Solid Organ Transplant Flashcards
1
Q
What three types of diagnostic evidence can be used to detect ABMR?
A
- Histologic evidence of acute tissue injury
- Microvascular injury (glomerulitis or peri-tubular capilaritis)
- Difference between acute and chronic rejection
- Evidence of current/recent antibody interaction with vascular endothelium
- C4d staining on biopsy (complement activation)
- Serologic evidence of donor specific antibodies (DSA)
- Pre-transplant DSA vs. de novo DSA
2
Q
What is the time course of antibody-mediated graft damage?
A
3
Q
What is the “triple whammy” of medication non-adherence when regarding solid organ transplants?
A
- Increased risk for antibody mediated rejection = Decreased graft life
- Development of DSA leads to elevated PRA and less likelihood of finding a match for next transplant
- Increase infection risk due to treatments required for AMR that develops after nonadherence
4
Q
calcineurin inhibitors
A
- Cyclosporine (Neoral, Gengraf, Sandimmune)
- Tacrolimus (Prograf, Envarsus, Astagraf)
5
Q
antiproliferative agents
A
- Mycophenolate mofetil/acid (Cellcept/Myfortic)
- Azathioprine (Imuran)
6
Q
co-stimulatory blocker
A
- Belatacept (Nulojix)
7
Q
inhibitors of late t-cell function
A
- Sirolimus (Rapamune)
- Everolimus (Zortress)
8
Q
monoclonal antibodies
A
- Basiliximab (Simulect)
- Alemtuzumab (Campath)
9
Q
polyclonal antibodies
A
- Antithymocyte globulin (thymoglobulin)
10
Q
dosing conversion of calcineurin inhibitors
A
- IV:PO dosing conversion
- CYA 1:3
- TAC 1:4
- SL:PO dosing conversion
- TAC 1:2
- Tacrolimus ER (Astagraf XL) 1:1 conversioν
- Tacrolimus XR (Envarsus, Tac LCPT) 1: 0.75 – 0.8 conversion
11
Q
calcineurin side effects
A
- Hyperglycemia
- Dyslipidemia
- Hypertension
- Hyperkalemia
- Hemolytic Uremic Syndrome
- Nephrotoxicity
- Patients may eventually require renal transplant/dialysis
- Gingival hyperplasia
- Increase infection/malignancy risk
TAC:
- Neurotoxicity
- Tremor
- Confusion/HA/Cloudiness
- Hyperglycemia (PTDM)
- Alopecia
CYA:
- Hirsutism
- Gingival hyperplasia
12
Q
differences in metabolism of CYA and TAC
A
CYA
- Extensively metabolized by CYP3A
- Inhibits:
- CYP3A4
- P-gp
- BCRP
- OATP1B1
Tacrolimus
- Extensively metabolized by CYP3A
- Substrate of:
- CYP3A4/5
- P-gp
13
Q
azole interaction with calcineurin inhibitors
A
- Azoles known inhibitors of CYP 3A4 and p-gp
- Concomitant administration requires dose decrease of calcineurin inhibitors
14
Q
grazoprevir/elbasvir interaction with calcineurin inhibitors
A
- Grazoprevir (GZR)
- Substrate for OATP1B1/3 transporter, CYP3A, and P-gp
- Elbasvir (EBR)
- Substrate of CYP3A4 and P-gp
- GE is not given with CYA because of 15x increase of GE; however, TAC/GE has minimal interaction
15
Q
letermovir interaction with calcineurin inhibitor
A
Substrate of drug metabolizing enzymes CYP3A, CYP2D6, UGT1A1, and UGT1A3, and transporters OATP1B1/3 and P-gp
Dose increase of letermovir required with CYA
16
Q
statin interaction with calcineurin inhibitor
A
Simvastatin and atorvastatin are contraindicated with use of CYA
17
Q
There are many interactions with calcineurin inhibitors. What are potential effects of these interactions?
A
- Increase creatinine
- Nephrotoxicity
- Decrease metabolism
- Increase metabolism
- Increase concentration of other agent
18
Q
patient education for calcineurin inhibitors
A
- Adherence
- Medication dosed every 12 hours or 24 hours for TAC ER
- Do not take medication prior to trough draw
- Follow up with provider for labs
- DDIs
- Contact provider if develop any s/sx of infection (i.e., fever, cold/flu symptoms, urinary symptoms)
19
Q
corticosteroid side effects
A
- Hyperglycemia
- Dyslipidemia
- Hypertension
- Insomnia
- Psychosis
- Osteoporosis
- Weight gain
- Infection
- PUD
- Cataracts
- Impaired wound healing
20
Q
Findings of Astellas Corticosteroid Withdrawal Study Group
A
- Corticosteroid Arm
- More bone fractures + avascular necrosis
- More serious adverse effects due to DM or infection
- More ATG for acute rejection
- Higher fasting triglyceride level
- Steroid Withdrawal Arm
- Higher AR rate
- Higher incidence of hyperkalemia and neutropenia
- Similarities between 2 arms
- LDL and HDL cholesterol
- Blood pressure
- Mean weight change
- Cataracts
- Opportunistic infections
- Malignancies
- GI toxicity
- New onset diabetes (20% incidence)
21
Q
patient education of corticosteroids
A
- Adherence
- Dosing in the AM with food
- Side effects
- Discuss importance of diet and exercise to minimize some side effects
- Contact provider if develop any s/sx of infection (i.e., fever, cold/flu symptoms, urinary symptoms)
22
Q
mycophenolate MOA
A
- inhibits inosine monophosphatate dehydrogenase (IMPDH)
- inhibits de novo pathway of guanosine synthesis and blockade of lymphocyte proliferation (do not possess salvage pathway)
- diminishes proliferation of T and B cells
- decreases generation of CD8 cells
Significantly more effective in combination therapy than AZA
23
Q
mycophenolate side effects
A
- Leukopenia
- GI toxicity
- Diarrhea, nausea
- Increased risk of infection/malignancy
- Embryofetal toxicity – 1st trimester
- Recommend avoiding use if planning pregnancy
- Any female of childbearing potential must use highly effective contraception 4 weeks prior to starting mycophenolate and continue contraception until 6 weeks after stopping
24
Q
mycophenolate patient education
A
- Adherence
- Twice daily dosing. If intolerance can consider TID dosing
- Take with food (lower Cmax, but no change in AUC)
- Teratogenicity
- Contact provider if develop any s/sx of infection (i.e., fever, cold/flu symptoms, urinary symptoms)
25
azathioprine MOA
* Purine antagonist
* Inhibits DNA and RNA synthesis
26
azathioprine pros/cons
PROS
* Use in pregnancy as substitute for MMF
CONS
* Not commonly used with new transplants due to toxicity and safer alternative
* TPMT testing
* RDA
* CrCl \< 30 ml/min: reduce 25%
* CrCl \< 10 ml/min: reduce 50%
* CI with allopurinol and febuxostat (decreases AZA dose)
27
azathioprine side effects
* Bone marrow suppression
* Liver toxicity
* Pancreatitis
* Increase infection and cancer risk
* Alopecia
28
sirolimus/everolimus MOA
* Inhibits cellular response to interleukin-2
* Immunosuppressive via binding to FKBP and suppression of CD4 t-cell activation and proliferation
* Anti-proliferative mechanism through blocking kinase activity
29
sirolimus/tacrolimus side effects
* Hyperlipidemia
* Impaired wound healing
* Rash
* **Hyperglycemia**
* Proteinuria
* Oral ulcers
* Thrombocytopenia
* Increase risk for infection
* Arthralgias
* Pneumonitis
* Hepatic artery thrombosis
* ? DVT
Can be used in patients who are at risk of skin cancer
30
belatacept MOA
* Selective T-cell costimulation blocker
* Binds to CD80/CD86(B7-1/B7-2) on antigen-presenting cells resulting in inhibition of CD28-mediated costimulation of T lymphocytes
* Similar to 1st-generation blocker abatacept(10x less binding avidity)
* Fusion protein made of the modified extracellular domain of cytotoxic T lymphocyte antigen 4 (CTLA-4) found on helper T cells
31
calcinurin inhibitor free regimen
MMF + prednisone + belatacept
| (basiliximab induction)
32
belatacept side effects
* Post Transplant Lymphoproliferative Disorder (PTLD)
* Contraindicated in EBV neg patients
* Increased risk for infection
* CMV and other viral infections
* Anemia
* Infusion-related reactions
* Hypertension
33
Which monoclonal antibody is preferred during EBV infection post-transplant?
* Belatacept binds CD80/CD86 with a higher affinity (500-2500x) than does CD28, thus inhibiting the CD28 co-stimulatory action
* In immunocompetent setting: EBV infected B cells are balanced by stimulation of cytotoxic t cells.
* Cancer immunotherapy targets CTLA-4
* Ipilimumab (Yervoy), a monoclonal antibody against CTLA-4, approved for treatment of melanoma and renal cell carcinoma
34
Difference between belatacept and CYA? Tacrolimus?
Belatacept has higher acute rejection rates, but better renal function and lower DSA/improved adherence in the long-term.
TAC has lowest rejection rates.
35
When is belatacept preferred over TAC?
* Adverse effects to calcineurin inhibitor (CNIs) or mTOR inhibitor (mTORi) based regimen
* Adherence concern
* CNI nephrotoxicity toxicity
* “Poor” quality organ (i.e BENEFIT EXT) or patients with lower eGFR post transplant
36
belatacept side effects
* Adherence
* Every 2-4 week IV infusion
* Side Effects
* Infusion site reactions, confusion, new or worsening neurological, cognitive, or behavioral signs and symptoms
* Contact provider if develop any s/sx of infection (i.e. fever, cold/flu symptoms, urinary symptoms)
37
high-risk patients of acute rejection
* African-American
* Delayed graft function
* Previous transplant
* Multiple transplants
* High PRA (\>40%)
* Pediatric patients
* Long cold ischemic time (\>24 hours)
38
polyclonal antibodies
* Antibodies derived from non-human sources and targeted to T-lymphocyte cell surface proteins
* Mechanism of action
* Antibodies specific for \>20 CD receptors and markers involved in the immune response
* Depletes T-cells opsonization and direct lyses of lymphocytes
* Indicated for induction therapy and treatment of acute rejection
39
polyclonal side effects
