PREventing Delayed Graft Function by Driving Immunosuppressive InduCtion Treatment (PREDICT-DGF): study protocol for a randomized controlled trial

Marion Chapal, Yohann Foucher, Monique Marguerite, Karine Neau, Emmanuelle Papuchon, Pascal Daguin, Emmanuel Morélon, Georges Mourad, Elisabeth Cassuto, Marc Ladrière, Christophe Legendre, Magali Giral, Marion Chapal, Yohann Foucher, Monique Marguerite, Karine Neau, Emmanuelle Papuchon, Pascal Daguin, Emmanuel Morélon, Georges Mourad, Elisabeth Cassuto, Marc Ladrière, Christophe Legendre, Magali Giral

Abstract

Background: In kidney transplantation, the use of Anti-Thymocyte Globulins (ATG) as induction therapy has been described as a possible treatment for reducing the prevalence of Delayed Graft Function (DGF). ATG possesses pharmaceutical proprieties that could help control the lesions caused by ischemia reperfusion injury. However, other studies have questioned this potential protective effect. We hypothesized that the benefits related to ATG for reducing DGF prevalence may be higher and more consistently recognized if only patients with high DGF risk are considered. We recently proposed a scoring system entitled DGFS (Delayed Graft Function Score) for such stratification of kidney transplant recipients according to their risk of DGF. Using the DGFS calculation, we aim to determine whether a short course of ATG can decrease the incidence of DGF in comparison with Basiliximab in kidney transplant recipients with low immunological risk but high DGF risk.

Methods: We conduct a phase IV, open label, randomized, multicentric and prospective study, to compare ATG in parallel with a control group treated by Basiliximab. The 1:1 randomized allocation of patients between groups is stratified on the clinical center, and on the hypothermic machine-perfusion device. We aimed to include a total of 384 patients to achieve a statistical power at 0.80. The study was initiated at the Nantes University hospital in July 2014, with data collection continuing until April 2018, and publication of the results proposed for 2019.

Discussion: The main expected benefits of this study are i) the reduction of unjustified ATG over-prescriptions associated with serious adverse events, ii) the reduction of chance losses related to ATG under-prescription, iii) the decrease in the incidence of DGF which was described as a risk factor of graft failure and patient death, and iv) the reduction in hospitalization duration and number of post transplantation dialysis sessions, both being associated with reduced medical costs. In conclusion, the current study is innovative by proposing a more efficient and personalized induction therapy.

Trial registration: The study was registered in the Clinical Trials Registry (# NCT02056938, February 5, 2014), and in the European Clinical Trials Database (EudraCT #2014-000332-42, January 30, 2014).

Figures

Fig. 1
Fig. 1
Preventing delayed graft function by driving immunosuppressive induction treatment (PREDICT-DGF) study: description of the study. This randomized trial aims to compare anti-thymocyte globulin (ATG)-treated patients in parallel with a control group treated by basiliximab. The 1:1 randomized allocation of patients between groups is stratified on the clinical center, and on the hypothermic machine-perfusion device. The participation of each patient is scheduled for 3 months

References

    1. Giral-Classe M, Hourmant M, Cantarovich D, Dantal J, Blancho G, Daguin P, et al. Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys. Kidney Int. 1998;54:972–8. doi: 10.1046/j.1523-1755.1998.00071.x.
    1. Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, et al. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial. Lancet. 2004;364:503–12. doi: 10.1016/S0140-6736(04)16808-6.
    1. Irish WD, Ilsley JN, Schnitzler MA, Feng S, Brennan DC. A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transpl. 2010;10:2279–86. doi: 10.1111/j.1600-6143.2010.03179.x.
    1. Jeldres C, Cardinal H, Duclos A, Shariat SF, Suardi N, Capitanio U, et al. Prediction of delayed graft function after renal transplantation. Can Urol Assoc J. 2009;3:377–82.
    1. Chapal M, Le Borgne F, Legendre C, Kreis H, Mourad G, Garrigue V, et al. A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors. Kidney Int. 2014;86:1130–9. doi: 10.1038/ki.2014.188.
    1. Kaden J, May G, Strobelt V, Groth J, Muller P. Intraoperative T-cell depletion prior to completion of anastomoses by high-dose single ATG bolus as a new approach to improve long-term results after kidney transplantation. Transpl Proc. 1997;29:344–7. doi: 10.1016/S0041-1345(96)00301-6.
    1. Kyllonen LE, Eklund BH, Pesonen EJ, Salmela KT. Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety. Transplantation. 2007;84:75–82. doi: 10.1097/01.tp.0000268084.64888.f3.
    1. Turunen AJ, Lindgren L, Salmela KT, Kyllonen LE, Makisalo H, Siitonen SM, et al. Association of graft neutrophil sequestration with delayed graft function in clinical renal transplantation. Transplantation. 2004;77:1821–6. doi: 10.1097/.
    1. Haririan A, Morawski K, Sillix DH, El-Amm JM, Garnick J, West MS, et al. Induction therapy with basiliximab versus Thymoglobulin in African-American kidney transplant recipients. Transplantation. 2005;79:716–21. doi: 10.1097/01.TP.0000153506.07816.F0.
    1. Mourad G, Rostaing L, Legendre C, Garrigue V, Thervet E, Durand D. Sequential protocols using basiliximab versus antithymocyte globulins in renal-transplant patients receiving mycophenolate mofetil and steroids. Transplantation. 2004;78:584–90. doi: 10.1097/.
    1. Sollinger H, Kaplan B, Pescovitz MD, Philosophe B, Roza A, Brayman K, et al. Basiliximab versus antithymocyte globulin for prevention of acute renal allograft rejection. Transplantation. 2001;72:1915–9. doi: 10.1097/00007890-200112270-00008.
    1. Ulrich F, Niedzwiecki S, Pascher A, Kohler S, Weiss S, Fikatas P, et al. Long-term outcome of ATG vs. Basiliximab induction. Eur J Clin Invest. 2011;41:971–8. doi: 10.1111/j.1365-2362.2011.02490.x.
    1. Noel C, Abramowicz D, Durand D, Mourad G, Lang P, Kessler M, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol. 2009;20:1385–92. doi: 10.1681/ASN.2008101037.
    1. Preville X, Flacher M, LeMauff B, Beauchard S, Davelu P, Tiollier J, et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation. 2001;71:460–8. doi: 10.1097/00007890-200102150-00021.
    1. Chappell D, Beiras-Fernandez A, Hammer C, Thein E. In vivo visualization of the effect of polyclonal antithymocyte globulins on the microcirculation after ischemia/reperfusion in a primate model. Transplantation. 2006;81:552–8. doi: 10.1097/01.tp.0000200305.48244.a6.
    1. Aiello S, Cassis P, Mister M, Solini S, Rocchetta F, Abbate M, et al. Rabbit anti-rat thymocyte immunoglobulin preserves renal function during ischemia/reperfusion injury in rat kidney transplantation. Transpl Int. 2011;24:829–38. doi: 10.1111/j.1432-2277.2011.01263.x.
    1. Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355:1967–77. doi: 10.1056/NEJMoa060068.
    1. Levey A, Coresh J, Greene T, STevens L, Zhang Y, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247–54. doi: 10.7326/0003-4819-145-4-200608150-00004.
    1. Meas-Yedid V, Servais A, Noel LH, Panterne C, Landais P, Herve N, et al. New computerized color image analysis for the quantification of interstitial fibrosis in renal transplantation. Transplantation. 2011;92:890–9. doi: 10.1097/TP.0b013e31822d879a.
    1. Walker AM. Low Power and Striking Results — A Surprise but Not a Paradox. N Engl J Med. 1995;332:1091–2. doi: 10.1056/NEJM199504203321609.
    1. Knottnerus JA, Bouter LM. The ethics of sample size: two-sided testing and one-sided thinking. J Clin Epidemiol. 2001;54:109–10. doi: 10.1016/S0895-4356(00)00276-6.
    1. R Core Team. R: A Language and environment for statistical computing. R Foundation for Statistical Computing Vienna, Austria; 2010. 3-900051-07-0. .

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