Solid Organ Transplant Flashcards
What patients are at the highest risk for organ rejection?
- high panel reactive antibody (PRA levels > 20-80%)
- HLA mismatching
- previous organ transplant
- african american patients
- younger recipient (< 35) & older donor (> 60)
- history of autoimmune disease
- higher risk organs (hep C infected livers)
Define: Panel Reactive Antibody (PRA)
a test that measures the precentage of recipients antibodies react against the doners HLA antigens
higher precentage = increased risk of rejection
Define: Human Leukocyte Antigen (HLA)
proteins found on the surface of cells that help cells recognize “self” from “non-self”- matching is crucial to reduce risk of rejection
What are the phases of immunosuppression?
- induction= high intensity immunosuppression
- maintenance= long term immunosuppression to avoid chronic rejection
- rejection
What is the purpose of induction phase of immunosuppression?
prevents early or immediate after transplant
When should induction immunosuppression therapy be given?
before and during transplant
What medications are used for induction immunosuppression therapy?
- antithymocyte globulin (ATG)= T cell depletion
- basiliximab= IL-2 receptor antagonist
- high dose corticosteroids
What drugs are considered non-depleting antibodies?
basiliximab
low risk patients
What drugs are considered depleting antibodies?
- equine ATG
- rabbit ATG
- alemtuzumab
high risk patients
What are the KDIGO recommendations for induction immunosuppressive therapy?
use antithymocyte globulin (ATG) in patients with higher immunologic risk: increased HLA mismatch, younger recipients with older donors, african american patients, blood group incompatibility
What is the mechanism of action of antithymocyte globulins (ATG)?
bind and deplete T-lymphocytes
What is the black box warning of antithymocyte globulins (ATG)?
must be administered under physician supervision due to anaphylaxis risk
What are the adverse effects of antithymocyte globulins (ATG)?
- infusion-related reactions (fever, chills, hypotension)
- cytokine release syndrome
- thrombocytopenia, leukopenia
- hypertension
What is the monitoring required for antithymocyte globulins (ATG)?
- CBC
- renal function
- signs of infection
What are the medications required before administration of antithymocyte globulins (ATG)?
- benadryl
- acetaminophen
- corticosteroids
due to infusion-related reactions
What is the mechanism of action of basliximab?
bind IL-2 receptors (CD25) on T cells
What is the black box warning of basliximab?
must be administered under physician supervision
What are the adverse effects of basliximab?
- hypertension
- fever
- GI upset
- peripheral edema
- tremor
- infection risk
- upper respiratory tract infection
- dysuria
- psypnea
What is the monitoring required for basliximab?
- S/S of infection
- hypersensitivity reactions
- liver function
What medications are used during the maintenance phase of immunosuppression?
- calcineurin inhibitors = tacrolimus, cyclosporine
- antiproliferative agents= mycophenolate, azathioprine
- mTOR inhibitors= sirolimus, everolimus
- low dose corticosteroids
What calcineurin inhibitor is associated with greater hypertension and hyperlipidemia?
cyclosporine
What calcineurin inhibitor is associated with diabetes and neurotoxicity?
tacrolimus
What are the monitoring requirements for calcineurin inhibitors?
cyclosporine & tacrolimus
- trough levels (tacrolimus= 5-15, cyclosporine= 100-400)
- kidney function (very nephrotoxic!)
- BP, glucose, lipids, and electrolytes (K+ in particular due to AE of hyperkalemia)
What are the drug interactions of calcineurin inhibitors?
- CYP3A4 inhibitors can INCREASE levels (grapefruit juice, azoles, macrolides, diltiazem/verapamil, amiodarone)
- CYP3A4 inducers can DECREASE levels (rifampin, phenytoin, carbamazepine, St Johns Wart
narrow therapeutic index, risk of toxicity or rejection
What drugs are antiproliferative agents?
mycophenolate (Cellcept, Myfortic), azathioprine
Which mycophenolate preparation has less GI upset?
Myfortic (enteric coated)
What are the adverse effects of mycophenolate?
- GI distress (nausea, diarrhea)
- leukopenia, anemia, thrombocytopenia
- teratogenic (BBW for pregnancy loss)
What is the black box warning of mycophenolate?
teratogenic (pregnancy loss)
What are the monitoring parameters for mycophenolate?
- CBC
- liver function
- renal function
What are the patient counseling points for mycophenolate?
- take on an empty stomach
- avoid pregnancy
- avoid live vaccines
What can be done if the GI effects from mycophenolate become intolerable to the patient?
1st choice: reduce dose & divide it, switch to enteric coated form (Myfortic)
2nd choice: administer with food (may decrease absorption), add loperamide (short-term only), or try a different immunosuppressant
What are the adverse effects of azathioprine?
- bone marrow suppression (leukopenia, thrombocytopenia)
- hepatotoxicity
- pancreatitis (rare)
What are the drug interactions of azathioprine?
avoid allopurinol/febuxostat to avoid severe toxicity
TPMT genotyping recommended before use
What drugs are mTOR inhibitors?
sirolimus, everolimus
What is the mechanism of action of mTOR inhibitors?
inhibit mTOR= prevents T-cell proliferation and antibody production
What is the place in therapy for mTOR inhibitors?
add-on to regimens or when patients cannot tolerate calcineurin inhibitors
What are the trough goals of the mTOR inhibitors?
sirolimus= 10-15, everolimus= 3-8
What are the significant drug interactions of mTOR inhibitors?
CYP3A4
What is the black box warning of mTOR inhibitors?
increased risk of infection and malignancy
What are the adverse effects of Sirolimus?
- hyperlipidemia
- edema
- mouth ulcers
- myalgias
- VTE
What are the adverse effects of Everolimus?
- anemia
- thrombocytopenia
- GI upset
- rash
- acne
What are the monitoring parameters of mTOR inhibitors?
- CBC
- LFTs
- lipids
- kidney function
When should steroids be used in transplant maintenance therapy?
stop steriods from induction phase if patient is low immunologic risk, but use lowest effective dose if long-term use warranted
steroid withdrawal can reduce long-term complications from steroid use
What are the adverse effects of steroids?
- acute= hyperglycemia, mood changes, insomnia
- chronic= osteoprosis, weight gain, cushings appearance
What are the types of rejection?
- hyperacute rejection (within minutes, remove organ immediately)
- acute rejection (1 week-3 months post transplant)
- chronic (progressive immune mediated over several years)
What are the steps to treating rejection?
1st line: high dose corticosteroids (methylprednisolone)
if severe or steroid resistant: T-cell depleting agents (Thymoglobulin, Alemtuzumab)
antibody-mediated rejection (AMR): preoteasome inhibitors (Bortezomib, Carfilzomib)
if patient is calcineurin inhibitor intolerant: costimulation blocker (Belatacept)
What is the management of acute rejection?
- mild cases: high-dose corticosteroids
- severe/recurrent cases: cellular rejection= lymphocyte depleting agents (Muromonab-CD3), antibody-mediated rejection= plasma exchange, IV immunoglobulin, anti-CD20 antibodies, lymphocyte depleting agents +/- steroids, add mycophenolate or switch antiproliferative agent
How can chronic rejection be managed?
increase dose of immunosuppressants and/or switch therapies
What is the difference between drug-induced nephrotoxicity and kidney rejection?
kidney rejection= rapid rise in SCr, proteinuria, T-cell infiltrate evident on biopsy
What are the risk associated with rejection treatment?
- infection
- malignancy
- bone marrow suppression
What are the monitoring parameters while treating rejection?
- regular kidney function tests
- trough levels of immunosuppressants
- signs of oppurtunistic infections
What infections are a concern while a patient is on immunosuppressants?
- CMV
- PCP pneumonia
- UTI
- candida
What drugs can be used for infection prophylaxis while patients recieve immunosuppressants?
- CMV= ganciclovir or valganciclovir x >3 months
- PCP= bactrim x 3-6 months
- UTI= bactrim x 6 months
- candida= fluconazole, clotrimazole lozenge, or nystatin x 1-3 months
What kind of malignancy are transplant patients at a high risk for?
squamous cell carcinoma
What is the goal A1C for transplant patients?
7-7.5%
avoid < 6%
What is the target BP for transplant patients?
<130/80
What are the preferred medications to treat hypertension in transplant patients?
ACE-inhibitors or ARBs
