The kidney proximal tubule (PT) is a principal site of nutrient and electrolyte reabsorption, metabolism, and clearance of drugs and toxins. However, owing to its high mitochondrial content, exposure to concentrated filtrate, and dense expression of broad transporters, such as organic cation tranporters, organic anion tranporters, multidrug and toxin extrusion proteins, and ATP-binding cassette superfamily members, the PT is particularly vulnerable to nephrotoxic injury arising from xenobiotic-induced damage. Accurate models are essential for predicting nephrotoxicity and drug–drug interactions. However, traditional animal models and 2D PT cell cultures have faced barriers such as limited human-relevance, dedifferentiation, and PT segment–specific identity, presenting challenges for their translational utility. Recent advances in 3D culture systems, perfusion, kidney-on-chip platforms, and pluripotent stem cell technologies have sought to restore physiological relevance and native architecture, improving functional transporter expression and nephrotoxic injury responses. Emerging stem cell–derived kidney organoid strategies to bias engineered tissue towards distinct PT cell types has strengthened this approach. Despite this progress, challenges such as incomplete maturation, variability, throughput, and limited vascular and immune components present ongoing hurdles. This review explores recent developments in PT-specific modelling systems, evaluating their predictive performance for drug-induced injury compared to traditional models, and discusses future directions towards physiologically relevant and scalable platforms for nephrotoxicity assessment.
Kshirsagar et al. (Thu,) studied this question.