Critical combined conference

1. Critical combined conference 2014.02.21 R5 杜文志

2. Personal Profile • Name:戴X榮 • Age : 50-year-old • Gender: male • Blood type: O+ • Admission date: 2013-12-10 • Dischargedate:2014-02-12

3. Personal Profile • Systemic disease: • 1. Liver cirrhosis Child-pughscore C, with massive ascites • 2. Chronic hepatitis B under baraclude use. • 3. Anemia • 4. GV, EV bleeding s/p band ligation

4. MAIN HOSPITAL COURSES 2013/12/09 Tarry stool with abdominal fullnessER AnemiaBlood transfusion Hepatic encephalopathylactulose enema. Massive ascitesparacentesis with 5000c.c ascites(transudate) 7D admission persistent tarry stoolDuring EGD, desaturation was notedintubation for impending respiration failure Transfer to 3A2 12/10 12/10

5. MAIN HOSPITAL COURSES 12/10 ~12/18 • 12/13 EGD: EV with red color signs, s/p band ligation x3, and one duodenal ulcer keep Glypressin and PPI use weaning and extubation on 12/16 12/18 ~12/21 Transfer to 7D ward Liver function descendingLiver transplant evalaution and transfered to 9B

6. MAIN HOSPITAL COURSES 12/21 ~01/05 • Liver donar liver transplant (Son Blood type:B+) Anti-A IgG and Anti-B IgG titer: x128 01/03 Rituximab 01/05 Tacrolimus (0.5mg, Q12H)+ MMF (500mg, Q12H)+Solu-medrol (40mg, QN) DFPP during 01/05-01/14 (QOD, total 5 course) With one extra course for AK clot at 1/10

7. MAIN HOSPITAL COURSES Tacrolimus (0.5mg, Q12H)+ MMF (500mg, Q12H)+Solu-medrol (40mg, QN) DFPP during 01/05-01/14 (QOD, total 5 course) With one extra course for AK clot at 1/10 1/10 Anti-A/B IgG titer: 64/32 1/13 Anti-A/B IgG titer: 32/16 inform high risk for rejection 01/05 ~01/14 Liver transplantation 01/15

8. Final diagnosis • Liver cirrhosis Child-pugh score C status post ABOi living donor liver transplantation • Chronic hepatitis B under baraclude use • GV, EV and DU bleeding status post band ligation

9. Discussion • ABO-incompatible liver transplantation

10. ABO-incompatible organ transplantation • May result in severe antibody-mediated rejection (AMR) and early graft loss • In USA • Poor outcomes combined with improvement in results using deceased-donor allograftslimit ABOi transplantation • In Japan • extreme lack of available deceased-donor kidneys encouraged investigation into desensitization for ABOI/living-donor allografts

11. Early trials of ABO-incompatible livertransplantation • In the 1980s and the early 1990s • Outcome was extremely poor, with severe rejection crises, hepatic artery thrombosis and intractable intrahepatic bile duct injury • single organ disseminated intravascular coagulation (Single organ DIC) • deposition of antibody to sinusoidal and arteriolar endothelium, and hemorrhagic necrosis of the liver parenchyma • Intense immunosuppression and plasmapheresis had little influence AmJ Pathol 1988;132:489–502. Lancet 1990;336:519–23.

12. 2 types of graft failure • Liver necrosis • 1–2 weeks after transplantation, leading to massive graft necrosis within a month • Usually >8-year-old • Intrahepatic bile duct injury • slowly 2–3 months after transplantation, with development of extensive irregularities of the intrahepatic bile duct, resulting in graft failure • Usually >1-year-old • Adult has very poor outcome compared to child Transpl Int 2007;20:675–81

14. Kidney transplantation: the first to overcome the ABO blood group barrier • In 1985, Alexandre et al, antibodyremoval by • plasmapheresis, splenectomy, combined with intensive immunosuppressionwith carcineurin inhibitors, steroids and cyclophosphamide • ABOi kidney transplantation spread rapidly, and • 1025 had been performed in 92 institutions by the end of 2006 • In ABOi liver transplantation: Success was reported sporadically, but reproducibility was poor until the end of the 1990s Transplant Proc1985;17:138–43.

15. Portal vein infusion therapy (PVIT) • In 1998, Tanabe M et al developed a novel anti-rejection regimen employing PVIT in 2 successful cases • Protocol include • multiple perioperative plasmapheresis • Splenectomy • systemic triple immunosuppressive regimen consisting of tacrolimus, methylprednisolone and cyclophosphamide or azathioprine. Transplantation 2002;73:1959–61

16. Portal vein infusion therapy (PVIT) • Theory: • Agents with a wide spectrum of action must be used after ABOi liver transplantation to control ‘single organ DIC’ • local prophylactic therapy may be more effective and favourable than systemic therapy

17. Portal vein infusion therapy (PVIT) • Methylprednisolone • wide spectrum of anti-inflammatory and immunosuppressive effects • Prostaglandin E1 • improves microcirculation through vasodilatation and inhibition of platelet aggregation • Gabexate mesilate • inhibits platelet aggregation, thrombin and other coagulation factors

18. Portal vein infusion therapy (PVIT) • increase of the 2-year adult recipient survival rate after ABO-I LDLT in Japan from approximately 40% to 60% since 2002 Isyoku 2005;40:518–26

19. Complications of PVIT : Portal vein thrombosis • Technique to avoid this complication • catheter is inserted from the middle colic vein, preserving blood flow from the inferior mesenteric vein • Tip of the catheter should be placed peripheral to the superior mesenteric vein, because deep insertion beyond the portal vein anastomosis induces thrombosis Department of Internal Medicine

20. Hepatic arterial infusion therapy (HAIT) • In 2005, Kyoto et al developed • to avoid portal vein thrombosis caused by PVIT • theoretically more appropriate than PVIT because the intra-hepatic bile duct is only supplied by hepatic artery Ther Apher Dial 2005;9:285–91.

21. HAIT vs PVIT • retrospective review of the Japanese national registry has shown that the graft survival is not significantly different • The incidence of catheter-related complications was lower in HAIT • However, the complications of bleeding or thrombosis were more life threatening in HAIT Hepatology 2008;47:143–52.

22. Rituximab in ABO-incompatible liver and kidney transplantation • Most of the episodes of AMR occur within 2–7 days of transplantation • “Accommodation” : usually induced by 1–2 weeks after transplantation. Once accommodation is established, AMR does not occur

23. Rituximab in ABO-incompatible liver and kidney transplantation • Prophylactic use of rituximab in 2002 improved outcome of ABOi liver and renal transplantation dramatically in Japan • In 2004, combine therapy with • perioperative plasmapheresis + rituximab • splenectomy, • postoperative PVIT • systemic immunosuppression with carcineurin inhibitors, steroids, and antimetabolites • 3-year survival is 76%, which is almost identical to ABO-identical or -compatible cases

25. Rituximab in ABO-incompatible liver and kidney transplantation • Rituximab prophylaxis acted synergistically with local graft infusion, with current recipient survival remarkably improved to nearly 80% (almost same as that of ABO-identical or –compatible cases) Hepatology 2008;47:143–52.

26. Clinical significance of splenectomy • Spleen is a major antibody-producing organ, containing large amounts of B cells and plasma cells • Splenectomy in ABOi transplantation remains controversial Hepatology 2008;47:143–52..

27. Clinical significance of splenectomy • ABOi kidney transplantation under conventional immunosuppressive therapy, the incidence of AMR was lower in splenectomized patients • Mor et al. used plasma exchange and quadruple immunosuppression, including cytoxan, prednisone, OKT3 and Neoral, but did not splenectomize any of their patients • 30% early graft loss attributable to AMR • even this strong immunosuppressive regimen did not substitute for splenectomy Hepatology 2008;47:143–52.. Transplantation 1995;59:986–90.

28. Clinical significance of splenectomy • Kyoto group: Rituximab administered earlier than 7 days before transplantation combined with HAIT without splenectomy • terminated AMR and increased the 1-year survival rate to 80% • early prophylaxis with rituximab might replace splenectomy Liver Transpl 2007;13:579–88.

29. Intravenous immunoglobulin(IVIG) • Mechanism • blockade of Fc receptors on mononuclear phagocytes, direct neutralization of alloantibodies, inhibition of expression of CD19 on activated B cells, inhibition of complement and inhibition of alloreactive T cells • IVIG was used with plasmapheresis for presensitized recipients or rescue treatment for AMR Am J Transplant 2003;3:653–64.. Transplantation2004;78: 1225–1228. J Clin Apher 2008;23:55–62.

30. IVIG: omitting local graft infusion? • In 2009, Kyusyu group reported successful use of IVIG for induction therapy in adult ABOi LDLT • rituximab, plasma exchange, splenectomy and postoperative IVIG (0.8 g/kg) were employed. • all four recipients survived and one developed reversible AMR Transplantation 2009;88:303–7.

31. Role of Plasmapheresis forABO Incompatible Living Donor Liver Transplantation • From June 1990 to November 2004, 1010 patients underwent 1060 LDLT cases at Kyoto University Hospital. • 139 LDLT cases (13.1%) received ABO-incompatible living-donor liver grafts Ther Apher Dial, Vol. 9, No. 4, 2005

32. Relationshipbetween complications and preoperativeanti-IgM/anti-IgGtiter Ther Apher Dial, Vol. 9, No. 4, 2005

34. Plasmaphresis– rescue therapy

36. Plasmapheresis - rescue treatment for AMR • Used with IVIG for presensitized recipients or rescue treatment for AMR Am J Transplant 2003;3:653–64.. Transplantation2004;78: 1225–1228. J Clin Apher 2008;23:55–62.

37. Plasmapheresis - Early preoperative desensitization • Early preoperative desensitization (such as rituximab and plasma exchange )  the key to successful ABOi LDLT • The Japanese registry : • if the donor-specific anti-blood group antibody titer was more than x16 at the time of LDLT • incidence of AMR was significantly greater Hepatology 2008;47:143–52...

38. Plasmapheresis - Early preoperative desensitization • Preoperative plasma exchange should be performed unless the original titres are x16 or less • If re-evaluation of the titer > x256combine with local graft infusion and/or IVIG Hepatology 2008;47:143–52...

39. THANKS FOR YOUR LISTENING