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Home , Hemolysis

Hemolytic uremic syndrome

Doyeun Oh

Department of Internal Medicine CHA University School of Medicine Disclosures for Doyeun 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

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria No relevant conflicts of interest to declare

Scientific Advisory Board No relevant conflicts of interest to declare Contents

. Pathogenesis of STEC-HUS and aHUS

. Differential diagnosis of TMA

. Guidelines to manage STEC-HUS and aHUS

01

Initial recognition of HUS

. Microangiopathic hemolytic (MAHA)

Hb <10 g/dL

shistocytes, increased counts, negative

elevated LDH

low . Thrombocytopenia

(< 150K/mm3) . Acute kidney injury

(Cr ≥ 1.5 x normal) 02 AB

C D 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.

04 Definition and terminology

. Thrombotic microangiopathy (TMA): A that results in in capillaries and arterioles, due to an endothelial injury characterized by and thrombocytopenia . Hemolytic uremic syndrome (HUS) : a disease characterized by hemolytic anemia, acute , and a low count, without severe ADAMTS13 deficiency . Shiga 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 TMA Noris M and Remuzzi G. N Engl J Med 2009;361:1676-87 George JN and Nester CM. N Engl J Med 2014; 371:654-666 05 Loirat C, et al. Pediatr Nephrol 2016;31:15-39 Classification of HUS

. 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)

Loirat C, et al. Pediatr Nephrol 2016;31:15-39 TMA aHUS USS

STEC‐HUS TTP

Secondary TMA Transplantation Infection Pregnancy, , preeclampsia, HELLP Drugs (SLE, scleroderma) Malignancy and Malignant Glomerulopathy

TTP : thrombotic thrombocytopenic purpura 06 USS : Upshaw-Schulman syndrome Pathogenesis of HUS

STEC- Complement infection dysregulation

Hemolysis Endothelial damage Platelet activation activation

Microcirculatory platelet-rich thrombus formation

Acute kidney injury 07 Pathogenesis of STEC‐HUS

. 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 , 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;2:56-76 Jokiranta TS. 2017;129:2847-56 08 Stx-Gb3 binding Gb3

Endocytosis Inhibition of tRNA-ribosome Golgi binding

Cytosol

Retrograde traffic

ER

Valerio E, et al. 2010;2:2359-410 Shiga toxin producing E. Coli infection

Stx Stx

Stx Stx

Gb3

Stx- induced renal damage Endothelial damage Infectious enterocolitis TF-induced fibrin formation Complement activation

bloody diarrhea renal failure

Stx : Shiga toxin Gb3 : globotriaosylceramide 09 Pathogenesis of atypical HUS

. 5-10% of HUS

. 50-60% has genetic abnormalities.

. Genetic mutations (autosomal dominant or recessive) or against regulatory proteins in the

. 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, , and renal failure.

Noris M and Remuzzi G. N Engl J Med 2009;361:1676-87 Jokiranta TS. Blood 2017;129:2847-56 11 Classical and lectin Alternative pathway pathways (C3 tick-over)

C3 convertase C3 convertase (C4b2a) (C3bBb)

C3

Factor H C3b Factor I (C5-convertase)

C5 (activation)

MAC: Membrane attack complex MCP: Membrane cofactor protein MAC C5-9 THBD: thormbomodulin (formation) MCP THBD

12 Complement gene abnormalities in patients with aHUS

Noris M, et al. Clin J Am Soc Nephrol 2010;5: 1844–1859 13 Factor H

N-terminal C-terminal 123456 789 10 11 12 13 14 15166 17 18 19 20

. 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;361:1676‐87 Jozsi M, et al. Blood. 2008;111:1512‐1514 14 Sinha A, et al. Kidney Int. 2014;85:1151‐60 Genetic abnormalities in patients with aHUS

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

Noris M and Remuzzi G. Semin Nephrol. 2017 Sep;37(5):447-463 15 Jokiranta TS. Blood 2017;129:2847-56 Summary

. The pathogenesis of STEC-HUS is infection. . The major pathogenesis of aHUS is dysregulation of complement system caused by genetic abnormalities or autoantibody development.

16 Diagnosis of TTP, STEC‐HUS and aHUS

TMA ADAMTS13<10% TTP

TMA

STEC (+) STEC-HUS

TMA

Secondary TMA Secondary TMA

aHUS 17 Initial recognition of aHUS

MAHA Thrombocytopenia Acute kidney injury Hypertension Neurologic disturbances Respiratory disturbances GI disturbances Existence of triggers Poor response to PEX

18 Multiple hits are necessary for aHUS to manifest

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.

Kavanagh D. and Goodship THJ, Am Soc 19 Hematol Educ Program. 2011;2011:15-20 Triggers of aHUS

. Infection . Drugs . Vaccination . Autoimmune disease . Pregnancy . Malignancy or cancer chemotherapy . Transplantation

Noris M and Remuzzi G. N Engl J Med 2009;361:1676-87 Kavanach D, et al. Seminars Nephrol 2013;33:508-30 20 aHUS patients’ characteristics at onset

Fremeaux-Bacchi, et al. Clin J Am Soc Nephrol 2013;8: 554–562 21 Diagnosis of aHUS

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 Secondary TMA (coexisting diseases)

. 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;33:508-30 Campistol JM, et al. Nefrologia 2013;33:27-45 Cataland SR, et al. Blood 2014;123:2478-84 Scully M, Goodship T. Br J Haematol 2014;164:759-66 23 Detection of complement dysregulation: Serologic diagnosis

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; 2:591-6 Mannucci Cataland Johnson S, et al. Pediatr Nephrol 2014;29:1967-78 Loirat C, et al. Pediatr Nephrol 2016;31:15-39 24 Detection of complement dysregulation: Genetic diagnosis

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; 2:591-6 25 Mannucci Cataland Johnson S, et al. Pediatr Nephrol 2014;29:1967-78 Investigational assay of atypical hemolytic uremic syndrome

. Modified HAM test

. Quantitative hemolytic assay coupled with RFLP

. In vitro activity assay

. Skin biopsy

Gavriilaki E, et al. Blood 2015;125:3637-46 Yoshida Y, et al. PLoS One 2015;10:e124655 Heinen S, et al. Mol Immunol 2013;54:84-8 26 Magro CM, et al. Am J Dermatopathol 2015;37:349-56 Summary

. 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 Needs for guidelines on aHUS

. 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 . 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 28 Management of HUS and aHUS

TMA Medical Emergency, Multidisciplinary approach

TTP PEX steroid ADAMTS13<10%

STEC-HUS Supportive care PEX STEC (+)

Secondary TMA Treatment for secondary TMA

aHUS Eculizumab PEX KT/LT PEX : plasma exchange KT : kidney transplantation 29 LT : transplantation Management of STEC‐HUS

. Supportive care is the mainstay of therapy.

Fluid and electrolyte control, blood pressure control, 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 Prognosis

. Excellent outcome

. Full recovery in > 80%

. End-stage renal disease: less than 5%

. Death: less than 5%

. and mortality is higher in old age adults.

Page AV, Liles WC. Med Clin N Am 2013;97:681-95 31 Recommendations for the treatment of STEC‐ HUS

Supportive care is the mainstay of therapy. Fluid and electrolyte control, blood pressure control, red blood cell transfusion, 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 or glucocorticosteroids. and their use in STEC-HUS is not recommended.

Page AV, Liles WC. Med Clin N Am 2013;97:681-95 Igarashi T, et al. Clin Exp Nephrol 2014;18:525-57 32 Management of aHUS

. 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.

Scully M, Goodship T. Br J Haematol 2014;164:759-66 Fremeaux-Bacchi V, et al. Clin J Am Soc Nephrol 2013;8:54-62 33 Plasma therapy on 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, , 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;33:27-45 Loirat C, et al. Semin Thromb Hemost 2010;36:673-81 Noris M, et al. Clin J Am Soc Nephrol. 2010;5(10):1844-1859 Caprioli J, et al. Blood. 2006;108(4):1267-1272 34 Kidney transplantation in 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 35 Liver transplantation in aHUS

. 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;67:31-42 36 Franchini M. Clin Chem Lab Med 2015;53:1679-88 Eculizumab (Soliris®)

. 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;364:2561-3 Menne J, et al. BMJ 2012;345:e4565 Legengdre CM et al. N Engl J Med 2013;368:2169-81 37 Lectin Pathway Classical Pathway Alternative Pathway

C3

Natural Inhibitors: Factor H, I, MCP, Eculizumab CD55

C5

Tissue injury, TMA (?)

38 More than 50%

Less than 20% ESRD and Death Patient (%)

PEX/PI Eculizumab

Caprioli J, et al. Blood. 2006;108(4):1267-1272 Noris M, et al. Clin J Am Soc Nephrol. 2010;5(10):1844-1859 Legengdre CM et al. N Engl J Med 2013;368:2169-81 Fakhouri F, et al. Am J Kidney Dis. 2016 Jul;68(1):84-93 Greenbaum LA, et al. Kidney International (2016) 89, 701–711 39 Eculizumab is effective in aHUS

Trial 1 Trial 2 (n=17) (n= 20) Complete TMA response 11 (65%) 5(25%) TMA event free 15 (88%) 16 (80%) Platelet normalization 14 (82%) NA LDH 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%)

Legengdre CM et al. N Engl J Med 2013;368:2169-81 40 Eculizumab is a safe and effective treatment in patients with aHUS: outcomes by 26 weeks of treatment

Pediatric Adult aHUS aHUS (n= 41) (n=22) 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%)

Fakhouri F, et al. Am J Kidney Dis. 2016 Jul;68(1):84-93 Greenbaum LA, et al. Kidney International (2016) 89, 701–711; 41 Prophylaxis of infections before eculizumab

. 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 42 Management of aHUS with anti‐CFH antibody: immunosuppressive treatment

. Indicated in anti-CFH autoantibody . Combined with PEX . Steroid, cyclophosphamide, RTX, MMF, azathioprine

Franchini M. Clin Chem Lab Med 2015;53:1679-88 Sinha A, et al. Kidney Int. 2014;85:1151-60 43 Recommendations for the treatment of aHUS

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;31:15-39 Kato H, et al. Clin Exp Nephrol 2016;20:536-43 Cheong HI, et al. J Kor Med Sci 2016;31:1516-28 Taylor CM, et al. Br J Haematol. 2010;148:37-47 Campistol JM, et al. Nefrologia. 2015;35:421-47 44 Summary

. 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 Conclusions

. 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 ขอบคุณสาหรํ ับการฟัง

2020 APSTH Gwangju, KOREA September 3 ‐5, 2020