Final - Transplant Flashcards
Immunology behind immunosuppression:
_____ mediated rejection = infiltration of the allograft by lymphocytes and other inflammatory cells
T cell mediated (cellular response)
Immunology behind immunosuppression:
_____ mediated rejection = circulating donor-specific antibodies/immunological evidence of an antibody mediated destruction
B cell (antibody) rejection (humoral response)
T cell activation requires __#__ signals
3 signals
T cell activation steps: #1. The T cell receptor (\_\_\_\_) interacts with \_\_\_\_\_\_\_
CD3 interacts with APC (antigen presenting cells)
T cell activation steps: #2. The co-stimulatory signal of \_\_\_\_\_\_ on the surface of APCs interacting with \_\_\_\_\_\_ on T cells
CD80/86 on APCs interacts with CD28 on T cells
T cell activation steps: #3. \_\_\_\_ binds to CD25 (which activates the mammalian target of \_\_\_\_\_\_) and subsequent proliferation and activation of the T-Cell
IL-2 binds to CD35;
target of rapamycin pathway
Rejection Timeline:
Hyperacute rejection – happens minutes to hours after transplant
& is mediated by ___________
preformed circulating antibodies
Rejection Timeline:
Acute rejection – occurs within days - months after transplant
& is mediated by _______
by host T-lymphocytes
Rejection Timeline:
Chronic rejection – happes over months to years after transplant
& is mediated by _________
& will see progressive decline in organ function….
mediated by BOTH cell mediated and humoral processes
Pre-Transplant Immunologic Evaluation:
what 4 things should be looked at?
ABO blood group determination
MHC
Determination of PRA (panel reactive antibodies)
Determination of Cross-Match
3 different types of immunosuppressive strategies
- induction therapy
- maintenance therapy
- rescue therapy
Patients who are at higher risk of rejection?
- Depends on the organ (intestines are the highest risk)
- Race: African Americans are at highest risk
- If poor PRA result
- Age: if younger = higher rejection risk
Induction Regimens consist of what?
Steroids + (Depleting agent or Non-Depleting Agent)
examples of Depleting agents?
Thymoglobulin
Atgam
Alemtuzumab
example of non-depleting agent?
basilximab
Thymoglobulin comes from what animal?
Atgam comes from what animal?
thymp: rabbit
Atgam: horse
The Antithymocyte globulins (Thymo and Atgam) are animal derived _____ antibodies directed against multiple _________
IgG antibodies;
multiple T cell specific antigens (aka polyclonal)
Antithymocyte globulins:
when the antibody and antigen bind:
it results in what things?
- opsonization (marking something for phagocyte to come get)
- T cell lysis
- rapid/profound lymphopenia
aka depleting allll lymphocytes in the body
What Immunosuppression strategy is it?
intense prophylactic therapy at the time of transplantation
induction
What Immunosuppression strategy is it?
chronic immunosuppression
Maintenace
What Immunosuppression strategy is it?
intense therapy utilized in response to a rejection episode
rescue
Antithymocyte globulins
which one is often capped at 150 mg/dose
Thymoglobulin
Antithymocyte globulins
which one is dosed as 10 - 15 mg/kg/day
atgam
Antithymocyte globulins
which one is dosed as 1-1.5 mg/kg/day for 4 - 7 days
Thymoglobulin
Antithymocyte globulins
ADEs?
- Myelosuppression (leukopenia/thrombocytopenia)
- cytokine release syndrome
- serum sickness
- infections
- lymphoproliferative disease
Antithymocyte globulins: ADEs
Has dose limiting myelosuppression — monitor what two things?
WBC and Platelets
Antithymocyte globulins: ADEs
Reduce dose by 50% when?
if WBC are 2000 - 3000 cells/mm3
OR
Platelet count is 50,000 - 75,000 cells/mm3
Antithymocyte globulins: ADEs
consider discontinuation when?
if WBC < 2000 cells/mm3
OR
Platelet count < 50,000 cells/mm3
Antithymocyte globulins: ADEs
sxs of cytokine release syndrome?
fever/chills
tachycardia
hypotension
Antithymocyte globulins: ADEs
how to prevent cytokine release syndrome?
pre-medicate: Steroids, diphenhydramine, APAP
also hella frequent vital sign monitoring :Q15 min for 1st hour then hourly
Antithymocyte globulins: ADEs
sxs of serum sickness?
arthralgias
myalgias
headaches
Antithymocyte globulins: ADEs
treat serum sickness how?
tx with corticosteroids
happens as a hypersensitivity reaction — thus do not retry any of the globulins
Antithymocyte globulins: ADEs
serum sickness happens when in relation to the dose?
it is a delayed rxn = can be up to 2 weeks post dose
Antithymocyte globulins: Administration
infused over _____ hours
______ line preferred
over 6 - 8 hours
central line
(can do peripheral — just add heparin/hydrocortisone to prevent phlebitis)
Antithymocyte globulins: How to manage infusion related rxns?
slow down the infusion by 50%
antihistamines/methylpred/epinephrine should be available
Alemtuzumab:
Is a _________ monoclonal antibody
humanized; ANTI-CD52
Alemtuzumab MOA:
is anti-CD52 antibody;
CD52 is a cell surface glycoprotein located on ______ and ______
but CD52 is not found on _____ or ____ that much = how it is selective
T and B lymphocytes
and natural killer cells
found on monocytes; macrophages
Dosing of Alemtuzumab?
30 mg IV or SQ as one dose (done during surgery)
IV is over 2 - 4 hours!! NEVER IV Push
ADEs of Alemtuzumab?
- Neutropenia/Thrombocytopenia, Pancytopenia
- hypotension/supracentricular tachycardia
- infusion related: chills, rigor, fever (pre-medicate: APAP/steroids/diphenhydramine)
Monitoring Parameters for Alemtuzumab?
WBC
Platelets
ALC (absolute lymphocyte count)
vital signs for at least 2 hours post infusion
Basiliximab:
MOA?
chimeric antibody that binds to alpha subunit of IL-2 receptor
Dosing considerations of Basiliximab?
- 20 mg IVPB AND post-op day 4
- yields 4 - 6 weeks of IL-2 receptor saturation
ADEs of Basiliximab?
Anaphylaxis/hypersensitivity rxns (rare tho)
well tolerated!! no pre-medications needed
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which does NOT have an approved indication for induction?
atgam and alemtuzumab do NOT
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is NOT depleting
basiliximab
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is chimeric (70% human/30% murine)
basiliximab (xi-=chimeric)
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is DNA-derived/humanixed
Alemtuzumab
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is CD52 targeted
alemtuzumab
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is CD25 targeted
basiliximab
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one has many targets?
thymoglobulin and atgam have many targets (polyclonal)
How to choose an induction agent:
Depleting or non-depleting is more commonly used?
depleting (especially when high immunologic risk)
How to choose an induction agent:
Basiliximab is reserved for what kind of patients?
pts with hx of malignancy
high infection risk/immunocompromised
Advanced age (> 65 yo)
Main classes of drugs used in maintenace therapy?
Calcineurin inhibitor m-TOR inhibitor Antimetabolite corticosteroids selective T-cell co-stimulation blocker
examples of calcineurin inhibitors?
Cyclosporine
Tacrolimus
examples of m-TOR inhibitors?
sirolimus
everolimus
examples of antimetabolites
azathioprine
mycophenolate (mofetil or sodium)
example of selective T cell costimulation blocker
Belatcept
Calcineurin Inhibitors MOA?
- inhibits first phase of T-Cell activation
- blocks synthesis of pro-inflammatory cytokines (IL-2)
Cyclosporine:
______ formulation has poor/erratic bioavailability
______ formulation has improved bioavailabiltiy
non-modified is wack
modified/microemulsion = better bioavailability
Cyclosporine:
what general drug interactions?
CYP3A4 and PGP
it is a substrate AND an inhibitor of CYP
Cyclosporine PO to IV conversion?
3:1 (90 mg of oral = 30 mg IV)
ADEs of Cyclosporine?
nephrotoxicity!!! hypertension!!! hypercholesterolemia/hypertriglyceridemia gingival hyperplasia hirustism neurotoxic hyperglycemia/diabetes hematologic adverse reactions
Tacrolimus is more or less potent than cyclosporine?
100 x more potent
Tacrolimus General Drug interaction?
is a CYP3A substrate (NOT an inhibitor like cyclosporine tho)
Tacrolimus: IV to PO conversion?
5:1 (2 mg IV = 10 mg PO)
which XR formulation of tacrolimus is 1:1 conversion b/w IR and which one needs to be administered at 80% of IR dose?
1:1 with IR is Astagraf XL
80% dose reduction: Envarsus
ADEs of Tacrolimus?
Neurotoxicity!! (headache, insomnia, tremor, dizziness) Hyperglycemia and Diabetes!! Nephrotoxic HTN GI Hematologic ADE Alopecia
What CYP related drugs will decrease Calcineurin inhibitors (aka are CYP enzyme inducers)
phenytoin
CBZ
phenobarbitol
rifampin
What CYP related drugs will increase Calcineurin inhibitors (aka are CYP enzyme inhibitors)
Erythryomycin/Clarithromycin Azole antifungals Diltiazem/Verapamil Ritonavir Grapefruit Juice
mTOR inhibitors:
which one is approved ONLY for kidney transplants
sirolimus
mTOR inhibitors:
which one is approved for kidney and liver transplants
everolimus (“every-one”)
MOA of mTOR inhibitors?
binds to FKBP-12 = inhibits mTOR aka inhibits serine/threonine kinase
the kinase normally regulates synthesis of proteins needed for cell cycle progression and T cell proliferation
drug interactions with mTOR inhibitors?
CYP3A4/PGP – same as Calcineurin inhibitors
mTOR ADEs??
Edema Elevated Lipids mouth ulcers DELAYED WOUND HEALING anemia hepatic artery thrombosis interstitial pneumonitis proteinuria
mTOR inhibitors: roles of therapy:
- replace ________ in patients with _____ toxicity (ex: nephrotoxicity)
- in combo with _____ to lower dose of both drugs
- to replace ______ in patients with intolerable side effects
- replace CNIs when CNI toxicity
- combo with CNIs
- replace mycophenolate
MOA of Azathioprine (AZA)?
- purine analog/converted to 6-mercaptopurine
- incorporated into nucleic acids = inhibits DNA and RNA synthesis = inhibits immune cell proliferation
main drug interaction with Azathioprine?
allopurinol
ADEs of Azathioprine?
- leukopenia/thrombocytopenia, macrocytic anemia,
- N/V, abdominal pain
- pancreatitis/hepatotoxicity
- malignancy
- infection
MOA of mycophenolic acid (MPA)?
inhibits de novo pathway of purine synthesis = selective for lymphocytes = limits progression of T and B cells
Mycophenolate mofetil or sodium?
which one is enteric coated/delayed release
sodium formulation
Mycofenolate mofetil PO to IV conversion?
1:1
drug interactions of mycophenolic acid?
Aluminum/Magnesium containing antacids
Cholestyramine
(both decrease AUC of mycophenolic acid)
ADEs of mycophenolic acid?
GI events!!!
Hematologic/Lymphatic adverse events
FDA pregnancy category D!!
MOA of corticosteroids:
- non specific immunosuppressive effects
- down regulation of IL-2 (aka cytokine gene expression)
MOA of Belatacept?
selective T cell costimulation blocker
binds to CD80/86 on APCs to block the CD28 mediated costimulation of T lymphocytes
Belatacept: it is contraindicated for use in _______ transplant
liver!!!
ADEs of Belatacept?
well tolerated…
but also PTLD (post transplant lymphoproliferaetive disorder)
Anemia
GI complications
what is PTLD (post transplant lymphoproliferaetive disorder)
mainly involves the central nervous system…
if EBV seronegative had a MUCH higher risk….. therefore contraindicated in EBV seronegative patients!!
common immunosuppresive regimen?
- Calcineurin inhibitor (tacrolimus or cyclosporine)
- antiproliferative agent (mycophenolate or azathioprine)
- corticosteroids
Options that are good if pt needs to avoid/minimize calcineurin inhibitors
- Belatacept + mycophenolic acid + corticosteroids
- Sirolimus + mycophenolic acid or azathioprine + corticosteroids
- Everolimus + low dose tacro/cyclo + corticosteroids
