|Year : 2018 | Volume
| Issue : 3 | Page : 159-163
Immunosuppression for postcardiac transplant patients
Department of Cardiology, AIIMS, New Delhi, India
|Date of Web Publication||11-Jan-2019|
Dr. Dhara Singh
AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
After the introduction of immunosuppressive drugs in the management of postheart transplant patients, the incidence of rejection has decreased significantly resulted in improvement in mortality and long-term outcome. Induction regimens provide intense early postoperative immune suppression while maintenance regimens are used throughout the patient's life to prevent both acute and chronic rejection. An immunosuppressive regimen tailored individually for each patient will help in decreasing the incidence of adverse events and complications. A complete understanding of currently available immunosuppressive agents is therefore essential.
Keywords: Heart transplant, immunosuppression, rejection, rejection therapy
|How to cite this article:|
Singh D. Immunosuppression for postcardiac transplant patients. J Pract Cardiovasc Sci 2018;4:159-63
| Introduction|| |
On December 3, 1967, Christian Barnard performed the world'sfirst successful heart transplant. However, most patients after heart transplant died within a year, with a 1-year survival of only 11%. Therefore, the initial enthusiasm subsided, and very few centers continued to perform the heart transplants. In the beginning, the focus was exclusively on the technical aspects of surgery without an adequate understanding of the transplant immunology. It was Norman Shumway and his team who continued their work on understanding the immunological aspects of donor and recipients in relation to heart transplant. They also made efforts to develop a better understanding of infections in transplant recipients, improve the donor pool, develop better techniques for organ preservation and heart biopsies, and develop newer drugs to prevent the rejection. Cyclosporine was introduced in the late 1980s to decrease the rejection. In the postcyclosporine era, the heart transplantation has emerged as a viable therapeutic strategy for select patients with end-stage heart disease. The current survival rate after heart transplantation has been reported as approximately 50% at 12 years by the International Society for Heart and Lung Transplantation registry.
| Postoperative Medical Management of Cardiac Transplants|| |
Approximately 50% of heart transplant programs currently use the strategy of induction therapy, during the early postoperative period. The idea of induction therapy is to provide intense immunosuppression when the risk of allograft rejection is highest. The advantage of induction therapy is to allow delayed initiation of nephrotoxic immunosuppressive drugs in patients with compromised renal function and to allow early glucocorticoids weaning or use of glucocorticoids sparing baseline regimens after transplantation. The absolute indications for induction therapy are not clearly defined, however, those patients at high risk for rejection (>5% at 1 year), younger patients, black race, patients with a high number of human leukocyte antigen mismatches, and patients supported with ventricular assist devices with high levels of preformed antibodies, may get benefit from the induction therapy.
Drugs for induction
Drugs which are used for induction are summarized in [Table 1].,,
A Cochrane review included 22 randomized controlled trials comparing any type of induction versus no induction and various types of induction regimens against each other. No significant differences were found for any of the comparisons of outcomes of mortality, infection, posttransplant lymphoproliferative disorder, cancer, adverse events, or cardiac allograft vasculopathy. There was a reduction in the incidence of acute rejection among patients treated with interleukin 2 (IL-2) receptor antagonists compared with no induction. There were fewer rejection episodes among patients treated with polyclonal antibody induction compared with IL-2 receptor antagonist therapy, though the numbers of events were small so an effect of chance cannot be excluded. In a retrospective analysis, anti-thymocyte globulin (ATG) was associated with better long-term survival at 5 and 10 years as compared to basiliximab.
Most maintenance immunosuppressive protocols use a three-drug regimen consisting of a calcineurin inhibitor (cyclosporine or tacrolimus), an antimetabolite (mycophenolate mofetil or azathioprine) or cell cycle inhibitor (sirolimus or everolimus) and glucocorticoids. Our protocol for immunosuppression includes tacrolimus, mycophenolate mofetil, and glucocorticoides [Table 2].
It is a calcineurin inhibitor derived from the fungus Tolypocladium inflatum. It acts by binding to cyclophilin protein in T-cell cytoplasm. Cyclophilin and cyclosporine complex binds and inhibits the calcineurin, responsible for the activation of nuclear factor of activated T cells, which participate in the activation of IL-2, IL-4, and CD40L, results in decreased activation and proliferation of T lymphocyte.
The drug is available in two formulations, the older oil-based formulation (Sandimmune) and new microemulsion formulations (Gengraf and Neoral). A randomized, multicenter, double-blind study has shown that the microemulsion formulation was associated with fewer rejection episodes requiring antilymphocyte antibody therapy compared to an oil-based formulation at 24 months. Major side effects are hypertension, nephrotoxicity, neurotoxicity, diabetes mellitus, dyslipidemia, hyperuricemia, hyperkalemia, and hypomagnesemia, gingival hyperplasia, hirsutism, and rarely osteoporosis.
Macrolide compound derived from the fungus Streptomyces tsukubaensis. It acts by binding to cytoplasmic FK-binding protein and inhibits the calcineurin. The side effect profile is similar between cyclosporine and tacrolimus. Compared to cyclosporine, use of tacrolimus is associated with less hypertension and dyslipidemia but higher risk of developing new-onset diabetes mellitus. Alopecia is a peculiar side effect of tacrolimus.,
Multiple single center and multicenter trials have shown similar patient survival and a more favorable side effect profile with tacrolimus as compared to cyclosporine.,,,,,,
In the prospective, large randomized trial, tacrolimus group had a lower incidence of biopsy-proven moderate or severe acute cellular rejection at 6 months compared to the cyclosporine group. The incidence of new-onset diabetes mellitus was more common with tacrolimus as compared to cyclosporine, while hypertension and dyslipidemia were more common with cyclosporine, the infection rate was similar between the two groups.
- Mycophenolate mofetil.
It is a prodrug, hydrolyzed in the blood to its active metabolite 6-mercaptopurine, and subsequently converted to a purine analog, thioinosine monophosphate. This antimetabolite is incorporated into DNA and inhibits further nucleotide synthesis, thus preventing mitosis and the proliferation of rapidly dividing cells such as activated T and B lymphocytes. The major side effects are dose-dependent myelosuppression.
It is also a prodrug that is rapidly hydrolyzed to its active form, mycophenolic acid (MPA). MPA is a reversible inhibitor of inosine monophosphate dehydrogenase, a critical enzyme for the de novo synthesis of guanine nucleotides. Lymphocytes lack a key enzyme in the guanine salvage pathway and are dependent on the de novo pathway for the production of purines necessary for RNA and DNA synthesis. Therefore, both T and B lymphocytes proliferation is selectively inhibited. In a multicenter, active-controlled, randomized trial, mycophenolate mofetil was compared with azathioprine when used in conjunction with cyclosporine and corticosteroids in 650 de novo heart transplant recipients. Survival and rejection were similar in both.
Mammalian target of rapamycin inhibitors
Proliferation signal inhibitors is a macrolide antibiotic derived from the fungus Streptomyces hygroscopicus, the mother is involved in the transduction signals from the IL-2 receptor to the nucleus, causing cell cycle arrest at the G1 to S phase results in inhibition of both T and B Cell proliferation in response to cytokine signals. The efficacy of sirolimus as an alternative to azathioprine was evaluated in a prospective, open-label, randomized trial of 136 de novo heart transplant recipients. Patients were randomized 2:1 to receive one of two sirolimus doses (3 or 5 mg) or to azathioprine. Sirolimus doses were subsequently adjusted in both groups to achieve similar target blood levels. All patients received concurrent immune suppression with cyclosporine and glucocorticoids. Compared to azathioprine, the proportion of patients with a biopsy-proven moderate-to-severe acute cellular rejection episode at 6 months was lower in both the 3 mg/day (32% vs. 57%, P = 0.027) and 5 mg/day sirolimus groups (33% vs. 57%, P = 0.013). In addition, the progression of cardiac allograft vasculopathy significantly reduced in the sirolimus group at both 6 months and 2 years. It is inherently not nephrotoxic but can potentiate the efficacy and nephrotoxic effects of the calcineurin inhibitors. The dosage of the calcineurin inhibitor should be reduced by approximately 25% when used together. The most common side effects are hyperlipidemia, oral ulcerations, lower extremity edema, and bone marrow suppression, poor wound healing, pleural and pericardial effusions requiring drainage, and rarely pulmonary toxicity.
Approved for clinical use in the United States for the prevention of rejection in kidney and liver transplantation, the major difference between sirolimus and everolimus is that the half-life of everolimus (30 h) is approximately half that of sirolimus (60 h). Everolimus was studied in 24 months, multicenter, randomized, open-label, noninferiority trial involving 721 de novo heart transplant recipients. Patients were randomized to one of two everolimus drug exposures (1.5 or 3.0 mg/day in divided doses) with reduced-dose cyclosporine, or to mycophenolate mofetil with standard dose cyclosporine. Patients received corticosteroids with or without induction therapy, according to individual transplant center protocols. Enrollment into the higher dose (3.0 mg/day), everolimus arm was stopped prematurely due to a higher incidence of early mortality, mostly due to infections, in this group. Everolimus was found to be noninferior to mycophenolate mofetil with respect to the primary efficacy endpoint of biopsy-proven acute cellular rejection, acute rejection with hemodynamic compromise, graft loss or retransplantation, death, or loss to follow-up. Patients on everolimus had reduced progression of coronary artery intimal wall thickening on intravascular ultrasound at 12 months' posttransplantation. More nonfatal serious adverse events, particularly pericardial effusions, and a higher rate of drug discontinuations due to adverse events were reported in the everolimus group compared to the mycophenolate mofetil group. Finally, everolimus was noted to be inferior to mycophenolate mofetil with respect to renal function, but a post hoc analysis indicated that this finding was largely driven by a subset of study centers that were not successful in reducing the cyclosporine exposure in the everolimus group. Similar toxicity profile compared with sirolimus.
Glucocorticoids are nonspecific anti-inflammatory agents that interrupt multiple steps in immune activation, including antigen presentation, cytokine production, and proliferation of lymphocytes. Although steroids are highly effective for the prevention and treatment of acute rejection, their long-term use is associated with a number of adverse effects, including new onset or worsening diabetes mellitus, hyperlipidemia, hypertension, fluid retention, myopathy, osteoporosis, and a predisposition toward opportunistic infections. Thus, while most programs employ corticosteroids as one of the three maintenance immunosuppressive agents, they are used in relatively high doses in the early postoperative period, but then tapered to low doses or discontinued altogether after thefirst 6–12 months. Certain low-risk patients may tolerate earlier (within 1–2 months' posttransplantation) steroid withdrawal without long-term adverse consequences.
Drugs that increase levels of cyclosporine, tacrolimus, and sirolimus
Calcium channel blockers: Diltiazem, nifedipine, nicardipine, verapamil.
Antifungal drugs: Itraconazole, fluconazole, ketoconazole, voriconazole, posaconazole.
Others: Macrolide antibiotics, fluoroquinolone, protease inhibitors, amiodarone, metoclopramide, grapefruit juice.
Drugs that decrease levels of cyclosporine, tacrolimus, and sirolimus
Rifampin, phenytoin, phenobarbital, octreotide, St. John's wart, etc.
Although immunosuppressive agents significantly reduce acute and long-term rejection after cardiac transplant, nevertheless rejection remained between 25% and 30% between discharge and 1 year.
Methylprednisolone intravenously (IV) 20 mg/kg (up to a maximum of 1 g/day) divided into two equal doses for 3 days, then 1 mg/kg/day. In nonresponders ATG in a dose of 1.5 mg/kg/day for 7–10 days can be used [Table 3].
Methylprednisolone IV 20 mg/kg (up to a maximum of 1 g/day) divided into two equal doses for 3 days, then 1 mg/kg/day. If no improvement in 1 week, rituximab can be administered IV in a dose of 500 mg. The patient required to be premedicated with IV promethazine (50 mg), hydrocortisone (100 mg), and paracetamol (1 g) before giving rituximab. Plasmapheresis on alternate day follwed by IV immunoglobulin at a dose of 0.5 mg/kg, after every cycle of plasmapheresis. With each plasmapheresis, 15 ml/kg of fresh frozen plasma and 4 ml/kg of 20% albumin to be exchanged with plasma.
| Conclusion|| |
Immunosuppressive therapy is essential after heart transplant. The three-drug regimen (corticosteroids, calcineurin inhibitors, and antiproliferative agents) is the cornerstone for maintenance of immunosuppression. Newer drugs like mammalian target of rapamycin inhibitors are promising. Induction therapy prevents rejection in the early postoperative period with the advantage of delaying initiation of nephrotoxic calcineurin inhibitors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]