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Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study.

ABSTRACT: Despite excellent short-term results, long-term survival of transplanted kidneys has not improved accordingly. Although alloimmune responses and calcineurin inhibitor-related nephrotoxicity have been identified as main drivers of fibrosis, no effective treatment options have emerged. In this perspective, mesenchymal stromal cells (MSCs) are an interesting candidate because of their immunosuppressive and regenerative properties. Of importance, no other clinical studies have investigated their effects in allograft rejection and fibrosis. We performed a safety and feasibility study in kidney allograft recipients to whom two intravenous infusions (1 million cells per kilogram) of autologous bone marrow (BM) MSCs were given, when a protocol renal biopsy at 4 weeks or 6 months showed signs of rejection and/or an increase in interstitial fibrosis/tubular atrophy (IF/TA). Six patients received MSC infusions. Clinical and immune monitoring was performed up to 24 weeks after MSC infusions. MSCs fulfilled the release criteria, infusions were well-tolerated, and no treatment-related serious adverse events were reported. In two recipients with allograft rejection, we had a clinical indication to perform surveillance biopsies and are able to report on the potential effects of MSCs in rejection. Although maintenance immunosuppression remained unaltered, there was a resolution of tubulitis without IF/TA in both patients. Additionally, three patients developed an opportunistic viral infection, and five of the six patients displayed a donor-specific downregulation of the peripheral blood mononuclear cell proliferation assay, not reported in patients without MSC treatment. Autologous BM MSC treatment in transplant recipients with subclinical rejection and IF/TA is clinically feasible and safe, and the findings are suggestive of systemic immunosuppression.

SUBMITTER: Reinders ME

PROVIDER: S-EPMC3659754 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study.

Reinders Marlies E J ME de Fijter Johan W JW Roelofs Helene H Bajema Ingeborg M IM de Vries Dorottya K DK Schaapherder Alexander F AF Claas Frans H J FH van Miert Paula P M C PP Roelen Dave L DL van Kooten Cees C Fibbe Willem E WE Rabelink Ton J TJ

Stem cells translational medicine 20130124 2

Despite excellent short-term results, long-term survival of transplanted kidneys has not improved accordingly. Although alloimmune responses and calcineurin inhibitor-related nephrotoxicity have been identified as main drivers of fibrosis, no effective treatment options have emerged. In this perspective, mesenchymal stromal cells (MSCs) are an interesting candidate because of their immunosuppressive and regenerative properties. Of importance, no other clinical studies have investigated their eff ...[more]

PMID: 23349326

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Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a genetic ciliopathy disease characterized by progressive formation and enlargement of cysts in multiple organs. The kidneys are particularly affected and patients may eventually develop end-stage renal disease (ESRD). We hypothesize that bone marrow mesenchymal stromal cells (BMMSCs) are renotropic and may improve kidney function via anti-apoptotic, anti-fibrotic, and anti-inflammatory effects. In this study, we aim to assess the safety and tolerability of a BMMSC infusion in ADPKD patients.MethodsWe performed a single-arm phase I clinical trial with a 12-month follow-up. This study enrolled six eligible ADPKD patients with an estimated glomerular filtration rate (eGFR) of 25-60 ml/min/1.73 m2. Patients received autologous cultured BMMSCs (2 × 106 cells/kg) through the cubital vein according to our infusion protocol. We investigated safety issues and kidney function during the follow-up visits, and compared the findings to baseline and 1 year prior to the intervention.ResultsThere were no patients lost to follow-up. We observed no cell-related adverse events (AE) and serious adverse events (SAE) after 12 months of follow-up. The mean eGFR value of 33.8 ± 5.3 ml/min/1.73 m2 1 year before cell infusion declined to 26.7 ± 3.1 ml/min/1.73 m2 at baseline (P = 0.03) and 25.8 ± 6.2 ml/min/1.73 m2 at the 12-month follow-up visit (P = 0.62). The mean serum creatinine (SCr) level of 2 ± 0.3 mg/dl 1 year before the infusion increased to 2.5 ± 0.4 mg/dl at baseline (P = 0.04) and 2.5 ± 0.6 mg/dl at the 12-month follow-up (P = 0.96). This indicated significant changes between the differences of these two periods (12 months before infusion to baseline, and 12 months after infusion to baseline) in SCr (P = 0.05), but not eGFR (P = 0.09).ConclusionsThis trial demonstrated the safety and tolerability of an intravenous transplantation of autologous BMMSCs. BMMSC efficacy in ADPKD patients should be investigated in a randomized placebo-controlled trial with a larger population, which we intend to perform.Trial registrationClinicalTrials.gov, NCT02166489 . Registered on June 14, 2014.

Project description:Kidney 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.70 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 1,5 x 10(6), Range 1-2 x 10(6) 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.This 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.NCT02057965.

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Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study.

Publications

Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study.

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