Solid Organ Transplant Flashcards
1
Q
Indications for Transplant
A
- Kidney: diabetes, HTN, lupud, PCKD
- Liver: alcoholic cirrhosis, NASH, HBV/HCV, HCC, APAP toxicity
- Pancreas: Diabetes, congenital abnormalities
- Heart: Ischemic heart disease, congenital abnormalities, idiopathic cardiomyopathy, valvular disease
- Lung: CF, pulmonary HTN. pulmonary fibrosis, COPD, emphysema
2
Q
Goals of Immunosuppression
A
- Prevent rejection
- Avoid complications with high dose immunosuppressants
- Patient and grant survival
- Patient adherence
3
Q
Induction Therapy Goals
A
- Prevent early acute allograft rejection using intense, prophylactic immunosuppression therapy
- Produces profound deficiency on T and/or B cells that can last months
4
Q
Induction Therapy Options
A
- Basiliximab
- Antithymocyte globulin
- Alemtuzumab
5
Q
Basiliximab
A
- Simulect
- MoA: Blocks T-proliferation via interleukin-2 reception antaognism (anti-CD25 antibodies)
- Used in lowest immunologic risk patients
- Decreased infection rates when compared to other agents
- Does not lead to sustained depletion of lymphocytes and related CD4 helper T-cells
6
Q
Antithymocyte Globulin
A
- Thymoglobulin
- MoA: Binds to T-cell surfaces antigens leading to the elimination of T-cells
- Used in moderate to high immunologic risk
- Increased risk for CMV and BKV
- PJP and other invasive fungal pathogens have been associated with thymoglobulin
7
Q
Alemtuzumab
A
-Campath
-MoA: binds to CD52 on T-cells,
B-cells, NK cells, and monocytes/macrophages and causes complement activation and antibody-dependent cellular toxicity
-“AIDS” in a bottle, results to pan T-cell depletion
-Used as steroid sparing induction
-CD4/CD8 counts nadir at 4 weeks, 1+ years for recovery
-Associated with many opportunistic infections
8
Q
Maintenance Therapy Goals
A
- Prevent allograft rejection
- Maintain an adequate balance of graft fxn, AE, and prevention of infection
- Lifelong immunosuppression
9
Q
Maintenance Therapy Options
A
- Corticosteroids
- Calcineurin inhibitors
- Antimetabolites
- mTOR inhibitors
10
Q
Corticosteroids
A
- Oldest immunosuppresive agent used in transplant
- MoA: inhibition of cytokine gene expression, modification of lymphocyte distribution and fxn, anti-inflammatory effects
- Dosing: Prednisone 5-10 mg/day (maintenance dose), higher doses are used for induction and rejection therapy
- TONS of SE (short and long term)
11
Q
Tacrolimus
A
- Calcineurin Inhibitors
- Capsules (ER and IR), IV, or oral suspension
- Also called FK506
- MoA: Inhibits T-cell activity through inhibition of IL-2 production
12
Q
Tacrolimus ADME
A
- Absorption: incomplete and variable, best absorbed on an empty stomach
- Highly lipophilic (99% protein bound)
- Metabolism: extensive CYP3A4, p-gp (IR 1/2 life ~9 hours, ER 1/2 life ~34 hours)
13
Q
Tacrolimus Dosing
A
- IR: 0.05-0.1 mg/kg/day in divided doses
- ER: 0.1-0.2 mg/kg/day one time daily
- Dose adjust based on [trough] and renal fxn
- [Goal] varies: time after transplant, type of organ transplanted, infection
- Therapeutic range: 5-15 ng/mL
14
Q
Tacrolimus Interactions
A
- Primarily through hepatic metabolism CYP3A4, inhibition or induction
- P-gp substrate
- Antacids: physical interaction => reduced absorption, separate by at least 2 hours
15
Q
Cyclosporine
A
- Calcineurin Inhibitor
- Modified microemulsion formulation, unmodified formulation as well
- MoA: Inhibits T-cell proliferation through inhibition of IL-2 production
16
Q
Cyclosporine ADME
A
- Absorption: erratic and incomplete, non-modified is largely dependent on food/bile/GI motility while modified is not
- Distribution: highly lipophilic (98% protein bound)
- Metabolism: CYP3A4 (extensive), p-gp
17
Q
Cyclosporine Dosing
A
- 10-15 mg/kg/day in divided doses to attain target trough levels
- Dose adjusted based on [trough] and renal fxn ([goal] varies based on time after transplant, organ transplanted, infection)
- Therapeutic Range: 50-200 ng/mL
18
Q
Cyclosporine Interactions
A
- Primarily through hepatic metabolism, CYP3A4 induction or inhibition
- P-gp substrate
- Anticipate and manage: high inter/intra-patient variability
- Nephrotoxic drugs should be used with caution
- Consistent administration with or without food
19
Q
Mycophenolate
A
- Antiproliferative
- Products: MMF, mycophenolate sodium
- Prodrugs for MPA
- MoA: inhibition of ionsine monophosphate dehydrogenase IMPDH => inhibits de novo guanosine nucleotide synthesis
- Prevents T and B lymphocytes proliferation
20
Q
Mycophenolate Dosing
A
- 200-1000 mg PO BID (MMF)
- 180-720 mg PO BID (Myfortic)
- Dosing conversion 1000 mg cellcept = 720 mg myfortic
- Myfortic is EC for DR, claims to reduce GI SE
21
Q
Mycophenolate SE
A
- GI intolerance: N/V, diarrhea
- Leukopenia, anemia, thrombocytopenia
22
Q
Mycophenolate Drug Interactions
A
- Aluminum/magnesium containing antacids (separate by at least 2 hours)
- Cholestyramine
- Divalent/trivalent cations (iron)
- PPI
- Oral contraceptives
23
Q
Mycophenolate + Pregnancy
A
- Shown to cause fetal harm
- Negative pregnancy test prior to starting medication
- Women of child-bearing age required to use at least two methods of contraception
24
Q
Azathioprine
A
- Antiproliferative
- Prodrug of 6-MP
- MoA: antagonist of purine metabolism, prevents T and B lymphocytes proliferation
- Rare Uses: intolerance to mycophenolate, women that want to become pregnant
- Dosing: 3-5 mg/kg/day initially, then decrease to 1-3 mg/kg/day
25
Azathioprine AE
- GI Intolerance
- Leukopenia, anemia, thrombocytopenia
- Increased alkaline phosphatase, total bilirubin, and transaminases
26
Azathioprine Drug Interactions
- 6-MP: profound myelosuppression
| - Allopurinol: inhibits metabolism of azathioprine and 6-MP leading to profound myelosuppression
27
Sirolimus
- mTOR Inhibitor
- MoA: Binding to FKTB-12 => inhibits MTOR, suppresses cytokine mediated T-cell proliferation
- Use: May be used to replace mycophenolate or a calcineurin inhibitor
- Dosing: 1-5 mg/day to attain target trough levels
28
Sirolimus AE/Interactions
AE
- Edema
- Anemia
- Impaired wound healing
- Interstitial lung disease
- Proteinuria
- Hyperlipidemia
Interactions
- Metabolized through CYP3A4
- Similar interactions with cyclosporine and tacrolimus
29
Everolimus
- mTOR inhibitor
- MoA: Binding to FKRP-12 => inhibits mTOR, suppresses cytokine mediated T-cell proliferation
- Use: renal transplant rejection prophylaxis
- Off-label use: heart transplant rejection prophylaxis
- Dosing: 0.75-1 mg PO BID to attain target trough levels
30
Everolimus
AE
- Edema
- Anemia
- Impaired wound healing
- Proteinuria
- Hyperlipidemia
Interactions
- Metabolized CYP3A4: similar drug interactions as cyclosporine and tacrolimus
- Consistent administration in regards to food
31
Belatacept
- Indication: maintenance immunosuppression therapy in renal transplant recipients
- MoA: Binds to CD80 and CD86 receptors on APCs and blocking CD-28 mediated costimulation of T-cells
32
Belatacept Dosing
Initial
- 10 mg/kg IV post-operative day 0 and 5
- 10 mg/kg IV end of week 2, 4, 8, 12
Maintenance Phase
- End of week 16
- 5 mg/kg every 4 weeks
33
Belatacept AE
- Post-transplant lymphoproliferation disorder
- GI disturbances
- HTN
- Peripheral edema
- Anemia, leukopenia
- NO long term renal toxicity
Black-Box Warning
- Increased risk of infections
- PTLD associated with EBV seronegative
34
Generic Medications
- Tacrolimus
- Mycophenolate
- Cyclosporine
- Sirolimus
* *Patients are encouraged to maintain consistency with the product they use**
35
Immunosuppresion Considerations
- Rejection
- Toxicity
- AE
- Variability
- Infection
- Malignancy
- Cost
- DDI
36
Immunosuppression Complications
- CV
- Infectious
- Malignancy
37
CV Complications
- Leading cause of mortality in renal transplant recipients
- HTN
- Hyperlipidemia
- Diabetes
38
Infectious Complications
- Highest risk immediately following transplant and rejection treatment: related to degree of immunosuppression
- Opportunistic infections
- Atypical organisms
- Prophylaxis
39
Malignancy
- Related to degree of immunosuppression: increased risk with increased survival
- Lung, breast, colon, and prostate cancer are not increased compared to general population
- Increased risk of lymphomas and lymphoproliferative disorders, Kaposi's sarcoma, renal carcinoma, and skin cancers
40
Rejection
- Cellular rejection: hyperacute rejection, acute rejection
| - Antibody-mediated rejection (AMR): acute or chronic AMR
41
Barriers to Adherence (SMURF)
- System: PA, transportation
- Motivation: depression, feeling "different"
- Understanding: education level, language barriers
- Recall: variable schedule, distractions
- Financial: cost of medications
42
Limitations in Transplant
- Every center practices differently
- Most evidence based on retrospective single-center experiences
- Many medications are used "off-label"
