MSCs for Renal Repair
Acute kidney injury (AKI), the abrupt loss of renal function that results from ischemia, sepsis, or nephrotoxin-induced damage to vascular and tubular structures, is characterized by inflammatory processes, cellular apoptosis, and necrosis. Patient mortality remains high and treatment is largely supportive. Even mild AKI can lead to chronic kidney disease (CKD), further underscoring the urgent need for therapeutic innovations. Mesenchymal stromal cells’ (MSCs) potent anti-inflammatory, immunomodulatory, organ protective, and reparative properties make them excellent potential candidates for prevention and treatment of AKI. Multiple preclinical studies using various AKI models have confirmed that, via paracrine mechanisms, MSC treatment improves survival, ameliorates and reverses injury, and prevents progression to CKD. Preliminary results from the first Phase I clinical trial (safety, preliminary efficacy), in which we infused allogeneic MSCs into subjects at high risk for AKI following on-pump cardiac surgery, paralleled preclinical observations, suggesting that MSC therapy is safe and effective in preventing both postoperative AKI and progression to CKD.
KeywordsChronic Kidney Disease Coronary Artery Bypass Grafting Acute Kidney Injury Mesenchymal Stromal Cell Acute Kidney Injury Network
At the time of the Phase I clinical trial, both Christof Westenfelder and Anna Gooch were either consultants to or recipients of research support from AlloCure, Inc., the trial’s sponsor. Currently, both authors declare they have no competing interests. The authors’ research was also in part supported by funds from the Merit Review program of the Veterans Administration, Washington, DC, the National Institutes of Health, the American Heart Association, the National Kidney Foundation, the Western Institute for Biomedical Research, and AlloCure, Inc. The human MSCs that were administered to study subjects in the Phase I clinical trial were prepared in the cGMP Cell Therapy Facility of the University of Utah. The outstanding skills of the PIs (Dr. John Doty, Intermountain Medical Center, Murray, Utah; Dr. David Affleck, St. Mark’s Hospital, Salt Lake City, Utah), Co-PIs (Drs. Benjamin Horne and Brent Muhlestein, Intermountain Medical Center; Drs. Shreekanth Karwande and Gilbert Schorlemmer, St. Mark’s Hospital), and study nurses (Jean Flores, Intermountain Medical Center; Analee Creer, St. Mark’s Hospital) are gratefully acknowledged. The contributions of the members of the Data and Safety Monitoring Board for this trial, Drs. C. Kablitz, George R. Reiss, and Srinivasan Beddhu, are also greatly appreciated. Finally, the excellent bench and regulatory work of Zhuma Hu and Drs. Ping Zhang and Florian Tögel was invaluable for the successful conduct of the preclinical studies and the clinical trial.
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