Thrombotic Microangiopathy (TMA) The Clinical Facets of TMA

Transcription

1 International Consensus on Management Atypical Hemolytic Uremic Syndrome in Children Loirat C. et al. Pediatr Nephrol 31: 15-39, 2016 Ruth A. McDonald, MD Professor and Vice Chair Clinical Affairs Department Pediatrics, University of Washington Pediatrician In Chief, Seattle Children s Hospital Thrombotic Microangiopathy (TMA) Hemolytic Anemia Activated Platelets (Thrombocytopenia) Endotheliosis The Clinical Facets of TMA Infection Induced Shigatoxin HUS Strep Pneumoniae HUS Disorders of Complement Regulation (ahus) Hereditary Acquired eg. antibodies Metabolism Mediated Cobalamin Deficiency Drug Mediated Hypertension Mediated TMA ADAMTS 13 Mediated (TTP) Hereditary Acquired Pregnancy Coagulation Mediated (DIC) Malignancy Connective Tissue Disorders SLE Antiphospholipid syndrome Pediatr Nephrol Apr;26(4):

2 Classification of TMA Rule out HUS with Coexisting Disease/ Condition In children, mostly in those who have marrow transplantation Some due to drugs Rare due to malignant hypertension Reports of autoimmune disease and HUS Malignancy DIC Infection (HIV) Rule out HUS Associated with S. Pneumonia Develops in 0.5% children after pneumococcal disease May be a complication of influenza A Pathophysiology: - Neuraminidase cleaves sialic acid exposes Thompson- Friedenreich antigen (TF antigen) and bound by IgM - Desialyation by neuraminidase disrupts CFH binding sites which results in unregulated complement activation Diagnosis - Culture, soluble polysaccharide, 16s rrna PCR - Direct coombs, TF antigen detection

3 Rule out Influenza A/H1N1 HUS May be an independent cause of HUS or trigger HUS in patients with complement dysregulation (mostly MCP mutation) Influenza A culture, antigen detection, PCR nasal swab Rule out Thrombocytopenic Purpura (TTP) von Willebrand Factor Multimeric glycoprotein Essential for both platelet adhesion and aggregation The largest multimers of VWF are the most effective to act as a bridge between platelets and form platelet aggregates If things get carried away spontaneous platelet thrombi in the microvessels To the rescue. VWF cleaving protease (ADAMTS 13) 13 th member of the A Desintegrin-like And Metalloprotease with ThromboSpondin type 1 motif family

4 ADAMTS13 Deficiency Measure ADAMTS13 activity and antibodies Inherited TTP - VWF-cp/ADAMTS13 activity is zero - Due to mutations in genes for ADAMTS13, 9q34 - Neonatal presentation Acquired/Idiopathic TTP - Inhibitor/antibody to ADAMTS13 Therapy - Plasma infusion/exchange - Immunosuppression Rule out STEC-HUS Develops in 22% of infected patients Diarrhea prodrome E. coli O157:H7 most common Shiga-toxin Directly activates the alternative compliment pathway Interferes with complement regulation by binding to CFH

5 Rule out STEC-HUS Stool or rectal swab - Culture sorbitol MacConkey Agar for 0157:H7 - Culture selective media for non-0157:h7 - PCR for Stx genes - Immunologic tests for free Stx genes, or 0157:H7 LPS antigen Serum for antibody against STEC serogroups Can trigger ahus in 1% of patients with complement mutation (mostly MCP) Rule out Cobalamin C Deficiency High homocysteine and low methionine plasma levels and increased methyl-malonic acid in plasma and/or urine Diagnosis confirmed by MMAHC direct sequencing Two patients have been reported with Cbl-C deficiency and mutations in complement regulators (1 CFH and 1 MCP mutation) ahus likely Measure C3, C4, CFH, CFI + CFB Anti CFH antibodies MCP surface expression on leukocytes Genetic screening

6 Complement Pathway Dysregulation Lectin Pathway Classical Pathway Alternative Pathway Proximal Immune complex clearance Microbial opsonisation Weak anaphylatoxin C3a + Gain of Function Mutations: C3, CFB C3 C3 + H 2 O: always active (chronic) Amplification C3b ic3b C5-convertase Thrombomodulin Natural Inhibitors: Factor H, I, MCP Terminal Anaphylaxis Inflammation Consequences Thrombosis C5a Potent anaphylatoxin Chemotaxis Pro-inflammatory Leukocyte activation Endothelial activation Pro-thrombotic C5 C5b C6 C7 C8 C9 C5b-9 Membrane attack complex Cell lysis Pro-inflammatory Platelet activation Leukocyte activation Endothelial activation Pro-thrombotic Cell destruction Consequences Inflammation Thrombosis Ongoing Research in ahus Mutations Most genetic mutations have been discovered in the past 20 years % of patients with ahus have no identifiable genetic mutation 2 Link with RCA CFH mutations (SCR20) CFI mutations C3 mutations Thrombomodulin mutations Link with low C3 Homozygous CFH deficiency Heterozygous CFH deficiency Hybrid (CFH-CFHRI) DGKE mutations Association with low CFH MCP mutations Anti-FH auto-antibodies Plasminogen gene mutations ΔCFHR1/ΔCFHR3 deletion Homozygous MCP deficiency CFB mutations 1. Timeline adapted from: Le Quintrec M et al. Semin Thromb Hemost 2010;36: ; 2. Noris M et al. Clin J Am Soc Nephrol 2010;5: Why Genetic Screening? Confirmation that the disease is complement-dependent Establishing prognosis, risk of relapses and ESRD Genetic counselling to parents and family Decisions for kidney transplantation: choice of the donor, treatment schedule to prevent or treat post-transplant recurrence, decision of combined kidney-liver transplantation Further prospective studies are required to establish the safety of complement blockade treatment discontinuation, according to the genetic background

7 Genetic Screening First episode of ahus: - If no causative disease - no STEC infection - no severe ADAMTS13 deficiency - no hyperhomocysteinemia /methyl-malonic aciduria Start genetic screening without delay if - Relapse of HUS - Familial history of non-synchronous HUS - Pregnancy/post-partum-HUS - De novo post-transplant HUS Genetic screening required before kidney tx for ahus Not justified for STEC-HUS, unless this diagnosis was uncertain/ unproven Genetic Screening Screening for mutations in CFH, CFI, MCP, C3, CFB, THBD, plasminogen and DGKE by direct sequencing or Next Gen Screen for CFH hybrid gene and copy number variation in CFH and CFHRP 1 and 3 Eculizumab: Humanized Anti-C5 Antibody Human Framework Regions No mutations Germline CL CH1 Hinge Complementarity Determining Regions (murine origin) CH2 Human IgG 2 Heavy Chain Constant Region 1 and Hinge (eliminates Fc receptor binding) CH3 Human IgG 4 Heavy Chain Constant Regions 2 and 3 (eliminates complement activation) IgG = immunoglobulin G. Please see full prescribing information for Soliris (eculizumab). 1. Soliris (eculizumab). Prescribing information. Alexion Pharmaceuticals, Inc.; 2014; 2. Rother R et al. Nat Biotech. 2007;25:

8 Eculizumab Co mp le me nt Ca sc ad e 2,3 Eculizumab Proximal C3 C3b C3a Eculizumab binds with high affinity to C5 1,2 Terminal complement - C5a and C5b-9 activity blocked 1,2 Terminal C5 C5b C5a C5b-9 Proximal functions of complement remain intact 1,2 Weak anaphylatoxin 2,4 Immune complex clearance 2 Microbial opsonization 2 1. Soliris (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; Rother RP et al. Nature Biotech. 2007;25(11): Walport MJ. N Engl J Med. 2001;344(14): Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3): Treatment Clinical Diagnosis ahus Eculizumab first line, avoid PE Anti-CFH antibody positive see algorithm If on PE/PI - Not responding after 5 Rx- switch to eculizumab - Any extra-renal manifestations switch to eculizumab - Continue if responding with - Full hematologic remission - Normal renal function - No hematuria or proteinuria - No multidrug resistant hypertension - On a schedule compatible with daily activity - Without catheter complications - No plasma intolerance Anti Factor H Antibody PE without immunosuppression poor outcome - Death 9% - Relapse in 58% - CDK in 39% - ESRD in 27% Dragon-Durey MA et al. JASN 21: , 2010

9 Anti Factor H Antibody PE with immunosuppression 138 Indian children - 77% received PE and oral pred, cytoxan/ritux - Hematologic remission significantly higher - Significant reduction egfr < 30 or death - Anti-CFH antibody titer (> 2000 AU/ml) guided therapy with steroids, MMF/AZA Sinha A et al. KI 85: , 2014 Algorithm Anti-CFH Antibodies First episode of ahus Eculizumab (or PE if eculizumab not available) within hours Positive for anti-cfh antibodies No or mild extra-renal manifestations Severe extra-renal manifestations Continue eculizumab Consider adding corticosteroids and/or MMF in attempt to reduce antibody titer Efficiency / benefits to be established Switch to PE or continue PE + cyclophosphamide pulses (x2-5) or rituximab +corticosteroids Consider combining PE with eculizumab + cyclophosphamide pulses or rituximab +corticosteroids Stop PE / eculizumab when anti-cfh antibody titer < 1000 AU/ml Maintenance treatment with MMF + corticosteroids, guided by anti-cfh antibody titer Consider treatment withdrawal after 1 year in patients with stabilized remission of HUS, anti-cfh antibody titer < 1000 AU/ml and normal C3 Further studies are required to document which option is the best for which patient Assessment of Blockade Most have full blockade between doses Consider assessing at day 7, before 2 nd dose Children less than 40 kg Nephrotic syndrome If not responding or relapse between doses Trough levels eculizumab Neutralizing antibody C5 polymorphism in Asian patients

10 Testing of Blockade CH50 is most available, ecu should suppress < 10% of normal In trials, most patients had suppression of CH50 and eculizumab trough levels > 150 υg/ml In PNH patients, ecu trough levels > 100 υg/ml reduce CH50 where levels < 50 υg/ml do not Hillman P et al. Br J Haematol 162:62-73, 2013 Soluble serum C5b9 (MAC) levels can still be elevated even when patient in remission Noris M, et al. Blood 124: , 2014 Volokhina EB et al. Clin Exp Immun, 2014 Alexion no longer offering eculizumab trough levels or neutralizing antibody testing Brad Dixon, Cincinnati Children s, offers trough level, CH50 and soluble serum MAC testing Treatment Burden and Cost Long term IV infusions may lead to vascular access obstacles Twice monthly IV treatment particularly if performed in hospital may be unacceptable as a life-long social commitment Access to eculizumab both logistically and financially may be limited in some settings Tapering Not recommended If stretch out interval between treatments or decrease dose should monitor eculizumab trough level and CH50 Cugno M et al recently reported success in tapering patients who maintain CH50 activity < 10% Cugno M et al. J Throm Haemost 12: , 2014

11 Discontinuation Limited experience - prospective trials needed first in those who still have good native kidney function Unknown relapse rate after discontinuation in those who have survived with renal function Withdrawal should not be considered Life-threatening initial presentation or relapses (neurologic, cardiac) Those who did not fully recover normal renal function Consider withdrawal MCP mutation Other or unknown mutations, postpone until greater than 3-5 years of age because of less frequent childhood illness Strict monitoring (twice weekly urine dip) for early detection of relapse and immediate re-initiation of eculizumab Ardissino G et al. AJKD 64: , 2014 Kidney Transplant Donor Selection Deceased donor or non-related living donor Transplantation can be considered in a well informed recipient and/or donor provided that eculizumab will be available to prevent or treat HUS recurrence Related living donor The mutation found in the recipient has an indisputable role in the pathogenesis of ahus and is not found in the Low risk of HUS for donor Living-related donor donor transplantation can be done Assessment of the risk of ahus in the donor The donor has the same mutation as the recipient - The role of the variant found in the recipient is uncertain (unreported and with unknown functional consequences - No mutation identified in the recipient or the donor High risk of HUS for donor Living-related donor transplantation should not be done Intermediate risk of HUS for the donor who may share an unknown risk factor with the recipient Prophylaxis Against Recurrence High risk CFH, C3/CFB gain of function mutation Prior graft lost due to recurrence Prophylactic eculizumab Intermediate risk CFI mutation Combined MCP mutation Prophylactic eculizumab or PE Low risk DGKE mutation Isolation MCP mutation No mutation identified Low anti-cfh antibody titer No Prophylaxis

12 Protect Against Endothelial Damage Delayed graft Function Infections, mostly CMV Immunosuppressants Rejection Hypertension / atherosclerosis Avoid Prolonged cold time Non-heart beating donor Prefer young deceased donor Consider living-donor CMV prophylaxis CNI are not contraindicated CNI-free mtor-based immunosuppressive regimens should be avoided Avoid transplantation across positive crossmatch and preformed donor-specific antibody ACEI / ARB / statins Conclusions Geographical disparity in treatment availability due to $ of eculizumab is a major problem Anticipate cost may fall if there are other approved indications and as new agents emerge Need carefully designed studies and registry data to establish safe withdrawal of treatment to reduce treatment burden to the patient and overall cost to health care Questions Insert Picture of CJ