Councils - Basic Science and Translational Research - BSTR Bright Lights



Scientific Council on Basic Science & Translational Research


BSTR Bright Lights is a web-based forum for the submission of significant contributions (manuscripts) and reviews of these contributions to place the significance in context for clinicians.

The Council is interested in increasing the interaction of its liaisons and their respective councils with the BSTR Council. As BSTR touches all aspects of transplantation, we believe that each council will have important and meaningful contributions that we could leverage and make available to our membership through this webpage.

If you are interested in providing a manuscript review for future posting, please contact the BSTR Council Chair.



PAST REVIEWS:

June 2016 Review (PDF) by Simon Pecha

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BSTR BRIGHT LIGHTS


CURRENT REVIEW: November 2016

Induction with anti-thymocyte globulin in heart transplantation is associated with better long-term survival compared with basiliximab

Nicole casciello

Nicole Casciello, PharmD, MBA
Indiana University Health Methodist Hospital
Indianapolis, IN, USA
Ncasciello@gmail.com



jill krisl

Jill Krisl, PharmD
Houston Methodist Hospital
Houston, TX, USA
krisl.jill@gmail.com



The role of induction immunosuppression in heart transplant has not been clearly identified.  According to the 2013 OPTN/SRTR annual report, only about half of all heart transplant recipients (HTRs) receive induction therapy. [1] Conversely, robust literature is available to support the use of induction therapy in kidney transplantation, and is routinely used in this population. Agent selection is based on epidemiologic and immunologic considerations, such as risk of rejection or delayed graft function, desire to delay or avoid calcineurin inhibitors (CNIs), or plan for steroid withdrawal. The most compelling evidence exists for the lymphocyte-depleting agents, anti-thymocyte globulin (ATG) and alemtuzumab, and the interleukin-2 receptor antagonist, basiliximab (BAS), with consensus among experts as to general use criteria for these agents. [2-9]

Several studies assessing the efficacy of BAS and ATG induction in HTRs have demonstrated a reduction in incidence of acute rejection; however, available studies have not shown a difference in long-term survival associated with the use of either drug. [10-15] These studies have also had varying incidence of infectious complications, leaving conflicting evidence for the risk of infections with the use of induction therapy. [11-14]

Ansari et al conducted a review of the ISHLT registry of adult HTRs from 2000 to 2011 who received induction therapy with BAS or ATG. The purpose of this study was to compare long-term outcomes, including survival, incidence of acute rejection, infection, and malignancy. A total of 9,282 patients met criteria and the median follow-up was 3.0 years. One-year survival was similar among the groups (90% vs 91%; p=0.858), but patients receiving ATG induction had improved survival at 5 years (82% vs 77%; p=0.005) and at 10 years (67% vs 64%; p=0.007). BAS was associated with an increased risk of death due to graft failure, cardiovascular events, and infection; however, no difference was found for risk of malignancy between the two groups. The authors concluded that ATG induction may be associated with better long-term outcomes than BAS. [16]

Although this study has a large cohort, the retrospective nature limits the availability of data. Treatment protocols changed during the study, with an increase in BAS induction and a preference for tacrolimus/mycophenolate maintenance in the latter half of the study period. Additionally, the selection criteria used to determine induction therapy and infection prophylaxis regimens were not reported. Despite the higher immunologic risk, patients in the ATG group had a higher rate of survival. Moreover, the BAS group had a higher incidence of infections, which may be related to differences in prophylaxis regimens.

Ansari et al suggest that either ATG or BAS may be reasonable options for induction, but they do not specifically address how the outcomes compare to no induction. Emin et al compared ATG versus no induction in a retrospective study of 2,086 HTRs. Overall survival was similar between the groups; ATG induction was associated with a decreased incidence of acute rejection and an increase in infectious complications. [11] Also, in a study comparing ATG to no induction in 50 HTRs, Zhang et al found no difference in survival between the groups; however, the results did suggest that ATG may prevent cardiac allograft vasculopathy (CAV). [15]

While current evidence for induction therapy does not show a survival advantage for HTRs, it may provide other benefits for this population. Chronic renal dysfunction is a common post-transplant complication that increases morbidity and mortality. [17] A recent study by Hong et al showed significantly worse survival among HTRs with baseline renal insufficiency. The difference in survival was noted as early as 3 months post-transplant and persisted through the 10-year follow-up period, supporting ISHLTs recommendation that renal dysfunction may be considered a relative contraindication to heart transplant. [14] Delayed initiation of CNIs through use of induction therapy, which has been shown to improve long term renal function in both heart and liver transplant recipients, may be a strategy for patients with baseline and immediate post-transplant renal dysfunction. [19-22]

Prevention and/or delayed progression of CAV is another potential benefit for induction therapy HTR. Jimenez et al and Kobashigawa et al investigated the relationship between rejection and CAV. Jimenez et al showed a significant correlation between rejection severity and the rate of CAV progression (r=0.42; p=0.01). [23] Kobashigawa et al suggested that recurrent rejection episodes early post-transplant may increase the likelihood of developing CAV. [24] By reducing acute rejection through the use of induction therapy, the potential to develop CAV following recurrent rejection episodes could be minimized.

Despite the outcomes reported by Ansari et al, the question still remains - how do outcomes for patients receiving induction with ATG or BAS differ from patients receiving no induction? A prospective study comparing the induction BAS and ATG to no induction may provide additional information to assist with the development of appropriate induction protocols for HTRs.

Literature:
  1. Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirtieth official adult heart transplant report - 2013; focus theme: age. J Heart Lung Transpl 2013;32(10):951-964.
  2. Kahan BD, Rajagopalan PR, Hall M, et al. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2 -receptor monoclonal antibody. Transplantation 1999;67(2):276-284.
  3. Nashan B, Moore R, Amlot P, et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997;350:1193-1198.
  4. Webster AC, Playford EG, Higgins G, et al. Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials. Transplantation  2004;77(2)166-176.
  5. Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation.  N Engl J Med  2006;355:1967-1977.
  6. Hellemans R, Bosmans J-L & Abramowicz D. Induction therapy for kidney transplant recipients: do we still need anti-IL2 receptor monoclonal antibodies?. Am J Transplant 2016;XX:1-6.
  7. Special Issue: KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9: S1-S155.
  8. Hardinger, K. L., Brennan, D. C. and Klein, C. L. Selection of induction therapy in kidney transplantation. Transpl Int 2013;26: 662-672.
  9. Malvezzi1 P, Jouve1 T, and Rostaing L. Induction by anti-thymocyte globulins in kidney transplantation: a review of the literature and current usage.  J Nephropathol. 2015; 4(4): 110-115.
  10. Carrier M, Leblanc MH, Perrault LP, et al. Basiliximab and rabbit anti- thymocyte globulin for prophylaxis of acute rejection after heart transplantation: a non-inferiority trial. J Heart Lung Transpl 2007; 26:258-263.
  11. Emin A, Rogers CA, Thekkudan J, et al. Steering Group, UK Cardiothoracic Transplant Audit. Antithymocyte globulin induction therapy for adult heart transplantation: a UK national study. J Heart Lung Transplant 2011;30:770-777.
  12. Mehra MR, Zucker MJ, Wagoner L, et al. A multicenter, prospective, randomized, double-blind trial of basiliximab in heart transplantation. J Heart Lung Transpl 2005;24:1297-1304.
  13. Flaman F, Zieroth S, Rao V, et al. Basiliximab versus rabbit anti-thymocyte globulin for induction therapy in patients after heart transplantation. J Heart Lung Transpl 2006;25:1358-1362.
  14. Mattei MF, Redonnet M, Gandjbakhch I, et al. Lower risk of infectious deaths in cardiac transplant patients receiving basiliximab versus anti-thymocyte globulin as induction therapy. J Heart Lung Transpl 2007;26:693-699.
  15. Zhang R, Haverich A, Struber M, et al. Delayed onset of cardiac allograft vasculopathy by induction therapy using anti-thymocyte globulin. J Heart Lung Transpl  2008;27(6):603-609.
  16. Ansari D, Lund LH, Stehlik J, et al. Induction with anti-thymocyte globulin in heart transplantation is associated with better long-term survival compared with basiliximab. J Heart Lung Transpl  2015;34(10):1283-1291.
  17. Ojo AO. Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol 2007;27(4):498-507.
  18. Hong KN, Merlo A, Chauhan D, et al. Evidence supports severe renal insufficiency as a relative contraindication to heart transplantation. J Heart Lung Transpl 2016;35(7):893-900.
  19. Rosenberg PB, Vriesendorp AE, Drazner MH, et al. Induction therapy with basiliximab allows delayed initiation of cyclosporine and preserves renal function after cardiac transplantation. J Heart Lung Transpl 2005;24(9):1327-1331.
  20. Delgado DH, Miriuka SG, Cusimano RJ, et al. Use of basiliximab and cyclosporine in heart transplant patients with pre-operative renal dysfunction. J Heart Lung Transpl 2005;24(2):166-169.
  21. Bajjoka I, Hsaiky L, Brown K, et al. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors. Liver Transplant 2008;14:66-72.
  22. Soliman T, Hetz H, Burghuber C, et al. Short-term induction therapy with anti-thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation. Liver Transplant 2007;13:1039-1044.
  23. Jimenez J, Kapadia SR, Yamani MH, et al. Cellular rejection and rate of progression of transplant vasculopathy: a 3-year serial intravascular ultrasound study. J Heart Lung Transpl 2001;20(4):393-398.
  24. Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol 2005;45(9):1532-1537.

About the author

Nicole Casciello, PharmD, MBA, is a Transplant Clinical Specialist at Indiana University Health Methodist Hospital in Indianapolis, Indiana supporting the heart and lung transplant programs. She earned her PharmD at The University of Texas at Austin College of Pharmacy and her MBA at The Wharton School at the University of Pennsylvania. She completed her clinical training at Duke University Hospital and Houston Methodist Hospital.

Jill Krisl, PharmD, is a Transplant Clinical Specialist with the heart and lung transplant programs at Houston Methodist Hospital in Houston, TX.  She earned her Bachelor of Arts in technical journalism at Colorado State University, and her PharmD at University of Colorado Anschutz Medical Campus.  She then completed her PGY1 and PGY2 critical care specialty residencies at the Medical University of South Carolina, followed by a transplant fellowship at the University of Cincinnati.

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