Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study

Maria Chiara Meucci, Marlies E J Reinders, Koen E Groeneweg, Suzanne Bezstarosti, Nina Ajmone Marsan, Jeroen J Bax, Johan W De Fijter, Victoria Delgado, Maria Chiara Meucci, Marlies E J Reinders, Koen E Groeneweg, Suzanne Bezstarosti, Nina Ajmone Marsan, Jeroen J Bax, Johan W De Fijter, Victoria Delgado

Abstract

Background After renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of the TRITON trial evaluated the cardiovascular effects of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in renal transplant recipients. Methods and Results Renal transplant recipients were randomized to MSC therapy, infused at weeks 6 and 7 after transplantation, with withdrawal at week 8 of tacrolimus or standard tacrolimus dose. Fifty-four patients (MSC group=27; control group=27) underwent transthoracic echocardiography at weeks 4 and 24 after transplantation and were included in this substudy. Changes in clinical and echocardiographic variables were compared. The MSC group showed a benefit in blood pressure control, assessed by a significant interaction between changes in diastolic blood pressure and the treatment group (P=0.005), and a higher proportion of patients achieving the predefined blood pressure target of <140/90 mm Hg compared with the control group (59.3% versus 29.6%, P=0.03). A significant reduction in left ventricular mass index was observed in the MSC group, whereas there were no changes in the control group (P=0.002). The proportion of patients with left ventricular hypertrophy decreased at 24 weeks in the MSC group (33.3% versus 70.4%, P=0.006), whereas no changes were noted in the control group (63.0% versus 48.1%, P=0.29). Additionally, MSC therapy prevented progressive left ventricular diastolic dysfunction, as demonstrated by changes in mitral deceleration time and tricuspid regurgitant jet velocity. Conclusions MSC strategy is associated with improved blood pressure control, regression of left ventricular hypertrophy, and prevention of progressive diastolic dysfunction at 24 weeks after transplantation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.

Keywords: immunosuppression; left ventricular diastolic function; left ventricular hypertrophy; mesenchymal stem cells; renal transplantation.

Figures

Figure 1. Population included in the cardiovascular…
Figure 1. Population included in the cardiovascular subanalysis of the TRITON study.
Of 70 renal transplant recipients randomly assigned to MSC therapy or standard tacrolimus regimen, 57 patients received the allocated treatment and were included in the TRITON trial. Patients who underwent transthoracic echocardiography at 4 and 24 weeks after renal transplantation (n=54) were selected for this substudy. MSC indicates mesenchymal stromal cells; and Tx, transplantation.
Figure 2. Changes in left ventricular mass…
Figure 2. Changes in left ventricular mass (LVM) index over time.
Changes in estimated marginal means of LVM index between 4 and 24 weeks after transplantation in each treatment group. Error bars denote the standard error of the mean. *P<0.05 vs baseline within each treatment group. †P value calculated using an ANCOVA model with baseline adjustment. MSC indicates mesenchymal stromal cells.
Figure 3. Example of the changes in…
Figure 3. Example of the changes in left ventricular (LV) hypertrophy in each treatment group.
This figure illustrates an example of the changes in linear dimensions and LV hypertrophy between 4 and 24 weeks after transplantation in each treatment group. The upper panels (A and B) show the worsening of LV hypertrophy in a male patient of the control group (increase of left ventricular mass [LVM] index from 95 to 130 g/m2). The lower panels (C and D) display the regression of LV hypertrophy in a male patient of the mesenchymal stromal cells group (decrease of LVM index from 118 to 102 g/m2).

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