Solid Organ Transplantation (2) Flashcards
What is the most common type of organ transplant?
Kidney
What is the goal of transplant for heart, liver, and lung transplant vs other transplants?
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
What is an allograft
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)
Preventing __________ of the __________ is crucial to optimize graft function and survival
rejection of the allograft
Which are some factors that increase risk of rejection?
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
HLA compatibility
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
How are rejections classified
Time of onset
-hyperacute
-acute
-chronic
Immunologic mechanism
-T cell mediated (TCMR)
-antibody mediated (AMR)
Hyperacute rejections
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
Acute rejections
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)
Chronic rejection
Delayed and slow onset (months/years after transplant)
TCMR and AMR
Progressive and irreversible
Transplant rejection immune response
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)
3 signal t cell activation
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
________________ are the primary target of immunosuppression
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
Phases of immunosuppression
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)
Which drugs can be used for maintenance immunosuppression
- Tacrolimus
- Cyclosporine
- Azathioprine
- Mycophenolate
- Sirolimus
- Everolimus
- Belatacept
- Steroids
Which 2 drugs are calcineurin inhibitors
Tacrolimus
Cyclosporine
Calcineurin inhibitor mechanism of action
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
What does cyclosporine and tacrolimus bind to?
They both inhibit calcineurin, but bind to different immunophilins
Cyclosporine binds to CpN
Tacrolimus binds to FKBP
Calcineurin inhibitor pharmacokinetics
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
Cyclosporine forms (2)
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
Cyclosporine TDM is done by obtaining… (4)
C0, trough, C2, AUC
(C0 used most frequently)
Tacrolimus formulations (3)
TAC-IR
-BID
-half life 12-18h
TAC-XL
-QD
-half life 38h
TAC-XR
-QD
-half life 31h
NOTE - formulations are NOT interchangeable
Tacrolimus TDM is done by obtaining… (2)
C0, trough
(C0 used most frequently)
Calcineurin inhibitor food counseling points
Be consistent with food (whether or not taking with or without food), because food will effect drug concentrations
Which ADR is the biggest drawback of calcineurin inhibitors?
Nephrotoxicity
(long term use - which they usually are long term - can lead to CKD)
Cyclosporine main ADRs (3)
Nephrotoxicity
Dyslipidemia
Hypertension
Tacrolimus main ADRs (5)
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
Calcineurin inhibitor monitoring parameters (7)
- TDM
- Serum creatinine/GFR
- Electrolytes
- Blood pressure
- Blood sugar
- Lipids
- Tremors
Which 2 drugs are antimetabolites
Mycophenolate
Azathioprine
Mycophenolate MOA
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
2 forms of mycophenolate
Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)
-both are BID
Mycophenolate pharmacokinetics
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
Mycophenolate food counseling considerations
Should be taken consistently in regards to meals
(food may effect concentrations)
Azathioprine MOA
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
Azathioprine metabolism
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
Is TDM required for antimetabolites?
No
-can be done with mycophenolate, but not done much in practice
Antimetabolite ADRs
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
Antimetabolite monitoring considerations (2)
- CBC
-due to dose dependent myelosuppression risk - TDM can be done with MPA
-AUC preferred, not done much in practice
Which 3 corticosteroids are used for immunosuppression
Prednisone
Prednisolone
Methylprednisolone
Corticosteroid MOA
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
Corticosteroid main ADRs
- Glucose intolerance/diabetes
- Dyslipidemia
- Hypertension
- Increased appetite/weight gain
- Osteopenia, osteoporosis
- Neuropsychiatric effects (insomnia, delirium)
- Cataracts/glaucoma risk
Corticosteroid monitoring
- Blood glucose
(CS stimulate gluconeogenesis and reduce insulin sensitivity) - Blood pressure
- Bone density
(CS increase osteoclast and decrease osteoblast function) - Weight, BMI, waist to hip ratio (Cushingoid features)
- Lipids
-ASCVD risk assessment should be done - Ophthalmology examination (annual)
(cataracts/glaucoma risk)
Which 2 drugs are mTOR inhibitors
Sirolimus
Everolimus
mTOR inhibitor MOA
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
mTOR inhibitor pharmacokinetics
(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
mTOR inhibitor main ADRs (4)
- proteinuria
-not nephrotoxic, but can worsen nephrotoxicity of CNIs if used together - dyslipidemia
- impaired wound healing
- Aspermia (males)
What ADR do mTOR inhibitors NOT cause, that all other immunosuppressants do?
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)
mTOR inhibitor monitoring
Before initiation:
1. Wound healing
-generally surgical wounds should be healed before starting mTORi because they can cause impaired wound healing
- Urinary protein to creatinine ratio
-due to proteinuria risk (avoid if significant proteinuria) - 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)
Which drug is a costimulation blocker?
Belatacept
Belatacept MOA
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
Belatacept adminstration
IV only, monthly infusion
Belatacept ADRs and BBW
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
Belatacept monitoring
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
Maintenance therapy regimen considerations
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)
How to determine new dose for tacrolimus, cyclosporine, sirolimus, and everolimus if concentration was not being met? How is mycophenolate different?
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)
IV cyclosporine and tacrolimus considerations
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
Cyclosporine IV to PO conversion
1:3 (IV to PO)
Tacrolimus IV to PO conversion
1:4 (IV to PO)
Mycophenolate IV to PO conversion
1:1 but it needs to be MMF first
and MMF to MPA PO is 1000:720
