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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 159-163

Immunosuppression for postcardiac transplant patients


Department of Cardiology, AIIMS, New Delhi, India

Date of Web Publication11-Jan-2019

Correspondence Address:
Dr. Dhara Singh
AIIMS, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_56_18

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  Abstract 

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

How to cite this URL:
Singh D. Immunosuppression for postcardiac transplant patients. J Pract Cardiovasc Sci [serial online] 2018 [cited 2019 May 19];4:159-63. Available from: http://www.j-pcs.org/text.asp?2018/4/3/159/249938


  Introduction Top


On December 3, 1967, Christian Barnard performed the world'sfirst successful heart transplant.[1] However, most patients after heart transplant died within a year, with a 1-year survival of only 11%.[2] 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.[3] 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.[4] 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.[5]


  Postoperative Medical Management of Cardiac Transplants Top


Induction therapy

Approximately 50% of heart transplant programs currently use the strategy of induction therapy, during the early postoperative period.[5] 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.[6] 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.[7]

Drugs for induction

Drugs which are used for induction are summarized in [Table 1].[8],[9],[10]
Table 1: Drugs for induction

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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.[11] 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.[11] In a retrospective analysis, anti-thymocyte globulin (ATG) was associated with better long-term survival at 5 and 10 years as compared to basiliximab.[12]

Maintenance therapy

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].
Table 2: All India Institute of Medical Sciences protocol[13]

Click here to view


Calcineurin inhibitor

  • Tacrolimus
  • Cyclosporine.


Cyclosporine

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,[14] responsible for the activation of nuclear factor of activated T cells, which participate in the activation of IL-2, IL-4, and CD40L,[15] 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.[16] Major side effects are hypertension, nephrotoxicity, neurotoxicity, diabetes mellitus, dyslipidemia, hyperuricemia, hyperkalemia, and hypomagnesemia, gingival hyperplasia, hirsutism, and rarely osteoporosis.

Tacrolimus (FK506)

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.[17],[18]

Multiple single center and multicenter trials have shown similar patient survival and a more favorable side effect profile with tacrolimus as compared to cyclosporine.[19],[20],[21],[22],[23],[24],[25]

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.[19]

Antiproliferatives

  • Azathioprine
  • Mycophenolate mofetil.


Azathioprine

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.[26]

Mycophenolate mofetil

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.[27] 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

  • Sirolimus
  • Everolimus.


Sirolimus

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.[28] 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.

Everolimus

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.[28] 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.[29]

Glucocorticoids

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.[30] 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.[31]

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.

Antirejection therapies

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.[32]

Cell-mediated rejection

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].[32]
Table 3: Medications used for treatment of acute cellular rejection

Click here to view


Antibody-mediated rejection

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.[32]


  Conclusion Top


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

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Barnard CN. The operation. A human cardiac transplant: An interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J 1967;41:1271-4.  Back to cited text no. 1
    
2.
Patterson C, Patterson KB. The history of heart transplantation. Am J Med Sci 1997;314:190-7.  Back to cited text no. 2
    
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Stephenson LW, Ruggiero R. Heart Surgery Classics. Boston: Adams Publishing Group; 1994. p. 316.  Back to cited text no. 3
    
4.
McGregor CG, Oyer PE, Shumway NE. Heart and heart-lung transplantation. Prog Allergy 1986;38:346-65.  Back to cited text no. 4
    
5.
Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, et al. The registry of the international society for heart and lung transplantation: Thirty-second official adult heart transplantation report-2015; focus theme: Early graft failure. J Heart Lung Transplant 2015;34:1244-54.  Back to cited text no. 5
    
6.
Rosenberg PB, Vriesendorp AE, Drazner MH, Dries DL, Kaiser PA, Hynan LS, et al. Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation. J Heart Lung Transplant 2005;24:1327-31.  Back to cited text no. 6
    
7.
Higgins R, Kirklin JK, Brown RN, Rayburn BK, Wagoner L, Oren R, et al. To induce or not to induce: Do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy? J Heart Lung Transplant 2005;24:392-400.  Back to cited text no. 7
    
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Gajarski RJ, Blume ED, Urschel S, Schechtman K, Zheng J, West LJ, et al. Infection and malignancy after pediatric heart transplantation: The role of induction therapy. J Heart Lung Transplant 2011;30:299-308.  Back to cited text no. 8
    
9.
Urschel S, Altamirano-Diaz LA, West LJ. Immunosuppression armamentarium in 2010: Mechanistic and clinical considerations. Pediatr Clin North Am 2010;57:433-57.  Back to cited text no. 9
    
10.
Teuteberg JJ, Shullo MA, Zomak R, Toyoda Y, McNamara DM, Bermudez C, et al. Alemtuzumab induction prior to cardiac transplantation with lower intensity maintenance immunosuppression: One-year outcomes. Am J Transplant 2010;10:382-8.  Back to cited text no. 10
    
11.
Penninga L, Møller CH, Gustafsson F, Gluud C, Steinbrüchel DA. Immunosuppressive T-cell antibody induction for heart transplant recipients. Cochrane Database Syst Rev 2013;(12):CD008842.  Back to cited text no. 11
    
12.
Ansari D, Lund LH, Stehlik J, Andersson B, Höglund P, Edwards L, et al. Induction with anti-thymocyte globulin in heart transplantation is associated with better long-term survival compared with basiliximab. J Heart Lung Transplant 2015;34:1283-91.  Back to cited text no. 12
    
13.
Bram RJ, Hung DT, Martin PK, Schreiber SL, Crabtree GR. Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: Roles of calcineurin binding and cellular location. Mol Cell Biol 1993;13:4760-9.  Back to cited text no. 13
    
14.
Cardenas ME, Hemenway C, Muir RS, Ye R, Fiorentino D, Heitman J, et al. Immunophilins interact with calcineurin in the absence of exogenous immunosuppressive ligands. EMBO J 1994;13:5944-57.  Back to cited text no. 14
    
15.
Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: Regulation and function. Annu Rev Immunol 1997;15:707-47.  Back to cited text no. 15
    
16.
Eisen HJ, Hobbs RE, Davis SF, Carrier M, Mancini DM, Smith A, et al. Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: A randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine – Results at 24 months after transplantation. Transplantation 2001;71:70-8.  Back to cited text no. 16
    
17.
Talbot D, Rix D, Abusin K, Mirza D, Manas D. Alopecia as a consequence of tacrolimus therapy in renal transplantation? Transplantation 1997;64:1631-2.  Back to cited text no. 17
    
18.
Tricot L, Lebbé C, Pillebout E, Martinez F, Legendre C, Thervet E, et al. Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients. Transplantation 2005;80:1546-9.  Back to cited text no. 18
    
19.
Grimm M, Rinaldi M, Yonan NA, Arpesella G, Arizón Del Prado JM, Pulpón LA, et al. Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients – A large European trial. Am J Transplant 2006;6:1387-97.  Back to cited text no. 19
    
20.
Groetzner J, Meiser BM, Schirmer J, Koglin J, vScheidt W, Klauss V, et al. Tacrolimus or cyclosporine for immunosuppression after cardiac transplantation: Which treatment reveals more side effects during long-term follow-up? Transplant Proc 2001;33:1461-4.  Back to cited text no. 20
    
21.
Meiser BM, Uberfuhr P, Fuchs A, Schmidt D, Pfeiffer M, Paulus D, et al. Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection. J Heart Lung Transplant 1998;17:782-8.  Back to cited text no. 21
    
22.
Rinaldi M, Pellegrini C, Martinelli L, Goggi C, Gavazzi A, Campana C, et al. FK506 effectiveness in reducing acute rejection after heart transplantation: A prospective randomized study. J Heart Lung Transplant 1997;16:1001-10.  Back to cited text no. 22
    
23.
Reichart B, Meiser B, Viganò M, Rinaldi M, Martinelli L, Yacoub M, et al. European multicenter tacrolimus (FK506) heart pilot study: One-year results – European tacrolimus multicenter heart study group. J Heart Lung Transplant 1998;17:775-81.  Back to cited text no. 23
    
24.
Taylor DO, Barr ML, Radovancevic B, Renlund DG, Mentzer RM Jr., Smart FW, et al. Arandomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: Decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 1999;18:336-45.  Back to cited text no. 24
    
25.
Kobashigawa JA, Miller LW, Russell SD, Ewald GA, Zucker MJ, Goldberg LR, et al. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant 2006;6:1377-86.  Back to cited text no. 25
    
26.
Costanzo MR. New immunosuppressive drugs in heart transplantation. Curr Control Trials Cardiovasc Med 2001;2:45-53.  Back to cited text no. 26
    
27.
Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, et al. The registry of the international society for heart and lung transplantation: Thirty-first official adult heart transplant report-2014; focus theme: Retransplantation. J Heart Lung Transplant 2014;33:996-1008.  Back to cited text no. 27
    
28.
González-Vílchez F, de Prada JA, Exposito V, García-Camarero T, Fernández-Friera L, Llano M, et al. Avoidance of calcineurin inhibitors with use of proliferation signal inhibitors in de novo heart transplantation with renal failure. J Heart Lung Transplant 2008;27:1135-41.  Back to cited text no. 28
    
29.
Keogh A, Richardson M, Ruygrok P, Spratt P, Galbraith A, O'Driscoll G, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: A randomized clinical trial. Circulation 2004;110:2694-700.  Back to cited text no. 29
    
30.
Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002;96:23-43.  Back to cited text no. 30
    
31.
Teuteberg JJ, Shullo M, Zomak R, McNamara D, McCurry K, Kormos RL, et al. Aggressive steroid weaning after cardiac transplantation is possible without the additional risk of significant rejection. Clin Transplant 2008;22:730-7.  Back to cited text no. 31
    
32.
Airan B, Singh SP, Seth S, Hote MP, Sahu MK, Rajashekar P, et al. Heart transplant in India: Lessons learned. J Pract Cardiovasc Sci 2017;3:94-9.  Back to cited text no. 32
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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