A Tissue Engineered
Bioartificial Renal Tubule (Renal Assist Device)
Executive Summary
Overview
The laboratory of H. David Humes, Chairman of The Department of Internal Medicine at The University of Michigan, Ann Arbor, has successfully completed in vivo testing of a Renal Tubule Assist Device (RAD) for treating acute renal failure. The only treatments currently available for ARF are hemofiltration and dialysis. Mortality rates remain above 50%. The new approach holds the promise of dramatically improving these outcomes while making treatment much less costly.
Patients in acute renal failure succumb not to inadequate clearance of toxic metabolic waste (which may be adequately managed with hemofiltration or dialysis), but from multiple organ failure due to ischemia, brought on most frequently by overwhelming infection.
The RAD holds the promise of enhancing ARF patients' ability to maintain homeostasis and stave off infection with recurrent episodes of shock and resulting multiorgan failure. This enhancement could be the key to vastly improving outcomes for roughly 190,000 patients (US) who suffer episodes of ARF annually (costing an estimated $2B) and now receive dialytic or hemofiltration support. Further value may be added by speeding time to recovery; typically an episode of ARF adds 10 days to a stay in intensive care.
The homeostatic and immunologic function lost in ARF, rendering these patients susceptible to infections, derives from metabolic activity of the renal proximal tubule cells. These cells are incorporated into the RAD. A key discovery by the Humes’ lab was a technique for isolating a subpopulation of these cells from adult mammalian kidneys that can be grown outside the body. The daughter cells of this selected population properly align themselves to function in concert as proximal renal tubule tissue.
The Renal Assist Device and Tissue Engineering
The RAD device consists of living kidney proximal tubule cells grown along the inner diameters of high flux hollow fiber membranes, pre-coated with a lining of extracellular matrix. The cell-lined fibers are bundled within bioreactor cartridges with input and outflow ports for attachment to an extracorporeal blood circuit. The Humes lab has successfully used various mammalian cells, including human. Because of their ready availability
-- a key factor for ultimately making this technology widely available -- we have chosen to concentrate on using cells from pigs. Clinical use of such xenotransplants is possible because the cells are encapsulated within the hollow fibers, isolated from the host's immune system.This work falls within the field of tissue engineering, the burgeoning science of designing living tissue for "manufacture." Engineered renal tubule tissue
-- the RAD -- provides the metabolic, endocrine, and transport function of healthy kidney tubules. These critical functions are unobtainable from current, inanimate renal replacement therapies.In Vivo/In Vitro Success to Date
In the Nature-Biotechnology article the Humes lab reports constructing devices using porcine cells that, in vitro, perform key functions of renal tubule tissue, achieving rates comparable to a whole kidney:
Active transport functions of kidney duplicated in RAD
• active vectorial transport of sodium, bicarbonate, glucose and organic anions. Demonstrating that the device transports solutes like natural kidney tubule, maintaining blood fluid volume, electrolyte balance and nutritional state
Metabolic functions of kidney duplicated in RAD
• glutathione metabolism, cytokine production, production of free radical scavenging enzymes and ammoniagenesis.
Critical in host defense; blood chemistry homeostasis
Endocrine functions of kidney duplicated in RAD
• Activation of Vitamin D
Endocrine functioning of cells in RAD responds to physiologic regulating signals
With physiologic function achieved and quantified the lab then scaled up to devices containing clinically useful doses of cells.
Next steps showed the RAD could remain viable and functioning when connected in series with standard hemofiltration devices in the extracorporeal