Mesenchymal stromal cell therapy with early tacrolimus withdrawal prevents left atrial remodelling in renal transplant recipients: an analysis of the TRITON trial

Abstract

Abstract Background After renal transplantation, there is a need for immunosuppressive regimens that effectively prevent allograft rejection, while minimizing cardiovascular side effects. The TRITON study is the first randomized clinical trial that tested a strategy with autologous bone marrow derived mesenchymal stromal cell (MSC) therapy and complete withdrawal of calcineurin inhibitors (CNIs). The combination of MSC therapy and CNIs discontinuation was associated with improved blood pression control and regression of left ventricular hypertrophy. Nevertheless, the impact of this immunosuppressive strategy on left atrial (LA) structural and functional remodelling, which has been proven as an independent predictor of cardiovascular outcomes, has not been investigated. Purpose To assess the effects of MSC therapy combined with CNIs withdrawal on longitudinal changes of LA structure and function, evaluated by two-dimensional transthoracic echocardiography. Methods The TRITON trial randomized renal transplant recipients to MSC therapy – infused at week 6 and 7 after transplantation, with complete withdrawal at week 8 of tacrolimus (MSC group) – or standard tacrolimus dose (control group). Patients who underwent transthoracic echocardiography with speckle-tracking analysis at week 4 and 24 after renal transplantation were included in this sub-analysis. Changes in echocardiographic variables between 4 and 24 weeks post-transplantation were evaluated and compared between randomization arms using an analysis of covariance model, adjusted for baseline variable. Results 54 patients (MSC group =27; control group =27) were included. Between 4 and 24 weeks after transplantation, an increase in indexed minimal LA volume (LAVImin) was observed in the control group, whereas in the MSC group there were no changes in LAVImin over the time, leading to a significant difference between groups (p=0.021). Moreover, patients randomized to MSC therapy showed a benefit in LA function, assessed by a significant interaction between changes in LA emptying fraction (LAEF) and LA reservoir strain and the treatment group (p=0.012 and p=0.027, respectively) (Table 1). The association between changes in LA structural and functional parameters and the randomization arm remained significant after adjustment for changes in systolic blood pressure, diastolic blood pressure and estimated glomerular filtration rate over the time (Figure 1). Conclusion The combination of MSC therapy and early CNIs withdrawal prevents LA structural and functional remodelling in the first six months after renal transplantation. MSC therapy appears a promising approach in renal transplant recipient, effective in the prevention of graft rejection, while exerting potential cardioprotective effects. Funding Acknowledgement Type of funding sources: None.