Embracing sex-specific differences in engineered kidney models for enhanced biological understanding of kidney function.

In vitro models serve as indispensable tools for advancing our understanding of biological processes, elucidating disease mechanisms, and establishing screening platforms for drug discovery. Kidneys play an instrumental role in the transport and elimination of drugs and toxins. Nevertheless, despite the well-documented inter-individual variability in kidney function and the multifaceted nature of renal diseases-spanning from their origin, trigger and which segment of the kidney is affected-to presentation, progression and prognosis, few studies take into consideration the variable of sex. Notably, the inherent disparities between female and male biology warrants a more comprehensive representation within in vitro models of the kidney. The omission of sex as a fundamental biological variable carries the substantial risk of overlooking sex-specific mechanisms implicated in health and disease, along with potential differences in drug responsiveness and toxicity profiles between sexes. This review emphasizes the importance of incorporating cellular, biological and functional sex-specific features of renal activity in health and disease in in vitro models. For that, we thoroughly document renal sex-specific features and propose a strategic experimental framework to integrate sex-based differences into human kidney in vitro models by outlining critical design criteria to elucidate sex-based features at cellular and tissue levels. The goal is to enhance the accuracy of models to unravel renal mechanisms, and improve our understanding of their impact on drug efficacy and safety profiles, paving the way for a more comprehensive understanding of patient-specific treatment modalities.