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Abstract
The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three-dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs.
Highlights
Chronic renal failure (CRF), because of diminished kidney function and due to a direct inhibition of drug transporters and drug-metabolism enzymes by uremic toxins[14,15]
At the basolateral membrane the organic anion transporters 1 (OAT1; SLC22A6) and −3 (OAT3; SLC22A8) of the solute carrier family (SLC), are highly efficient in the uptake of the anionic uremic toxins such as the l-tryptophan, tyrosine and phenylalanine end-metabolites, shifting their protein binding to the free fraction[8,18,19]
As the removal of protein-bound uremic toxins via proximal tubule epithelial cells (PTEC) is associated with better patients survival, the engineering of a bioartificial kidney (BAK) containing PTEC cultured on hollow fiber membranes (HFM) could be a promising platform to advance uremic toxin clearance
Summary
CRF, because of diminished kidney function and due to a direct inhibition of drug transporters and drug-metabolism enzymes by uremic toxins[14,15]. As the removal of protein-bound uremic toxins via PTEC is associated with better patients survival, the engineering of a bioartificial kidney (BAK) containing PTEC cultured on hollow fiber membranes (HFM) could be a promising platform to advance uremic toxin clearance This was the focus of the current study using human conditionally immortalized PTEC (ciPTEC), expressing endogenously a broad range of functional transporters associated with uremic toxin handling[21,22]. The cells carry the temperature-sensitive mutant U19tsA58 of SV40 large T antigen (SV40T) and the essential catalytic subunit of human telomerase (hTERT), allowing the cells to proliferate at the permissive low temperature of 33 °C and differentiate to mature PTEC at 37 °C, and maintenance of telomere length preventing replicative senescence, respectively This resulted in stable cell lines that could be maintained over a long period of time, and a valuable tool for studying renal clearance processes as required for BAK engineering. As a crucial step in BAK engineering, the secretory clearance of human serum albumin-bound indoxyl sulfate and kynurenic acid was confirmed, as well as albumin reabsorption
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