Proximal Tubule aProximate™

• Drug transporter interactions
• Drug-drug interactions
• Species comparison
• Kidney toxicity assays
• Disease modelling

aProximate™ is an ideal model during early and late drug development for understanding drug handling in the kidney proximal tubule cells. In vitro drug testing and modelling in the proximal tubule is a common strategy for mitigating the risk of failure during preclinical and clinical development, especially as several drugs and metabolites are handled by the same transporters. Interactions between new drugs and renal transporters can easily and accurately be evaluated in vitro with aProximate™. The mechanistic insights provided can be used to support regulatory applications or as responses to regulatory agencies.

Primary kidney proximal tubule cells tend to dedifferentiate and lose key phenotypes overtime in culture, after a freeze-thaw cycle and after immortalization as shown by the loss of transporter and metabolic enzymes involved in drug transport and metabolism. They also display an altered balance between glycolytic and non-glycolytic pathways as well as altered redox activity compared to PTCs in vivo. aProximate™ PTCs distinguish themselves from other PTC cells as they are freshly isolated from kidney tissue, retaining accurate near-physiological phenotype and function.

Evaluation and prediction of nephrotoxicity remains a challenging priority during the early and late drug development process. For example, some classes of drugs such as anti-retrovirals, antibiotics, antisense oligonucleotides or siRNA therapies are known to accumulate in kidney proximal tubule cells affecting cell function, possibly inducing nephrotoxicity. Reliable predictive or investigative toxicology tools for early evaluation are needed to avoid drug-induced kidney injury during clinical studies, which are often undetected in animal models due to their low sensitivity. aProximate™ allows for the detection of FDA-qualified kidney-specific biomarkers in response to injury such as KIM-1, NGAL and Clusterin, which are more sensitive than blood and urine biomarkers such as creatinine. This confirms the suitability to assess kidney proximal tubule cell toxicity and evaluate renal drug safety during drug discovery using aProximate™ as an in vitro model.

aProximate™ is fully validated for many applications (For example, see our collaborative publication with Takeda pharmaceuticals: Bajaj et al., 2019 https://www.sciencedirect.com/science/article/abs/pii/S0300483X20301748?via%3Dihub

1. Fully differentiated and functional kidney proximal tubule cells
2. Form a polarised cell layer with tight junctions
3. Expression of all key basolateral and apical transporters involved in drug handling, including Megalin and Cubilin
4. Measurement of net flux
5. Detection of clinical biomarkers to detect early nephrotoxicity
6. Unique species comparison capability
7. High throughput

aProximate™ expresses most relevant kidney transporters unlike other primary and immortalised PTCs such as RPTEC, KH2 and HEPTEC, which express very low or negligible levels. See table below.

aProximate™ is now available for shipment to customers to perform kidney transporter and toxicity studies in-house. aProximate™ Assay-Ready plates (Human) are provided in either 24-well or 96-well Transwell® format. The cells are shipped in stasis media and require revival at 37^oC prior to use. The model is provided with maintenance medium and user guide with a detailed protocol for recovery.

Download our poster presentation to find out more about how we validated the shipping process of primary human proximal tubule cell monolayers between laboratories.

User Guide

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