Creation of bio-artificial kidney with renal cells (primary, immortalised or stem) as a model of renal transport

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Development of an in vitro human renal model is a key requirement for early stage drug development to predict renal clearance in human and potentially develop structure activity relationships. The aim of this project is to generate such a model which can also enable the determination in vitro to in vivo extrapolation (IVIVE) for renal clearance and drug-drug interactions (DDIs) via renal transporters. Key factors for successful development of an in vitro renal model are expression and function of renal transporters along with formation of tight cellular monolayer where both apical and basolateral compartments that can be accessed and sampled separately. A bioreactor system utilising polysulphone hollow fibres has previously been developed at Loughborough University. Tubular orientation, application of flow to mimic the in vivo environment of the proximal tubule and the structural composition of bioreactor system have been shown to improve proximal tubule cell growth and viability, however, the effect of this platform on expression and function renal uptake and efflux transporters remains to be studied. In this project, human kidney cells (HK2) are therefore going to be used to determine the optimum conditions in terms of cell culture medium composition, cell density, flow rate, cell culture surface on the polysulphone fibres and extrusion method to produce consistent hollow fibres for renal cells growth on the bioreactor system. Subsequently, human renal proximal tubule cells including primary and immortalized cells will be tested in the bioreactor to assess the uptake and efflux transporters expression, function and formation of tight cellular monolayer. Once cell types with optimum growth, viability, and renal transporter expression in the bioreactor system are selected they will be utilised as an in vitro human renal model to determine an IVIVE for renal clearance, prediction of renal secretion and drug-drug interactions via renal transporters. The data produced by this model may also be included in physiologically based pharmacokinetic modelling packages to evaluate in vivo DDIs predictions in humans.