(M-105) Sex differences in patients with chronic kidney disease: A quantitative systems pharmacology modeling study

Anita Layton, Ph.D. – Professor, Applied Mathematics, Computer Science, Pharmacy, and Biology, University of Waterloo

Objectives: Chronic kidney disease (CKD) is a global health concern, impacting about 10-15% of the world’s population. Among patients with CKD, there are sex differences in both the prevalence and pathophysiological profiles, with women being more affected than men [1]. While quantitative systems pharmacology (QSP) models have proven to be valuable tools in studying calcium-phosphate regulation and bone health in CKD patients [2,3], these models have yet to consider the impact of sex differences. Our study addresses this gap by developing the first sex-specific QSP models of calcium-phosphate regulation in patients with CKD. Using these models, we quantify how sex differences impact patients with CKD as well as predict clinical outcomes while considering sex as a biological variable.

Methods: We developed sex-specific QSP models of calcium-phosphate homeostasis which describe changes in plasma phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) as well as bone remodeling during CKD progression in males versus females. Our models are based on existing sex-specific data [1,4] and QSP models [2,3]. Through model simulation and analysis, we quantify how sex differences impact calcium-phosphate homeostasis through CKD progression as well as the clinical impacts of various therapies.

Results: Female susceptibility to hyperphosphatemia can be explained by underlying sex differences in pathophysiological profiles of patients with CKD.

Conclusions: Impacts of sex differences in pathophysiological profiles of patients with CKD are unraveled using mathematical modeling.

Citations: [1] Wyld, Melanie L. R., Nicole L. De La Mata, Andrea Viecelli, et al. 2022. “Sex-Based Differences in Risk Factors and Complications of Chronic Kidney Disease.” Seminars in Nephrology, Sex and Gender in Kidney Health and Disease, 42 (2): 153–69.
[2] Peterson, Mark C., and Matthew M. Riggs. 2010. “A Physiologically Based Mathematical Model of Integrated Calcium Homeostasis and Bone Remodeling.” Bone 46 (1): 49–63.
[3] Gaweda, Adam E., Devin E. McBride, et al. 2021. “Development of a Quantitative Systems Pharmacology Model of Chronic Kidney Disease: Metabolic Bone Disorder.” American Journal of Physiology-Renal Physiology 320 (2): F203–11.
[4] Feldman, Harold I., Lawrence J. Appel, et al. 2003. “The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods.” Journal of the American Society of Nephrology 14.