solid organ transplant

autotransplantation

transplant of tissue from 1 part of the body to another

allotransplantation

transplant of tissue from 1 person to another person

xenotransplantation

transplant of tissue from a different species

orthotopic

transplanted into recipient in the same place (ex: heart, lung)

heterotopic

transplanted into recipient in a different place (example: kidney)

types of organ donors

• living

• deceased by brain death (primary brain death with intact cardiac and respiratory function)

• deceased by circulatory death

ABO groups

A = have anti-B antibodies and A antigen

B = have anti-A antibodies and B antigen

AB = have A and B antigens

O = have anti-A and anti-B antibodies and no antigens

HLA typing

• an association of genes found on short arm of chromosome 6 that code for antigen-presenting structures for T cells and play an important role in distinguishing self from non-self

• A, B, DR

sensitizing events

• blood transfusions

• pregnancy

• previous transplant

PRA

• panel reactive antibodies

• amount of pre-formed HLA antibodies

• higher PRA = increased sensitization to MHC antigens

determination of crossmatch

testing the transplant recipient’s serum against donor T cells

• qualitative: positive or negative (positive = high risk of rejection)

• quantitative: degree of antibody activity

Risk of rejection increases depending on organ

amount of lymphoid tissue

1 highest: small bowel, lung

2 heart

3 kidney, pancreas

4 least: liver

How does age affect risk of rejection?

older age decreases risk of rejection, but increases risk of infection and malignancies

How does ethnicity affect risk of rejection?

African Americans are at higher risk

• rapid metabolizers of tacrolimus (higher dose requirements)

types of allograft rejection

• T-cell mediated = acute cellular rejection

• antibody-mediated

hyperacute rejection

• minutes-hours

• mediated by preformed circulating antibodies

acute rejection

• days-months

• mediated by T-cells

chronic rejection

• months-years

• cellular- and antibody-mediated

• manifests as progressive decline in organ function

induction agents

• polyclonal: Thymoglobulin, ATGAM

• monoclonal: alemtuzumab

• IL-2a receptor antagonists: basiliximab

duration of action of thymoglobulin

~ 30 days, lymphocyte depletion persists for ~ 3 months

adverse effects of thymoglobulin

• leukopenia

• thrombocytopenia

• fever, chills, pruritus, erythema, rash, tachycardia, hypotension

  • pre-medicate with diphenhydramine and APAP

• serum sickness

thymoglobulin

composed of polyclonal IgG against human T-lymphocytes derived from rabbits

alemtuzumab

humanized anti-CD52 monoclonal antibody used off-label for SOT induction

duration of action of alemtuzumab

profound depletion of T cells persists for up to 12 months (after 1 dose)

alemtuzumab adverse effects

infusion-related: chills rigors, fever

• pre-medicate with diphenhydramine and APAP

basiliximab mechanism

• recombinant chimeric monoclonal antibody against CD25 (IL-2 receptor)

• inhibits activation of lymphocytes

• non-lymphodepleting

basiliximab is reserved for…

• hx of malignancy

• high risk of infection (immunocompromised)

• HIV

• untreated HCV

• age > 65

Which medications induce immunosuppression by inhibiting signal-1 of T-cell activation through inhibition of calcineurin phosphatase?

cyclosporine and tacrolimus (cornerstone of immunosuppression)

target trough concentration of cyclosporine

• 100-400 ng/ml (higher in initial post-transplant period)

• depends on transplant type and organ

preferred tacrolimus formulation

• extended release!

• Astagraf and Evarsus

• benefits: lower overall dose, improved adherence, less peak effects (reduced ADEs and less variability in troughs)

goal trough concentration for tacrolimus

5-15 ng/ml

Prograf to Envarsus conversion

1 mg Prograf = 0.8 mg Envarsus

Prograf PO to Prograf SL conversion

2 mg PO = 1 mg SL = 0.3 mg IV

half-life of CNIs

• cyclosporine: highly variable, 10-40 hours

• tacrolimus: 12-18 hours

CNI drug interactions

• cyclosporine: metabolized by CYP3A4 and P-gp

• tacrolimus: metabolized by CYP3A4

cyclosporine adverse effects

• hypertension

• increased cholesterol and TGs

• gingival hyperplasia

• hirsutism

tacrolimus adverse effects

• neurotoxicity: headache, insomnia, tremor, dizziness

• hyperglycemia, post-transplant diabetes mellitus

• alopecia

CYP450 inducers

(decrease CNI concentrations)

• phenytoin

• carbamazepine

• phenobarbital

• rifampin

CYP450 inhibitors

(increase CNI concentrations)

• erythromycin, clarithromycin

• azole antifungals

• diltiazem, verapamil

• ritonavir

• grapefruit juice

CNIs require dose adjustment in __________ dysfunction.

liver

(not renal)

azathioprine mechanism

converted to 6-MP in the blood → incorporated into nucleic acids → inhibits RNA and DNA synthesis

azathioprine adverse effects

• affects cells of high turnover

• GI: abdominal pain, n/v/d, dyspepsia

• bone marrow suppression

• alopecia

• hepatotoxicity

azathioprine drug interactions

xanthine oxidase inhibitors (allopurinol and febuxostat) decrease AZA concentration by 50-70%

________ is primarily used as an adjunct therapy to CNIs.

mycophenolate

mycophenolic acid mechanism

inhibits de novo synthesis of purines (specific for lymphocytes)

What are the 2 formulations of mycophenolic acid?

• mycophenolate mofetil: immediate release in the stomach

• mycophenolate sodium: delayed release in the small intestine

• MMF 250 mg:MPS 180 mg

• IV:PO 1:1

adverse effects of mycophenolic acid

• GI

• bone marrow suppression

• teratogen

  • REMS program- requires 2 forms of contraception

mycophenolic acid drug interactions

interacts with other myelosuppressive drugs: valganciclovir, sirolimus

mTOR inhibitors

sirolimus and everolimus

________ act synergistically with other immunosuppressants and are combined with CNI and/or corticosteroids.

mTOR inhibitors

mechanism of mTOR inhibitors

bind to FKBP12, which fuses with mTOR → inhibits T-cell proliferation

Sirolimus and everolimus are metabolized by…

CYP3A4 and P-gp (same drug interactions as CNIs)

Sirolimus is FDA-approved for

kidney transplant rejection prophylaxis

Everolimus is FDA-approved for…

kidney and liver transplant rejection prophylaxis

adverse effects of mTOR inhibitors

• edema

• hyperlipidemia and hypertriglyceridemia

• impaired wound healing

• mouth ulcers

• proteinuria

• increased risk of thrombosis post-op

*can be dose-limiting

place in therapy of mTOR inhibitors

• cannot use immediately post-op due to impaired wound healing and increased risk of thrombosis

• replace CNIs in patients who experience nephrotoxicity

• use in combination with CNIs to lower required dose

• replace mycophenolate in patients with intolerable adverse effects (GI, bone marrow suppression)

• used in steroid-free protocols

What corticosteroids are used in maintenance immunosuppression?

methylprednisolone, prednisone, or dexamethasone

adverse effects of corticosteroids

• hyperglycemia

• hypertension

• psychosis

• mood swings

• osteoporosis, fracture

• weight gain due to fluid retention and increased appetite

belatacept mechanism

blocks signal-2 of T-cell activation

• blocks CD28-mediated costimulation by binding CD80 and CD86 on APCs

Which medication has a relative contraindication in liver transplant?

belatacept

belatacept PK

• IV only

• given Q4weeks (long half-life)

belatacept place in therapy

• replace CNI

• adjunct to CNI (similar efficacy to cyclosporine)

Which medication is contraindicated in EBV seronegative patients?

belatacept

most common triple-drug regimen

tacrolimus + mycophenolate + prednisone

Which medications may be avoided due to nephrotoxicity?

tacrolimus, cyclosporine

Which medications may be avoided due to concern for CV risk, glucose intolerance, weight gain, or bone loss?

corticosteroids

treatment for acute cellular rejection

• mild-moderate: high-dose corticosteroids

• moderate-severe: Thymoglobulin (rabbit anti-thymocyte immunoglobulin)

• refractory: alemtuzumab

treatment for antibody-mediated rejection

steroids ± rituxumab ± IVIG

rituximab

anti-CD20 chimeric monoclonal antibody

adverse effects of rituximab

• first-dose infusion reaction complex (within 24 hours of infusion)

  • ARDS

  • ventricular fibrillation, cardiogenic shock

  • stop infusion if symptoms occur

  • pre-medicate with APAP, diphenhydramine, and methylprednisolone

IVIG

• intravenous immune globulin

• derived from pooled human plasma consisting of intact IgG molecules

causative organisms of opportunistic infection in transplant patients and preferred prophylaxis

• PJP: SMX/TMP

• CMV: valganciclovir

• Aspergillus, especially in lung transplant: posaconazole