Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: A randomized controlled trial

Jianming Tan, Weizhen Wu, Xiumin Xu, Lianming Liao, Feng Zheng, Shari Messinger, Xinhui Sun, Jin Chen, Shunliang Yang, Jinquan Cai, Xia Gao, Antonello Pileggi, Camillo Ricordi

Research output: Contribution to journalArticle

312 Citations (Scopus)

Abstract

Context: Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. Objective: To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. Design, Setting, and Patients: One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. Intervention: Patients were inoculated with marrow-derived autologous MSC (1-2 × 10 6/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibodyplusstandard-dose CNIs. Main OutcomeMeasures: The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. Results: Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P=.04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P=.046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P=.02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m 2 (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m 2 (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42;95%CI, 0.20-0.85, P=.02) Conclusion Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. Trial Registration clinicaltrials.gov Identifier: NCT00658073

Original languageEnglish
Pages (from-to)1169-1177
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume307
Issue number11
DOIs
StatePublished - Mar 21 2012

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Mesenchymal Stromal Cells
Randomized Controlled Trials
Transplants
Kidney
Therapeutics
Opportunistic Infections
Control Groups
Interleukin-2 Receptors
Graft Survival
Glomerular Filtration Rate
Antibodies
Incidence
Living Donors
Poisons
Autografts
Graft vs Host Disease
Infection Control
Calcineurin Inhibitors
Chronic Kidney Failure
Reperfusion

ASJC Scopus subject areas

  • Medicine(all)

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Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants : A randomized controlled trial. / Tan, Jianming; Wu, Weizhen; Xu, Xiumin; Liao, Lianming; Zheng, Feng; Messinger, Shari; Sun, Xinhui; Chen, Jin; Yang, Shunliang; Cai, Jinquan; Gao, Xia; Pileggi, Antonello; Ricordi, Camillo.

In: JAMA - Journal of the American Medical Association, Vol. 307, No. 11, 21.03.2012, p. 1169-1177.

Research output: Contribution to journalArticle

Tan, Jianming ; Wu, Weizhen ; Xu, Xiumin ; Liao, Lianming ; Zheng, Feng ; Messinger, Shari ; Sun, Xinhui ; Chen, Jin ; Yang, Shunliang ; Cai, Jinquan ; Gao, Xia ; Pileggi, Antonello ; Ricordi, Camillo. / Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants : A randomized controlled trial. In: JAMA - Journal of the American Medical Association. 2012 ; Vol. 307, No. 11. pp. 1169-1177.
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abstract = "Context: Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. Objective: To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. Design, Setting, and Patients: One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. Intervention: Patients were inoculated with marrow-derived autologous MSC (1-2 × 10 6/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80{\%} of standard); 51 patients in the control group received anti-IL-2 receptor antibodyplusstandard-dose CNIs. Main OutcomeMeasures: The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. Results: Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5{\%}) in the autologous MSC plus standard-dose CNI group (95{\%} CI, 0.4{\%}-14.7{\%}; P=.04) and 4 of 52 patients (7.7{\%}) in the low-dose group (95{\%} CI, 0.5{\%}-14.9{\%}; P=.046) compared with 11 of 51 controls (21.6{\%}; 95{\%} CI, 10.5{\%}-32.6{\%}) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8{\%}) in the control group did (95{\%} CI, 0.6{\%}-15.1{\%}; overall P=.02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m 2 (95{\%} CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m 2 (95{\%} CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42;95{\%}CI, 0.20-0.85, P=.02) Conclusion Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. Trial Registration clinicaltrials.gov Identifier: NCT00658073",
author = "Jianming Tan and Weizhen Wu and Xiumin Xu and Lianming Liao and Feng Zheng and Shari Messinger and Xinhui Sun and Jin Chen and Shunliang Yang and Jinquan Cai and Xia Gao and Antonello Pileggi and Camillo Ricordi",
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TY - JOUR

T1 - Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants

T2 - A randomized controlled trial

AU - Tan, Jianming

AU - Wu, Weizhen

AU - Xu, Xiumin

AU - Liao, Lianming

AU - Zheng, Feng

AU - Messinger, Shari

AU - Sun, Xinhui

AU - Chen, Jin

AU - Yang, Shunliang

AU - Cai, Jinquan

AU - Gao, Xia

AU - Pileggi, Antonello

AU - Ricordi, Camillo

PY - 2012/3/21

Y1 - 2012/3/21

N2 - Context: Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. Objective: To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. Design, Setting, and Patients: One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. Intervention: Patients were inoculated with marrow-derived autologous MSC (1-2 × 10 6/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibodyplusstandard-dose CNIs. Main OutcomeMeasures: The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. Results: Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P=.04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P=.046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P=.02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m 2 (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m 2 (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42;95%CI, 0.20-0.85, P=.02) Conclusion Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. Trial Registration clinicaltrials.gov Identifier: NCT00658073

AB - Context: Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. Objective: To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. Design, Setting, and Patients: One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. Intervention: Patients were inoculated with marrow-derived autologous MSC (1-2 × 10 6/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibodyplusstandard-dose CNIs. Main OutcomeMeasures: The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. Results: Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P=.04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P=.046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P=.02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m 2 (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m 2 (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42;95%CI, 0.20-0.85, P=.02) Conclusion Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. Trial Registration clinicaltrials.gov Identifier: NCT00658073

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