Immunosuppression for Renal Transplant Patients and Common Medical Problems in Renal Transplantation
Renal transplantation is the best treatment for most patients with end-stage renal disease and is associated with significant improvements in quality of life and survival of patients with successful kidney grafts. Because patient and graft survival rates 1 year after transplantation are currently higher than 90% for living and deceased donor kidney recipients, there will be large numbers of successful recipients requiring long-term care in the context of chronic immunosuppression. Primary care physicians and internists are becoming increasingly involved in the care of these patients and will need basic information about immunosuppression and the medical management of these patients.
OVERVIEW OF IMMUNOSUPPRESSION FOR RENAL TRANSPLANTATION
Calcineurin inhibitors (CNIs), including cyclosporine (CSA) (Neoral, Gengraf, or the earliest form, Sandimmune) and tacrolimus (TAC; Prograf) have been the cornerstones of an immunosuppressive regimen, which usually includes two or more additional agents, such as glucocorticoids, a purine antagonist (mycophenolic acid [CellCept] or azathioprine [Imuran]). Sirolimus (SRL; Rapamune) has been used as a substitute for CNIs. The choice of agents is often protocol driven but is usually adapted to each recipient’s risk profile. High-risk recipients treated with more intensive immunosuppression include those with increased levels of preformed antibody (panel-reactive antibody [PRA] >20%-50%), repeat transplantation after early immunologic loss of a previous graft, and African Americans. High-risk recipients typically receive induction therapy consisting of monoclonal or polyclonal antibodies administered intravenously beginning in the perioperative period. The mechanisms of action of these and other immunosuppressants have recently been reviewed.1,2
Agents for Induction Treatment
Polyclonal IgG antibodies are derived from horse (Atgam) or rabbit (Thymoglobulin) sera after injecting the animals with human lymphocytes or human thymocytes, respectively. They target several T cell surface epitopes (CD2, CD3, CD4, and CD25) and, in the case of Thymoglobulin, induce long-term depletion of T lymphocytes. Thymoglobulin’s major early side effect is the cytokine release syndrome: fever, chills, myalgias, and shortness of breath. Late side effects include prolonged (up to years) depletion of T lymphocytes, thereby increasing the potential risk of opportunistic infections, post-transplantation lymphoproliferative disorder (PTLD), and possibly autoimmune disease.
Daclizumab (Zenapax) and basiliximab (Simulect) are monoclonal antibodies modified to be humanized or chimeric antibodies that bind to the alpha chain of the interleukin-2 receptor (IL-2R) on T cells and thereby impair lymphocyte proliferation. They typically have minimal side effects and do not increase the recipient’s susceptibility to infection or malignancy. Alemtuzumab (Campath), originally approved for the treatment of chronic lymphocytic leukemia, is a humanized murine monoclonal antibody directed against the surface protein CD52 expressed on T and B lymphocytes, monocytes, and macrophages. It can cause prolonged T lymphocyte depletion, with risks for opportunistic infection, PTLD, and possibly autoimmune disease.
Maintenance Immunosuppression
Basic maintenance immunosuppression for many years consisted of three types of drugs in combination: glucocorticosteroid (GC) (prednisone), a purine antagonist (azathioprine or mycophenolate mofetil) and a CNI (CSA) or TAC. Because of numerous potential glucocorticoid (GC) toxicities (Box 1) and CNI toxicities (Table 1), many new regimens have been developed that incorporate rapid GC elimination, or CNI dose reduction or elimination. Rapid GC withdrawal within the first few days after transplantation is usually achieved with antibody induction. Late withdrawal of GC has a high risk of rejection.3 CNI withdrawal has been attempted by conversion to less nephrotoxic SRL. Alternatively, careful dose reduction can be successfully achieved in select patients.4 Combined use of a CNI and SRL has the potential for severe nephrotoxicity.
Glucocorticoids
GCs are used for both induction and maintenance immunosuppression. Their immunosuppressant actions are mediated through a number of pathways, mainly directed toward redistribution of lymphocytes and macrophages to the lymphoid tissue and inhibition of the production of cytokines (e.g., IL-1, IL-2, IL-6), tumor necrosis factor α (TNF-α), and interferon gamma (IFN-γ). Prednisone dosage is gradually decreased after transplantation to 5 to 7.5 mg daily unless the patient has been on a rapid GC withdrawal protocol.
Calcineurin Inhibitors
CNIs include CSA and TAC; each functions as a base immunosuppressant agent around which additional agents are added to construct the complete immunosuppressant regimen. Initiation of CSA in the post-transplantation period usually requires signs of renal recovery because of potential nephrotoxicity. The usual starting dosage is about 5 to 6 mg/kg/day, divided into two doses. Many CSA formulations are now available. The original formulation (Sandimmune) has been largely replaced by the newer CSA formulations (Neoral) or modified CSA (e.g., Gengraf, Eon, other generics) that exhibit better absorption and bioavailability. These CSA preparations should not be casually substituted for each other because of increased risk of rejection or toxicity. The interval for monitoring CSA blood levels remains controversial. Monitoring trough levels (C0) is the appropriate way to monitor Sandimmune, but the newer formulations may be better monitored with levels determined 2 hours after the dose is taken (C2). The approximate CSA level is determined by the type of CSA being used, the assay method, the time after transplant, and the clinical status of the patient.5
TAC is a macrolide antibiotic somewhat more potent than CSA and has side effects that are distinct from and overlap with those of CSA (see Table 1). TAC has high bioavailability and thus its trough levels correlate with dose. The maintenance dosage is usually approximately 0.1 mg/kg/day divided into two doses, with target trough levels of 5 to 15 ng/mL in the initial 12 months after transplantation and 5 to 10 ng/mL beyond 12 months. Both CSA and TAC are metabolized by the hepatic enzyme system cytochrome P-450 3A4 (CYP 3A4), which is responsible for the metabolism of numerous drugs (Box 2). Consequently, for these drugs and those described later, it is worthwhile to consider the treatment approaches shown in Table 2.
Box 2 Calcineurin Inhibitors and Other Drug Interactions*,†
* The safest procedure is to specifically check any drug added to or eliminated from those taken by a transplant recipient to determine its effect on calcineurin levels. The drugs listed here are only a partial list.
† Calcineurins can significantly increase the levels, effects, and toxicity of other drugs, notably many statins7 and sirolimus. Careful dosing and monitoring are necessary.
Purine Antagonists
Purine antagonists include azathioprine and mycophenolate mofetil. Azathioprine is a prodrug converted in the body via a nonenzymatic reaction to 6-mercaptopurine, a purine analogue that acts as an antimetabolite and blocks the synthesis of nucleotides, thereby inhibiting T and B cell proliferation.1 Its major side effects are leukopenia and possible myelosuppression, increased susceptibility to infection, increased susceptibility to cancer, particularly PTLD and skin cancer, hepatotoxicity, and alopecia. The usual dosage varies from 1 to 2 mg/kg/day. The concomitant use of azathioprine with allopurinol, a xanthine oxidase inhibitor used to lower serum uric acid levels, typically in patients with gout, increases the risk of side effects and requires dose adjustments (see Table 2). Mycophenolate mofetil has largely replaced azathioprine.
Mycophenolate mofetil (MMF) is converted to mycophenolic acid, which inhibits inosine 5′-monophosphate dehydrogenase, a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, thereby inhibiting DNA synthesis for replication of T and B cells.1 The usual dose is 1 to 2 g/day in two divided doses. Its major side effects are diarrhea, leukopenia, anemia, and tissue-invasive cytomegalovirus (CMV) disease. Often, diarrhea can be avoided by dosing three times daily rather than twice daily using the same total daily dose.
Mammalian Target of Rapamycin Inhibitors
The immunosuppressants SRL (Rapamune) and everolimus bind to the same immunophilin (FKBP12) as TAC and modulate the intracellular protein mammalian target of rapamycin (mTOR), resulting in cell cycle arrest in the G1-S phase.1 The maintenance dosage is usually 2 to 5 mg/day, with target trough levels of 5 to 15 ng/mL. SRL has a very long half-life (approximately 65 hours), so that trough level monitoring should be done 5 to 7 days after initiating the medication. It should be noted that although mTOR inhibitors and reduced doses of TAC or CSA may be used together, they can be more nephrotoxic and have inferior graft survival. Initially, mTOR inhibitors alone were not believed to be nephrotoxic. However, SRL may prolong acute tubular necrosis and cause proteinuria, certain glomerulopathies, and thrombotic microangiopathy. SRL, as well as CSA and TAC, also can cause renal magnesium wasting and potentially significant hypomagnesemia. Other side effects, typically dose-related, include hypercholesterolemia, hypertriglyceridemia, edema, hypertension, anemia, thrombocytopenia, leukopenia, interstitial pneumonitis, delayed wound healing, skin rash, mouth ulcers, and myalgia. More frequent acute rejections and inferior allograft survival have been reported with SRL than with CNI.
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