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)