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

Describe the pathophysiology of hyperacute solid organ transplant rejection.
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Describe the pathophysiology of hyperacute solid organ transplant rejection.
- typically involves pre-formed antibodies (either from the donor or recipient)
- the body rejects the organ in minutes to hours
- typically only removal of the organ can correct it
- uncommon in kidney/heart transplants
Describe the pathophysiology of acute solid organ transplant rejection.
- usually occurs in the first months (but can happen any time)
- mediated by alloreactive T-lymphocytes (after infiltration by lymphocytes, cytotoxic cells target and kill functioning cells in the allograft; lymphokines stimulate macrophages to produce tissue damage)
- s/sx include pain and tenderness over graft site, fever, and lethargy
Describe the pathophysiology of humoral/chronic solid organ transplant rejection.
- 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
What calcineurin inhibitors are used for solid organ transplant rejection?
- cyclosporine
- tacrolimus

**block T-cell proliferation
Describe cyclosporine.
- 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)
The usual adult dose of cyclosporine is _____. If you start on an oral cyclosporine and want to convert to IV, the IV dose is _____.
- 2-8 mg/kg/day in two divided doses
- 1/3 of the total daily dose of the oral regimen
Describe tacrolimus.
- PO dosing 0.1-0.2 mg/kg/day in two divided doses
- associated with increased occurrence of neurologic complications
- hyperglycemia more common with tacrolimus
- reported to cause alopecia
- trough concentrations must be monitored (4-15 μg/L)
- more predictable absorption than cyclosporine
Describe the nephrotoxicity associated with calcineurin inhibitors.
- acute and chronic
- elevated serum creatinine, BUN, hyperkalemia, hyperuricemia, proteinuria, decreased fractional excretion of sodium

Strategies to Prevent:
- delay therapy in high-risk patients
- monitor trough concentrations
- reduce dosage
- avoid other nephrotoxins
Describe azathioprine for solid organ transplant rejection.
- prodrug for 6-mercaptopurine
- broken down by xanthine oxidase (reduce dose by 75% when given with allopurinol)
- option for patients who are intolerant of other options

ADRs:
- dose-limiting hematologic ADRs (leukopenia, anemia, thrombocytopenia)
- n/v (take with food if this occurs)
Describe mycophenolic acid derivatives.
- antimetabolite
- mycophenolate mofetil and mycophenolate sodium (enteric-coated; more used out of the two)
- reduces lymphocyte proliferation
- approved for use in kidney, liver, and heart transplantation (recommended for maintenance immunosuppression regimens for most kidney and heart transplant patients)
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