Renal Transplantation Medication
- Author: Bradley H Collins, MD; Chief Editor: Ron Shapiro, MD more...
The goals of pharmacotherapy are to prevent graft rejection, reduce morbidity, and prevent complications. Immunosuppression is often started prior to or during surgery. Transplant recipients are maintained on an immunosuppression regimen that includes 1-3 drugs. Immunosuppressant drug classes include calcineurin inhibitors, corticosteroids, antimetabolites, mTor inhibitors, and other immunosuppressants. Several regimens can be used, including pretransplantation induction therapy and simple postoperative maintenance therapy; the choice of regimen depends on the training and experience of the transplantation center. For additional information, see the Medscape topic Immunosuppression.
These agents induce immunosuppression by inhibiting the first phase of T-cell activation by binding to immunophilins (eg, cyclophilin, FK binding proteins) to form complexes that then bind to and inhibit the activated calcineurin phosphatase . Calcineurin is essential for the dephosphorylation of the nuclear factor of activation of T cells (NFAT) that activates T-cells. The first phase of T-cell activation causes transcriptional activation of interleukin (IL)-2, IL-3, IL-4, tumor necrosis factor (TNF) alpha, and interferon gamma that allow T-cells to progress from the G0- to G1-phase.
Tacrolimus is a calcineurin inhibitor with 2-3 times the potency of cyclosporine. Tacrolimus can be used at lower doses than cyclosporine, but its adverse effects include renal dysfunction, neurotoxicity (tremor, insomnia, and paresthesias of the extremities), and new-onset diabetes. Levels are adjusted according to renal function, hepatic function, and adverse effects. Tacrolimus has essentially replaced cyclosporine as the calcineurin inhibitor of choice, because of less rejection, less steroid-resistant rejection, more salvage after conversion from cyclosporine because of rejection, and in some studies, superior graft survival. Currently, 80-90% of patients receive tacrolimus after renal transplantation instead of cyclosporine, and this change has persisted over the past 10-15 years. Astagraf and Envarsus are once-daily formulations of tacrolimus. A number of generic formulations of the original tacrolimus are available.
Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for various organs.
For children and adults, base dosing on ideal body weight. Maintaining appropriate levels of the drug in the bloodstream is crucial to the maintenance of the allograft. Foods and time of administration can alter the level of the drug. Medication must be taken at the same time every day.
Neoral is the capsular form of the newer formulation of cyclosporine, available in 25- and 100-mg capsules. Sandimmune is the liquid form of the original formulation. Genraf is the branded generic form of the newer formulation, available in 25- and 100-mg capsules. There are many generic formulations of both the original and modified formulations.
At pharmacologic doses, glucocorticoids suppress immune responses.
Prednisone is an immunosuppressant used for the prevention or treatment of rejection. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is an oral steroid with approximately 4 times the potency of endogenous steroids. All patients receive steroids around the time of the transplant; perhaps one third have steroids withdrawn within a few days of the transplant (steroid near-avoidance), and perhaps 10% have steroids withdrawn at a subsequent date. In spite of the numerous side effects, most transplant patients are maintained on long-term low-dose steroids.
Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Prednisolone is very similar to prednisone.
Methylprednisolone is an immunosuppressant used to prevent or treat rejection. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It is the intravenous (IV) form of prednisone.
Used for maintenance therapy in conjunction with a calcineurin inhibitor and prednisone.
Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thus inhibiting their proliferation. It inhibits antibody production. It is the most prescribed immunosuppressive agent in transplantation. Two forms exist, mycophenolate mofetil (MMF, CellCept) a prodrug for mycophenolic acid (MPA, Myfortic). These agents are used in regimens containing a calcineurin inhibitor and corticosteroids for prevention of renal allograft rejection. There are many generic formulations.
Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity. Antimetabolites are used to block the uptake of vital nutrients needed by the cells. As implied, these drugs affect not only the cells of the immune system but also other cells of the body. The potency of therapy is dose-dependent. Azathioprine is not effective treatment for acute rejection episodes but remains an economical choice for long-term immunosuppression. It was supplanted very quickly by mycophenolate mofetil when the latter became available.
Inhibit T-cell activation and proliferation. Unlike calcineurin inhibitors, sirolimus and everolimus inhibit the second phase of T-cell activation. The second phase involves signal transduction and clonal proliferation of T-cells. These agents inhibit interleukin-induced proliferation of T-cells resulting in cell cycle arrest in hte late G1-phase and prevents progression to the S-phase. Sirolimus inhibits interleukin (IL)-2, IL-4, IL-7, IL-15, and IL-17. Everolimus inhibits IL-2 and IL-15.
Sirolimus, known in the past as rapamycin, is a macrocyclic lactone produced by Streptomyces hygroscopicus. It is a fairly potent immunosuppressant that inhibits T-cell activation and proliferation by a mechanism that is unknown but distinct from that used by all other immunosuppressants. This inhibition suppresses cytokine-driven T-cell proliferation by inhibiting progression from the G1 phase to the S phase in the cell cycle. It is used in a minority of transplant recipients.
Everolimus is indicated for prophylaxis of organ rejection in patients with low to moderate immunologic risk following kidney transplantation. It is used in combination with reduced-dose cyclosporine, as well as basiliximab and corticosteroids. It inhibits the second phase of T-cell activation.
These agents may be used in various immunosuppressant regimens.
Belatacept is a monoclonal antibody that inhibits T-cell CD28 activation and proliferation by binding costimulatory ligands (CD80, CD86) of antigen presenting cells. It is indicated for use in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids to prevent kidney transplant rejection.
Interleukin-2 receptor antagonist indicated for prophylaxis of kidney transplant rejection. It is used as part of a regimen that includes a calcineurin inhibitor and corticosteroids. More recently, it has been used as part of induction regimens.
Acts against human T-cell surface antigens and depletes CD4 lymphocytes. It is indicated for treatment of renal transplant acute rejection in conjunction with concomitant immunosuppression. It is also widely used off-label for induction.
Alemtuzumab is a humanized recombinant monoclonal antibody against CD52 that is approved by the FDA for chronic lymphocytic leukemia and multiple sclerosis. It is used off-label as part of various induction regimens in patients undergoing kidney transplantation. In numerous phase 3 clinical trials, alemtuzumab has demonstrated steroid-sparing effects, including improved glycemic stability. Leukopenia and neutropenia were reported. Careful patient selection is required. Long-term follow-up results from the 3C trial (NCT01120028) is pending regarding alemtuzumab’s role in reducing calcineurin inhibitor exposure by using a more potent induction regimen.
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- Table 1. Demographics of adult patients on the waiting list for kidney transplants, United States, 2012
- Table 2. Primary causes of ESRD in adult patients on the kidney transplant waiting list: United States, 2012
- Table 3. Demographics of pediatric patients awaiting kidney transplant: United States, 2012
- Table 4. Primary causes of end-stage renal disease in pediatric patients on the kidney transplant waiting list: United States, 2012
- Table 5. Five-year post-transplant survival with a functioning kidney graft: United States, 2012
|Patient Characteristic||Number of Patients||Percentage|
|Age 18-34 y||8811||9.5|
|Age 35-49 y||24,799||26.7|
|Age 50-64 y||40,523||43.6|
|Age 65-74 y||16,779||18.1|
|Age >75 y||1973||2.1|
|Cause of ESRD||Number of Patients||Percentage|
|Other or unknown cause||17||18.5|
|ESRD = End-stage renal disease|
|Age <1 y||1.0|
|Age 1-5 y||15.9|
|Age 6-10 y||14.1|
|Age 11-17 y||69.0|
|Other or unknown||1.8|
|Cause of Renal Failure||Percentage|
|Focal segmental glomerulosclerosis||12.0|
|Other or unknown||50.3|
|ESRD = End-stage renal disease|
|Age <11 y, deceased donor||75|
|Age <11 y, living donor||89|
|Age 11-17 y, deceased donor||67|
|Age 11-17, live donor||77|
|Adults, deceased donor||73|
|Adults, living donor||84|
|Adults transplanted for diabetes||71|
|Adults transplanted for hypertension||70|
|Adults transplanted for glomerulonephritis||77|
|Adults transplanted for cystic kidney disease||82|