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Hemolytic Uremic Syndrome 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 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 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 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;361:1676-87 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, Eclampsia, preeclampsia, HELLP Drugs Autoimmune disease (SLE, scleroderma) Malignancy and chemotherapy Malignant hypertension Glomerulopathy TTP : thrombotic thrombocytopenic purpura 06 USS : Upshaw-Schulman syndrome Pathogenesis of HUS STEC- Complement infection dysregulation Hemolysis Endothelial damage Platelet activation Coagulation 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 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;129:2847-56 08 Stx-Gb3 binding Gb3 Endocytosis Inhibition of tRNA-ribosome Golgi binding Cytosol Retrograde traffic ER Valerio E, et al. Toxins 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 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;361:1676-87 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 autoantibody 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, Hematology 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 .
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