Transcript Principles of Transplantation

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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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.)
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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
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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
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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
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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
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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
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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
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Corticosteroids
• A mainstay of post-transplant immunosuppression
• Many deleterious effects
• Growing emphasis on early withdrawal of steroids in
transplant
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Antimetabolites
• Azathioprine (Imuran) Purine antimetabolite derivative of
6-mercaptopurine
• Mycophenolate mofetil (Cellcept)
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Calcineurin Inhibitors
• Cyclosporin (Sandimmune, Neoral) The first T-cell
selective agent, nephrotoxic
• Tacrolimus (Prograf, FK 506)
• Proliferation signal inhibitors Sirolimus (Rappamune),
Everolimus
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Calcineurin Inhibitors
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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
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Antibodies
• Campath (Alemtuzumab) Anti CD52 on multiple different
lymphocytes causing lympholysis
• Infliximab (Remicade) Anti TNF, binds to receptor and
prevents TNF activation of lymphocytes
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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
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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
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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
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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
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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
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• Francis D, Transplantation
surgery: Blackwell Co; 2006
• Wood K, McCartney J,
Management of the potential
organ donor. Transplantation
reviews 21 (2007) 204-218
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