Treatment of acute renal failure with allogeneic marrow stromal cells: short and long term effects in experimental models and clinical trials

The Medical Problem The acute loss of kidney function (Acute Renal Failure caused by Acute Kidney Injury) due to shock, trauma, major cardiac surgery, toxic drugs and agents, results, if severe, in a patient mortality of > 50%. This unacceptable outcome has remained unchanged over the last 30 years, despite the availability of kidney replacement therapy (dialysis) and treatment in an Intensive Care Unit setting. This continued treatment resistance of AKI makes it urgent that new, effective treatment modalities are developed for this major medical problem. Pathophysiology of AKI Although the kidney has a robust capacity to repair itself after an acute insult, once its intrinsic regenerative capacity is exceeded, uremic, systemic complications develop and cause high levels of morbidity and mortality. In AKI, vascular and epithelial cells are injured, become dysfunctional, undergo apoptosis and necrosis, all associated with a major inflammatory component. These processes result in the abrupt loss of excretory and other functions of the kidney, functions that are only incompletely replaced by dialysis. Successful repair of the injured kidney and thus return of function depends directly on the survival of sublethally injured vascular and epithelial cells, and replacement of cells that have been permanently lost. Multiple pharmacological interventions that have been tested clinically have to date not succeeded to significantly improve patient survival and overall outcome. Pre‐Clinical Data Extensive work from our laboratory and other investigators has shown that bone marrow‐derived Multipotent Stromal Cells, also termed Mesenchymal Stem Cells (MSC) are largely immune privileged and can thus be used in allogeneic protocols, i.e., tissue typing or blood group matching is not required for their safe use in animals and patients. We demonstrated that the administration of allogeneic MSC to animals with severe ischemia/reperfusion‐induced AKI results in powerful protection of renal function, stimulated regeneration and excellent animal survival. Administered MSC are recruited to the injured kidney by specific homing signals that the organ elaborates. In the microvasculature of the kidney, MSC attach for 1‐3 days, respond to cues that are present in the injured microenvironment through complex paracrine mechanisms. These include anti‐inflammatory, anti‐apoptotic, immune modulating, anti‐thrombotic, anti‐fibrotic, angiogenic and mitogenic actions. Unexpectedly, MSC do not differentiate into renal target cells, and thus do not replace cells that have been lost. Importantly, early treatment of AKI with MSC results in well preserved renal function late after injury. This effect may be of major benefit clinically as well. Clinical Trials MSC therapy in humans is being tested in patients with Graft versus Host Disease, Crohn's disease, osteogenesis imperfecta, ischemic heart disease and others. Our group is currently conducting a Phase I Clinical Trial in which allogeneic MSC are infused into patients who are at high risk for cardiac surgery‐induced AKI. So far, no safety issues have been encountered. We will conduct a second clinical trial in Europe, in which kidney transplant‐associated AKI will be treated with allogeneic MSC.