To our knowledge, this is the first meta-analysis for MSCs therapy as induction treatment in kidney transplantation. The results from our meta-analysis showed that the infusion of MSCs as induction therapy was safe and effective, in some aspects was even superior to standard induction regimens.
First of all, the infusion of MSCs as induction therapy was safe. It was reported that, despite the low expression of HLA molecules on their surface and the inherent immunosuppressive properties, injection of allogeneic MSCs still bear the risk to active recipients’ immune responses and induce the development of donor-specific antibodies [19, 20]. Embolism has also been reported in some cases . In our meta-analysis, during the period of MSCs infusion, no related adverse effects happened in all of the five included cohorts, indicating the tolerance of MSCs injections.
Second, the infusion of MSCs as induction therapy was effective. There still existed concern that the infusion of MSCs would cause damage to the grafted kidney based on the undesirable results by Perico et al. in 2011. Perico et al. were the pioneers to attempt the application of MSCs in patients undergoing kidney transplantation. However, both of the two patients receiving MSCs treatment in their study experienced transient serum creatinine increasing during 7–14 days after MSCs infusion, dampening expectations of this regimen . According to our meta-analysis, a major difference between the above mentioned study conducted by Perico et al. and those studies included in our research was the timepoint of MSCs infusion. Perico et al. tried to injected MSCs at 7 days after surgery, rather than pre- or peri-transplant infusion. After surgery, those infused MSCs would follow the graft originated inflammatory stimulus into the kidney, turned into a pro-inflammatory type rather than an immunoregulatory type which localized in lymphoid organs when injected pre-transplant . One of the patient in their study undertook graft biopsy, and presented with focal interstitial inflammatory cells infiltration and deposition of complement C3 without signs of AR, much like engraftment syndrome which was commonly seen in bone marrow transplantation patients, also verifying this explanation . In our meta-analysis, all of the five included cohorts choose to inject the first dose of MSCs pre- or peri-transplant. Compared with standard induction regimens, utilization of MSCs as induction therapy did not increase the risk of AR or DGF (Fig. 2, Fig. 6). Meanwhile, 1-year graft survival rate, renal graft function at 1, 3, 6, 12 month post surgery were all comparable between these two groups (Fig. 3, Fig. 7–10). Moreover, in subgroup analysis, after replacement of anti-IL-2 receptor antibody with MSCs, the outcomes still remained the same (Fig. 14–16). These evidence suggested the equal efficacy of MSCs with standard induction regimens in inducting renal graft immune tolerance. MSCs could be an alternative choice for induction treatment in kidney transplantation patients.
Third, but the most important, our meta-analysis demonstrated a lower infection incidence in MSCs group. The RR for 1-year infection rate was 0.73 (95% CI: 0.58–0.93, P = 0.01) in the MSCs group as compared with standard induction therapy group (Fig. 4). In term of opportunistic infection, result remained the same (RR = 0.59, 95% CI: 0.37–0.93, P = 0.02) (Fig. 5). One major doubt for the application of MSCs in kidney transplantation patients was whether such an expensive therapy was suitable to be used to merely prevent AR, an event which has already been well controlled by conventional immunosuppressive drugs. Results from our research provided another meaningful advantage for its application. The attention of the transplant community has turned from the inhibition of rejection reaction to long-term event-free survival . Infection was an important part. Contrast with a small samples former study by Reinders et al. that demonstrated a high opportunistic viral infection risk , our data providing evidence that patients who received MSCs infusion developed less infections than those in control group. The different immune state of patients might account for this contradiction, for those paitent in Reinders’s study all had signs of rejection or interstitial fibrosis/tubular atrophy (IF/TA) before MSCs infusion.
Last, according to our meta-analysis, strategy with MSCs successfully reduced total dosage of CNIs during maintenance period. Lifelong intake of immunosuppressive drugs which were necessary to circumvent graft rejection inevitably imposed increasing risks of morbidity and mortality in kidney transplantation recipients. An interesting concept to make use of MSCs as induction therapy was indented to minimize immune suppression, especially during maintenance period. Animal experiments showed that combination therapy with MSCs contributed to a subtherapeutic dose of rapamycin in promoting graft tolerance . Subgroup analysis in our meta-analysis also revealed that none of the 1-year AR rate, DGF rate and renal graft function at 12 month post surgery in low-dose CNIs group were different with those in standard-dose CNIs group, suggesting the successful CNIs withdrawl (Fig. 11–13).
Despite the promising future, some limitations in our meta-analysis should also be mentioned. First, the sample in our meta-analysis is still not large enough. Only four studies with five cohorts contained a total of 301 patients are available to be included in the meta-analysis. We still need more well-designed, multi-centre, large-samples RCTs to further discuss this issue. Second, the follow-up time is still not long enough. Most patients in our study are followed up for one year. The short follow-up time is insufficiency to get a tough conclusion. Last but not the lease, the risk of tumor formation is not analyzed in our research, nor in those original articles. The concern for the development of tumor is a major hurdle for translation into clinical settings. Although no study right now reported the de novo formation of tumor after MSCs infusion in humans, this caution should always be kept an eye on.
In conclusion, our meta-analysis demonstrated a similar, even better, inducing immune tolerance effect of MSCs therapy on the recipients in kidney transplantation as compared with that of other regimens. Some ongoing clinical trials will provide more evidence about the long-term risks and benefits of MSCs therapy. We believe a promising future of MSCs as induction therapy in kidney transplantion and call for more studies in this field.