Allogeneic mesenchymal stem cells as induction therapy are safe and feasible in renal allografts: pilot results of a multicenter randomized controlled trial

Abstract

Background: Kidneys from deceased donors are being used to meet the growing need for grafts. However, delayed graft function (DGF) and acute rejection incidences are high, leading to adverse effects on graft outcomes. Optimal induction intervention should include both renal structure injury repair and immune response suppression. Mesenchymal stem cells (MSCs) with potent anti-inflammatory, regenerative, and immune-modulatory properties are considered a candidate to prevent DGF and acute rejection in renal transplantation. Thus, this prospective multicenter paired study aimed to assess the clinical value of allogeneic MSCs as induction therapy to prevent both DGF and acute rejection in deceased donor renal transplantation.

Methods: Forty-two renal allograft recipients were recruited and divided into trial and control groups. The trial group (21 cases) received 2 × 106/kg human umbilical-cord-derived MSCs (UC-MSCs) via the peripheral vein before renal transplantation, and 5 × 106 cells via the renal artery during the surgical procedure. All recipients received standard induction therapy. Incidences of DGF and biopsy-proven acute rejection were recorded postoperatively and severe postoperative complications were assessed. Graft and recipient survivals were also evaluated.

Results: Treatment with UC-MSCs achieved comparable graft and recipient survivals with non-MSC treatment (P = 0.97 and 0.15, respectively). No increase in postoperative complications, including DGF and acute rejection, were observed (incidence of DGF: 9.5% in the MSC group versus 33.3% in the non-MSC group, P = 0.13; Incidence of acute rejection: 14.3% versus 4.8%, P = 0.61). Equal postoperative estimated glomerular filtration rates were found between the two groups (P = 0.88). All patients tolerated the MSCs infusion without adverse clinical effects. Additionally, a multiprobe fluorescence in situ hybridization assay revealed that UC-MSCs administered via the renal artery were absent from the recipient's biopsy sample.

Conclusions: Umbilical-cord-derived MSCs can be used as clinically feasible and safe induction therapy. Adequate timing and frequency of UC-MSCs administration may have a significant effect on graft and recipient outcomes. Trial registration NCT02490020 . Registered on June 29 2015.

Keywords: Acute rejection; DGF; Delayed graft function; MSC; Mesenchymal stem cell; Renal transplantation.

Figures

Fig. 1

Study design and protocol for UC-MSCs administration in renal transplantation to prevent DGF and acute rejection

Fig. 2

The eGFR curves at different time points during the follow-up period in UC-MSCs and non-MSC groups. No significant difference in eGFR changes postoperatively between the two groups was found (P = 0.88)

Fig. 3

Kaplan–Meier survival estimates after renal transplantation in recipients of kidneys with or without UC-MSCs. a Graft survival in the MSC group was comparable to that in the non-MSC group (P = 0.97). b A similar analysis revealed no significant difference in recipient survival between the two groups (P = 0.15)

Fig. 4

Detection of UC-MSCs in a recipient’s biopsy sample by a multiprobe FISH assay. No UC-MSCs with chromosomes “XY” were found in a female recipient’s biopsy sample. A The female recipient’s biopsy sample showed two red signals representing chromosomes “XX”. Original magnification of FISH images, oil objective (×100). B The FISH assay showed one red and one green signals representing chromosomes “XY” in a control male recipient’s biopsy sample. Original magnification of FISH images, oil objective (×100)