Allogeneic mesenchymal stem cell as induction therapy to prevent both delayed graft function and acute rejection in deceased donor renal transplantation: study protocol for a randomized controlled trial

Qipeng Sun, Liangqing Hong, Zhengyu Huang, Ning Na, Xuefeng Hua, Yanwen Peng, Ming Zhao, Ronghua Cao, Qiquan Sun, Qipeng Sun, Liangqing Hong, Zhengyu Huang, Ning Na, Xuefeng Hua, Yanwen Peng, Ming Zhao, Ronghua Cao, Qiquan Sun

Abstract

Background: Using kidneys from deceased donors is an available strategy to meet the growing need of grafts. However, higher incidences of delayed graft function (DGF) and acute rejection exert adverse effects on graft outcomes. Since ischemia-reperfusion injury (IRI) and ongoing process of immune response to grafts are the major causes of DGF and acute rejection, the optimal induction intervention should possess capacities of both repairing renal structure injury and suppressing immune response simultaneously. Mesenchymal stem cells (MSCs) with potent anti-inflammatory, regenerative and immune-modulatory properties are considered as a candidate to prevent both DGF and acute rejection in renal transplantation. Previous studies just focused on the safety of autologous MSCs on living-related donor renal transplants, and lack of concomitant controls and the sufficient sample size and source of MSCs. Here, we propose a prospective multicenter controlled study to assess the clinical value of allogeneic MSCs in preventing both DGF and acute rejection simultaneously as induction therapy in deceased-donor renal transplantation.

Methods/design: Renal allograft recipients (n = 100) will be recruited and divided into trial and control groups, and 50 patients in the trial group will be administered with a dose of 2 × 106 per kilogram human umbilical-cord-derived MSCs (UC-MSCs) via peripheral vein injection preoperatively, and a dose of 5 × 106 cells via renal arterial injection during surgery, with standard induction therapy. Incidences of postoperative DGF and biopsy-proved acute rejection (BPAR) will be recorded and analyzed. Additionally, other clinical parameters such as baseline demographics, graft and recipient survival and other severe postoperative complications, including complicated urinary tract infection, severe pneumonia, and severe bleeding, will be also assessed.

Discussion: This study will clarify the clinical value of UC-MSCs in preventing DGF and acute rejection simultaneously in deceased-donor renal transplantation, and provide evidence as to whether allogeneic MSCs can be used as clinically feasible and safe induction therapy.

Trial registration: ClinicalTrials.gov, NCT02490020 . Registered on 29 June 2015.

Keywords: Acute rejection; Delayed graft function; Mesenchymal stem cell; Renal transplantation.

Conflict of interest statement

Ethics approval and consent to participate

The study is approved by the Medical Ethical Committees of the third affiliated hospital of Sun Yat-sen University (Ref: (2015)]2-106), Zhujiang hospital of Southern Medical University (Ref: SMU 101-2015), and the second affiliated hospital of Guangzhou Traditional Chinese Medicine University (Ref: GTCMU-2015-22). Participation in the study is completely voluntary. Informed consent will be obtained from all participants in this study. Participants will be able to withdraw from it at any time. The decision to participate or withdraw will not affect their existing treatment or service received. All personal information collected will be kept strictly confidential and used for research purposes only. Research team members will be responsible for safekeeping of the personal data.

Consent for publication

Written informed consent was obtained from the participant for publication of their individual details and accompanying images in this manuscript. The consent forms are held by the authors and the participants.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Summary of enrollment, interventions, assessments, and timing for measurements (Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)). DGF, delayed graft function; BPAR, biopsy-proven acute rejection
Fig. 2
Fig. 2
Overview of this trial procedure UC-MSCs, umbilical-cord-derived mesenchymal stem cells

References

    1. Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu ASL, Brenner BM. Brenner’s and Rector’s the kidney. 9. Philadelphia: Elsevier Saunders; 2012.
    1. Eurotransplant: yearly statistics 2014. Eurotransplant International Foundation. The Netherlands, Leiden. 2014.
    1. Summers DM, Johnson RJ, Allen J, Fuggle SV, Collett D, Watson CJ, et al. Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study. Lancet. 2010;376:1303–11. doi: 10.1016/S0140-6736(10)60827-6.
    1. Snoeijs MG, Winkens B, Heemskerk MB, Hoitsma AJ, Christiaans MH, Buurman WA, et al. Kidney transplantation from donors after cardiac death: a 25-year experience. Transplantation. 2010;90:1106–12. doi: 10.1097/TP.0b013e3181f83b0b.
    1. Bellingham JM, Santhanakrishnan C, Neidlinger N, Wai P, Kim J, Niederhaus S, et al. Donation after cardiac death: a 29-year experience. Surgery. 2011;150:692–702. doi: 10.1016/j.surg.2011.07.057.
    1. Barlow AD, Metcalfe MS, Johari Y, Elwell R, Veitch PS, Nicholson ML. Case-matched comparison of long-term results of non-heart beating and heart-beating donor renal transplants. Br J Surg. 2009;96:685–91. doi: 10.1002/bjs.6607.
    1. Singh RP, Farney AC, Rogers J, Zuckerman J, Reeves-Daniel A, Hartmann E, et al. Kidney transplantation from donation after cardiac death donors: lack of impact of delayed graft function on post-transplant outcomes. Clin Transplant. 2011;25:255–64. doi: 10.1111/j.1399-0012.2010.01241.x.
    1. Nagaraja P, Roberts GW, Stephens M, Horvath S, Fialova J, Chavez R, et al. Influence of delayed graft function and acute rejection on outcomes after kidney transplantation from donors after cardiac death. Transplantation. 2012;94:1218–23. doi: 10.1097/TP.0b013e3182708e30.
    1. Bahde R, Vowinkel T, Unser J, Anthoni C, Hölzen JP, Suwelack B, et al. Prognostic factors for kidney allograft survival in the Eurotransplant Senior Program. Ann Transplant. 2014;19:201–9. doi: 10.12659/AOT.890125.
    1. Pallet N, Rabant M, Legendre C, Martinez F, Choukroun G. The nephroprotective properties of recombinant human erythropoietin in kidney transplantation: experimental facts and clinical proofs. Am J Transplant. 2012;12:3184–90. doi: 10.1111/j.1600-6143.2012.04287.x.
    1. Vargas GA, Hoeflich A, Jehle PM. Hepatocyte growth factor in renal failure: promise and reality. Kidney Int. 2000;57:1426–36. doi: 10.1046/j.1523-1755.2000.00987.x.
    1. Castaneda MP, Swiatecka-Urban A, Mitsnefes MM, Feuerstein D, Kaskel FJ, Tellis V, et al. Activation of mitochondrial apoptotic pathways in human renal allografts after ischemia reperfusion injury. Transplantation. 2003;76:50–4. doi: 10.1097/01.TP.0000069835.95442.9F.
    1. Damman J, Daha MR, van Son WJ, Leuvenink HG, Ploeg RJ, Seelen MA. Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury. Am J Transplant. 2011;11:660–9. doi: 10.1111/j.1600-6143.2011.03475.x.
    1. Rosenberg ME. Cell-based therapies in kidney disease. Kidney Int Suppl(2011) 2013;3:364–7. doi: 10.1038/kisup.2013.78.
    1. Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell. 2012;10:709–16. doi: 10.1016/j.stem.2012.05.015.
    1. Zhuo W, Liao L, Xu T, Wu W, Yang S, Tan J. Mesenchymal stem cells ameliorate ischemia-reperfusion induced renal dysfunction by improving the antioxidant/oxidant balance in the ischemic kidney. Urol Int. 2011;86:191–6. doi: 10.1159/000319366.
    1. Hoogduijn MJ, Popp FC, Grohnert A, Crop MJ, van Rhijn M, Rowshani AT, et al. MISOT Study Group: Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT) Transplantation. 2010;90:124–6. doi: 10.1097/TP.0b013e3181ea4240.
    1. Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011;6:412–22. doi: 10.2215/CJN.04950610.
    1. Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, et al. Induction therapy with autologous mesenchymal stem cells in living related kidney transplants: a randomized controlled trial. JAMA. 2012;307:1169–77. doi: 10.1001/jama.2012.316.
    1. Reinders ME, Dreyer GJ, Bank JR, Roelofs H, Heidt S, Roelen DL, et al. Safety of allogeneic bone marrow derived mesenchymal stromal cell therapy in renal transplant recipients: the neptune study. J Transl Med. 2015;13:344. doi: 10.1186/s12967-015-0700-0.
    1. Peng Y, Ke M, Xu L, Liu L, Chen X, Xia W, et al. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation. 2013;95(1):161–8. doi: 10.1097/TP.0b013e3182754c53.
    1. World Health Organization. Operational guidelines for ethics committees that review biomedical research. 2000. . Accessed 16 Jun 2017.
    1. World Health Organization WHO guiding principles on human cell, tissue and organ transplantation. Transplantation. 2010;90(3):229–33. doi: 10.1097/TP.0b013e3181ec29f0.
    1. Declaration of Istanbul Custodian Group. Declaration of Istanbul. 2014. . Accessed 16 Jun 2017.
    1. Deng Y, Yi S, Wang G, Cheng J, Zhang Y, Chen W, et al. Umbilical cord-derived mesenchymal stem cells instruct dendritic cells to acquire tolerogenic phenotypes through the IL-6-mediated upregulation of SOCS1. Stem Cells Dev. 2014;23:2080–92. doi: 10.1089/scd.2013.0559.
    1. Shoskes DA, Hodge EE, Goormastic M, Goldfarb DA, Novick AC. HLA matching determines susceptibility to harmful effects of delayed graft function in renal transplant recipients. Transplant Proc. 1995;27:1068–9.
    1. Haas M. The Revised (2013) Banff classification for antibody-mediated rejection of renal allografts: update, difficulties, and future considerations. Am J Transplant. 2016;16:1352–7. doi: 10.1111/ajt.13661.
    1. Mikhalski D, Wissing KM, Ghisdal L, Broeders N, Touly M, Hoang AD, et al. Cold ischemia is a major determinant of acute rejection and renal graft survival in the modern era of immunosuppression. Transplantation. 2008;85:S3–9. doi: 10.1097/TP.0b013e318169c29e.
    1. Sacks SH, Zhou W. The role of complement in the early immune response to transplantation. Nat Rev Immunol. 2012;12:431–42. doi: 10.1038/nri3225.
    1. Zhou HP, Yi DH, Yu SQ, Sun GC, Cui Q, Zhu HL, et al. Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft. Transplant Proc. 2006;38:3046–51. doi: 10.1016/j.transproceed.2006.10.002.
    1. Casiraghi F, Azzollini N, Todeschini M, Cavinato RA, Cassis P, Solini S, et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transplant. 2012;12:2373–83. doi: 10.1111/j.1600-6143.2012.04115.x.
    1. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Developmental Committee of the European Group for Blood and Marrow Transplantation: mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–86. doi: 10.1016/S0140-6736(08)60690-X.
    1. Najar M, Raicevic G, Boufker HI, Fayyad Kazan H, De Bruyn C, Meuleman N, et al. Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: combined comparison of adipose tissue, Wharton’s Jelly and bone marrow sources. Cell Immunol. 2010;264:171–9. doi: 10.1016/j.cellimm.2010.06.006.
    1. Lu Y, Liu J, Liu Y, Qin Y, Luo Q, Wang Q, et al. TLR4 plays a crucial role in MSC-induced inhibition of NK cell function. Biochem Biophys Res Commun. 2015;464:541–7. doi: 10.1016/j.bbrc.2015.07.002.
    1. Mohammadpour H, Pourfathollah AA, Zarif MN, Tahoori MT. TNF-α modulates the immunosuppressive effects of MSCs on dendritic cells and T cells. Int Immunopharmacol. 2015;28:1009–17. doi: 10.1016/j.intimp.2015.07.045.
    1. Franquesa M, Hoogduijn MJ, Baan CC. The impact of mesenchymal stem cell therapy in transplant rejection and tolerance. Curr Opin Organ Transplant. 2012;17:355–61. doi: 10.1097/MOT.0b013e328355a886.
    1. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–41. doi: 10.1016/S0140-6736(04)16104-7.
    1. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67:1187–94. doi: 10.1001/archneurol.2010.248.
    1. Franquesa M, Herrero E, Torras J, Ripoll E, Flaquer M, Gomà M, et al. Mesenchymal stem cell therapy prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. Stem Cells Dev. 2012;21:3125–35. doi: 10.1089/scd.2012.0096.
    1. Chen J, Park HC, Addabbo F, Ni J, Pelger E, Li H, et al. Kidney-derived mesenchymal stem cells contribute to vasculogenesis, angiogenesis and endothelial repair. Kidney Int. 2008;74:879–89. doi: 10.1038/ki.2008.304.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever