Solid Organ Transplant

Question 1

Indications for Transplant

Answer 1

• 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

Question 2

Goals of Immunosuppression

Answer 2

• Prevent rejection
• Avoid complications with high dose immunosuppressants
• Patient and grant survival
• Patient adherence

Question 3

Induction Therapy Goals

Answer 3

• Prevent early acute allograft rejection using intense, prophylactic immunosuppression therapy
• Produces profound deficiency on T and/or B cells that can last months

Question 4

Induction Therapy Options

Answer 4

• Basiliximab
• Antithymocyte globulin
• Alemtuzumab

Question 5

Basiliximab

Answer 5

• 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

Question 6

Antithymocyte Globulin

Answer 6

• 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

Question 7

Alemtuzumab

Answer 7

-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

Question 8

Maintenance Therapy Goals

Answer 8

• Prevent allograft rejection
• Maintain an adequate balance of graft fxn, AE, and prevention of infection
• Lifelong immunosuppression

Question 9

Maintenance Therapy Options

Answer 9

• Corticosteroids
• Calcineurin inhibitors
• Antimetabolites
• mTOR inhibitors

Question 10

Corticosteroids

Answer 10

• 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)

Question 11

Tacrolimus

Answer 11

• Calcineurin Inhibitors
• Capsules (ER and IR), IV, or oral suspension
• Also called FK506
• MoA: Inhibits T-cell activity through inhibition of IL-2 production

Question 12

Tacrolimus ADME

Answer 12

• 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)

Question 13

Tacrolimus Dosing

Answer 13

• 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

Question 14

Tacrolimus Interactions

Answer 14

• Primarily through hepatic metabolism CYP3A4, inhibition or induction
• P-gp substrate
• Antacids: physical interaction => reduced absorption, separate by at least 2 hours

Question 15

Cyclosporine

Answer 15

• Calcineurin Inhibitor
• Modified microemulsion formulation, unmodified formulation as well
• MoA: Inhibits T-cell proliferation through inhibition of IL-2 production

Question 16

Cyclosporine ADME

Answer 16

• 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

Question 17

Cyclosporine Dosing

Answer 17

• 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

Question 18

Cyclosporine Interactions

Answer 18

• 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

Question 19

Mycophenolate

Answer 19

• 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

Question 20

Mycophenolate Dosing

Answer 20

• 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

Question 21

Mycophenolate SE

Answer 21

• GI intolerance: N/V, diarrhea

- Leukopenia, anemia, thrombocytopenia

Question 22

Mycophenolate Drug Interactions

Answer 22

• Aluminum/magnesium containing antacids (separate by at least 2 hours)
• Cholestyramine
• Divalent/trivalent cations (iron)
• PPI
• Oral contraceptives

Question 23

Mycophenolate + Pregnancy

Answer 23

• 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

Question 24

Azathioprine

Answer 24

• 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

Question 25

Azathioprine AE

Answer 25

- GI Intolerance - Leukopenia, anemia, thrombocytopenia - Increased alkaline phosphatase, total bilirubin, and transaminases

Question 26

Azathioprine Drug Interactions

Answer 26

- 6-MP: profound myelosuppression | - Allopurinol: inhibits metabolism of azathioprine and 6-MP leading to profound myelosuppression

Question 27

Sirolimus

Answer 27

- 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

Question 28

Sirolimus AE/Interactions

Answer 28

AE - Edema - Anemia - Impaired wound healing - Interstitial lung disease - Proteinuria - Hyperlipidemia Interactions - Metabolized through CYP3A4 - Similar interactions with cyclosporine and tacrolimus

Question 29

Everolimus

Answer 29

- 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

Question 30

Everolimus

Answer 30

AE - Edema - Anemia - Impaired wound healing - Proteinuria - Hyperlipidemia Interactions - Metabolized CYP3A4: similar drug interactions as cyclosporine and tacrolimus - Consistent administration in regards to food

Question 31

Belatacept

Answer 31

- 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

Question 32

Belatacept Dosing

Answer 32

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

Question 33

Belatacept AE

Answer 33

- 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

Question 34

Generic Medications

Answer 34

- Tacrolimus - Mycophenolate - Cyclosporine - Sirolimus * *Patients are encouraged to maintain consistency with the product they use**

Question 35

Immunosuppresion Considerations

Answer 35

- Rejection - Toxicity - AE - Variability - Infection - Malignancy - Cost - DDI

Question 36

Immunosuppression Complications

Answer 36

- CV - Infectious - Malignancy

Question 37

CV Complications

Answer 37

- Leading cause of mortality in renal transplant recipients - HTN - Hyperlipidemia - Diabetes

Question 38

Infectious Complications

Answer 38

- Highest risk immediately following transplant and rejection treatment: related to degree of immunosuppression - Opportunistic infections - Atypical organisms - Prophylaxis

Question 39

Malignancy

Answer 39

- 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

Question 40

Rejection

Answer 40

- Cellular rejection: hyperacute rejection, acute rejection | - Antibody-mediated rejection (AMR): acute or chronic AMR

Question 41

Barriers to Adherence (SMURF)

Answer 41

- System: PA, transportation - Motivation: depression, feeling "different" - Understanding: education level, language barriers - Recall: variable schedule, distractions - Financial: cost of medications

Question 42

Limitations in Transplant

Answer 42

- Every center practices differently - Most evidence based on retrospective single-center experiences - Many medications are used "off-label"