1). A phase I clinical trial (NCT00733876) has been designed to determine if the administration of kinase inhibitors allogeneic MSCs at defined doses is safe in patients who are at high risk of developing AKI after undergoing on-pump cardiac surgery. Preliminary data shown that kidney function is preserved up to 16 mo and that none of the patients required dialysis. Any therapy-related adverse events were noted in these patients[52]. The explorative study (phase I) on three patients who have developed acute renal failure after cisplatin treatment for solid cancer has demonstrated that intravenous infusion of autologous ex-vivo expanded MSCs improves renal function and the procedure is safe (NCT 01275612).

Another

phase II trial (NCT 01602328) to assess human MSC safety and efficacy in patients that develop AKI after cardiac surgery is ongoing with 156 patients enrolled. The results from these clinical studies will clarify the potential of mesenchymal stem cells in AKI management. An overall view of the preliminary results currently available confirm the safety of the treatment, but other data are required to assess clinical benefit and long term safety. Up to date, none clinical study on microvescicles and AKI is ongoing. Table 1 Clinical studies on the application of mesenchymal stem cells in acute kidney injury CONCLUSION The use of MSC for AKI therapy is encouraging and is generally considered as safe. The experience from the increasing use of mesenchymal stem cells before or after renal transplant will furnish important suggestions to implement other clinical protocols with MSC in acute kidney injury. However, some concerns about the use of living cells should keep in account. In progressive rat model of glomerulonephritis, intrarenal injection of MSCs initially ameliorated acute renal failure; however, long-term examination has demonstrates that approximately 20% of the glomeruli of MSC-treated rats

contained single or clusters of large adipocytes with pronounced surrounding fibrosis, thus indicating an abnormal and detrimental adipogenic differentiation of MSC[53]. MVs should be evaluated as a possible alternative of living MSCs. The delivery and internalization of MVs are receptor- mediated and targeted within specific cells and MVs may contain biological macromolecules that can be protected from degradation enzymes of plasma and tissue. Before moving to clinical trials, GSK-3 some important issues should be addressed, especially in terms of safety. Large scale production of MVs should be validated and optimized before clinical use; bio-distribution and pharmacokinetic properties should be determined and also long-term safety in animal models has to be tested before implementation in humans. Finally, the use of soluble factors that are released from MSCs for renoprotection may be pursued.