationale of PEX in
STEC-HUS is lacking.
Eculizumab: controversial effects
Page AV, Liles WC. Med Clin N Am 2013;97:681-95 30
Management of STEC‐HUS
Excellent outcome
Full recovery in > 80%
End-stage renal disease: less than 5%
Death: less than 5%
Complication and mortality is higher in old age adults.
Page AV, Liles WC. Med Clin N Am 2013;97:681-95
Prognosis
31
Supportive care is the mainstay of therapy.Fluid and electrolyte control, blood pressure control, red blood celltransfusion, and hemodialysis are necessary..
Antibiotics should be avoided in children with STEC-HUS..
The benefit of therapeutic plasma exchange is controversial and it should be avoided when STEC-HUS is confirmed.
Eculizumab is not recommended in STEC-HUS.
No clinical benefit has been found with therapeutic anticoagulation, administration of fresh frozen plasma or glucocorticosteroids. and their use in STEC-HUS is not recommended.
Page AV, Liles WC. Med Clin N Am 2013;97:681-95Igarashi T, et al. Clin Exp Nephrol 2014;18:525-57
Recommendations for the treatment of STEC‐ HUS
32
Scully M, Goodship T. Br J Haematol 2014;164:759-66Fremeaux-Bacchi V, et al. Clin J Am Soc Nephrol 2013;8:54-62
A half of patients with aHUS treated with supportive care
and plasma therapy had died or reached ESRD in 3 years.
Eculizumab is the treatment of choice as first line
treatment.
33
Management of aHUS
Plasma exchange (PEX) : 1.5 plasma volume Plasma infusion: 10-20ml/Kg Replacement of complement and elimination of inhibitors. Evidence from retrospective case studies Not effective in patients with MCP mutation because MCP is not
circulating but a anchored protein in cell membrane. Complete hematologic and renal recovery rates are lower than 50%.
Mortality and progression to ESRD are high. Complications: anaphylaxis, hypotension, hypervolemia, central
venous access obstruction Empirically recommended only in the case with good response or
when eculizumab is not available.
Campistol JM, et al. Nefrologia 2013;33:27-45Loirat C, et al. Semin Thromb Hemost 2010;36:673-81Noris M, et al. Clin J Am Soc Nephrol. 2010;5(10):1844-1859 Caprioli J, et al. Blood. 2006;108(4):1267-1272 34
Plasma therapy on aHUS
High rate of recurrence (up to 50%) Living donor kidney transplantation is contraindicated due
to high rate of recurrence. Eculizumab is effective to treat and prevent the recurrence
of aHUS in kidney transplantation.
Franchini M. Clin Chem Lab Med 2015;53:1679-88
Kidney transplantation in aHUS
35
Complement factor H, B, C3 and I are synthesized in the liver.
Results of surgery are improving. Isolated or combined kidney and liver transplantation may
be an option for the treatment of patients having aHUS without access to eculizumab treatment.
Nester CM, et al. Mol Immunol 2015;67:31-42Franchini M. Clin Chem Lab Med 2015;53:1679-88
Liver transplantation in aHUS
36
A humanized monoclonal antibody directed against the
complement protein C5 that inhibits terminal complement
activation.
Successfully used to treat patients with aHUS.
Controversial effects on typical HUS
Nurnberger J, et al. N Engl J Med 2009 29;360:542-4.Zuber J, et al. Am J Transplant 2012;12:3337-542. Lapeyraque AL, et al. N Engl J Med 2011;364:2561-3Menne J, et al. BMJ 2012;345:e4565Legengdre CM et al. N Engl J Med 2013;368:2169-81
Eculizumab (Soliris®)
37
38
C3
C5
Lectin Pathway Alternative PathwayClassical Pathway
Eculizumab
Tissue injury, TMA (?)
Natural Inhibitors:Factor H, I, MCP,CD55
Caprioli J, et al. Blood. 2006;108(4):1267-1272Noris M, et al. Clin J Am Soc Nephrol. 2010;5(10):1844-1859 Legengdre CM et al. N Engl J Med 2013;368:2169-81Fakhouri F, et al. Am J Kidney Dis. 2016 Jul;68(1):84-93Greenbaum LA, et al. Kidney International (2016) 89, 701–711
More than 50%
Less than 20%
ES
RD
and
Dea
th P
atie
nt (%
)
PEX/PI Eculizumab
39
Legengdre CM et al. N Engl J Med 2013;368:2169-81
Trial 1(n=17)
Trial 2(n= 20)
Complete TMA response 11 (65%) 5(25%) TMA event free 15 (88%) 16 (80%)Platelet normalization 14 (82%) NALDH normalization 13(82%) 19 (95%)Hb improvement by ≥ 2g/dL 11 (65%) 9 (45%)eGFR improvement by ≥ 15ml/min/1.73m2 8 (47%) 1 (5%)
40
Eculizumab is effective in aHUS
Fakhouri F, et al. Am J Kidney Dis. 2016 Jul;68(1):84-93Greenbaum LA, et al. Kidney International (2016) 89, 701–711;
Pediatric aHUS(n=22)
Adult aHUS (n= 41)
Complete TMA response 14 (64%) 30 (73%)
TMA event free 21 (95%) 37 (90%)
Platelet normalization 21 (95%) 40 (98%)
LDH normalization 18 (82%) 37 (90%)
Hb improvement by ≥ 2g/dL 15 (68%) 25 (61%)
eGFR improvement by ≥ 15ml/min/1.73m2 19 (86%) 22 (54%)
Eculizumab is a safe and effective treatment in patients with aHUS: outcomes by 26 weeks of treatment
41
Complement system is responsible for immunity against infections. Immunity against N. meningitis depends on the lytic terminal complement complex.
Eculizumab use is susceptible to meningitis and hemophilus infection.
Vaccination 2 weeks prior to ecculizumab is required. Antibiotic treatment with vaccination can be started in the
case that treatment with eculizumab cannot be delayed. Neither vaccines nor antibiotic prophylaxis guarantee full
protection against infections. Patient/family/caregiver education on signs of infection is necessary.
Loirat C, et al. Pediatr Nephrol 2016;31:15-39
Prophylaxis of infections before eculizumab
42
Indicated in anti-CFH autoantibody Combined with PEX Steroid, cyclophosphamide, RTX, MMF, azathioprine
Franchini M. Clin Chem Lab Med 2015;53:1679-88Sinha A, et al. Kidney Int. 2014;85:1151-60
Management of aHUS with anti‐CFH antibody: immunosuppressive treatment
43
Eculizumab should be considered as a first-line treatment for patients with symptomatic aHUS
All patients who are clinically suspected of having aHUS should be offered a trial of PEX and/or plasma infusions if eculizumab is not available
Live-related renal transplantation alone should be avoided in cases of aHUS
All patients receiving eculizumab should receive a meningococcal vaccination or antibioprophylaxis prior to receiving the first dose of eculizumab
Loirat C, et al. Pediatr Nephrol 2016;31:15-39Kato H, et al. Clin Exp Nephrol 2016;20:536-43Cheong HI, et al. J Kor Med Sci 2016;31:1516-28Taylor CM, et al. Br J Haematol. 2010;148:37-47Campistol JM, et al. Nefrologia. 2015;35:421-47
Recommendations for the treatment of aHUS
44
HUS is highly recommended to care in the hospital by
multidisciplinary approach.
Supportive care including plasma exchange is the main treatment of
HUS and should be initiated until the differential diagnosis is
clarified.
The benefit of therapeutic plasma exchange is controversial and it
should be avoided when STEC-HUS is confirmed.
Eculizumab is recommended as a first-line treatment for patients
with symptomatic aHUS.
45
Summary
HUS is a heterogeneous syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury.
The pathogenesis of STEC-HUS is infection and the major pathogenesis of aHUS is dysregulation of complement system.
Diagnosis of STEC-HUS can be made by the demonstration of Shiga toxin in the stool.
Diagnosis of aHUS can be made by excluding TTP, STEC-HUS and secondary TMA.
HUS is highly recommended to care in the hospital by multidisciplinary approach.
Supportive care including plasma exchange and hemodialysis is the main treatment of HUS and should be initiated until the differential diagnosis is clarified.
The benefit of therapeutic plasma exchange is controversial and it should be avoided when STEC-HUS is confirmed.
Eculizumab is recommended as a first-line treatment for patients with symptomatic aHUS.
46
Conclusions
2020 APSTH Gwangju, KOREA
September 3 ‐5, 2020
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