CKDu and Ochratoxin-A: risk assessment studies in a microphysiological system

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Project Summary/Abstract CKDu (CKD of unknown etiology) occurs primarily in the developing world, and is associated with living and working in agricultural communities in hot climates. The cost of treating CKDu is unattainable in low-income countries, where 30 days of essential medications can cost up to 18 days wages. One proposed risk factor of CKDu is chronic exposure to Ochratoxin A (OTA), a common mycotoxin found in cereal grains, beans, dried fruits, wine, coffee, and tea. OTA is a demonstrated renal carcinogen in several animal species, however hazard identification in humans has been elusive due to the lack of adequate models that include hepatic bioactivation as a source of the ultimate toxic moiety. We have recently developed a coupled liver>kidney microphysiologic system (MPS) that was used to identify the specific hepatic enzymes, renal transporters, and intermediate chemical metabolites associated with aristolochic acid mediated CKDu. Cultured under constant flow, primary liver and kidney cells demonstrated localized phase-I/II enzymes and transporters, a significant advance over immortalized cell lines that rapidly lose enzyme expression and transporter polarization. In addition, primary kidney proximal tubule cells exhibited robust and biomimetic secretion of biomarkers of kidney injury. For this proposal, we have developed an innovative integrated liver>kidney MPS that incorporates both a coupled and uncoupled kidney MPS on a single chip. We propose to define the dose-response relationships of ochratoxin A and heat stress-induced nephropathy, identify the transport proteins involved in renal ochratoxin A uptake and efflux, and determine the role of first pass metabolism in ochratoxin A-induced nephropathy. A better understanding of the mechanisms of OTA-induced kidney injury will support changes in risk assessment, regulatory agency policies on allowable exposure levels, and determination of genetic risk factors in high-risk populations.