Solid Organ Transplant

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