IMPACT OF POLYPHARMACY ON KIDNEY FUNCTION: AGE- AND SEX-DEPENDENT EFFECTS IN A MOUSE MODEL

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Abstract Title *

IMPACT OF POLYPHARMACY ON KIDNEY FUNCTION: AGE- AND SEX-DEPENDENT EFFECTS IN A MOUSE MODEL

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Co-author 1

Yuting Zhang yzha9156@uni.sydney.edu.au Kolling Institute, Faculty of Medicine and Health, the University of Sydney Renal Laboratory Sydney, NSW Australia *

Co-author 2

Kevin Winardi kevin.winardi@sydney.edu.au Kolling Institute, Faculty of Medicine and Health, the University of Sydney Laboratory of Ageing and Pharmacology Sydney, NSW Australia -

Co-author 3

John Mach john.mach@sydney.edu.au Kolling Institute, Faculty of Medicine and Health, the University of Sydney Laboratory of Ageing and Pharmacology Sydney, NSW Australia -

Co-author 4

Sarah Hilmer sarah.hilmer@sydney.edu.au Kolling Institute, Faculty of Medicine and Health, the University of Sydney Laboratory of Ageing and Pharmacology Sydney, NSW Australia -

Co-author 5

Xin-Ming Chen xin-ming.chen@sydney.edu.au Kolling Institute, Faculty of Medicine and Health, the University of Sydney Renal Laboratory Sydney, NSW Australia -

Co-author 6

Carol Pollock carol.pollock@sydney.edu.au Kolling Institute, Faculty of Medicine and Health, the University of Sydney Renal Laboratory Sydney, NSW Australia -

Co-author 7

Chunling Huang chunling.huang@sydney.edu.au Kolling Institute, Faculty of Medicine and Health, the University of Sydney Renal Laboratory Sydney, NSW Australia -

Co-author 8

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

Polypharmacy refers to the concurrent use of five or more medications, which is common in older patients and those with chronic kidney disease due to the high prevalence of multimorbidity. Polypharmacy has been shown to disrupt normal cardiac and hepatic functions. However, its impact on kidneys remains uncertain and may vary across age and sex cohorts. This study aimed to investigate the impact of polypharmacy on kidneys and to explore potential age- or sex-polypharmacy interactions in a mouse model.

Methods

Young (4 months) and old (23 months) male and female C57BL/6 mice were randomly allocated to a control or a polypharmacy group receiving the combination of simvastatin, metoprolol, oxybutynin, citalopram, and oxycodone at therapeutic oral doses for 10 weeks. Urinary albumin to creatinine ratio (UACR), as well as fibrosis, inflammation and cellular senescence-related markers were assessed.

Results

Compared to control, UACR was not affected by polypharmacy. However, mRNA expression of fibrotic markers fibronectin (P<0.05) and type 1 collagen (P<0.01), inflammatory markers TGF-β1 (P<0.01) and F4/80 (P<0.01), and cellular senescence marker p53 (P<0.01) and p21 (P<0.05) were significantly increased in animals that received polypharmacy, irrespective of their age and sex. Furthermore, an interaction between polypharmacy and age was observed in p21 expression (P<0.05), with old mice showing a significantly greater upregulation compared to young mice. In addition, a polypharmacy-sex interaction was also found in type 1 collagen (P<0.01), with male mice having a more pronounced increase than the females.

Conclusion

Given the absence of change in UACR, polypharmacy likely contributes to kidney fibrosis via interstitial rather than glomerular pathology, promoting inflammation and cellular senescence at the molecular scale. Its impact differs across age and sex cohorts, with the old male exhibiting more polypharmacy-induced impairment in kidney biological markers.

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