Hemolytic uremic syndrome

Transcription

1 Hemolytic uremic syndrome Doyeun Oh Department of Internal Medicine CHA University School of Medicine

2 Disclosures for Doyeun Oh Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare

3 Contents Pathogenesis of STEC-HUS and ahus Differential diagnosis of TMA Guidelines to manage STEC-HUS and ahus 01

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5 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) 02

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7 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

8 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 TMA Noris M and Remuzzi G. N Engl J Med 2009;361: George JN and Nester CM. N Engl J Med 2014; 371: Loirat C, et al. Pediatr Nephrol 2016;31:

9 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

10 ahus TMA USS STEC HUS TTP TTP : thrombotic thrombocytopenic purpura USS : Upshaw-Schulman syndrome Secondary TMA Transplantation Infection Pregnancy, Eclampsia, preeclampsia, HELLP Drugs Autoimmune disease (SLE, scleroderma) Malignancy and chemotherapy Malignant hypertension Glomerulopathy 06

11 Pathogenesis of HUS STECinfection Complement dysregulation Hemolysis Coagulation activation Endothelial damage Platelet activation Microcirculatory platelet-rich thrombus formation Acute kidney injury 07

12 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 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;2:56-76 Jokiranta TS. Blood 2017;129:

13 Stx-Gb3 binding Gb3 Endocytosis Golgi Inhibition of trna-ribosome binding Cytosol Retrograde traffic ER Valerio E, et al. Toxins 2010;2:

14 Shiga toxin producing E. Coli infection Stx Stx Stx Stx Gb3 Infectious enterocolitis Stx- induced renal damage Endothelial damage TF-induced fibrin formation Complement activation bloody diarrhea renal failure Stx : Shiga toxin Gb3 : globotriaosylceramide 09

15 Pathogenesis of atypical HUS 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: Jokiranta TS. Blood 2017;129:

16 Classical and lectin pathways Alternative pathway (C3 tick-over) C3 convertase (C4b2a) C3 convertase (C3bBb) C3 C3b (C5-convertase) Factor H Factor I MAC: Membrane attack complex MCP: Membrane cofactor protein THBD: thormbomodulin C5 (activation) MAC C5-9 (formation) MCP THBD 12

17 Complement gene abnormalities in patients with ahus Noris M, et al. Clin J Am Soc Nephrol 2010;5:

18 Factor H autoantibody N-terminal C-terminal 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: Jozsi M, et al. Blood. 2008;111: Sinha A, et al. Kidney Int. 2014;85:

19 Genetic abnormalities in patients with ahus Gene Frequency in ahus, % CFH 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 Factor XII NA NA Noris M and Remuzzi G. Semin Nephrol Sep;37(5): Jokiranta TS. Blood 2017;129:

20 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

21 Diagnosis of TTP, STEC HUS and ahus TMA ADAMTS13<10% TTP TMA STEC (+) STEC-HUS TMA Secondary TMA Secondary TMA ahus 17

22 Initial recognition of ahus MAHA Thrombocytopenia Acute kidney injury Hypertension Neurologic disturbances Respiratory disturbances GI disturbances Existence of triggers Poor response to PEX 18

23 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, Hematology Am Soc 19 Hematol Educ Program. 2011;2011:15-20

24 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: Kavanach D, et al. Seminars Nephrol 2013;33:508-30

25 ahus patients characteristics at onset Fremeaux-Bacchi, et al. Clin J Am Soc Nephrol 2013;8:

26 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

27 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: Campistol JM, et al. Nefrologia 2013;33:27-45 Cataland SR, et al. Blood 2014;123: Scully M, Goodship T. Br J Haematol 2014;164:

28 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: Kavanach D, et al. Clin Am Soc Nephrol 2007; 2:591-6 Mannucci Cataland Johnson S, et al. Pediatr Nephrol 2014;29: Loirat C, et al. Pediatr Nephrol 2016;31:

29 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: Kavanach D, et al. Clin Am Soc Nephrol 2007; 2:591-6 Mannucci Cataland Johnson S, et al. Pediatr Nephrol 2014;29:

30 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: Yoshida Y, et al. PLoS One 2015;10:e Heinen S, et al. Mol Immunol 2013;54:84-8 Magro CM, et al. Am J Dermatopathol 2015;37:

31 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

32 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. 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 28

33 Management of HUS and ahus TMA Medical Emergency, Multidisciplinary approach TTP ADAMTS13<10% STEC-HUS STEC (+) PEX Supportive care steroid PEX Secondary TMA Treatment for secondary TMA ahus PEX : plasma exchange KT : kidney transplantation LT : liver transplantation PEX Eculizumab KT/LT 29

34 Management of STEC HUS 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:

35 Prognosis 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:

36 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 fresh frozen plasma or glucocorticosteroids. and their use in STEC-HUS is not recommended. Page AV, Liles WC. Med Clin N Am 2013;97: Igarashi T, et al. Clin Exp Nephrol 2014;18:

37 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: Fremeaux-Bacchi V, et al. Clin J Am Soc Nephrol 2013;8:

38 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, 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;33:27-45 Loirat C, et al. Semin Thromb Hemost 2010;36: Noris M, et al. Clin J Am Soc Nephrol. 2010;5(10): Caprioli J, et al. Blood. 2006;108(4):

39 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:

40 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 Franchini M. Clin Chem Lab Med 2015;53:

41 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 ;360: Zuber J, et al. Am J Transplant 2012;12: Lapeyraque AL, et al. N Engl J Med 2011;364: Menne J, et al. BMJ 2012;345:e4565 Legengdre CM et al. N Engl J Med 2013;368:

42 Lectin Pathway Classical Pathway Alternative Pathway Eculizumab C3 C5 Natural Inhibitors: Factor H, I, MCP, CD55 Tissue injury, TMA (?) 38

43 ESRD and Death Patient (%) More than 50% Less than 20% PEX/PI Eculizumab Caprioli J, et al. Blood. 2006;108(4): Noris M, et al. Clin J Am Soc Nephrol. 2010;5(10): Legengdre CM et al. N Engl J Med 2013;368: Fakhouri F, et al. Am J Kidney Dis Jul;68(1):84-93 Greenbaum LA, et al. Kidney International (2016) 89,

44 Eculizumab is effective in ahus 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%) NA LDH normalization 13(82%) 19 (95%) Hb improvement by 2g/dL 11 (65%) 9 (45%) egfr improvement by 15ml/min/1.73m 2 8 (47%) 1 (5%) Legengdre CM et al. N Engl J Med 2013;368:

45 Eculizumab is a safe and effective treatment in patients with ahus: outcomes by 26 weeks of treatment 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/1.73m 2 19 (86%) 22 (54%) Fakhouri F, et al. Am J Kidney Dis Jul;68(1):84-93 Greenbaum LA, et al. Kidney International (2016) 89, ; 41

46 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:

47 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: Sinha A, et al. Kidney Int. 2014;85:

48 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: Cheong HI, et al. J Kor Med Sci 2016;31: Taylor CM, et al. Br J Haematol. 2010;148:37-47 Campistol JM, et al. Nefrologia. 2015;35:

49 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

50 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

51 ขอบค ณส าหร บการฟ ง 2020 APSTH Gwangju, KOREA September 3 5, 2020