Using human iPSC-Derived Renal Cells to enhance safety toxicity testing during drug development
Kidneys play a key role in removing waste and toxins from the body, as well as having essential endocrinological and homeostatic functions. If certain pharmaceuticals are abused, administered incorrectly or taken regularly, they can induce toxicity in the kidneys (nephrotoxicity). This can result in impaired renal function, and even death in the most severe cases. For example, nephrotoxic drugs (NDs) are responsible for 19-25% of acute kidney injury in critically ill patients .
Given this global health risk, nephrotoxicity assessments are crucial during drug development . Predicting nephrotoxicity has traditionally relied on organism-level responses in laboratory animals. But the many drawbacks of this approach are now widely recognized, particularly the need to adjust for differences in how humans and animal models respond to nephrotoxic agents.
There is now a drive towards developing toxicity assays that measure the responses of human cells or cell lines to drug candidates in vitro , by using high-throughput tests and robotic assistance ( National Academy of Sciences/National Research Council, 2007 ). Recent advances in stem cell biology, including the development of renal cells and tissues derived from human induced pluripotent stem cells (hiPSCs), are enabling great strides towards this goal.
Read on to find out how recently developed hiPSC-derived Renal Proximal Tubular Cells can revolutionize toxicity screening during drug development, by providing ready-to-use, physiologically relevant in vitro renal cell cultures that accurately predict the nephrotoxicity of your drug candidates.
Screening for nephrotoxic drugs: From animal models to stem cells
Identifying nephrotoxic agents during drug development has historically been challenging. The animal models used to assess the nephrotoxicity of a drug candidate do not fully translate to the human cellular response, limiting their predictivity. Recent advances in stem cell biology in the last five years have enabled the development of more physiologically relevant in vitro renal cell models that offer much higher levels of predictivity.
Renal proximal tubular cells (PTCs) form a major part of the main functional part of the kidney (the nephron) and are frequently affected by drug-induced toxicity. A recent study showed how human primary PTCs differentiated from human embryonic stem cells (hESCs) could detect compounds that cause nephrotoxicity and injure the kidney . Compared to primary PTCs, hESC-derived renal PTC-like cells took 20 days to differentiate and exhibited relatively low sensitivity, limiting their application.
This ignited the development of new protocols enabling the differentiation of renal PTCs from hiPSCs . These protocols now provide a more efficient way of sourcing high-quality renal cells that accurately recapitulate human kidney function, primarily for disease modelling and regenerative medicine. Only very recently have hiPSC-derived renal PTCs been applied to compound screening, offering exciting opportunities to enhance nephrotoxicity testing during drug development.
How are human iPSC-derived Renal Proximal Tubular Cells enhancing safety toxicity testing?
A recent study demonstrated that human iPSCs could be differentiated into PTC-like cells with a high level of purity. Following this protocol enabled the researchers to begin compound screening without needing to perform cell harvesting or purification. Crucially, the researchers found that combining the in vitro hiPSC-based renal model with machine learning methods enabled them to predict drug-induced proximal tubular toxicity in humans with 87% (test) accuracy .
This research suggests that using hiPSC-derived renal PTCs offers a highly sensitive nephrotoxicity screening assay for your drug development research. Axol has developed the first hiPSC-Derived Renal PTCs that are ready to use after arriving at the bench (just four days after thawing). This offers you a guaranteed supply of high-quality human-relevant renal cells for more reliable and efficient in vitro safety toxicity testing.
Expression of the ZO-1, URO10, Na+/K+ ATPase and GLUT1 proteins were confirmed in Axol iPSC-derived Renal Proximal Tubular Cells using immunocytochemistry (A, B, C and D).
Applying hiPSC-derived Renal PTCs to your toxicity assessments can also help you identify underlying injury mechanisms and drug-induced cellular pathways, enable automated cellular imaging to efficiently analyse larger numbers of compounds, and develop novel personalized patient-specific therapies.
Nephrotoxicity assessments are evidently moving away from animal models towards more physiologically relevant human cell-based assays. Novel stem cell-based technologies can benefit your safety toxicity testing by providing renal cells of human origin that have the potential to predict drug-induced nephrotoxicity. Now that ready-to-use hiPSC-derived Renal PTCs are available for the first time, it is now easier than ever before to boost the reliability and efficiency of your toxicity tests.
