Acute kidney injury (AKI) is a serious clinical entity, and no specific treatment is currently available. Stem cell therapy has been shown to be a promising multimodal approach directed at different pathophysiologic aspects of AKI. Bone marrow-derived mesenchymal stem cells provide a promising therapeutic perspective due to their immunomodulatory and antiapoptotic properties and the secretion of various growth factors. However, the optimal dosing regimen and source of multipotent marrow stromal cells (MSCs) are currently unknown. Here we tested both the early renoprotective potential and the long-term contribution of various doses (0.5/2/5 × 106) of allogeneic and syngeneic MSCs in a rat model of ischemic AKI. MSC from human placental alkaline phosphatase (hPAP) transgenic Fischer rats were used in an allogeneic and syngeneic setting. Postreflow administration of hPAP + MSCs from Fischer to Sprague-Dawley rats with severe AKI improved both recovery of renal function on days 1 and 3 after AKI, with the lowest dose being the most protective. In an autologous setting, MSCs improved recovery after AKI in a dose-dependent fashion, but there was no difference between 2 and 5 × 106 MSCs administered. After 3 months creatinine clearance was better preserved in MSC-treated animals (2.1) versus controls (1.5 mL/min), whereas there were no differences in blood pressure, hematocrit, and weight. Compared with controls, MSC-treated animals had a lower renal fibrosis score (1.8 vs 2.3), and renal TGF-β and PAI-1 mRNA levels were significantly down-regulated. hPAP + MSCs could not be detected in kidneys, brain, liver, lung, and spleen by highly sensitive PCR, whereas the bone marrow in 3 of 6 animals was positive for hPAP, suggesting low-level engraftment. We conclude that allogeneic MSCs enhance early recovery from AKI as well as isogeneic cells and appear safe in the long term. They do not contribute to significant replacement of renal cell types, while ameliorating both long-term fibrotic changes and loss in renal function after AKI.
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