7487 Week 4, Day 1 Solid Organ Transplant PPT (NEWSOME)

Describe the pathophysiology of hyperacute solid organ transplant rejection.
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Terms in this set (42)
- occurs over time
- no treatment
- usually requires a re-transplantation
- antibody-mediated rejection involves the presence of antibodies directed against human leukocyte antigen antigens present on the donor vascular endothelium
- chronic rejection is a major cause of graft loss, irreversible, and involves the humoral immune system and antibodies agains the vascular endothelium
- depends on bile for intestinal absorption
- backbone of maintenance therapy (tacrolimus preferred due to less DIs and ADRs)
- cyclosporine, USP and cyclosporine, USP (MODIFIED) are not bioequivalent
- extensively metabolized by CYP3A4 (DIs with statins, antifungals, etc.)
- associated with hirsutism and gingival hyperplasia
- approved for prophylaxis of organ rejection in kidney, liver, and heart transplantation
- must monitor trough levels (50-400 ng/mL)
What are the common side effects, drug interactions, etc. for mycophenolic acid derivaties?ADRs: - n/v, diarrhea, abdominal pain - myelosuppression Other Notes: - central venous administration may be the preferred route (peripheral lines can lead to edema) - concomitant administration with divalent/trivalent cations or cholestyramine should be avoided (use 1 hour before or 2 hours after mycophenolate) - only highly protein-bound agentWhat are the proliferation signal inhibitors used for solid organ transplant rejection?- sirolimus - everolimusWhat is the MOA, notable PK, etc., for the proliferation signal inhibitors?- inhibits the body's response to cytokines by binding to mammalian target of rapamycin (mTOR) - p-gp inhibitors increase concentrations Individual Agents: - sirolimus is metabolized by CYP3A4 - sirolimus troughs should be 3-10 ng/mL - everolimus approved for kidney and liver transplantation (does not affect wound healing) - everolimus troughs should be 3-8 ng/mLWhat are the notable ADRs for sirolimus?- leukopenia - thrombocytopenia - hyperlipidemia - enhances cyclosporine neurotoxicity and calcineurin inhibitor nephrotoxicity - Black Box Warning not to be used for at least 3-6 months in post-liver and -lung transplants due to life-threatening ADRs **everolimus has similar ADRs, but no black box warningDescribe costimulatory signal inhibitors used for solid organ transplant rejection.- agent used is belatacept - prevents T-cell activation (used as prophylaxis for rejection) Common ADRs: - anemia, neutropenia, diarrhea, UTIs, HA, hyper- and hypokalemia, and peripheral edema - Black Box Warning for incidence of post-transplant lymphoproliferative disease in patients who are Epstein-Barr virus naive (must be screened prior to starting; must be seropositive)Describe corticosteroids used for solid organ transplant rejection.- block cytokine activation and interfere with cell migration and recognition - play a role in both treatment rejection and immunosuppression - two most common: methylprednisolone and prednisone - alternate day dosing or withholding until rejection occurs is common with childrenWhat are common ADRs for corticosteroids?- increased appetite - insomnia - indigestion - mood changes - prednisone decreases the effectiveness of vaccines/toxoids - prednisone should be taken with foodWhat types of agents are used for induction therapy for solid organ transplant rejection?- depleting antibodies: antithymocyte globulin (ATG/RATG), alemtuzumab - non-depleting antibodies: IL-2 receptor antagonists (basilixumab)Describe ATG/RATG.- neither are preferred over the other - ATG indicated for treatment of acute allograft rejection and induction therapy to prevent acute rejection in kidney transplants - RATG indicated for treatment of acute allograft rejection in kidney transplantsWhat are common ADRs of antithymocyte globulin (ATG/RATG)?- myelosuppression (dose-limiting) - infusion-related febrile reactions - anaphylaxis, hypotension, HTN, tachycardia, dyspnea, urticaria, and rashAll depleting antibodies require......pre-medication with APAP, antihistamine (e.g., diphenhydramine), and a corticosteroid to prevent infusion-related reactions.Describe alemtuzumab.- not FDA approved - effective as induction therapy to prevent acute rejection in kidney, liver, heart, pancreas, intestinal, and lung transplants •Effective for corticosteroid and antibody-resistant rejectionWhat are common ADRs for alemtuzumab?- anemia - neutropenia - thrombocytopenia - HA - dizziness - n/v - diarrhea - infusion-related reactionsDescribe IL-2 receptor antagonists.- basilixumab is the primary agent - reduces activity of B-cells - approved for kidney transplantation in combination with cyclosporine and steroids - clearance is increased in patients who have received a liver transplant (recommended that patients with >10 L of ascites receive an additional dose on post-op day 8) **no pre-medication neededWhat are the desired outcomes for initiating induction/maintenance therapy?- prevent hyperacute and acute rejection - rapid dosage reductions are used to minimize ADRs - immunosuppression must be balanced to optimize both graft and patient survival **induction therapy is becoming more common in liver, intestine, and kidney transplantsWhat is the general approach to treatment for induction/maintenance therapy?- multidrug approach - IV methylprednisolone 500-1000 mg used intraoperatively (may taper over 5-7 post-operative days; always given) - if rejection is suspected and a biopsy is not done, empiric therapy can be started (except for heart transplants, which require biopsy before treating rejection) - if confirmed by biopsy, treatment may be based on severity of rejection general approach to treatment: - induction therapy - maintenance therapy - acute rejectionWhat do protocols generally follow for induction/maintenance therapy?protocols combine 2-3 of the following classes: - calcineurin inhibitors (cornerstone; always included unless the patient cannot tolerate them) - antimetabolites or proliferation signal inhibitors - corticosteroidsWhen is induction therapy recommended?patients with a high risk of acute rejection - pre-formed antibodies - hx of previous transplants - multiple HLA mistakes - transplantation of organs with prolonged cold ischemic time or from expanded-criteria donorsDescribe induction therapy.- high level immunosuppression at time of transplantation (with or without immediate introduction of cyclosporine or tacrolimus) - allows lower doses to be used and delays the initiation of calcineurin inhibitors (reduces nephrotoxicity risk) - not mandatory two strategies: - highly intense immunosuppression based on patient risk factors - antibody therapyDescribe maintenance therapy.- prevents acute and chronic rejection while minimizing drug-related toxicity - as acute rejection risk decreases, doses can be gradually reduced or withdrawn over a period of 6-12 monthsWhat are factors to consider regarding maintenance therapy?- organ and type (cadaveric or living) - degree of HLA mismatch - time after transplantation - post-transplantation complications - previous immunosuppressive adverse reactions - compliance - financial considerationsDescribe the algorithm for induction and maintenance therapy.Induction Therapy? Yes: give ATG/RATG or IL-2RA ALL receive IV methylprednisolone regardless of induction therapy. Maintenance therapy is based on center-specific protocols. It usually consists of calcineurin inhibitors (cyclosporine or tacrolimus) ± mycophenolate or sirolimus ± steroidsWhat is the primary goal of treating acute rejection?- minimize intensity of immune response - prevent irreversible injury to allograftWhat are the options for treating acute rejection?- acute rejection? IV methylprednisolone (high-dose; 1-3 doses) unless the patient is African American (then give ATG instead of corticosteroids) - second rejection? biopsy, then do second course of steroids OR ATG/RATG OR alemtuzumab UNLESS IT'S A HEART TRANSPLANT - acute rejection? immediate biopsy - rejecting: mild gets steroids; moderate-to-severe gets steroids OR ATG/RATG - not rejecting: continue maintenance therapyWhat are opportunistic infections associated with solid organ transplantation?- PCP - CMV - fungalDescribe PCP prophylaxis.- used in all transplant recipients - 6-12 months after transplant - Bactrim is the drug of choice (DS preferred over SS)Describe CMV prophylaxis.- continued for the first 200 days or longer after transplantation - agents used as valganciclovir and IV ganciclovirDescribe fungal infection prophylaxis.- oral nystatin and clotrimazole for prevention of oral thrush - antifungal prophylaxis recommended in liver, lung, intestine, and pancreas transplantationWhat role do vaccinations play in solid organ transplantation?- required vaccinations should be received before transplantation - healthcare workers and family members should wear mask and practice good hygiene if recently received a live vaccineHow are therapeutic outcomes evaluated in solid organ transplantation?- success is measured by length of graft and patient survival - routine surveillance of appropriate biochemical markers and serum drug concentrations (assess daily to weekly for first 1-3 months after transplant)CYP3A4 inducers from the highlighted table- carbamazepine - efavirenz - fosphenytoin/phenytoin - phenobarbital - primidone - rifabutin - rifampin - ripilvirine - St. John's wortCYP3A4 inhibitors from the highlighted table- amiodarone - atazanavir/darunavir/ritonavir - azoles - CCBs - cimetidine - clarithromycin/erythromycin - cobicistat - cyclosporine - fluoxetine - grapefruit juice - ripilvirine