Sangita Swapnasrita

Computational models of peritoneal dialysis (PD) are increasingly useful for optimizing treatment in patients with kidney disease requiring dialysis (KDRD). However, although several mathematical models have been developed in the past few decades, a direct comparison of the models’ accuracy with respect to predicting in vivo data is needed to further create robust personalized models. Here, we used a dataset obtained in a previous in vivo experimental model of PD in pigs (23 sessions of 4 h 2 L dwells in four pigs) and humans (20 sessions in 20 patients) to compare six computational models of PD: the Graff model (UGM), the three-pore model (TPM), the Garred model (GM), and the Waniewski model (WM), as well as two variations of these (UGM-18, SWM). We conducted this comparison to predict the dialysate concentrations of key uremic toxins and electrolytes (four in humans) throughout a 4 h dwell. The model predictions can provide insight into inter-individual differences in ultrafiltration, which are critical for tailoring PD regimens in KDRD. While TPM offered improved physiological reality, its computational cost suggests a trade-off between model complexity and clinical applicability for real-time or portable kidney support systems. In future applications, such models could provide adaptive PD regimens for tailored care based on patient-specific toxin kinetics and fluid dynamics.

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.

The authors have done a targeted steady state model of glucose homeostasis in the brain with an underlying diabetes condition. As has been pointed out by the author, the most popular models are entangled in a loop, where proper model calibration is m...

In vitro models play a crucial role in advancing our understanding of biological processes, disease mechanisms, and developing screening platforms for drug discovery. Kidneys play an instrumental role in transport and elimination of drugs and toxins. However, despite the well-established patient-to-patient differences in kidney function and disease manifestation, progression and prognostic, few studies take this variability into consideration. In particular, the discrepancies between female and male biology warrants a better representation within kidney in vitro models. The omission of sex as a biological variable poses the significant risk of overlooking sex-specific mechanisms in health and disease and potential differences in drug efficacy and toxicity between males and females. This review aims to highlight the importance of incorporating sex dimorphism in kidney in vitro models by examining the sexual characteristics in the context of the current state-of-the-art. Furthermore, this review underscores opportunities for improving kidney models by incorporating sex-specific traits. Ultimately, this roadmap to incorporating sex-dimorphism in kidney in vitro models will facilitate the creation of better models for studying sex-specific mechanisms in the kidney and their impact on drug efficacy and safety.

The kidney plays an essential role in homeostasis, accomplished through the regulation of pH, electrolytes and fluids, by the building blocks of the kidney, the nephrons. One of the important markers of the proper functioning of a kidney is the glomerular filtration rate. Diabetes is characterized by an enlargement of the glomerular and tubular size of the kidney, affecting the afferent and efferent arteriole resistance and hemodynamics, ultimately leading to chronic kidney disease. We postulate that the diabetes-induced changes in kidney may exhibit significant sex differences as the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, and (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes. The simulation results indicate that diabetes enhances Na⁺ transport, especially along the proximal tubules and thick ascending limbs, to similar extents in male and female patients, which can be explained by the diabetes-induced increase in glomerular filtration rate. Additionally, we conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Model simulations also suggest that SGLT2 inhibition raises luminal [Cl^–] at the macula densa, twice as much in males as in females, and could indicate activation of the tubuloglomerular feedback signal. By inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis. Those effects on urinary excretion are blunted in women, in part due to their higher distal transport capacity.

The kidney plays an essential role in homeostasis, accomplished through the regulation of pH, electrolytes and fluids, by the building blocks of the kidney, the nephrons. One of the important markers of the proper functioning of a kidney is the glomerular filtration rate. Diabetes is characterised by an enlargement of the glomerular and tubular size of the kidney, affecting the afferent and efferent arteriole resistance and hemodynamics, ultimately leading to chronic kidney disease. We postulate that the diabetes-induced changes in kidney may exhibit significant sex differences as the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, and (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes. The simulation results indicate that diabetes enhances Na ⁺ transport, especially along the proximal tubules and thick ascending limbs, to similar extents in male and female patients, which can be explained by the diabetes-induced increase in glomerular filtration rate. Additionally, we conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Model simulations also suggest that SGLT2 inhibition, which constricts the afferent arteriole to attenuate glomerular hyperfiltration, can then limit Na ⁺ -glucose transport, consequently raising luminal [Cl ^- ] at the macula densa and finally restoring the tubuloglomerular feedback signal. By inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis. Those effects on urinary excretion are blunted in women, in part due to their higher distal transport capacity.