Experimental Nephrotoxicity Models for Screening Nephroprotective Agents: Comparative Evaluation, Biomarkers, Translational Relevance, and Emerging Alternatives

Abstract

Background: Nephrotoxicity is a significant contributor to both acute and long-term renal damage, and it continues to be a significant obstacle to the creation of successful nephroprotective treatments. The translation of experimental nephrotoxicity models to human disease may be limited by variations in pathophysiology, biomarkers, pharmacokinetics, and species responses. However, these models are frequently employed to study mechanisms of renal injury and assess possible nephroprotective drugs. Objective: This review aimed to critically evaluate established experimental nephrotoxicity models used for screening nephroprotective agents, compare their pathological and translational relevance, evaluate conventional and emerging biomarkers of renal injury, and assess advanced human-relevant alternatives for improving the predictive value of preclinical nephrotoxicity studies. Methods: Using PubMed/MEDLINE, Scopus, Web of Science, and Embase, a systematic literature search was carried out in accordance with PRISMA 2020 standards. Peer-reviewed English-language research released between 2000 and 2026 was taken into account. Renal damage biomarkers, nephroprotective treatments, experimental nephrotoxicity models, and new nephrotoxicity evaluation platforms were all assessed. A qualitative synthesis was made of pertinent data on nephrotoxicants, model features, mechanisms of injury, biomarkers, histopathological results, and nephroprotective effects. Animal studies were methodologically evaluated using the SYRCLE Risk of Bias tool. Drug-induced, chemical-induced, disease-based, surgical, and advanced in vitro platforms were the categories into which the models were divided. Results: Drug-induced models, particularly cisplatin- and gentamicin-induced nephrotoxicity, provide reproducible systems for investigating acute tubular injury and screening nephroprotective compounds, whereas disease-based models such as diabetic and hypertensive nephropathy better represent chronic and progressive renal injury. Although surgical models offer valuable methods for examining ischemia and obstructive renal injury, they may have drawbacks in terms of clinical extrapolation and technical complexity. While kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin-C, clusterin, osteopontin, microRNAs, proteomic, and metabolomic markers offer complementary information regarding structural, functional, and molecular changes, conventional biomarkers like serum creatinine and blood urea nitrogen have limited sensitivity for early renal injury. Conclusion:Although no single model can accurately replicate the complexities of human kidney disease, experimental nephrotoxicity models are crucial for examining renal damage pathways and evaluating nephroprotective medicines. While disease-based models like diabetic and hypertensive nephropathy are better suited for chronic renal injury, drug-induced models like cisplatin and gentamicin are helpful for acute tubular injury. While KIM-1, NGAL, cystatin-C, and other new molecular biomarkers offer complementary information, conventional biomarkers like blood creatinine and BUN have low sensitivity for early damage. As a result, the particular kind and mechanism of renal injury under investigation should be taken into consideration while choosing models and biomarkers. Future research on nephroprotection should incorporate pharmacokinetic analysis, histopathology, and multimarker evaluation while concentrating on consistent and repeatable experimental procedures. To increase translational relevance and uphold the 3Rs principle, human-relevant techniques such as kidney organoids, 3D cultures, kidney-on-a-chip systems, humanized models, 3D bioprinting, and artificial intelligence-based prediction should be used more frequently. An integrated approach that combines proven biomarkers with complementing animal and human-relevant models may help close the gap between preclinical research and human application and enhance the prediction of clinical nephroprotective efficacy.