aProximate™ Kidney Nephrotoxicity Assays - Newcells

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The most advanced near-physiological high throughput kidney proximal tubule cells (PTC) model to investigate drug transport modalities in vitro.

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aProximate™

Nephrotoxicity Assays

Predictive and investigative renal toxicology

aProximate™ platform: The most advanced near-physiological HT kidney proximal tubule cell (PTC) model for kidney nephrotoxicity assays and efficacy studies. 

Validated model: The data obtained with the aProximate™ platform is validated for renal drug safety evaluation and kidney nephrotoxicity assays.  

Kidney toxicity assays in drug development

The prediction of renal toxicity during new drug development remains inaccurate. Around 20% of drug compounds have an expected dose-dependent toxicity profile. For the remaining 80%, safety related issues occur unexpectedly, sometimes because of repeated exposure and accumulation in the kidney over time. 

Known cytotoxic drugs

Most drugs in this category damage any type of cell they are taken up by, (e.g., cancer drugs specifically designed for this purpose such as cisplatin and ifosfamide) or compound derived from other with known nephrotoxic risks. The strategy to mitigate kidney damage by these drugs is to reduce PTCs exposure or drug uptake.

Non cytotoxic drugs

These drugs more often affect cell function rather than cell viability by interacting with signalling or metabolic pathways in PTCs. Examples of these type of drugs are anti-retroviral drugs such a tenofovir, antibiotics (gentamicin and vancomycin), anticonvulsants (like valproate) and iron chelators. 

We need an accurate predictive tool

Reliable predictive or investigative toxicology tools for early evaluation of renal safety profiles are needed, to avoid to drug-induced organ injury often undetected during pre-clinical development. Drug induced Kidney injury (DIKI) is still difficult to predict as existing animal models show high specificity but low sensitivity for renal safety profiles. 

Example Protocol

Assay Format

  • Primary isolated kidney proximal tubule epithelial cells cultured on a 96-well Transwell® plates

Species Available

  • Human, rat, dog, NHP

Measurements

  • KIM-1, NGAL, Clusterin and others as required (Meso Scale Discovery)
  • ATP, LDH
  • Trans-epithelial electrical resistance (TEER)

Time points and replicates

  • 0, 24h up to 7 days multiple dosing
  • Triplicates per concentration
  • Multiple kidney repeats on request

Test article requirements

  • Volumes added 0.1 ml (apical) and 0.2 ml
  • (basolateral) per well
  • • Six dose concentrations



Controls

  • Cisplatin as positive control
  • TA vehicle as negativecontrol

Case Study: Drug safety profiling collaboration with Takeda Pharmaceuticals  

The aProximate™ model has been used in a collaborative study with Takeda Pharmaceuticals designed to assess drug safety as part of a collaborative series of kidney nephrotoxicity assays. The study evaluated 36 known drugs and 9 new drugs (Takeda’s internal candidate compounds) using aProximate™ PTCs.

Why aProximate™?

The model allows the detection of FDA qualified kidney-specific injury biomarkers, such as KIM-1, NGAL and Clusterin, confirming that it is a reliable tool to assess PTC toxicity and evaluate renal drug safety during drug discovery.

Results

Four out of six toxic compounds and two out of three non-toxic compounds were correctly identified using human aProximate™ PTCs. The predictivity of in vivo outcomes using the aProximate™ PTCs was achieved with 60% sensitivity and 93% specificity

Conclusion

aProximate™ is an ideal in vitro model for the prediction of new drugs safety profiles and PTC toxicity in vivo.  

Kidney nephrotoxicity assays
Hight content comparison of two compounds for drug safety prediction using the aProximate™ platform indicating a possible nephrotoxic effect for compound B with increased levels of injury biomarkers and decrease of non-specific injury end points. Compound A is predicted as no toxic. 
In vivo nephrotoxicity prediction using the aProximate™ PTCs was achieved with 60% sensitivity and 93% specificity as shown by the overall analysis of the 36 compounds. Adapted from Baja et al., (2020).

Newcells aProximate™ platformDe-risk your drug discovery pipeline

Accelerate your research with a reliable and consistent supply of proximal tubule cells validated for drug safety & efficacy as well and drug transporter assays. The highly predictive platform provides detailed mechanistic insights into drug handling.  
Using in vitro aProximate™ platform accelerates and de-risk drug discovery and reduces the requirement for animal experiments for investigational studies of the kidney. 

aProximate™ The most advanced near-physiological high throughput kidney proximal tubule cell (PTC) model.

Recapitulates Proximal tubule physiology

  • Expression of all key renal transporters 
  • High throughput solution for industry 
  • Outperforms competitor in vitro models 
  • FDA approved kidney biomarkers 
  • Enables mitochondrial health monitoring 

Have any questions? Check out our Frequently Asked Questions.

RESOURCES:  

In vitro models for accurate prediction of renal tubular xenobiotic transport in vivo . Vriend J. et al., Current Opinion in Toxicology, 2021, Vol 25,2021,Pages 15-22,ISSN 2468-2020, https://doi.org/10.1016/j.cotox.2020.12.001. 

Freshly isolated primary human proximal tubule cells as an in vitro model for the detection of renal tubular toxicity. Bajaj et al., Toxicology. 2020 Sep;442:152535. doi: 10.1016/j.tox.2020.152535. Epub 2020 Jul 2.  

in vitro platforms for de risking nephrotoxicity during drug development, Brown and Primrose, Drug Target Review, Sept 20200 

Derivation of a System-Independent Ki for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC50 Data. Chaudhry A, et al., Drug Metab Dispos. 2018 Mar;46(3):279-290. doi: 10.1124/dmd.117.075606. Epub 2018 Jan 9.  

Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling Brown CD et al.,  Toxicol Appl Pharmacol. 2008 Dec 15;233(3):428-38. doi: 10.1016/j.taap.2008.09.018. Epub 2008 Oct 1. PMID: 18930752. 

Abundance of Drug Transporters in the Human Kidney Cortex as Quantified by Quantitative Targeted Proteomics. Prasad B,. etal., Drug Metab Dispos. 2016 Dec;44(12):1920-1924. doi: 10.1124/dmd.116.072066. Epub 2016 Sep 12.  

Predictive in vitro primary proximal tubule models for understanding nephrotoxicity in drug develppment programs.  Brown C., March 2020, Webinar  

Reducing compound attrition by predicting renal tubular toxicity with in vitro PTEC models. Brown C., Sept 2020 , Webinar