Adrian Gadano - Argentina - Tuesday 29 - Liver Transplantation Towards New Horizons

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  • Un peu chargé. Tu aurais pu faire 2 diapos distinctes.
  • Un peu chargé. Tu aurais pu faire 2 diapos distinctes.
  • Es por eso que las infecciones bacterianas son mas frecuentes en pacientes con enfremedad más avanzada
  • J’ajouterais quelque part les notions de « remplacement des fonctions de synthèse » du côté foie bioartificiel et « remplacement des fonctions d’épuration » du côté épuration extra hépatique.
  • Un peu chargé. Tu aurais pu faire 2 diapos distinctes.
  • Avec la diapo précédente, on peut illustrer le principe de l’interposition d’un circuit de dialyse à l’albumine.
  • Adrian Gadano - Argentina - Tuesday 29 - Liver Transplantation Towards New Horizons

    1. 1. Bridging Devices to Transplant: Is there need to establish a distribution criteria ? Hospital Italiano de Buenos Aires Unidad de Hígado y Trasplante Hepático Adrián Gadano, MD Sección de Hepatología Hospital Italiano de Buenos Aires Fundación Icalma
    2. 2. Acute Liver failure Liver function and histology are normal 2-8 weeks before the onset Liver Failure: Two different Scenarios…
    3. 3. “ A devastating condition, potentially reversible , which is a consequence of massive hepatic necrosis and is characterized by the presence of hepatic encephalopathy within the first 12 (24) weeks after the onset of symptoms “ Durand y Bernuau, 2006 Acute Liver Failure
    4. 4. Acute Liver failure Acute on Chronic Liver Failure Liver function and histology are normal 2-8 weeks before the onset Pre-existing damaged liver Liver Failure: Two different Scenarios…
    5. 5. Acute on Chronic Liver Failure (AoCLF) Cirrhosis…
    6. 6. Pathophysiology of Liver Failure Regeneration Cell damage Virus Drugs, Toxins, etc…
    7. 7. Jaundice, ↑ transaminases Pathophysiology of Liver Failure Coagulation Syntesis Metabolic functions
    8. 8. Initial damage Complement FAS- Antigen MAC (Membrane Attack Complex) Apoptosis Cytolisis Other hepatocyte damage Cytoquines DMArg … ? Systemic damage!
    9. 9. Shock Bacterial infections Renal failure Encephalopathy Jaundice, ↑ transaminases Pathophysiology of Liver Failure MOF Coagulation Syntesis Metabolic functions
    10. 10. <ul><li>Alteration of syntetic and metabolic functions </li></ul><ul><ul><li>Glucose </li></ul></ul><ul><ul><li>Lipids </li></ul></ul><ul><ul><li>Proteins (albumine, coagulation) </li></ul></ul><ul><li>Alteration of detoxification function </li></ul><ul><ul><li>Acumulation of toxins: NO, ammonia, lactates, aromatic AA , pro-inflammatory cytoquines, BZD, oxidative stress mediators, mercaptans… </li></ul></ul>Regeneration Cell damage Virus Drugs, Toxins, etc… Pathophysiology of Liver Failure Systemic damage!
    11. 11. AoCLF: Inflammation and hepatic encephalopathy Infection Inflammation ↑ Cytoquines (TNF, IL1, IL6) ↑ NO Oxydative stress Alt. astrocitic function Encephalopathy
    12. 12. Liver Transplantation for Acute Liver Failure Hospital Italiano 1992-2010
    13. 13. “” liver transplantation cannot be accepted as the perfect and ideal treatment for fulminant hepatic failure” S Sherlock Liver Transplantation: - Procedure risk - Overindication - Life-long immunosuppression Liver transplantation in ALF
    14. 14. <ul><li>To transplant as soon as possible those patients that will otherwise die from liver and multiorgan failure. </li></ul><ul><li>Not to transplant those patients that will survive with their native livers. </li></ul><ul><li>Not to transplant those patients that are too sick and will not tolerate the procedure or will remain with irreversible neurological damage. </li></ul>Liver Transplantation in ALF: The ideal scenario…
    15. 15. Acute Liver Failure Indication for Transplantation < 20% recovery and survival > 80% bad outcome and dead OLT emergency King’s and Clichy criteria
    16. 16. Time on the waiting list for OLT in patientes with ALF: Hospital Italiano - 2010
    17. 17. MEDICAL SUPPORT IN ALF WITH III-IV HEPATIC ENCEPHALOPATHY <ul><li>Corrección disturbios Ac. Base, Hidroelectrolíticos, PArt </li></ul><ul><li>Sedación, ARM, TAC </li></ul><ul><li>Monitoreo Neurológico, cabecera 30°, PIC </li></ul>ATB PIC  20 y PPC  50 mmHg PIC  20 o PPC  50 mmHg PIC  20 o PPC  50 mmHg PIC  20 o PPC  50 mmHg Manitol, Hemofiltración Manitol – Hiperventilacion HiperNatremia Hipotermia:32-35 °C NAC ?, Hipotermia ?
    18. 18. 20 % Outcome after inclusion on the waiting list Hospital Italiano: outcome of 119 ALF patients listed for transplantation
    19. 19. Liver Transplantation for Acute Liver Failure Hospital Italiano 1992-2010
    20. 20. Como Optimizar el Manejo de estos Pacientes ? TxH Recuperación Muerte Soporte hepático artificial ? Soporte médico
    21. 21. SOPORTE HEPATICO ARTIFICIAL Puente hacia la regeneración hepática We need a bridge… Puente hacia el trasplante hepático
    22. 22. ARTIFICIAL LIVER SUPPORT Bridge to Liver Regeneration Bridge to Liver Transplantation
    23. 23. ARTIFICIAL LIVER SUPPORT SYSTEMS Clasification <ul><li>Bioartificial liver </li></ul><ul><li>Xenogeneic support </li></ul><ul><li>Hepatocyte transplantation </li></ul><ul><li>Artificial liver Non biological </li></ul><ul><li>detoxification </li></ul><ul><li>detoxification </li></ul><ul><li>biotransformation </li></ul><ul><li>biosyntesis </li></ul>Biological
    24. 24. HIBA - 1966
    25. 26. Bio-artificial liver support * Except in a subgroup System origin hepatocytes blood/ plasma Controlled study Survival benefit ELAD USA human blood yes no HepatAssist USA porcine plasma yes no* TECA-HALSS China porcine plasma no - BLSS USA porcine blood no - RFB Italy porcine plasma no - LSS/MELS Germany porcine/human plasma no - AMC-BAL Holland porcine plasma no - HBAL China porcine plasma no -
    26. 27. HIGADO BIOARTIFICIAL <ul><li>Hepatocitos Humanos </li></ul><ul><li>Hepatocitos Porcinos </li></ul><ul><li>Síntesis urea </li></ul><ul><li>Síntesis proteica </li></ul><ul><li>Gluconeogenesis </li></ul><ul><li>Metabolización </li></ul><ul><li>de drogas </li></ul><ul><li>Hepatocitos aislados </li></ul><ul><li>Hepatocitos agregados </li></ul><ul><li>Co-cultivos </li></ul>0,5 x 10 8 - 2.0 x 10 10 células
    27. 28. IT TAKES A VILLAGE TO BUILD A LIVER BLOOD In Flow Nutrients Nature Biotech 2005;23:1237-9 Scaffold Proteins Stem cells Hedgehog Notch Wnt Signaling Factors
    28. 29. Sistemas de Soporte Hepatico <ul><li>Higado « bioartificial » </li></ul><ul><li>Principio: Perfusion extracorporal de hepatocitos (animales, humanos transformados) </li></ul><ul><li>Eficacia no demostrada </li></ul><ul><li>Tecnica discontinuada: riesgo de zoonosis (hepatocitos animales) y neoplasias (hepatocitos humanos) </li></ul>
    29. 30. <ul><li>MARS </li></ul><ul><li>Prometheus </li></ul>ARTIFICIAL LIVER SUPPORT SYSTEMS Clasification <ul><li>Bioartificial liver </li></ul><ul><li>Xenogeneic support </li></ul><ul><li>Hepatocyte transplantation </li></ul><ul><li>Artificial liver Non biological </li></ul><ul><li>detoxification </li></ul><ul><li>detoxification </li></ul><ul><li>biotransformation </li></ul><ul><li>biosyntesis </li></ul>
    30. 31. Falla Hepática Aguda Falla Hepática Aguda sobre Crónica
    31. 32. <ul><li>Alteration of syntetic and metabolic functions </li></ul><ul><ul><li>Glucose </li></ul></ul><ul><ul><li>Lipids </li></ul></ul><ul><ul><li>Proteins (albumine, coagulation) </li></ul></ul><ul><li>Alteration of detoxification function </li></ul><ul><ul><li>Acumulation of toxins: NO, ammonia, lactates, aromatic AA , pro-inflammatory cytoquines, BZD, oxidative stress mediators, mercaptans… </li></ul></ul>Regeneration Cell damage Virus Drugs, Toxins, etc… Pathophysiology of Liver Failure X Systemic damage!
    32. 33. Albumin dialysis diaMARS ® AC250 adsorber (Adsorbente de carbón activado) diaMARS ® IE250 adsorber (intercambiador de aniones) Non Biologic Liver Support MARS (Molecular Adsorbents Recirculating System)
    33. 34. Patient‘s blood Albumine MARS Albumine-bound substances (cytokines, bilirrubina, fenoles, etc) Free substances Low molecular weight Albumine 20% Oncotic gradient Albumine patient
    34. 35. Albumin dialysis (MARS ® )
    35. 36. Albumin dialysis (MARS ® ) Creatinine - 48% (p<.05) Urea - 66% (p<.05) Heemann, Hepatology 2002: 949-58
    36. 37. Albumin dialysis (MARS ® ) Ammonia - 76% (p<.05) Lactates - 57% (p<.05) Heemann, Hepatology 2002: 949-58
    37. 38. Albumin dialysis (MARS ® ) Guo LM. LIver Int 2003; 23: 16. before after p NO (µmol/L) 45 ± 20 29 ± 17 <0.01 TNF-  (pg/mL) 2.8 ± 1.7 1.8 ± 1.4 <0.01 IL-6 (µmol/L) 45 ± 30 24 ± 19 <0.01 IL-8 (pg/mL) 155 ± 121 70 ± 47 <0.01 INF-  (pg/mL) 54 ± 51 38 ± 30 <0.05 IL-4 (pg/mL) 175 ± 51 110 ± 31 <0.05
    38. 39. MARS ® in patients with acute liver failure * Mild hypothermia Schmidt LE et al. Liver Transplantation 2003; 9:290-297 MARS (8) Control (5)* p Paracetamol 6/8 4/5 Temperature 36.2 35.8 ns MAP (mmHg) +20% 0% <0.001 SVR (dyn/cm 5 /m 2 ) +46% +6% <0.001 CI (L/min/m 2 ) -20% -7% <0.001 DO2 (ml/min/m 2 ) -22% -8% ns PCWP (mmHg) 0% +11% ns
    39. 40. Albumin dialysis (MARS ® ) Sorkine, Crit Care Med 2001: 1332-6 Prothrombin index (ns)
    40. 41. MARS ® in patients with acute liver failure MARS Control p Change in ICP (mmHg) ? ? ? Change in CPP (mmHg) ? ? ? Waiting list mortality ? ? ? Survival after transplantation ? ? ?
    41. 42. MARS ® in patients with acute liver failure Schmidt LE et al. Liver Transplantation 2003; 9:290-297 Pre-MARS Post-MARS p Creatinine (µmol/L) 256 ± 235 151 ± 111 <0.05 Ammonia (mmol/L) 110 ± 41 103 ± 42 ns Lactates (mmol/L) 2.6 ± 0.7 2.7 ± 1.3 ns pH 7.42 ± 0.05 7.41 ± 0.04 ns Platelets (10 9 /L) 103 ± 60 76 ± 41 <0.05
    42. 43. MARS ® in patients with acute liver failure Schmidt LE et al. Liver Transplantation 2003; 9:290-297 <ul><li>9 patients fulfilling KCH criteria </li></ul><ul><li>4 died </li></ul><ul><li>3 recovered </li></ul><ul><li>2 transplated with one death </li></ul>Hospital Italiano: outcome of 119 ALF patients listed for transplantation
    43. 44. ARTIFICIAL LIVER SUPPORT SYSTEMS Clasification <ul><li>Bioartificial liver </li></ul><ul><li>Xenogeneic support </li></ul><ul><li>Hepatocyte transplantation </li></ul><ul><li>Artificial liver Non biological </li></ul>Biological <ul><li>detoxification </li></ul><ul><li>detoxification </li></ul><ul><li>biotransformation </li></ul><ul><li>biosyntesis </li></ul>Prometheus Can we do better ?
    44. 45. Haemodialysis Liver Support with Prometheus
    45. 46. Liver Support with Prometheus FPSA: Fractionated Plasma Separation and Adsorption Haemodialysis
    46. 47. - Duration: 4-6 hs - N° de treatments: variable Prometheus
    47. 48. a) First examination b) 4 days later
    48. 49. Blood Purif 2005;23:298–302
    49. 50. P. Krisper et al. / Journal of Hepatology 43 (2005) 451–457
    50. 51. Prometheus vs. Mars -0,10 0, 00 0,10 0,20 0,30 0,40 0,50 0,60 0,70 Urea Reduction Ratios (RR) p < 0.01 9 Patients MARS vs. 9 Patients Prometheus p < 0.05 Total Bilirubin Bile Acids Creatinin Evenepoel P, 2005 p < 0.05 * = not significant * MARS Prometheus
    51. 52. 0 5 10 15 20 25 30 35 40 1. Treatm. Total Bilirubin concentration (mg/dl) pre treatment post treatment Treatment duration 6.5 h Mo Tu 2. Treatm. We Th 3. Treatm. Fr Sa So Mo Tu 4. Treatm. We by courtesy of S. Herget-Rosenthal, U. Treichel, F. Saner, F. Pietruck, C. Broelsch, G. Gerken, T. Philipp, A. Kribben - 2006 Decrease of Bilirubin with Prometheus® OLT
    52. 53. Case report Nephrology dep. Univ. Frankfurt, Aug. 2004: 38 y, male, end stage liver failure with ascites, HE II-III, Child C, HRS, T2 listed 23 treatments, average 4.5 h, every 2nd day for 51 days By courtesy C.Betz, Frankfurt - 2006 Puente al Trasplante Disminución de la Bilirubina con Prometheus® 0 5 10 15 20 25 30 35 40 45 50 55 0 5 10 15 20 25 30 35 (days) (mg/dl) LTX total serum bilirubin
    53. 54. Treatment of Refractory Pruritus with Prometheus Rifai K, Scand J Gastroenterol. 2006 Oct;41(10):1212-7. OLT 3 - 5 Treatments
    54. 55. <ul><li>- Duración: 6 hs </li></ul><ul><li>N° de tratamientos: 3 </li></ul><ul><li>85% FHA </li></ul>
    55. 56. Apart from invaluable increase of survival rate, the application of Prometheus therapy led to a considerable economic relief of public health care costs. In comparison to the saved costs of 900,000 € for nine avoided liver transplantations including follow-up costs in the first year (regardless costs and consequences of immunosuppression for the rest of live) the expenditure of about 200,000 € for 85 performed Prometheus treatments seems to make good economic sense. In other words, cost saving is about 700,000 €. Seen from this point of view the Prometheus therapy is quite an economically meaningful therapy option in liver failure.
    56. 57. <ul><li>- 8 pacientes </li></ul><ul><li>- Duración: 6 hs </li></ul><ul><li>N° de tratamientos: 2 </li></ul>Vardar et al, Hepato-Gastroenterol 2010
    57. 58. Vardar et al, Hepato-Gastroenterol 2010
    58. 59. The challenge of Acute on Chronic Liver Failure (AoCLF)…
    59. 60. HELIOS Study Promet h eus  E uropean L iver D i sease O utcome S tudy Aim: Demonstration of clinical benefits of Prometheus ® therapy for patients with acute-on-chronic liver failure ( AOCLF) Hospitals: 10 university hospitals from 7 european countries (e.g.: Univ. Frankfurt, Hannover, Barcelona, London) Patients: 145 patients; AOCLF ( bilirubin ≥ 5 mg/dl and Child Pugh Score ≥ 10) Analysis: All Patients Subgroups: - Patients with HRS Typ 1 - Patients with MELD Score > 30 Rifai et al, AASLD 2010
    60. 61. HELIOS Study: - Decompensated cirrhosis - Age 51+30 - Etiology: Alcohol 56%, Hepatitis 20% - MELD 27+10 - Survival at 28 and 90 days SMT (n=68) vs SMT+Prometheus (n=77) acute-on-chronic liver failure (AOC) EXTRACORPOREAL LIVER SUPPORT BY FRACTIONATED PLASMA SEPARATION AND ADSORPTION (PROMETHEUS®) IN PATIENTS WITH ACUTE-ON CHRONIC LIVER FAILURE (HELIOS STUDY): A PROSPECTIVE RANDOMIZED CONTROLLED MULTICENTER STUDY Rifai et al, AASLD 2010
    61. 62. Promet h eus  E uropean L iver D i sease O utcome S tudy Study Design HELIOS Study 1. Screening phase 3 days Randomisation 1:1 2. Treatment phase 21 days 3. Follow up phase 69 days SMT SMT + FPSA (8  11x) d 21 d 0 d 28 d 7 d 14 Study visits : : SMT d 90 69 days : :
    62. 63. Day 28 Diff. ~ 23%; NS Day 90 Diff. ~ 36%; p < 0,05 Prometheus + SMT SMT Subgroup: HRS Type 1 Days Survival Probability / % Probability of survival was 36% higher in “Prometheus group” at day 90 (p=0,02) HELIOS Study Results Rifai et al, AASLD 2010
    63. 64. Subgroup: MELD Score > 30 Probability of survival was 39% higher in “Prometheus group” at day 90 (p=0.04) Day 28 Diff. ~ 15%; NS Day 90 Diff. ~ 39%; p < 0,05 Prometheus + SMT SMT Days Survival Probability / % HELIOS Study Results Rifai et al, AASLD 2010
    64. 65. Prometheus aumenta la sobrevida en AOC: - MELD score >30 (p=0.02) - Sindrome Hepatorenal tipo I (p=0.04) EXTRACORPOREAL LIVER SUPPORT BY FRACTIONATED PLASMA SEPARATION AND ADSORPTION (PROMETHEUS®) IN PATIENTS WITH ACUTE-ON CHRONIC LIVER FAILURE (HELIOS STUDY): A PROSPECTIVE RANDOMIZED CONTROLLED MULTICENTER STUDY Rifai et al, AASLD 2010 AOC MELD score >30 P<0.02 P<0.02
    65. 66. <ul><ul><ul><ul><li>Potential Candidates </li></ul></ul></ul></ul><ul><li>1. Hepato-Renal Syndrome  SI </li></ul><ul><li>2. AoCLF (MELD > 30)  SI </li></ul><ul><li>3. Severe Cholestasis  SI </li></ul><ul><li>4. Acute Liver Failure ? </li></ul>Bridging Devices in Patients with Liver Failure
    66. 67. Positive prognostic value, negative prognostic value and diagnostic accuracy of the MELD score in detecting patients with acetaminophen and non-acetaminophen-induced ALF MELD > 30 in 94% of pts who died without OLT MELD < 30 in 91% of pts who survived with medical support Wei, HPDI 2010 Yantorno, Liver Transpl 2007
    67. 68. <ul><li>Corrección disturbios Ac. Base, Hidroelectrolíticos, PArt </li></ul><ul><li>Sedación, ARM, TAC </li></ul><ul><li>Monitoreo Neurológico, PIC </li></ul>ATB PIC  20 y PPC  50 mmHg PIC  20 o PPC  50 mmHg PIC  20 o PPC  50 mmHg PIC  20 o PPC  50 mmHg Manitol, Hemofiltración Manitol – HiperNa - Hiperventilación Hipotermia:32-35 °C NAC ? , Hipotermia Prometheus… MEDICAL SUPPORT IN ALF WITH III-IV HEPATIC ENCEPHALOPATHY
    68. 69. Conclusions <ul><li>ALF and AoCLF are critical and systemic conditions, that need a multidisciplinary support and therapy in liver transplant units. </li></ul><ul><li>Mortality is closely related to the development of cerebral edema and multiorgan failure. </li></ul><ul><li>From a pathofisiological aproach, several substances that are accumulated as a consequence of impaired liver function and inflammation, may play a crucial rol. </li></ul><ul><li>Liver support using artificial liver devices has demonstrated to be able to eliminate these substances and to increase survival in a selected subgroup of patients. </li></ul>
    69. 70. Gracias!
    70. 72. Gracias!
    71. 73. Hepatology 2011

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