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health care issues associated with solid organ transplants
primary disease recurrence, source of donation (cadaveric vs living), medical costs associated with procedure, medical costs for patients vs insurer, immunosupressive therapy (cost, efficacy, ADRs)
what are the steps in T-cell mediated rejection
the host and donor antigen presenting cells move to lymphoid organs —→ naiive and central memory T cells recirculate between secondary lymphoid organs ——> effector T cells move hom to graft from lymph node
how many kidney transplants are done each year in the US?
~15,000-17,000
how many liver transplants are done each year in the US?
~5,000-6,000
who receives pancreas transplants
diabetics with or with no kidney
define allotransplantation
transplantation of cells, tissues, or organs from a donor that is not genetically identical to the recipient (host) but of the same species
what are the types of organ transplants?
allograft, allogenic transplant, or homograft
most organ or tissue transplants are:
allografts
what is a transplant rejection?
the immune attack of recipient to the allograft of donor after transplant
what are HLAs
self-antigens (AG) defined as histocompatibility AG on human leukocytes and tissue to allow host’s immune system to detect difference between self from foreign cells (i.e. allograft from donor)
functions of HLA
organ transplantation - immune mediated resulting in either survival or rejection of donor organ from recipient
what is a hyperacute transplant rejection
occurs within minutes to hours after graft placement and is often irreversible
why do hyperacute rejections occur?
due to patient having pre-existing AB in recipient which reacts with Class I HLA or ABO blood group antigens found on grafted tissue
Clinical responses to transplant rejection
serum creatinine increase, GFR decline, urine output decreases
what is acute transplant rejection
can occur days to years after transplant with fast clinical manifestation - generally reversible but can impact overall organ function
cause of acute rejection
due to the development of cell-mediated immune response (mediated by Th) against Class II HLA on graft
which transplant rejection is the most common?
acute
what must acute rejections be differentiatied from?
drug-induced toxicity
what is cell-mediated rejection
most common rejection that results from alloreactive T lymphocytes (due to release of IL-2) in circulation that infiltrate the allograft with targeted destruction of graft by sensitized cytotoxic T cells, cytokines with macrophage directed graft destruction
what is antibody-mediated rejection (AMR) or humoral rejection?
antibodies from activated B cells target HLA antigens on the donor’s vascular endothelium - circulating immune complexes can precede AMR
when does direct recognition of alloantigens occur?
when T cells bind directly to intact allogenic major MHC molecules found on antigen presenting cells in the allograft
when does indirect alloantigen recognition occur?
when allogenic MHC molecules from the graft are acknowledged and processed by the recipients APC and peptide fragments are presented by recipient (self) MHC molecule. Recipients APC may also process and present allograft proteins other than allogenic MHC molecules presented by recipient
what is the role of induction therapy?
allow for avoidance of full dose CYA or TAC in the immediate post-transplant period and block T-cell activation or other immunologic activation at the time of graft placement.
advantages of induction therapy
may improve early graft function, may prevent graft rejection, and improve graft
disadvantages of induction therapy?
may increased costs and risk of cytomegalovirus (CMV) infection and post-transplantation lymphoproliferative disease (PTLD)
define induction immunosuppression
more intense immunosuppression initiatiated just prior and during the acute post-transplant period
which agents are used in induction immunosuppression?
one induction agent (a polyclonal thymoglobulin or IL-2 receptor blocker or Alemtuzumab), mycophenolate mofetil (MMF) or azathioprine (AZA), and glucocorticoids (methylprednisolone or prednisone)
which medications follow the induction immunosuppresion agents?
delayed use or low doses of calcineurin inhibitors such as either cyclosporin (CYA) or tacrolimus (TAC)
when would polyclonal antibodies be used?
high risk patients for depleting induction (improves long-term survival of allograft)
what is anti-thymocyte globulin (ATG)
polyclonal antibody (gammaglobulin) preparation obtained from immunization animals with human lymphocytes
MOA of ATG
these antibodies coat the host’s T cells in the blood (opsonization) - these coated T-cells are then destroyed by the complement system
what is Campath approved for
B cell chronic lymphocytic leukemia and multiple sclerosis
unapproved use of Campath (alemtuzumab monoclonal AB)
induction agent in kidney transplant in high risk recipients
MOA of Campath
directly against the CD52 surface AG expressed on all lymphocytes (T > B), NK cells, macrophages, monocytes, and eosinophil, and male reproductive track. After the Fab domain binds to CD52, the Fc domain activates complement, antibody dependent cellular cytotoxicity (ADCC) and cell lysis
what are the two dosing regimens of alemtuzumab used in kidney transplant induction
two doses of 0.3 mg/kg/dose or a single dose of 20-30 mg IV over 2-3 hours
premedication to alemtuzumab
each dose proceeded by IV methylprednisolone (500 mg and 250 mg respectively) 30 minutes before infusion
what should transplant patients receive for at least 2 months after D/C of alemtuzumab or until CD4 counts are >= 200 cells/microliter
anti-infective prophylaxis
when do B cells return after alemtuzumab use
3-12 months
when do T cells return after alemtuzumab use
can be depressed for up to 3 years
ADRs of alemtuzumab
infusion related reactions with initial treatment (HAMA)signs and symptoms of HAMA, GI disorder (N/V/D), profound lymphopenia, profound neutropenia, thrombocytopenia, and increased risk of malignancy, infection or autoimmune reactions
signs and symptoms of alemtuzumab HAMA rxns
fever, rigors, nausea, diarrhea, or hypotension
who receives non-depleting induction therapy such as monoclonal antibodies?
low risk patients
what type of drug is basiliximab (Simulect)?
interleukin-2 receptor blockers
MOA of Simulect
monoclonal AB against CD25 (portion of IL-2 receptor) which will prevent activated T lymphocyte proliferation since the IL-2 receptor will be resistant to IL-2 stimulation
when are interleukin-2 receptor blockers effective?
when combined with other immunosuppressive agents
ADRs of interleukin-2 receptor blockers
GI diarrhea, vomiting, nausea
how does nephrotoxicity occur if patients take calcineurin inhibitors?
acute dose dependent increase in serum creatinine due to renal afferent arteriolar vasoconstriction
ADRs of CNI
hepatotoxicity, hyperkalemia, hypomagnesemia, HTN, diabetes, tremors, gingival hyperplasia, hirsutism, hypertrichosis, hyperlipidemia, and nephrotoxicity