PROPERTIES Allow user to leave interaction: Show ‘Next Slide’ Button: Completion Button Label: Anytime Show always View Presentation Principles of Transplantation Karl D. Pilson MD Suresh Agarwal MD, FACS, Boston University Medical School Boston Medical Center Boston, MA ™ 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 3 Hyper acute Rejection • Techniques such as mixed lymphocyte culture to prescreen 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 4 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 Bcells and release of graft specific antibodies ™ Page 5 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 6 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 7 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 8 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 posttransplant • Travel history consider Coccidioides, Blastomyces, Histoplasma, etc. • Prophylaxis for Pneumocystis and Nocardia is important ™ Page 9 AntimicrobialImmunosuppressive 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 10 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 11 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 12 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 13 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 14 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 15 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 16 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 17 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 18 Corticosteroids • A mainstay of post-transplant immunosuppression • Many deleterious effects • Growing emphasis on early withdrawal of steroids in transplant ™ Page 19 Antimetabolites • Azathioprine (Imuran) Purine antimetabolite derivative of 6-mercaptopurine • Mycophenolate mofetil (Cellcept) ™ Page 20 Calcineurin Inhibitors • Cyclosporin (Sandimmune, Neoral) The first T-cell selective agent, nephrotoxic • Tacrolimus (Prograf, FK 506) • Proliferation signal inhibitors Sirolimus (Rappamune), Everolimus ™ Page 21 Calcineurin Inhibitors ™ Page 22 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 23 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 24 Treating Acute Rejection • High dose corticosteroids- methylprednisolone 5001000mg/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 25 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 26 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 27 References • 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 Page 28 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) 241-251 • Jimenez C, Lopez M, Gonzalez E, Selgas R, Ultrasonography in kidney transplantation: value and new developments ™ Page 29 References Cont. • 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 Page 30