Tissue engineering of a bioartificial renal tubule assist device is the first step to produce an implantable device to displace current hemodialysis therapy of patients with chronic renal failure and a critical step to optimize current renal replacement therapy in patients with acute renal failure. The Phase I component of this project has been successful in producing a functional bioartificial renal tubule by combining mammalian renal tubule progenitor cells, extracellular matrix components, and polymeric synthetic hollow fibers. This success sets the stage for this Phase II project to construct a bioartificial renal tubule device having a membrane surface area between 0.5 and 1.0 M2 and to test its functional performance and durability both in vitro and in vivo. This Phase II proposal has three specific aims: 1) To design a prototype bioartificial renal tubule, by utilizing mathematical modeling of oxygen transport and fluid flow mechanics, for optimal performance and function, 2) To scale up and test this device ex vivo for important transport, metabolic, and synthetic renal tubucell functions. Transport measurements will include volume, electrolytes, glucose, amino acids, urea. Synthetic function measurements will include glutathione, glutathione peroxidase, tumor necrosis factor-alpha, and interleukin-6 as important parameters in host defense. Metabolic parameters will include insulin-like growth factor-1 synthesis, gluconeogenesis, and ammoniagenesis, factors important in wound healing and nutritional balance: 3) To test these functions in vivo in normal and uremic large animals with an extracorporeal blood circuit. The successful completion of this Phase II component will allow the initiation of human clinical trials to assess the utility of this device in patients in the intensive care unit who suffer from acute renal failure (ARF). ARF affects over 200,000 patients in the U.S. each year at a cost of $2.5 billion annually, with a mortality rate greater than 50%. The underlying pathogenesis of ARF is renal tubule cell necrosis, resulting not only in filtration failure but also loss of homeostatic, metabolic, and synthetic functions of the kidney. The addition of the bioartificial renal tubule device, as a form of cell therapy, will replace these critical renal functions not substituted for with current dialytic or filtration therapy and will optimize the therapeutic approach to patient suffering from this devastating disease process.
This device may prove useful to optimize the treatment of the 400,000 U.S. patients who have either acute or chronic renal failure. Not only may this device optimize current suboptimal care for these patients, but may provide cost savings for the treatment of these patients in the billions of dollars.
