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

™ Page 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

™ Page 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.

™ Page 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

™ Page 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

™ Page 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

™ Page 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

™ Page 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

™ Page 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

™ Page 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

™ Page 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.)

™ Page 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

™ Page 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

™ Page 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

™ Page 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

™ Page 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

™ Page 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

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

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

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

™ Page 22 Calcineurin Inhibitors

™ Page 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

™ Page 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

™ Page 25 Treating Acute Rejection High dose corticosteroids- methylprednisolone mg/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

™ Page 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

™ Page 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

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

™ Page 29 References Cont. 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) Jimenez C, Lopez M, Gonzalez E, Selgas R, Ultrasonography in kidney transplantation: value and new developments

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