transplant Flashcards
autotransplantation
transplant tissue from one part of the body to another
allotransplantation
transplant tissue from one person to another
orthotopic transplant
transplanted organ is placed in the same location at the original organ (heart, lung, liver)
heterotopic transplant
transplanted organ is placed in a different location as the original organ (pancreas, kidney)
which organs can have deceased or living donors
kidney, liver
which organs can have deceased donors only
heart, lung, pancreas
how does the immune system identify “self”
a self marker (MHC) labels the body’s cells as a friend
how does the immune system identify “non-self”
it recognizes an antigen as foreign and treats it as a foe
how do HLA molecules act in transplant
they are markers that determine compatibility of tissue for transplantation
MHC class I
found on all nucleated cells. presents antigenic peptides to CD8+ T cells
MHC class II
restricted expression on antigen presenting cells
presents antigenic peptides to CD4+ T cells
Type A blood
can only have A or O blood
Type B blood
can only have B or O blood
Type AB blood
universal recipient
Type O blood
universal donor
how do patients develop antibodies to other HLAs
transfusion, pregnancy, other organ transplant
sensitization is generally defined as PRA > __%
10
recipient risk factors for rejection
black race, highly sensitized, previous transplant, young age, prior pregnancy
when does hyperacute rejection occur
immediately (in the OR)
what is the mechanism by which hyperacute rejection occurs
activation of complement through antibody-mediated interactions– results in inflammation & microvascular thrombosis
how to prevent hyperacute rejection
screening: ABO, HLA
treatment of hyperacute rejection
retransplant
when does acute cellular rejection occur
can occur at any time after transplant but most common in the first 12 months
what is the mechanism by which acute cellular rejection occurs
recognition of foreign antigen leads to T- cell activation
cytokines are produced: CD8, NK and B cells are recruited and causes damage
what is the clinical presentation of acute cellular rejection
depends on organ transplanted:
kidney- abrupt change in SCr
liver- abrupt change in LFTs
heart- decrease in cardiac output or ejection fraction
lung- change in pulmonary function/breathing
management of acute cellular rejection
best treatment is prevention
pharmacologic therapy: corticosteroids (prednisone, methylprednisolone), lymphocyte depletion (antithymocyte globulin, alemtuzumab)
what is the general definition of antibody mediated rejection
a form of allograft rejection triggered by the production of antibodies directed toward donor HLA molecules
in antibody mediated rejection, what do the donor specific antibodies activate
the complement: attaches to and pokes holes into the allograft (membrane attack complex)
what are some therapy targets for antibody mediated rejection
proteasome inhibition (stop plasma cells from making antibodies)
cellular depletion (get effector cells out of circulation)
inhibit signals (IL-6)
inhibit complement cascade
what are the calcineurin inhibitors
cyclosporine and tacrolimus
what is the ultimate action of calcineurin inhibitors
block cytokine transcription by inhibiting calcineurin
true or false: you can substitute sandimmune for neoral or gengraf
FALSE: the bioavailability of cyclosporine depends on the formulation and you CANNOT substitute
different brand names of cyclosporine and their absorption
sandimmune: high variability. <10% up to 89% bioavailable. depends on enterohepatic recirculation
neoral, gengraf: 30% bioavailable, more consistent absorption, less dependent on bile
effects of food on the calcineurin inhibitors
high fat meal decreases absorption
cyclosporine causes drug interactions because of being _____ substrate
CYP3A4
cyclosporine elimination is extensive in the ____
bile
cyclosporine adverse effects
think c for cyclosporine and c for cosmetic: acne, hirsutism, gingival hyperplasia
as well as:
nephrotoxicity and neurotoxicity- dose limiting
hypertension
hyperlipidemia
hyperglycemia
CYP3A4 inhibitors will ______ cyclosporine levels. is this reaction immediate or delayed?
increase
interaction happens quick because the protein is already there and you just inhibit it
CYP3A4 inducers will ____ cyclosporine levels. is this reaction immediate or delayed?
decrease
interaction is delayed because you have to make new proteins, takes a couple weeks
cyclosporine interaction with OATP substrates
cyclosporine inhibits OATP and increases the OATP substrate concentration
IV doses of cyclosporine are ____ PO doses
1/3
counseling point for cyclosporine
maintain consistent administration with meals
don’t care if you eat or not just do it consistently
TDM for cyclosporine
narrow therapeutic window: methods are trough, AUC, peak monitoring
with extensive and intermediate CYP3A5 metabolizers, _____ doses of tacrolimus are needed
increased
with poor CYP3A5 metabolizers, _____ doses of tacrolimus are needed
standard
tacrolimus absorption
bioavailability 30%, erratic and variable absorption– decreased with high fat meal
tacrolimus side effects
nephrotoxicity (dose limiting): hyperkalemia, hypomagnesemia
neurotoxicity (dose limiting): headache, tremor, insomnia, seizure
hypertension
hyperlipidemia
hyperglycemia
pruritis
cosmetic- alopecia
tacrolimus drug interactions
decreased GI absorption with cationic compounds
CYP3A4 inducers decrease TAC levels, inhibitors increase TAC levels
IV doses of tacrolimus are ___ of PO doses
1/3
TDM for tacrolimus
narrow therapeutic window: trough concentrations are easiest to measure but may not correlate with efficacy/toxicity
which transplant drugs are purine analogs
mycophenolic acid, azathioprine, mercaptopurine
what is the basic mechanism of mycophenolic acid
to block T and B cell proliferation and activity. does so by inhibiting IMPDH to block purine nucleotide synthesis
adverse effects of mycophenolic acid
bone marrow suppression and GI toxicity are dose limiting
progressive multifocal leukoencephalopathy (PML)
drug interactions with mycophenolic acid
decreased GI absorption with cationic compounds, decreased elimination with acyclovir and ganciclovir
mycophenolate mofetil dose of 500 mg correlates to mycophenolic acid dose of ____
360 mg
TDM for mycophenolic acid
controversial; AUC monitoring most widely used
bioavailability of mycophenolate
depends on formulation:
MMF 94%; rapidly converted to MPA
MPA 72%: protected by enteric coating
mechanism of azathioprine and mercaptopurine
block de novo and salvage pathways for purine synthesis; suppresses T>B cells, anti-inflammatory
2 enzymes responsible for azathioprine/mercaptopurine metabolism
TPMT to inactive & active metabolites
xanthine oxidase to inactive metabolites
azathioprine/mercaptopurine side effects
bone marrow suppression (dose limiting)
GI toxicity (less than MPA)
alopecia, hepatitis, pancreatitis
azathioprine/mercaptopurine drug interactions
xanthine oxidase inhibitors (allopurinol, febuxostat) decrease metabolism and increase toxicity of azathioprine. requires decrease azathioprine doses to 1/3 or 1/4 of the usual dose but generally avoid the combination
TDM for azathioprine/mercaptopurine
TPMT activity
monitor CBC
name the pyrimidine synthesis inhibitor
leflunomide
leflunomide mechanism
ultimately blocks T and B cell proliferation and activity by blocking pyrimidine nucleotide synthesis
leflunomide side effects
bone marrow suppression, GI side effects, alopecia
leflunomide drug interaction
bile acid sequestrants
leflunomide PO dosing requires ____
loading dose
what drugs are the mTOR inhibitors
sirolimus and everolimus
mechanism of the mTOR inhibitors
inhibiting mTOR which is what moves the cell from G1 to S phase. ultimate activity is blocking response to IL-2 and effects on cell cycle
mTOR inhibitors: how does their absorption compare
sirolimus is erratic and variable (14% solution to 27% tablets)
everolimus is more consistent (30%)
both are impacted by high fat meals, highly distributed in WBCs
mTOR inhibitor side effects
bone marrow suppression
GI toxicity
wound dehiscence
hyperlipidemia
proteinuria
pulmonary infiltrates
mTOR inhibitors drug interactions
CYP3A4 inducers decrease
CYP3A4 inhibitors increase
with cyclosporine, you have to take sirolimus 4 hours after it
mTOR inhibitors: which one requires a loading dose
sirolimus
mTOR TDM
narrow therapeutic window: measure by whole blood assay and monitor by trough
which drug is folic acid antagonist
methotrexate
methotrexate mechanism
inhibits dihydrofolate reductase to interfere with DNA synthesis and cell proliferation
methotrexate bioavailability
higher doses are associated with lower bioavailability
Doses <30 mg/m2= 90% BA
Doses >40 mg/m2= 17% BA
methotrexate side effects
bone marrow suppression
GI toxicity
alopecia
nephrotoxicity
hepatotoxicity
cardiotoxicity
methotrexate drug interactions
overlapping toxicities, albumin displacement
higher doses of methotrexate are often given with ____
leucovorin rescue
methotrexate doses are based on ___
BSA
methotrexate TDM
generally based on therapeutic response
which drug is the alkylating agent
cyclophosphamide
cyclophosphamide mechanism
reacts with nitrogen atoms on purine bases, forms cross links in DNA, ultimately interferes with DNA synthesis and cell proliferation
cyclophosphamide side effects
bone marrow suppression
GI Toxicity
alopecia
amenorrhea
cardiotoxicity
pulmonary toxicity/fibrosis
very broad: glucocorticoid versus mineralocorticoid effects of corticosteroids
glucocorticoid: immune system, anti-inflammatory, metabolic, central nervous system, and bone metabolism effects
mineralocorticoid: kidneys (waste potassium and hold on to sodium)
effects of glucocorticoids on the innate immune system
decrease expression of adhesion molecules (the little feet that get the cells where they want to go- site of inflammation)
effects of glucocorticoids on the acquired immunity
at high doses (>100 mg prednisone): T cells, direct cytotoxicity
blocks expression of pro-inflammatory genes and increases expression of anti-inflammatory genes
glucocorticoid SIDE effects on immune system
increasing incidence of infection
anti-inflammatory actions of glucocorticoids
blocks release of arachidonic acid and COX-2 to block the pro-inflammatory prostaglandins and decrease inflammation
side effects of the anti-inflammatory actions of glucocorticoids
GI upset, bleeding, ulcers
anabolic effects of glucocorticoids
increase gluconeogenesis in liver
reduce protein stores in cells except liver
catabolic effects of glucocorticoids
increase lipolysis
inhibit uptake of glucose
inhibit protein synthesis
increase mobilization of fatty acids
side effects of the metabolic actions of glucocorticoids
hyperglycemia and hyperlipidemia
impaired wound healing
buffalo hump: deposits of fat in neck and torso
effects of glucocorticoids on the central nervous system
increases CNS excitability
side effects of glucocorticoids on the central nervous system
insomnia
mania
mood disorders
impaired cognition
increased appetite
effects of glucocorticoids on bone metabolism
decrease calcium
inhibit osteoblasts
decrease calcium absorption from intestines
increase calcium excretion from kidneys
side effects of glucocorticoids on bone metabolism
hypocalcemia, osteopenia/osteoporosis
mineralocorticoid actions
promotes sodium reabsorption and potassium excretion
side effects of mineralocorticoid actions
hypernatremia: water retention, truncal obesity, hypertension
hypokalemia: dysrhythmia
in summary: short term side effects of corticosteroids
sodium & water retention
psychosis
mood changes
poor wound healing
insomnia
hyperglycemia
GI upset
increased appetite
in summary: long term side effects of corticosteroids
hypertension
hyperglycemia
weight gain
adrenal suppression
cataracts
osteoporosis
acne
GI ulcers
_______ has the most mineralocorticoid activity
fludrocortisone
______ has the most anti-inflammatory activity
dexamethasone
corticosteroid dosing for transplant rejection vs maintenance
rejection: methylprednisolone 250-1000 mg IV daily x 3 days
maintenance: tapered over months to a low maintenance dose of 5-10 mg prednisone daily
high dose for short course, low dose for long course
symptoms of adrenal insufficiency
hypotension
decreased appetite
weight loss
fatigue
inability to mount response to stress
what causes iatrogenic adrenal insufficiency
HPA axis suppression from long term administration of supratherapeutic corticosteroids: negative feedback inhibits production of CRH and ACTH so body does not produce endogenous cortisol
how to prevent iatrogenic adrenal insufficiency
slowly taper steroids
decrease steroid dose by 10-20% every 1-2 weeks
what is the purpose of induction immunosuppression
to prevent T-cell mediated immune activity at the time of graft introduction: decrease incidence of acute cellular rejection, delay initiation of maintenance immunosuppression
for induction immunosuppression: what is depleting vs non-depleting agent
depleting: cause LYSIS of T cells (thymoglobulin and alemtuzumab)
non-depleting: inhibit T cell activity (Basiliximab)
thymoglobulin adverse effects
thrombocytopenia
leukopenia & infection
hyperkalemia
respiratory distress
tachycardia
fever, chills
alemtuzumab adverse effects
thrombocytopenia
leukopenia & infection
hyperkalemia
hypotension
fever, chills
basiliximab adverse effects
none– well tolerated!
time of effects for induction agents
thymoglobulin & alemtuzumab: 6-12 months
basiliximab: 3-6 months
pre-medication for induction
thymoglobulin and alemtuzumab: required acetaminophen, diphenhydramine, corticosteroid
not needed for basiliximab
which EBV serostatus gives the highest risk of PTLD
D+/R-
rejection risk based on age
young>elderly
more active immune system
rejection risk based on sex
female>male
rejection risk: pregnancy?
sensitizing event: increases antibodies
rejection risk based on race
black patients highest risk, more likely to have CYP3A5 mutation leading to tacrolimus rapid metabolism
rejection risk based on PRA
high PRA> low PRA
high means more antibodies against donor pool
what are some “sensitizing events”
pregnancy, blood transfusion, prior transplantation
rejection risk based on organ type: lowest risk to highest risk
liver<kidney<heart<lung< small bowel
which organ types typically require long term steroids
lung & small bowel
goals of maintenance immunosuppression
prevent acute cellular and antibody mediated rejection
what drugs are in the maintenance immunosuppression toolbox
calcineurin inhibitors
antimetabolites
mTOR inhibitors
corticosteroids
belatacept
preferred calcineurin inhibitor for maintenance
tacrolimus
cell cycle inhibitors use in pregnancy?
mycophenolate is contraindicated in pregnancy.
azathioprine is used in pregnancy.
timing with mTOR inhibitors
need to wait 90 days from transplant to initiate due to impaired wound/anastomosis healing
benefits of mTOR inhibitors?
benefit in malignancy and viral infections
what is belatacept mechanism of action
binds CD80/86 on antigen presenting cells which prevents second signal required for T cell activation
belatacept adverse effects
mostly well tolerated, some infusion related like HTN, HA, NVD, edema
*PTLD risk and fungal/viral infections
contraindications of belatacept
EBV high risk patients (D+/R-)
ALL cases of acute cellular rejection should receive ____
steroids
treatment of initial rejection episode in acute cellular rejection
methylprednisolone 1000 mg IV x 3 doses
treatment of refractory or recurrent rejection episode in acute cellular rejection
lymphodepleting agents: thymoglobulin, alemtuzumab
treatment of antibody mediated rejection
- remove antibodies: plasmapheresis
- inhibit new antibody production: IVIG
- inhibit/deplete B cells: rituximab, carfilzomib, bortezomib, daratumma
- inhibit/deplete T cells: corticosteroids, thymoglobulin
- inhibit C5 to prevent formation of MAC: eculizumab
drug of choice for PJP
sulfamethoxazole/trimethoprim
bactrim coverage
PJP, toxoplasmosis, listeria, nocardia
bactrim dosing PJP
DS MWF or SS daily
renal dose adjustments
bactrim adverse effects
increased SCr, photosensitivity, hyperkalemia
bactrim drug interaction
warfarin
use bactrim alternatives if __
sulfa allergy, hyperkalemia
bactrim alternatives
dapsone, atovaquone, pentamidine
dapsone disadvantages
covers only PJP, requires G6PD testing prior to initiation
atovaquone advantages/disadvantages
covers PJP and toxoplasmosis
ok in sulfa allergy or G6PD deficiency
pentamidine disadvantages
inhaled, high rates of bronchospasm
nystatin prevents ___
thrush
fluconazole prevents ___
candida spp infections
voriconazole prevents ____
candida and aspergillus spp infections
nystatin side effects and counseling
GI effects
shake well prior to using
no food/drink for 10 minutes before/after
fluconazole side effects
QT prolongation, LFT elevations, GI effects
fluconazole drug interactions
CYP3A4 inhibitor (increases CNI and mTOR levels)
voriconazole side effeccts
LFT elevations, photosensitivity, hallucinations, blurred vision, QT prolongation
voriconazole drug interactions
strong CYP3A4 inhibitor: decrease CNI dose by 50-75% upon starting
acyclovir covers ____
HSV prophylaxis
letermovir covers ____
CMV prophylaxis
ganciclovir & valganciclovir cover ____
HSV & CMV prophylaxis/treatment
acyclovir side effects
headache, neurotoxicity, nephrotoxicity, thrombocytopenia
ganciclovir & valganciclovir side effects
leukopenia, thrombocytopenia, AKI, GI
fetal risk: avoid in pregnancy and breastfeeding
letermovir side effects
headache GI
letermovir drug interactions
moderate CYP3A4 inhibitor
cyclosporine: inhibits letermovir metabolism
most common indications for a kidney transplant and which one is #1
1 is diabetes
others: hypertension, glomerulonephritis, cystic kidney disease
which HLA antigens are used for matching a kidney transplant
A, B, C, DR, DP, DQ
how does HLA matching affect kidney transplant outcomes
6 antigen match= best outcomes & least rejection
0-5 antigen match= not as good of a chance
what is the significance of the kidney donor prognosis index
calculates risk of graft failure based on DONOR factors
age, ht/wt, race, HTN, DM, cause of death, SCr, HCV, DCD
how does the cPRA affect the kidney transplant waitlist
the higher the number= the more reactive the patient is and the more chance they will have antibodies to the donor antigen. anything over a 20% is a high risk
how does living kidney donor affect kidney transplant outcomes
we can transplant patients much sooner instead of waiting for a deceased donor
living donor kidney is better: higher GFR
most common indication for adult liver transplantation
alcoholic liver disease
most common indication for pediatric liver transplantation
biliary astresia
you can donate part of your liver?
yes it is the only organ that can regenerate itself
do the majority of liver transplant recipients receive induction immunosuppression?
NO!
what maintenance immunosuppression regimen is most common in liver transplant recipients?
tacrolimus, mycophenolate, and a steroid
who has the lowest incidence of acute rejection in liver transplant recipients
ages 65+
what is MELD a predictor for
90 day mortality
components of MELD-BNa score
SCr, bili, INR, Na
components of child pugh score
albumin, bili, INR, ascites, encephalopathy
components of PELD score & who it applies to
Kids <12: age, size, albumin, bili, INR
most common indications for lung transplant
IPF, COPD, cystic fibrosis
the ______ assesses pre transplant urgency & post transplant survival to determine lung allocation offers
Lung CAS
median survival for lung transplant is _____ compared to most other transplanted organs
shorter
_____ is common in the first year after lung transplant
ACR
primary limitation to long-term survival after lung transplantation is _____
CLAD (chronic lung allograft dysfunction)
