Autologous bone marrow derived mesenchymal stromal cell therapy in combination with everolimus to preserve renal structure and function in renal transplant recipients

Abstract

BackgroundKidney transplantation has improved survival and quality of life for patients with end-stage renal disease. Despite excellent short-term results due to better and more potent immunosuppressive drugs, long-term survival of transplanted kidneys has not improved accordingly in the last decades. Consequently there is a strong interest in immunosuppressive regimens that maintain efficacy for the prevention of rejection, whilst preserving renal structure and function. In this respect the infusion of mesenchymal stromal cells (MSCs) may be an interesting immune suppressive strategy. MSCs have immune suppressive properties and actively contribute to tissue repair. In experimental animal studies the combination of mammalian target of rapamycin (mTOR) inhibitor and MSCs was shown to attenuate allo immune responses and to promote allograft tolerance. The current study will test the hypothesis that MSC treatment, in combination with the mTOR inhibitor everolimus, facilitates tacrolimus withdrawal, reduces fibrosis and decreases the incidence of opportunistic infections compared to standard tacrolimus dose.Methods/design70 renal allograft recipients, 18–75 years old, will be included in this Phase II, open label, randomized, non-blinded, prospective, single centre clinical study. Patients in the MSC treated group will receive two doses of autologous bone marrow derived MSCs IV (target 1,5x106, Range 1-2x106 million MSCs per/kg body weight), 7 days apart, 6 and 7 weeks transplantation in combination with everolimus and prednisolone. At the time of the second MSC infusion tacrolimus will be reduced to 50% and completely withdrawn 1 week later. Patients in the control group will receive everolimus, prednisolone and standard dose tacrolimus. The primary end point is to compare fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups at 6 months compared to 4 weeks post-transplant. Secondary end points include: composite end point efficacy failure (Biopsy Proven Acute Rejection, graft loss or death); renal function and proteinuria; opportunistic infections; immune monitoring and “subclinical” cardiovascular disease groups by assessing echocardiography in the different treatment groups.DiscussionThis study will provide information whether MSCs in combination with everolimus can be used for tacrolimus withdrawal, and whether this strategy leads to preservation of renal structure and function in renal recipients.Trial registrationNCT02057965.

Stem Cell Therapies in Clinical Trials: Progress and Challenges

“…Systemic immunosuppression by bone marrow MSCs (1 million/kg) has been indicated in kidney allograft transplant patients for the possible improvement of rejection and fibrosis in donor organs (Reinders et al, 2013(Reinders et al, , 2014. Graft versus host disease (GVHD) is a serious consequence of the host immune system recognizing and rejecting allogeneic grafts.…”

Chimeric Allografts Induced by Short‐Term Treatment With Stem Cell Mobilizing Agents Result in Long‐Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine

“…Endogenous autologous stem cells have also been shown to participate in injury repair and regeneration in many experimental (4)(5)(6) and clinical scenarios (7)(8)(9)(10), and some have compared the two sources of stem cells for relative clinical efficacy (11). In addition, investigators have shown an immunomodulatory effect of stem cells (12)(13)(14) and suggested a role as therapeutic adjunct after transplantation (15)(16)(17). Our researchers previously demonstrated that a Lewis-to-DA rat liver graft becomes a host-donor chimera via recipient stem cell repopulation and is accepted without immunosuppression (18).…”

Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients

“…In humans, rationale for use of MSCs in renal recipients includes a reduction in severity of IRI, prevention and reversal of acute transplant rejection, and reversal or stabilization of chronic transplant inflammation and fibrosis. In addition, adding MSCs to the immune suppressive regimen might facilitate CNI withdrawal with the aim of preserving renal function and structure [ 10 , 11 ].…”