Solid Organ Transplantation (2) Flashcards

1
Q

What is the most common type of organ transplant?

A

Kidney

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2
Q

What is the goal of transplant for heart, liver, and lung transplant vs other transplants?

A

For heart, liver, and lung - the goal is survival

For kidney, pancreas, and intestine - the goal is to initially improve quality of life, which will result in increased survival

For vascularized composite transplants (limb, face, genitals) - the goal is to improve quality of life

And for uterus transplant (due to uterine infertility) - the goal of transplant is to allow childbearing

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3
Q

What is an allograft

A

an organ or tissue graft from a donor of the same species as the recipient but which is not genetically identical.
(human to human transplant)

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4
Q

Preventing __________ of the __________ is crucial to optimize graft function and survival

A

rejection of the allograft

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5
Q

Which are some factors that increase risk of rejection?

A

Younger recipient (stronger immune response)
Black/AA recipient (more mismatches)
Prior transplant recipient
Older donor
Unrelated donor (greater than related donor)
Deceased donor (greater than living donor because there may be more ischemic injury and damage to organ)

Longer ischemia time (time that the organ was not being perfused)…
-longer warm ischemia (in operating room) and longer cold ischemia (on ice) = increased risk

ABO incompatibility
(should ideally by identical, but has to be at least compatible)

HLA compatibility

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6
Q

HLA compatibility

A

The major histocompatibility complex (MHC) is gene that codes for HLA (human leukocyte antigen) … there is high genetic diversity of HLA - mismatched donor antigens can be a target for the recipients immune system
(HLA is how the immune determines self vs non self, which is why if there is a mismatch, it causes a rejection)

Organs do not need to be perfectly matched, but they can not be incompatible (i.e. if the recipient has an antibody against the donor = incompatible)
-perfect match is ideal but not necessary, but the number of mismatched antigens is associated with rejection risk

When there is time, crossmatch testing is done before transplant
-donor and recipient blood is mixed, if the recipient has antibodies to donor they will bind and result in a positive crossmatch meaning they are incompatible

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7
Q

How are rejections classified

A

Time of onset
-hyperacute
-acute
-chronic

Immunologic mechanism
-T cell mediated (TCMR)
-antibody mediated (AMR)

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8
Q

Hyperacute rejections

A

Immediate rejections (occur within minutes/hours of transplant)
Occur due to the presence of pre formed circulating donor specific antibodies (AMR)

This is irreversible
But, it doesn’t occur a lot because we do crossmatch testing prior to the transplant

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9
Q

Acute rejections

A

Usually happen early (days/weeks) but can occur at anytime after transplant

Early acute rejection - within the first 3-6 months … result of recipient/donor rejection risk factors
Late acute rejection - beyond 6-12 months… usually due to under immunosuppression or non-adherence to immunosuppressants

Usually TCMR (but can be AMR)

This is treatable rejection (the only kind that is treatable, so when we talk about treating rejections in practice, we are talking about acute rejections)

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10
Q

Chronic rejection

A

Delayed and slow onset (months/years after transplant)
TCMR and AMR
Progressive and irreversible

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11
Q

Transplant rejection immune response

A

Ischemia/reperfusion injury “primes” the immune system - non-specific innate immune response

Mismatched HLA on donor cells will result in an adaptive immune response
-antigen presents to t cells (which are the primary immune cells that drive the rejection process)
-T cells become activated, those specific t cells replicate (clonal expansion) and differentiate into effector t cells (CD4 and CD8)
-CD8 will cause cytotoxicity, CD4 will release cytokines more cytotoxic t cells or macrophages or activate b cells (which can then form plasma cells and antibodies and cause cell death via CDC or ADCC)

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12
Q

3 signal t cell activation

A

There are 3 steps in the activation of t cells

Signal 1: TCR stimulating… APC presents antigen on MHC which binds to TCR on t cell

Signal 2: Co-simulation … molecule on APC cell binds to molecule on the t cell

Signal 3: Cytokine signaling …
-signal 2 allows for a full synapse to occur, leading to expression of cytokines, the most important one is interleukin 2
-The t cell will produce IL-2, and also has a receptor, that IL-2 will bind to
-When IL-2 binds to the receptor it will lead to DNA synthesis and clonal expansion of t cells

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13
Q

________________ are the primary target of immunosuppression

A

T cells are the primary target of immunosuppression

Drugs will work extracellularly (large molecules) via interactions with surface receptors or intracellularly (small molecules) to inhibit activation or proliferation signaling pathways
(i.e. to stop the 3 signals that activate t cells)

Note - belatacept works extracellularly, all the other drugs work intracellularly

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14
Q

Phases of immunosuppression

A

Desensitization
-this is done BEFORE transplant, not done much

Induction
-high intensity IV therapy for the first 5-7 days after transplant to prevent early acute rejection

Maintenance
-life long combination therapy to prevent acute and chronic rejection (combo allows us to use lower doses of individual agents to prevent toxicity)

Acute rejection therapy
-done whenever acute rejection occurs (high intensity therapy)

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15
Q

Which drugs can be used for maintenance immunosuppression

A
  1. Tacrolimus
  2. Cyclosporine
  3. Azathioprine
  4. Mycophenolate
  5. Sirolimus
  6. Everolimus
  7. Belatacept
  8. Steroids
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16
Q

Which 2 drugs are calcineurin inhibitors

A

Tacrolimus
Cyclosporine

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17
Q

Calcineurin inhibitor mechanism of action

A

Block 3rd signal (IL-2 induced proliferation of t cells)

Bind to immunophilins (cyclosporine to CpN and tacrolimus to FKBP) and inhibit calcineurin
(which inhibits production of IL-2)

Why? …
When signal 1 and 2 occur (t cell gets activated) - there is an increase in intracellular calcium
Calcium will activate calmodulin, which will then bind to calcineurin
The calcineurin/calmodulin complex will dephosphorylate NFAT, allowing it to move to the nucleus and cause transcription of IL-2

So, by blocking calcineurin, NFAT never gets dephosphorylated or moves to the nucleus to make IL-2

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18
Q

What does cyclosporine and tacrolimus bind to?

A

They both inhibit calcineurin, but bind to different immunophilins

Cyclosporine binds to CpN
Tacrolimus binds to FKBP

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19
Q

Calcineurin inhibitor pharmacokinetics

A

Low and variable oral bioavailability (effected by food, important to be consistent)

Highly protein bound and erythrocyte bound
-may be varying concentrations in patients with low protein or anemia

Many interactions due to CYP3A4 metabolism
But, is also metabolized by CYP3A5, when it is expressed in some people (some people express it, some don’t, so there is variability in metabolism as well, genetic testing is possible but not done in practice)
Substrate of PgP

Biliary elimination

Because of variability TDM is required

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20
Q

Cyclosporine forms (2)

A

There is a conventional and a modified form
-note there are differences in kinetics of these forms and they are NOT interchangeable

Most of the time when cyclosporine is ordered it is for the modified (micro emulsion form)
-this has more consistent bioavailability

Both are dosed BID

Conventional form has a half life of 10 hours
Modified form has a half life of 8.4 hours

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21
Q

Cyclosporine TDM is done by obtaining… (4)

A

C0, trough, C2, AUC
(C0 used most frequently)

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22
Q

Tacrolimus formulations (3)

A

TAC-IR
-BID
-half life 12-18h

TAC-XL
-QD
-half life 38h

TAC-XR
-QD
-half life 31h

NOTE - formulations are NOT interchangeable

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23
Q

Tacrolimus TDM is done by obtaining… (2)

A

C0, trough
(C0 used most frequently)

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24
Q

Calcineurin inhibitor food counseling points

A

Be consistent with food (whether or not taking with or without food), because food will effect drug concentrations

25
Q

Which ADR is the biggest drawback of calcineurin inhibitors?

A

Nephrotoxicity
(long term use - which they usually are long term - can lead to CKD)

26
Q

Cyclosporine main ADRs (3)

A

Nephrotoxicity
Dyslipidemia
Hypertension

27
Q

Tacrolimus main ADRs (5)

A

Nephrotoxicity

Electrolytes (increased potassium, decreased magnesium)

Glucose intolerance/diabetes (calcineurin is important to insulin production, so inhibition can result in increased blood sugar)

Tremors (neurotoxicity, usually peak level related)

Alopecia

28
Q

Calcineurin inhibitor monitoring parameters (7)

A
  1. TDM
  2. Serum creatinine/GFR
  3. Electrolytes
  4. Blood pressure
  5. Blood sugar
  6. Lipids
  7. Tremors
29
Q

Which 2 drugs are antimetabolites

A

Mycophenolate
Azathioprine

30
Q

Mycophenolate MOA

A

Inhibits de novo purine synthesis, therefore inhibiting lymphocyte replication

Purine (guanine) is needed for DNA synthesis, and therefore for B and T cell replication
IMPDH, is an enzyme that converts IMP to XMP, which is needed for guanine synthesis
Mycophenolate inhibits IMPDH, inhibiting guanine synthesis, therefore inhibiting b and t cell replication

31
Q

2 forms of mycophenolate

A

Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)
-both are BID

32
Q

Mycophenolate pharmacokinetics

A

high bioavailability
-MMF needs acidic pH for dissolution (but MPS does not) - consider drug interactions with PPIs and H2RAs

Highly protein bound

Metabolism: hydrolyzed to MPA, which undergoes glucuronidation to MPAG
MPAG is transported to the bile, and then undergoes enterohepatic recirculation - results in a second peak concentration
-this is important because some drugs may inhibit enterohepatic recirculation - eg, cyclosporine, cholestyramine

Excreted primarily in the urine

33
Q

Mycophenolate food counseling considerations

A

Should be taken consistently in regards to meals
(food may effect concentrations)

34
Q

Azathioprine MOA

A

AZA prodrug > 6-mercaptopurine (6-MP) purine analog
6-MP > TIMP by HRPT and eventually to tioguanine nucleotides (TGN) which get incorporated into DNA causing the cell to undergo apoptosis

TIMP is also converted to methyl-TIMP which inhibits purine synthesis and cell replication

35
Q

Azathioprine metabolism

A

6-MP is converted to inactive metabolites by xanthine oxidase and TPMT
-this is important to consider, as xanthine oxidase inhibitors (allopurinol, febuxostat) can therefore result in an increase in toxicity

NUDT15 converts cytotoxic TGNs to less cytotoxic TGNs

36
Q

Is TDM required for antimetabolites?

A

No
-can be done with mycophenolate, but not done much in practice

37
Q

Antimetabolite ADRs

A

Both:
-myelosuppression (decreased bone marrow function resulting in fewer RBCs, WBCs, and platelets)

Mycophenolate:
-GI disturbances (n/v/d) - this is the primary limiting toxicity for MPA
-teratogenicity

38
Q

Antimetabolite monitoring considerations (2)

A
  1. CBC
    -due to dose dependent myelosuppression risk
  2. TDM can be done with MPA
    -AUC preferred, not done much in practice
39
Q

Which 3 corticosteroids are used for immunosuppression

A

Prednisone
Prednisolone
Methylprednisolone

40
Q

Corticosteroid MOA

A

Inhibits gene transcription of important cytokines

Steroid binds to glucocorticoid receptor, this steroid-GR complex moves to the nucleus affecting gene transcription
-inhibits cytokine expression (including IL-1, IL-2, IFN-gamma, TNF-alpha) = reducing inflammation, causing t cell depletion, decreased APC/macrophage function, and altered leukocyte migration

41
Q

Corticosteroid main ADRs

A
  1. Glucose intolerance/diabetes
  2. Dyslipidemia
  3. Hypertension
  4. Increased appetite/weight gain
  5. Osteopenia, osteoporosis
  6. Neuropsychiatric effects (insomnia, delirium)
  7. Cataracts/glaucoma risk
42
Q

Corticosteroid monitoring

A
  1. Blood glucose
    (CS stimulate gluconeogenesis and reduce insulin sensitivity)
  2. Blood pressure
  3. Bone density
    (CS increase osteoclast and decrease osteoblast function)
  4. Weight, BMI, waist to hip ratio (Cushingoid features)
  5. Lipids
    -ASCVD risk assessment should be done
  6. Ophthalmology examination (annual)
    (cataracts/glaucoma risk)
43
Q

Which 2 drugs are mTOR inhibitors

A

Sirolimus
Everolimus

44
Q

mTOR inhibitor MOA

A

Bind to FKBP (like tacrolimus), but they do not inhibit calcineurin, they inhibit mTORC1

mTOR is a important regulator of cell growth, proliferation, metabolism, and survival

mTOR forms mTORC1 (mTOR complex 1) which activates proteins needed for cell proliferation (progression from G1 to S phase)
So, by inhibiting mTORC1, these drugs lead to cell cycle arrest and decreased cell proliferation

45
Q

mTOR inhibitor pharmacokinetics

A

(similar to CNIs)

Variable bioavailability
-effected by food (counsel patients to be consistent)
-requires TDM as a result

Metabolism:
CYP3A4 and PGP substrates

Very long half lives:
-62 hours for sirolimus
-30 hours for everolimus

46
Q

mTOR inhibitor main ADRs (4)

A
  1. proteinuria
    -not nephrotoxic, but can worsen nephrotoxicity of CNIs if used together
  2. dyslipidemia
  3. impaired wound healing
  4. Aspermia (males)
47
Q

What ADR do mTOR inhibitors NOT cause, that all other immunosuppressants do?

A

Malignancy
-unlike other immunosuppressants which can cause malignancy, mTOR inhibitors can actually be used to treat malignancy
(may be an incentive to switch someone with cancer to a mTOR inhibitor, but not necessarily used for all cancer patients with transplants)

48
Q

mTOR inhibitor monitoring

A

Before initiation:
1. Wound healing
-generally surgical wounds should be healed before starting mTORi because they can cause impaired wound healing

  1. Urinary protein to creatinine ratio
    -due to proteinuria risk (avoid if significant proteinuria)
  2. Lipids
    -due to dyslipidemia risk (initiate dyslipidemia therapy if needed)

While on therapy:
1. TDM
2. Urinary protein to creatinine ratio
3. Lipids
4. CBC (myelosuppression risk)

49
Q

Which drug is a costimulation blocker?

A

Belatacept

50
Q

Belatacept MOA

A

Inhibits signal 2

Signal 2 is the costimulatory signal of CD80/86 (B7) on the APC binding to CD28 on the T cell
(without this costimulation, the T cell will undergo apoptosis)

Once the T cell gets activated, it produced CTLA-4, which has a higher affinity for CD80/86, so it will bind and cause t cell cycle arrest
Belatacept is a fusion protein of CTLA-4 and a human IgG antibody - so it will bind to CD80/86 (preventing signal 2 from happening) and cause t cell cycle arrest

51
Q

Belatacept adminstration

A

IV only, monthly infusion

52
Q

Belatacept ADRs and BBW

A

BBW for: post-transplant lymphoproliferative disorder (PTLD) (type of lymphoma)
-high risk if recipient is Epstein barr negative and donor is Epstein Barr positive, so this can only be used in patients (recipients) who are have positive Epstein Barr serology

Other ADRs:
-infection
-infusion reactions
-malignancy

53
Q

Belatacept monitoring

A

Before initiation:
Epstein Barr Serology
-recipient MUST have positive EBV (otherwise high risk of PTLD)

During therapy
Weight
-because dose adjustments are required if >10% change in body weight

IV access

54
Q

Maintenance therapy regimen considerations

A

Therapy is life long combination therapy, usually a 3 drug regimen
-steroid free regimens may be tried in lower risk patients
-substitutions may be made to avoid toxicities
-rarely some transplant recipients may be able to wean down to one drug or no drugs overtime

But in general the regimen is…
Primary agent + Secondary Agent +/- Steroid

Primary agent:
-Calcineurin Inhibitor (Tacrolimus or cyclosporine)
Possible substitutions: mTOR inhibitor (sirolimus, everolimus) or belatacept

Secondary Agent:
-Antimetabolites (MMF or MPS or AZA)
Possible substitutions: mTOR inhibitor (sirolimus, everolimus) or belatacept

Steroid:
-Corticosteroids (Prednisone or prednisolone or methylprednisolone)

55
Q

How to determine new dose for tacrolimus, cyclosporine, sirolimus, and everolimus if concentration was not being met? How is mycophenolate different?

A

These follow linear kinetics, so you can just use a proportion to find what the new dose should be if you have a trough level and a goal level.

The difference with mycophenolate is you use and AUC level - so multiple levels need to be taken and a calculation needs to be done to determine AUC, but then you just plug in the AUC into the proportion the same way…

Dose(new) / Css(goal) = Dose(old) / Css(old)

56
Q

IV cyclosporine and tacrolimus considerations

A

There is a risk of anaphylactoid reaction with IV form because it contains castor oil - so we avoid IV if we can

It’s important that if IV is used PVC free tubing and bags are used - otherwise the drug will leach to the bags and the patient will not get the full dose

57
Q

Cyclosporine IV to PO conversion

A

1:3 (IV to PO)

58
Q

Tacrolimus IV to PO conversion

A

1:4 (IV to PO)

59
Q

Mycophenolate IV to PO conversion

A

1:1 but it needs to be MMF first
and MMF to MPA PO is 1000:720