TMA - pogled nefrologa

Transcription

1 TMA - pogled nefrologa Andreja Marn Pernat Klinični oddelek za nefrologijo UKC Ljubljana

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3 Plazmafereza s svežo zmrznjeno plazmo metoda izbora za zdravljenje TTP/aHUS Brez plazmafereze s SZP je bila smrtnost bolnikov s TTP 95%, bolnikov z ahus pa 50% S plazmaferezo s SZP za zdravljenje akutne epizode se je preživetje izboljšalo na %

4 Razlikovanje med različnimi TMA je nujno TTP/aHUS ni več skupna diagnoza Sodobno zdravljenje ahus in TTP se razlikuje

5 Patogeneza trombotične trombocitopenične purpure TTP

6 Mutacije genov regulatornih beljakovin komplementnega sistema pri atipičnem HUS

7 Vloga komplementa pri atipičnem HUS Genetic Loss of Natural Inhibitors Leads to Chronic Uncontrolled Complement Activation Proximal Lectin Pathway Immune Complex Clearance Microbial Opsonization Classical Pathway C3 Alternative Pathway C3 + H 2 O - ALWAYS ACTIVE (Chronic) Amplification Terminal Anaphylaxis Inflammation Thrombosis Consequences C5a Potent Anaphylatoxin Chemotaxis Proinflammatory Leukocyte Activation Endothelial Activation Prothrombotic C5 Natural Inhibitors: Factor H, I, MCP, CD55 C5b-9 Membrane Attack Complex Cell Lysis Proinflammatory Platelet Activation Leukocyte Activation Endothelial Activation Prothrombotic Natural Inhibitor: CD59 Consequences Cell Destruction Inflammation Thrombosis Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4: ; Walport MJ. N Engl J Med. 2001;344: ; Rother RP et al. Nature Biotech. 2007;25: ; Meyers G et al. Blood. 2007;110:Abstract 3683; Hill A et al. Br J Hematol. 2010;149: ; Hillmen P et al. Am J Hematol 2010; 85: , International PNH Interest Group. Blood. 2005;106: ; Hillmen P et al. N Engl J Med. 1995;333:1253; Nishimura J et al. Medicine.2004;83: ; Caprioli J et al. Blood 2006;108: ; Noris M, et al. Clin J Am Soc Nephrol. 2010;5: ; George JN et al. Blood. 2010;116: ; Loirat C, et al. Pediatr Nephrol. 2008;23: ; Stahl A, et al Blood. 2008;111: ; Hosler GA, et al Arch Pathol Lab Med. 2003; 127; ; Ariceta G et al. Pediatr Nephrol. 2009; 24: Alexion1

8 Slide 7 Alexion1 Adapted from: Rother/p1257/figure1 Figueroa/p363/figure1 Kose/p671 Alexion;

9 Kronična nenadzorovana čezmerna aktivnost komplementnega sistema sproži na žilnem endotelu, trombocitih in levkocitih vnetne in protrombotične procese, kar vodi v sistemsko okluzijo malih žil in nastanek trombotične mikroangiopatije ter klinično sliko atipičnega HUS Chronic Uncontrolled Complement Activation Endothelium Activation Endothelial Swelling and Disruption Platelet Consumption Mechanical Hemolysis (Schistocytes) Platelet Platelet Activation Leukocyte Activation Platelet Aggregation Blood Clots Inflammation Occlusion Ischemia Hypoxia Modified from Desch K et al. JASN. 2007;18: Modified from Licht C et al. Blood. 2009;114: Modified from Noris M et al. NEJM. 2009; 361: Modified from Stahl A et al. Blood. 2008;111: Modified from Camous L et al. Blood. 2011;117:

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11 Razlikovanje TMA glede na starost bolnika ob začetku bolezni

12 Membranska izmenjevalna plazmafereza s svežo zmrznjeno plazmo

13 Plazmafereza odstrani škodljive snovi v plazmi in s svežo zmrznjeno plazmo nadomesti manjkajoče snovi Odstrani inibitor in zmanjša količino cirkulirajočih protiteles proti ADAMTS13 Odstrani mutirani disfunkcionalni komplementni faktor H in njegova protitelesa Odstrani prekomerno količino membranskega attack kompleksa MAC S SZP nadomestimo pomanjkanje encimov in porabljene plazemske faktorje Umiri simptome, zmanjša trombotično mikroangiopatijo in izboljša delovanje organov Prepreči cirkulatorno preobremenitev s SZP Rock GA, Shumak KH, Buskard NA et al (August 1991). "Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group". N. Engl. J. Med. 325 (6): 393 7

14 Glavne klinične značilnosti bolnikov z ahus glede na nenormalnosti komplementa in učinkovitost plazmafereze

15 Naše izkušnje s terapevtsko plazmaferezo za zdravljenje TTP/aHUS ( )

16 37 Ž, 19 M 44 ± 21 let (4 80 let)

17 Methods Membrane plasmapheresis was initiated immediately and performed once or twice daily until the platelet count and evidence of hemolysis (red cell fragmentation, LDH, Hb) have normalized 1 to 1.5 plasma volumes were replaced with fresh frozen plasma: 3606 ± 991 ml per procedure Anticoagulation - heparin was used in 24 pts - 4% trisodium citrate was used in 32 pts Infusion of 1 M CaCl 2 into the venous line attenuated hypocalcaemia due to citrate load from fresh frozen plasma and citrate as an anticoagulant Metabolic alkalosis induced by citrat load was corrected with short heparin-free hemodialysis if needed The vascular access was hemodialysis femoral venous catheter All patients were monitored for hypocalcemia and other possible side-effects of the procedure.

18 5 M in 1Ž preboleli 1-5 relapsov 3 bolniki potrebovali splenektomijo

19 Follow up period A 46-year old female patient with relapsant TTP/aHUS Year Platelets before Platelets after Plasma volume replaced No. of procedures Days of treatment Oucome x10 9 /L 223 x10 9 /L 4500 ml ok x10 9 /L 257 x10 9 /L 3200 ml ok x10 9 /L >340 x10 9 /L 5000 ml died 15 x10 9 /L Fulminant hemolytic episode during treatment with plasma exchange therapy

20 Zdravljenje ahus 1. Plazmafereza s SZP je učinkovita na začetku zdravljenja, smrtnost se je znižala s 50% na 25% 1. Nadaljnji odziv na plazmaferezo le pri polovici bolnikov - težek potek, neučinkovite plazmafereze - alergične reakcije in neprenašanja sveže zmrznjene plazme - bakterijske okužbe, težave z žilnim pristopom za plazmaferezo Kljub plazmaferezi 33-40% jih umre ali je dializno odvisnih že pri prvi bolezni 65% umre, je na dializi ali imajo višjo stopnjo KLB po prvem letu bolezni

21 Recurrent ahus M, born He developed ahus at 7 years of age - ahus recurred at 13, 15, 18 years of age - In January 2007 he was admitted with a fourth relapse of ahus at 28 years of age which led to the loss of renal function needing RRT: Plasma exchange was performed (21 days of treatment, No of procedure 11, 1 volume replaced: ml of FFP) Despite this treatment his renal function deteriorated and he underwent hemodialysis After 2 months creatinine level decreased, indicating recovery of renal function He is stage 3 CKD (creatinine mcg/l), mild hypertension, Urine: normal, no proteinuria, S-C g/l low. 1. ahus started during childhood 2. Onset was triggered with a virus like flu or tonsillitis 3. End-stage renal disease developed after relapses 4. 9/1/2007: ADAMTS13 antigen: 538 ng/ml( ) ADAMTS13 antibodies: 10 E/mL (pozit nad 9.6) 5. Wait for another ahus relaps to initiate eculizumab immediately

22 Ekulizumab inhibira delovanje komplementa EKULIZUMAB

23 Study C bolnikov z dolgotrajnim ahus in precejšnjo prizadetostjo organov kljub kronični plazmaferezi Pred ekulizumabom so bili na plazmaferezi od 2,4 do 47 mesecev 90 % bolnikov s KLB % bolnikov brez znane mutacije

24 In 100% of Clinical Trial Patients, Soliris Reduced Complement Activity, the Cause of Symptoms and Clinical Manifestations of ahus 1,2 Change From Baseline to End of Study Period P< Reduction observed in all patients after commencement of Soliris in as early as one hour 1,3.4 Reduction sustained through the end of study (26 weeks) 1,3 *Based on a pharmacodynamic assay that quantified the complement activity in patient s serum by measuring the degree of hemolysis; the measure of hemolysis is the amount of hemoglobin release as determined via spectrophotometer. Less than 20% is considered complete blockade of hemolysis. 1. Soliris (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; Soliris (eculizumab) European Public Assessment Report a 3. Licht C et al. ASH Annual Meeting 2011 Poster. 4. Alexion Data on File.

25 Patients With Long Duration of ah0-003) Chronic Uncontrolled Complement Activation Complement-Mediated TMA Burden of Interventions (PE/PI or Dialysis) Renal Function HRQoL 90% of Patients With Hematologic Normalization During Soliris Treatment 1,2 % of Patients With Hematologic Normalization 90% (18/20) Hematologic normalization* 1 Normal platelet count and Normal LDH All patients were receiving chronic PE/PI prior to study entry 1 The benefit was sustained through the entire study period (median duration 62 weeks) 2 (N=20) *For at least 2 consecutive measurements that span a period of at least 4 weeks. 1. Soliris (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; Soliris (eculizumab) European Public available on [accessed December 15, 2011]. Alexion3 Alexion5 Alexion4 1

26 Slide 24 1 SmPC/p11/para 3/lines Andreja; Alexion3 SmPC/p11/para 5 Alexion; Alexion4 EPAR p68/para2 Alexion; Alexion5 SmPC/p12/Table 5 EPAR/p112/para2/lines 6-7 Alexion;

27 Patients With Long Duration of ahus (C08-003) Chronic Uncontrolled Complement Activation Complement-Mediated TMA Burden of Interventions (PE/PI or Dialysis) Renal Function HRQoL Median (range) TMA Intervention Rate (per patient per day) 100% of Patients Eliminated PE/PI and Did Not Require New Dialysis During Soliris Treatment 1, ( ) Before Soliris (N=20) P< (0-0) On Soliris Treatment (N=20) In every patient 1,2 Elimination of PE/PI AND No new dialysis Reduction from 1,2 Approximately median (range) 1.5 ( ) interventions per patient per week prior to Soliris treatment to 0 interventions in all 20 patients (P<0.0001) during the entire study period The benefit was sustained through the entire study period (median Soliris 62 weeks) 2 TMA intervention rate: Number of plasma exchange or plasma infusion interventions and number of new dialyses required per patient per day. 1. Soliris (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; Soliris (eculizumab) European Public Assessment Report available on [accessed December 15, 2011]. Alexion11 Alexion7 Alexion10 Alexion9 Alexion8 Alexion6

28 Slide 25 Alexion6 EPAR/p44/Table 29 SmPC/p13/Table 5/row 1 Alexion; Alexion7 Alexion8 Alexion9 EPAR p44/table29 Alexion; SMPC p12/para5 Alexion; EPAR p44/table 29 calculation 0.23 (daily rate) X 7 days = weekly rate of ~1.5 Alexion; Alexion10 EPAR p44/table 29 Alexion; Alexion11 EPAR p68/para2 Alexion;

29 Study C bolnikov z ahus in s progresivno TMA, vsi na plazmaferezi 41% bolnikov že s transplantirano ledvico 24% bolnikov brez znane mutacije

30 Study C08-002

31 Study C08-002

32 Plazmafereza s SZP je urgentna metoda izbora za zdravljenje TTP/aHUS 1. pričetek je akuten, klinični potek je fulminanten, bolezen je življenjsko ogrožujoča s hudo obolevnostjo in visoko umrljivostjo 1. Izvid aktivnosti ADAMTS13 dobimo v 24 urah, med vikendom ni možen 2-3 dni Zato takojšnji začetek zdravljenja s plazmaferezo pri ahus nato prehod na ekulizumab