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PHAR 358 > Transplants 1 > Flashcards

Transplants 1 Flashcards

1
Q

Define autograft

A

A transplant that occurs within one person’s body. i.e., a skin graft

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2
Q

Define allograft

A

A transplant that occurs between two people of the same species

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3
Q

What is the only organ that is transplanted in Saskatchewan?

A

Kidneys

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4
Q

What is the difference between medication coverage in Saskatchewan for renal vs. non-renal transplants?

A

Renal: medications covered under SAIL program
Non-renal: not covered by SAIL

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5
Q

How does recognition occur in the immune system? (3)

A
  1. Proteins produced by ‘non-self’ organism
  2. Signaling molecules created when inflammation is present
  3. The recipient recognizes the tranasplanted graft either as self or foreign based on the reaction to histocompatibilty antigens
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6
Q

What does the major histocompatibility complex (MHC)/Human leukocyte antigens (HLA) do? (2)

A
  1. Distinguishes ‘self’ from ‘non-self’
  2. Expressed on surface of antigen presenting cells
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7
Q

What are histocompatability antigens and what do they do? (3)

A
  1. Glycoprotein expressed on nucleated cells
  2. Major function is to bind peptides and present them at the cell surface for inspection by T-cells of the immune system
  3. Are encoded by the MHC genes that are referred to as HLA in humans
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8
Q

HLA genes are arranged into 3 classes based on their structure. What is class 1? (2)

A
  1. The proteins produced by these genes are present on most nucleated cells and platelets
  2. Primary target for t-lymphocyte reactions
    - HLA-A, HLA-B, HLA-C
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9
Q

HLA genes are arranged into 3 classes based on their structure. What is class 2?

A

Proteins are present on selective immunoreactive cells (macrophages, monocytes, activated t-lymphocytes, dendritic cells, epithelial cells)
- HLA-DR, HLA-DP, HLA-DQ

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10
Q

HLA genes are arranged into 3 classes based on their structure. What is class 3?

A

Part of complement system, do not play a specific role in graft rejection

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11
Q

HLA genes are ___________ and are genetically inherited as a _________

A

polymorphic; haplotype

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12
Q

“The T-cell 3 signal model”
What is ‘signal 1’? (2)

A
  1. Recognition
  2. APC presents MHC class II antigen to TH through the T-cell receptor (TCR)-CD3 complex
    - Downstream effect = begin to activate calcineurin pathway, also from the calcineurin pathway and the nucleus of the cell begin to generate IL-2
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13
Q

“The T-cell 3 signal model”
What is ‘signal 2’? (2)

A
  1. Activation of T-cells
  2. Occurs when co-stimulatory molecules, CD80 and CD86 which are present on the surface of the antigen-presenting cells interact with the co-stimulatory receptor CD-28
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14
Q

“The T-cell 3 signal model”
What is ‘signal 3’? (1)

A

IL-2 is relapsed and binds to IL-2 receptor on the T-cell, activating target of rapamycin necessary for cell proliferation

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15
Q

What is the end result of the T-cell 3 signal model?

A

End result is an activated, proliferating TH cell capable of recruiting other components of the immune system –> REJECTION –> DESTRUCTION OF THE GRAFT

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16
Q

In general, the closer the ___ ______ between the donor and the recipient, the better the outcome

A

HLA match

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17
Q

What role do B-cells play in transplant and rejection? (2)

A
  • B cells play a key role by the production of anti-donor antibodies that bind to allografts (termed Donor Specific Antibodies or DSA)
  • Rejection due to B-cell pathophysiology is termed B cell rejection or Humoral rejection
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18
Q

What is the panel reactive antibody (PRA) compatibility test?

A

Blood sample from the potential recipient is cross-matched with
cells from panel of previously typed donors selected to
represent as many HLA antigens as possible.

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19
Q

What is a panel reactive antibody (PRA)?

A

The percentage of positive reactions among the total cell panel

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20
Q

What does a high PRA indicate? What does it not reflect?

A

A high PRA indicates broad sensitization, but it does not reflect antibody strength or titer (concentration)

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21
Q

What is a lymphocyte cross-match? (2)

A
  1. Directly tests the reactivity between a patient’s serum and a potential donor’s cells
  2. Viable lymphocytes are isolated from samples of the donor’s blood, spleen or lymph nodes cross-matched with potential recipient blood to determine whether pre-formed antibodies to donor’s lymphocytes are present
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22
Q

What does a positive lymphocyte cross-match mean?

A

+ test indicates the presence of cytotoxic IgG antibodies to the donor (+ is BAD!)

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23
Q

Why is matching of blood type critical in a transplant patient?

A

Transplanting an organ with ABO incompatibility typically
results in a hyperacute rejection and destruction of the graft

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24
Q

The amount of immunosuppression required will vary depending on the organ transplanted. List the organs from high to low (in general)

A

Lung > heart, kidneys > liver

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25
Q

There are many other factors that also play a role in immunosuppression for organ transplantation. Such as? (7)

A
  1. Match between donor and recipient
  2. Time post-transplant
  3. Underlying disease
  4. Patient history
  5. Medication tolerance
  6. Patient age
  7. Race
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26
Q

What are the 4 types of organ rejection?

A
  1. Hyperacute
  2. Acute cellular rejection (ACR)
  3. Humoral rejection/Antibody mediated rejection (vascular rejection)
  4. Chronic rejection
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27
Q

What is hyperacute rejection?

A

Uncommon, immediate immunological response

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28
Q

What is acute cellular rejection (ACR)? (2)

A
  1. Occurs anytime
  2. Mediated by alloreactive T lymphocytes
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29
Q

What is humoral rejection/antibody mediated rejection? (2)

A
  1. Antibody mediated process
  2. Poorer prognosis
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30
Q

What is chronic rejection? (2)

A
  1. Most common cause of late graft loss
  2. No effective treatment
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31
Q

List the different classes of immunosuppressives (6)

A
  1. IL2 receptor antagonist
  2. Lymphocyte depleting antibody
  3. Corticosteroid
  4. Antiproliferatives
  5. Calcineurin inhibitors
  6. M-Tor inhibitors
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32
Q

What are the 2 phases of immunosuppressive therapy?

A
  1. Induction
  2. Maintenance
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33
Q

Why is induction therapy done? (2)
How is it done? (1)

A
  1. The risk of acute rejection is highest in the first 1-3 months, so higher doses of immunosuppressants are used during this time
  2. Induction therapy is treatment with a biologic agent begun at the time of transplant to deplete or modulate t-cell response
  3. Induction therapy improves the efficacy of immunosuppression by reducing acute rejection and allowing for the reduction in other maintenance medications
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34
Q

What are the drug combinations used in induction therapy? (4)

A
  1. IL-2 receptor antagonist (e.g., basiliximab) OR lymphocyte depleting antibody (e.g., antithymocyte globulin)
    +
  2. Corticosteroid
  3. Antiproliferative - azathioprine OR mycophenolate
  4. Calcineurin inhibitor - cyclosporine OR tacrolimus
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35
Q

What is the IL-2 receptor antagonist drug?

A

Basiliximab

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36
Q

What is the MOA of basiliximab?

A

Binds to the IL-2 receptor on activated lymphocytes preventing IL-2 binding to the receptor

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37
Q

What are the DIs and ADEs of basiliximab?

A
  • No DIs
  • Usually well tolerated, can have acute hypersensitivity
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38
Q

How is basiliximab given?

A

Standard dose (same for everyone) IV pre-transplant, and again on Day 4 or 5

39
Q

What is the lymphocyte depleting antibody medication?

A

Anti-thymocyte globulin (ATG)

40
Q

What is the MOA of anti-thymocyte globulin (ATG)?

A

The antibodies in ATG bind to antigens found on the surface of T-cells and depletes T-cells from circulation
- For induction or rejection (cell mediated)

41
Q

What are the side effects of ATG? (4)

A
  1. Bone marrow suppression
  2. Anaphylaxis
  3. Hepatic
  4. Infusion related reactions (premed to help prevent this)
42
Q

How is ATG dosed?

A

Weight based. Given daily for 3-10 days

43
Q

What is the maintenance immunosuppression regimen?

A
  1. Cyclosporine OR tacrolimus
  2. Azathioprine OR mycophenolate
  3. Corticosteroid
44
Q

How are corticosteroids dosed for transplant pts? (2)

A
  1. IV initially
  2. Switched to oral prednisone and tapered to the lowest effective dose
45
Q

What is the MOA of corticosteroids in transplant pts?

A

Broad spectrum immunosuppressant used in maintenance and induction therapy. Inhibits antigen presentation, cytokine production, and proliferation of lymphocytes

46
Q

What are some short term ADEs of corticosteroids? (4)

A
  1. Insomnia
  2. Personality changes
  3. Gastrointestinal
  4. Glucose alterations
47
Q

What are some long term ADEs of corticosteroids? (3)

A
  1. Musculoskeletal changes
  2. Osteoporosis
  3. Cataracts
48
Q

How should transplant pts on corticosteroids deal with osteoporosis (prevention/treat)? (2)

A
  1. Routine bone density measurements
  2. Pharmacotherapy to prevent or treat osteoporosis
    - Calcium, Vitamin D
    - Bisphosphonates
49
Q

How should transplant pts on corticosteroids deal with hyperglycemia? (3)

A

Hope it resolves with tapering doses
- Diet, oral hypoglycemic, insulin if needed
- Stop tacro?

50
Q

What are the 2 anti-proliferative agents?

A
  1. Azathioprine (AZA)
  2. Mycophenolic acid derivatives
51
Q

What is the MOA of azathioprine?

A

Purine analog, likely affects purine synthesis & metabolism, suppresses T & B cells (Pro-drug of 6-mercaptopurine)

52
Q

What are some adverse effects of AZA? (5)

A
  1. Bone marrow suppression
  2. Skin lesions
  3. Hepatic
  4. Pancreatitis
  5. Alopecia, etc.
53
Q

What DI is there with AZA?

A

Allopurinol - inhibits metabolism of AZA, increasing levels (can cause myelosuppression)

54
Q

How many antirejection medications will most kidney transplants be on during the maintenance phase of immunosuppression?

A

3

55
Q

AZA has largely been replaced by?

A

Mycophenolic acid derivatives

56
Q

What is the MOA of mycophenolic acid (MPA from now on) derivatives?

A

Purine analog: affects purine synthesis and metabolism, suppresses T & B cells
- More specific than azathioprine (does not affect other rapidly dividing cells)

57
Q

What are the 2 formulations of MPA?

A

Both oral
1. Mycophenolate mofetil (MMF) (Cellcept®)
- Prodrug: rapidly converted to mycophenolic acid (MPA) via first pass metobolism
- IV form also available
2. Mycophenolate sodium (EC-MPS) (Myfortic®)
- Enteric coated tablets , deliver active moiety (MPA)

58
Q

How is MPA dosed?

A

Empiric, based on type of organ (q12)

59
Q

Adverse effects of MPA are? (4)

A
  1. Neutropenia
  2. Diarrhea
  3. Nausea
  4. Indigestion
60
Q

What is a unique ADE of MPA?

A

Teratogenic - birth control required for MALES AND FEMALES

61
Q

What are the DIs of MPA? (3)

A
  1. Divalent cations (iron, calcium)
  2. Cholestyramine, colestipol
  3. Food decreases the rate but not the extent of absorption
62
Q

How might GI ADEs of MPA be managed? (7)

A
  1. Rule out infectious cause
  2. Administer with food
  3. Use of acid suppressive medications (PPI, H2RA)
  4. Divide total daily dose into 3 or 4 doses (or decrease if possible)
  5. Try alternate formulation (ie, Cellcept to Myfortic)
  6. Loperamide for diarrhea if non-infectious
  7. Consider change to azathioprine if unable to manage
63
Q

How might neutropenia caused by MPA be managed? (3)

A
  1. Reduce dose if possible
  2. Look for other drug causes and eliminate if possible (increased risk when given concurrently with valganciclovir)
  3. Filgrastim/GCSF if needed
64
Q

What are the calcineurin inhibitor medications? (2)

A
  1. Cyclosporine (CSA)
  2. Tacrolimus (TAC)
65
Q

What is the MOA of CSA and TAC?

A

Forms a complex with their cytoplasmic receptor proteins (cyclophilin) that binds with calcineurin. Inhibition of calcineurin impairs the expression of several cytokine genes that promote T-cell activation

66
Q

True or False? CSA and TAC can be given concurrently

A

False - should not be prescribed concurrently

67
Q

How is CSA metabolized and why is it important?

A

Metabolized via CYP3A4 (and PGP). Weak inhibitor of 3A4 and strong inhibitor of PGP. Meaning DIs are possible if other durgs using this pathway

68
Q

When are CSA drug levels taken? (3)

A
  1. Can do trough (C0) level or 2 hour post dose (C2) level.
  2. C2 preferably no more than 15 minutes from the 2 hour mark.
  3. C0 – 11.5-12.5 hours after last dose.
69
Q

What are the 3 brands of tacrolimus?

A
  1. Prograf
  2. Advagraf
  3. Envarsus
70
Q

Why do we care about knowing the brand names of TAC?

A

Because Advagraf and Prograf are NOT bioequivalent
- Advagraf is XR product intended for once daily dosing, while Prograf is intended for q12h dosing (both available in same strengths too)

71
Q

How often is Envarsus dosed?

A

Once daily b/c prolonged release formulation

72
Q

How is TAC metabolized?

A

CYP3A4

73
Q

When are TAC drug levels taken? (2)

A
  1. Trough level only (C0)
  2. Timing preferably no more than 30 minutes from the CO
    hour mark.
74
Q

Drug level range for CSA and TAC is dependent on various patient factors, such as? (5)

A
  1. Time since transplant
  2. Match
  3. Side effects
  4. History
  5. Organ
75
Q

What are the shared ADEs of the calcineurin inhibitors (TAC and CSA)? (6)

A
  1. Nephrotoxicity – acute and chronic
  2. Neurotoxicity
    - Headache, tremor, paresthesia, dizziness, fatigue, rarely seizures
  3. Hypertension
  4. Electrolyte imbalances: increase K, decrease Mg, decrease Po4
  5. GI
  6. Hepatotoxicity
76
Q

What are the CSA-specific ADEs? (4)

A
  1. Increased lipid and BP
  2. Hyperuricemia
  3. Cosmetic effects (hirsutism, acne)
  4. Gingival hyperplasia unique
77
Q

What are the TAC-specific ADEs? (3)

A
  1. Increased headache and GI (esp. diarrhea)
  2. Increased hyperglycemia
  3. Alopecia unique
78
Q

What are some of the most commonly seen DIs to be aware of when using CSA and TAC? (7)

A
  1. Erythromycin
  2. Clarithromycin
  3. Diltiazem
  4. Verapamil
  5. Antifungals (fluconazole)
  6. Rifampin
  7. Avoid NSAIDs too
79
Q

What are 2 non-drug DIs seen with TAC and CSA?

A
  1. Echinacea
  2. Grapefruit/grapefruit juice
80
Q

What is the mTor inhibitor medication?

A

Sirolimus

81
Q

What is the MOA of sirolimus?

A

Binds to FKBP but does not block calcineurin - engages the TOR
which reduces the cytokine-dependent cellular proliferation of
the G1-S phase of the cell division cycle. Both hematopoietic and
non-hematopoietic cells are affected.

82
Q

What are the 2 dosage forms of sirolimus?

A
  1. Tablets
  2. Liquid requiring refrigeration
83
Q

The half-life of sirolimus is long or short?

A

Long - ~60h

84
Q

How is sirolimus metabolized? What are the DIs?

A

CYP3A4
DIs = same as calcineurin inhibitors

85
Q

Why might we use sirolimus? (3)

A
  1. To replace the calcineurin inhibitor (Declining renal function due to calcineurin inhibitors)
  2. Malignancy (?anti-tumor properties)
  3. Potentially (used rarely) an add on therapy for those that need increased immunosuppression (lung transplants with declining therapy despite triple therapy)
86
Q

What are the ADEs of sirolimus? (9)

A
  1. Delayed wound healing
  2. Hyperlipidemia
  3. Arthralgias (statin confusion)
  4. Anemia, thrombocytopenia
  5. Hypertension
  6. Rash
  7. Mouth sores - idiosyncratic
  8. Edema – basement membrane leakage, non responsive to diuretic
  9. Proteinuria
87
Q

How is acute cellular rejection (ACR) treated? (2)

A

Generally responds well
1. High dose steroids (ex. methylpred 500-1000mg IV od x 3d)
2. Antibody therapy (anti-thymocyte globulin)

88
Q

How is humoral rejection/antibody mediated rejection treated? (3)

A

Less responsive
1. Plasmapheresis, corticosteroids, anti-thymocyte globulin, IV immune globulin
2. Rituximab
- Chimeric monoclonal antibody directed against CD20 antigen on B lymphocytes
3. Tocilizumab, Bortezomib

89
Q

How is chronic rejection treated?

A

Most common cause of late graft loss, no effective treatment
- Increase maintenance immunosuppression

90
Q

True or False? After a transplant, bloodwork needs to be done for life?

A

True - at minimum it will be q monthly (exception with heart transplants being 3 months)

91
Q

Why is bloodwork so important in transplant pts?

A

Helps us to monitor for rejection (exception hearts) and to monitor for toxicity from immunosuppressive medications

92
Q

What does standard bloodwork for a transplant pt consist of? (4)

A
  1. Drug levels (CSA, TAC, or SRL)
  2. Renal function (SCr, urea)
  3. Hematology/CBC
  4. Electrolytes (Na, Cl, K, CO2, Mg, PO4?)
93
Q

What additional bloodwork might be necessary for transplant pts that might not be part of the regular routine? (2)

A
  1. Cholesterol panel
  2. Renal function
  3. Etc.

PHAR 358 (16 decks)

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