Program Information

1. Program Information

2. Principles of Transplantation Karl D. Pilson MD Suresh Agarwal MD, FACS, Boston University Medical School Boston Medical Center Boston, MA

3. Principles of Transplantation • Advances in immunology and pharmacology have greatly increased graft survival in organ transplantation • Kidney graft survival 90%, 86%, 78% at 1, 3 and 5 yrs. Respectively • Liver graft survival 87%, 84% at 1 and 5 years • Cardiac graft survival 90%, 80% at 1 and 5 years • Pancreas graft survival 75%, 70% at 1 and 5 years

4. Hyper acute Rejection • Techniques such as mixed lymphocyte culture to pre-screen patients make this a rarity. Pre-formed, specific, cytotoxic antibodies in recipient react with vascular endothelium in the graft activating the complement cascade with subsequent thrombosis of the graft. Irreversible and often occurs in the OR.

5. Acute Rejection • Usually occurs 4-7 days after transplantation but may subsequently occur due to withdrawal of medications • May occur through T-cells directly recognizing donor antigens with MHC molecules and releasing IL-2 with development of CD-4/8+ effector T-cells which cause antigen-specific damage to the graft directly or via the release of cytotoxic antibodies • May also occur via stimulation of Th2 cells with production of IL-4/IL-5 promoting the production of B-cells and release of graft specific antibodies

6. Chronic Rejection • Occurs months to years after transplantation and is due to proliferation of endothelial cells in the graft vascular lumen. May result from indirect allorecognition of the graft by host T-cells • Both acute and chronic rejection are potentially reversible with immunotherapy • All rejection is likely due to activation of graft endothelium by the inflammatory process

7. Cell Types in Rejection • Most immunosuppressive drugs target T-cells but many cell types are involved in rejection • B-cells are known to reside in the graft forming an intragraft tertiary lymphoid organ • Antibody therapy targeting B-cells are increasingly important in treating rejection

8. Post-operative care of the Transplant Patient • General principles of care are similar to that of most critical care patients with specific attention to infection, graft function and immunosuppressive regimens

9. Post-Transplant Infection • Consider things potentially missed pre-op. Dental abscesses, dialysis catheters, surgical site infections, hematomas, bilomas, urinomas • Latent infections such as CMV may become active post-transplant • Travel history consider Coccidioides, Blastomyces, Histoplasma, etc. • Prophylaxis for Pneumocystis and Nocardia is important

10. Antimicrobial- Immunosuppressive interactions • Azole group on macrolides and anti-fungal agents are potent CYP inhibitors and increase levels of calcineurin inhibitors • Quinolones increase CSA levels • Aminoglycosides and other known nephrotoxic agents will generally increase the nephrotoxic effects of calcineurin inhibitors

11. Kidney Graft Function • A steady reduction in bun and creatinine along with a vigorous urine output is reassuring • Diuretics may be useful but at the discretion of the transplant surgeon as opinions vary • Post-operative complications such as hematomas, urinomas, ureteral leakage and vascular thrombosis may be reliably diagnosed with ultrasound modalities • As with all transplants early diagnosis of problems is the key to graft survival

12. Post-transplant management • Kidney- Expect high urine output and replace fluids as needed • Generally enteral route can be used early • Hypertension is common • Hyperkalemia is common • Early ambulation • Early ultrasound (24 hrs.)

13. Liver Transplantation • Lack of donors and liver regeneration has led to increased use of split livers • Living related donor is increasing • Primary non-function can be as high as 9% necessitating re-transplant • Vascular complications between 5-9% easily diagnosed with US

14. Liver Transplantation • Biliary complications are most common as high as 20% • Early diagnosis of biliary complications with prophylactic antibiotic use and percutaneous drainage have drastically reduced morbidity

15. Pancreas Transplantation • In whole pancreas transplantation the donor duodenum may be anastomosed to the sm. Bowel or bladder • Rejection is the major cause of graft loss. • Glucose intolerance occurs late in rejection so it is often diagnosed late

16. Lung Transplantation • May be done with or without heart. • Usual signs of declining pulmonary function often indicate rejection • Transbronchial biopsy and BAL useful for diagnosis • Absence of lymphatic drainage make the transplant highly susceptible to fluid overload

17. Lung Transplant • Poor vascularity of bronchi make the anastomosis highly susceptible to leakage which can be catastrophic • Low airway pressures and early extubation are critical • Collections in the mediastinum can be rapidly lethal

18. Immunosuppression • Steroids remain a mainstay • Antimetabolites, azathioprine (imuran) and mycophenolate mofetil (cellcept) • Calcineurin inhibitors, cyclosporine (sandimmune, neoral) and tacrolimus (prograf, FK 506) • Proliferation signal inhibitors, sirolimus (rapamune), everolimus • Polyclonal and monoclonal antibodies

19. Corticosteroids • A mainstay of post-transplant immunosuppression • Many deleterious effects • Growing emphasis on early withdrawal of steroids in transplant

20. Antimetabolites • Azathioprine (Imuran) Purine antimetabolite derivative of 6-mercaptopurine • Mycophenolate mofetil (Cellcept)

21. Calcineurin Inhibitors • Cyclosporin (Sandimmune, Neoral) The first T-cell selective agent, nephrotoxic • Tacrolimus (Prograf, FK 506) • Proliferation signal inhibitors Sirolimus (Rappamune), Everolimus

22. Calcineurin Inhibitors

23. Mono and Polyclonal Antibodies • (ATG)Antithymocyte globulin-Gamma globulin from rabbits, binds to multiple T-cell receptors and is cytotoxic • OKT3- Anti CD3 antibodies cause internalization of the receptor preventing antigen recognition • Daclizumab- Anti CD25, likely binds to IL-2 receptor of activated T-cells, does not cause depletion

24. Antibodies • Campath (Alemtuzumab) Anti CD52 on multiple different lymphocytes causing lympholysis • Infliximab (Remicade) Anti TNF, binds to receptor and prevents TNF activation of lymphocytes

25. Treating Acute Rejection • High dose corticosteroids- methylprednisolone 500-1000mg/day for 3 days followed by a taper • Mono or polyclonal antibody therapy for 1-2 wks. • Reassessment of the patient’s current immunosuppressive regimen

26. Strategies • Induction therapy-For patients at high risk for rejection or to avoid CNI in dysfunctional transplant. Anti-CD25, OKT3, ATGAM • Maintenance therapy, usually triple therapy. • Studies are ongoing evaluating early steroid withdrawal

27. Organ Donation • Scarcity of organs for transplant • Brain death and cardiac dysfunction • Brain death and endocrine dysfunction • Support of the potential donor • Donation after cardiac death (DCD) • Early involvement of the OPO

28. Parasuraman R, Samarapungavan D, Venkat K, Updated principles and caveats in the management of infection in renal transplant recipients. Transplantation reviews 24 (2010) 43-51 Colledan M, Split liver transplantation: technique and results Chiang A, Platt J, The role of antibodies in transplantation. Transplantation Reviews 23 (2009) 191-198 Zarkhin V, Chalasani G, Sarwal M, The yin and yang of B-cells in graft rejection and tolerance. Transplantation reviews 24 (2010) 67-78 References

29. Vo A, Peng A, Toyoda M, Kahwaji J, Cao K, Lai C, Reinsmoen N, Villicana R, Jordan S, Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation Chadban S, Morris R, Hirsh H, Bunnapradist S, Arns W, Budde K, Immunosuppression in renal transplantation. Transplantation reviews 22 (2008) 241-251 Jimenez C, Lopez M, Gonzalez E, Selgas R, Ultrasonography in kidney transplantation: value and new developments References Cont.

30. D’Alessandro A, The process of donation after cardiac death: a US perspective. Transplantation reviews 21 (2007) 230-236 Goodman and Gillman’s Pharmacology, McGraw-Hill Co. 2005 Francis D, Transplantation surgery: Blackwell Co; 2006 Wood K, McCartney J, Management of the potential organ donor. Transplantation reviews 21 (2007) 204-218 References Cont.