Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials

Abstract

Current therapies for acute kidney injury remain primarily supportive and have failed to reduce morbidity, mortality (>50%), and associated costs. This prompted our studies in which rats with bilateral ischemia/reperfusion-induced acute kidney injury were treated with bone marrow-derived, culture-expanded allogeneic mesenchymal stem cells. Their administration into the suprarenal aorta after reflow significantly protected renal function and hastened repair, mediated by complex antiapoptotic, mitogenic, anti-inflammatory, and immune modulating actions that were not elicited by isogeneic fibroblasts. Infused mesenchymal stem cells, recruited to renal sites of injury, did not significantly differentiate into target cells but rather disappeared from kidneys and other organs within 72 h. Furthermore, at 3 months, compared with vehicle-treated controls, renal function was well preserved and interstitial fibrosis was absent. These preclinical data served as the scientific basis for a recently completed Phase I Clinical Trial (http://www.clinicaltrials.gov; # NCT00733876), in which patients at high risk for cardiac surgery-associated AKI were treated with allogeneic mesenchymal stem cells. Until now, MSC therapy in the study subjects has been safe, and none of the patients has developed postoperative AKI or subsequent loss of renal function, suggesting that this novel form of therapy may have promise in this group of high-risk patients, which will be further investigated in a Phase II Trial.

Keywords: Bcl-2; cardiac surgery; chronic kidney disease; gene expression; paracrine actions; proinflammatory cytokines.

Figures

Figure 1

Treatment of severe acute renal failure (ARF) with syngeneic multipotent stromal cells (MSCs) or fibroblasts. (a) MSC administration immediately after reflow to animals with severe ARF (Fisher 344 rats) significantly improves renal function at 24 h after clamping, whereas vehicle- and fibroblast-treated animals show no such response. P=0.002, vehicle- versus MSC-treated animals; P=0.04, fibroblast- versus MSC-treated animals; P=0.05, vehicle- versus fibroblast-treated animals. (b) MSC administration significantly lowered cortical and outer medullary injury scores. (c) MSC-treated rats showed significantly higher numbers of proliferating cells, whereas it simultaneously reduced the number of apoptotic cells compared with controls. (d) PCNA, proliferating cell nuclear antigen; SCr, serum creatinine; TUNEL, terminal transferase-mediated dUTP nick-end labeling. Reproduced from Togel et al., with permission from the American Physiological Society.