Final - Transplant Flashcards
1
Q
Immunology behind immunosuppression:
_____ mediated rejection = infiltration of the allograft by lymphocytes and other inflammatory cells
A
T cell mediated (cellular response)
2
Q
Immunology behind immunosuppression:
_____ mediated rejection = circulating donor-specific antibodies/immunological evidence of an antibody mediated destruction
A
B cell (antibody) rejection (humoral response)
3
Q
T cell activation requires __#__ signals
A
3 signals
4
Q
T cell activation steps: #1. The T cell receptor (\_\_\_\_) interacts with \_\_\_\_\_\_\_
A
CD3 interacts with APC (antigen presenting cells)
5
Q
T cell activation steps: #2. The co-stimulatory signal of \_\_\_\_\_\_ on the surface of APCs interacting with \_\_\_\_\_\_ on T cells
A
CD80/86 on APCs interacts with CD28 on T cells
6
Q
T cell activation steps: #3. \_\_\_\_ binds to CD25 (which activates the mammalian target of \_\_\_\_\_\_) and subsequent proliferation and activation of the T-Cell
A
IL-2 binds to CD35;
target of rapamycin pathway
7
Q
Rejection Timeline:
Hyperacute rejection – happens minutes to hours after transplant
& is mediated by ___________
A
preformed circulating antibodies
8
Q
Rejection Timeline:
Acute rejection – occurs within days - months after transplant
& is mediated by _______
A
by host T-lymphocytes
9
Q
Rejection Timeline:
Chronic rejection – happes over months to years after transplant
& is mediated by _________
& will see progressive decline in organ function….
A
mediated by BOTH cell mediated and humoral processes
10
Q
Pre-Transplant Immunologic Evaluation:
what 4 things should be looked at?
A
ABO blood group determination
MHC
Determination of PRA (panel reactive antibodies)
Determination of Cross-Match
11
Q
3 different types of immunosuppressive strategies
A
- induction therapy
- maintenance therapy
- rescue therapy
12
Q
Patients who are at higher risk of rejection?
A
- 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
13
Q
Induction Regimens consist of what?
A
Steroids + (Depleting agent or Non-Depleting Agent)
14
Q
examples of Depleting agents?
A
Thymoglobulin
Atgam
Alemtuzumab
15
Q
example of non-depleting agent?
A
basilximab
16
Q
Thymoglobulin comes from what animal?
Atgam comes from what animal?
A
thymp: rabbit
Atgam: horse
17
Q
The Antithymocyte globulins (Thymo and Atgam) are animal derived _____ antibodies directed against multiple _________
A
IgG antibodies;
multiple T cell specific antigens (aka polyclonal)
18
Q
Antithymocyte globulins:
when the antibody and antigen bind:
it results in what things?
A
- opsonization (marking something for phagocyte to come get)
- T cell lysis
- rapid/profound lymphopenia
aka depleting allll lymphocytes in the body
19
Q
What Immunosuppression strategy is it?
intense prophylactic therapy at the time of transplantation
A
induction
20
Q
What Immunosuppression strategy is it?
chronic immunosuppression
A
Maintenace
21
Q
What Immunosuppression strategy is it?
intense therapy utilized in response to a rejection episode
A
rescue
22
Q
Antithymocyte globulins
which one is often capped at 150 mg/dose
A
Thymoglobulin
23
Q
Antithymocyte globulins
which one is dosed as 10 - 15 mg/kg/day
A
atgam
24
Q
Antithymocyte globulins
which one is dosed as 1-1.5 mg/kg/day for 4 - 7 days
A
Thymoglobulin
25
Antithymocyte globulins
| ADEs?
- Myelosuppression (leukopenia/thrombocytopenia)
- cytokine release syndrome
- serum sickness
- infections
- lymphoproliferative disease
26
Antithymocyte globulins: ADEs
| Has dose limiting myelosuppression --- monitor what two things?
WBC and Platelets
27
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
28
Antithymocyte globulins: ADEs
| consider discontinuation when?
if WBC < 2000 cells/mm3
OR
Platelet count < 50,000 cells/mm3
29
Antithymocyte globulins: ADEs
| sxs of cytokine release syndrome?
fever/chills
tachycardia
hypotension
30
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
31
Antithymocyte globulins: ADEs
| sxs of serum sickness?
arthralgias
myalgias
headaches
32
Antithymocyte globulins: ADEs
| treat serum sickness how?
tx with corticosteroids
| happens as a hypersensitivity reaction --- thus do not retry any of the globulins
33
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
34
Antithymocyte globulins: Administration
infused over _____ hours
______ line preferred
over 6 - 8 hours
central line
(can do peripheral --- just add heparin/hydrocortisone to prevent phlebitis)
35
Antithymocyte globulins: How to manage infusion related rxns?
slow down the infusion by 50%
| antihistamines/methylpred/epinephrine should be available
36
Alemtuzumab:
| Is a _________ monoclonal antibody
humanized; ANTI-CD52
37
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
38
Dosing of Alemtuzumab?
30 mg IV or SQ as one dose (done during surgery)
IV is over 2 - 4 hours!! NEVER IV Push
39
ADEs of Alemtuzumab?
- Neutropenia/Thrombocytopenia, Pancytopenia
- hypotension/supracentricular tachycardia
- infusion related: chills, rigor, fever (pre-medicate: APAP/steroids/diphenhydramine)
40
Monitoring Parameters for Alemtuzumab?
WBC
Platelets
ALC (absolute lymphocyte count)
vital signs for at least 2 hours post infusion
41
Basiliximab:
| MOA?
chimeric antibody that binds to alpha subunit of IL-2 receptor
42
Dosing considerations of Basiliximab?
- 20 mg IVPB AND post-op day 4
| - yields 4 - 6 weeks of IL-2 receptor saturation
43
ADEs of Basiliximab?
Anaphylaxis/hypersensitivity rxns (rare tho)
| well tolerated!! no pre-medications needed
44
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which does NOT have an approved indication for induction?
atgam and alemtuzumab do NOT
45
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is NOT depleting
basiliximab
46
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is chimeric (70% human/30% murine)
basiliximab (xi-=chimeric)
47
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is DNA-derived/humanixed
Alemtuzumab
48
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is CD52 targeted
alemtuzumab
49
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one is CD25 targeted
basiliximab
50
Comparing Induction Agents:
(Thymoglobulin, Atgam, Alemtuzumab, Basiliximab)
which one has many targets?
thymoglobulin and atgam have many targets (polyclonal)
51
How to choose an induction agent:
| Depleting or non-depleting is more commonly used?
depleting (especially when high immunologic risk)
52
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)
53
Main classes of drugs used in maintenace therapy?
```
Calcineurin inhibitor
m-TOR inhibitor
Antimetabolite
corticosteroids
selective T-cell co-stimulation blocker
```
54
examples of calcineurin inhibitors?
Cyclosporine
| Tacrolimus
55
examples of m-TOR inhibitors?
sirolimus
| everolimus
56
examples of antimetabolites
azathioprine
| mycophenolate (mofetil or sodium)
57
example of selective T cell costimulation blocker
Belatcept
58
Calcineurin Inhibitors MOA?
- inhibits first phase of T-Cell activation
| - blocks synthesis of pro-inflammatory cytokines (IL-2)
59
Cyclosporine:
______ formulation has poor/erratic bioavailability
______ formulation has improved bioavailabiltiy
non-modified is wack
| modified/microemulsion = better bioavailability
60
Cyclosporine:
| what general drug interactions?
CYP3A4 and PGP
| it is a substrate AND an inhibitor of CYP
61
Cyclosporine PO to IV conversion?
3:1 (90 mg of oral = 30 mg IV)
62
ADEs of Cyclosporine?
```
nephrotoxicity!!!
hypertension!!!
hypercholesterolemia/hypertriglyceridemia
gingival hyperplasia
hirustism
neurotoxic
hyperglycemia/diabetes
hematologic adverse reactions
```
63
Tacrolimus is more or less potent than cyclosporine?
100 x more potent
64
Tacrolimus General Drug interaction?
is a CYP3A substrate (NOT an inhibitor like cyclosporine tho)
65
Tacrolimus: IV to PO conversion?
5:1 (2 mg IV = 10 mg PO)
66
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
67
ADEs of Tacrolimus?
```
Neurotoxicity!! (headache, insomnia, tremor, dizziness)
Hyperglycemia and Diabetes!!
Nephrotoxic
HTN
GI
Hematologic ADE
Alopecia
```
68
What CYP related drugs will decrease Calcineurin inhibitors (aka are CYP enzyme inducers)
phenytoin
CBZ
phenobarbitol
rifampin
69
What CYP related drugs will increase Calcineurin inhibitors (aka are CYP enzyme inhibitors)
```
Erythryomycin/Clarithromycin
Azole antifungals
Diltiazem/Verapamil
Ritonavir
Grapefruit Juice
```
70
mTOR inhibitors:
| which one is approved ONLY for kidney transplants
sirolimus
71
mTOR inhibitors:
| which one is approved for kidney and liver transplants
everolimus ("every-one")
72
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
73
drug interactions with mTOR inhibitors?
CYP3A4/PGP -- same as Calcineurin inhibitors
74
mTOR ADEs??
```
Edema
Elevated Lipids
mouth ulcers
DELAYED WOUND HEALING
anemia
hepatic artery thrombosis
interstitial pneumonitis
proteinuria
```
75
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
76
MOA of Azathioprine (AZA)?
- purine analog/converted to 6-mercaptopurine
| - incorporated into nucleic acids = inhibits DNA and RNA synthesis = inhibits immune cell proliferation
77
main drug interaction with Azathioprine?
allopurinol
78
ADEs of Azathioprine?
- leukopenia/thrombocytopenia, macrocytic anemia,
- N/V, abdominal pain
- pancreatitis/hepatotoxicity
- malignancy
- infection
79
MOA of mycophenolic acid (MPA)?
inhibits de novo pathway of purine synthesis = selective for lymphocytes = limits progression of T and B cells
80
Mycophenolate mofetil or sodium?
| which one is enteric coated/delayed release
sodium formulation
81
Mycofenolate mofetil PO to IV conversion?
1:1
82
drug interactions of mycophenolic acid?
Aluminum/Magnesium containing antacids
Cholestyramine
(both decrease AUC of mycophenolic acid)
83
ADEs of mycophenolic acid?
GI events!!!
Hematologic/Lymphatic adverse events
FDA pregnancy category D!!
84
MOA of corticosteroids:
- non specific immunosuppressive effects
| - down regulation of IL-2 (aka cytokine gene expression)
85
MOA of Belatacept?
selective T cell costimulation blocker
| binds to CD80/86 on APCs to block the CD28 mediated costimulation of T lymphocytes
86
Belatacept: it is contraindicated for use in _______ transplant
liver!!!
87
ADEs of Belatacept?
well tolerated...
but also PTLD (post transplant lymphoproliferaetive disorder)
Anemia
GI complications
88
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!!
89
common immunosuppresive regimen?
1. Calcineurin inhibitor (tacrolimus or cyclosporine)
2. antiproliferative agent (mycophenolate or azathioprine)
3. corticosteroids
90
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
