Browsing by Author "Ruiz-Hurtado, Gema"

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    Effect of finerenone on ambulatory blood pressure in chronic kidney disease in type 2 diabetes
    (Wolters Kluwer, 2023) Agarwal, Rajiv; Ruilope, Luis M.; Ruiz-Hurtado, Gema; Haller, Hermann; Schmieder, Roland E.; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Rossing, Peter; Lambelet, Marc; Nowack, Christina; Kolkhof, Peter; Joseph, Amer; Bakris, George L.; Medicine, School of Medicine
    Objective: Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist with a short half-life. Its effects on cardiorenal outcomes were thought to be mediated primarily via nonhemodynamic pathways, but office blood pressure (BP) measurements were insufficient to fully assess hemodynamic effects. This analysis assessed the effects of finerenone on 24-h ambulatory BP in patients with chronic kidney disease and type 2 diabetes. Methods: ARTS-DN (NCT01874431) was a phase 2b trial that randomized 823 patients with type 2 diabetes and chronic kidney disease, with urine albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate of 30-90 ml/min per 1.73 m2 to placebo or finerenone (1.25-20 mg once daily in the morning) administered over 90 days. Ambulatory BP monitoring (ABPM) over 24 h was performed in a subset of 240 patients at screening, Day 60, and Day 90. Results: Placebo-adjusted change in 24-h ABPM systolic BP (SBP) at Day 90 was -8.3 mmHg (95% confidence interval [CI], -16.6 to 0.1) for finerenone 10 mg (n = 27), -11.2 mmHg (95% CI, -18.8 to -3.6) for finerenone 15 mg (n = 34), and -9.9 mmHg (95% CI, -17.7 to -2.0) for finerenone 20 mg (n = 31). Mean daytime and night-time SBP recordings were similarly reduced and finerenone did not increase the incidence of SBP dipping. Finerenone produced a persistent reduction in SBP over the entire 24-h interval. Conclusions: Finerenone reduced 24-h, daytime, and night-time SBP. Despite a short half-life, changes in BP were persistent over 24 h with once-daily dosing in the morning.
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    Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease
    (Elsevier, 2022) Yanucil, Christopher; Kentrup, Dominik; Campos, Isaac; Czaya, Brian; Heitman, Kylie; Westbrook, David; Osis, Gunars; Grabner, Alexander; Wende, Adam R.; Vallejo, Julian; Wacker, Michael J.; Navarro-Garcia, Jose Alberto; Ruiz-Hurtado, Gema; Zhang, Fuming; Song, Yuefan; Linhardt, Robert J.; White, Kenneth; Kapiloff, Michael S.; Faul, Christian; Medical and Molecular Genetics, School of Medicine
    Fibroblast growth factor (FGF) 23 is a phosphate-regulating hormone that is elevated in patients with chronic kidney disease and associated with cardiovascular mortality. Experimental studies showed that elevated FGF23 levels induce cardiac hypertrophy by targeting cardiac myocytes via FGF receptor isoform 4 (FGFR4). A recent structural analysis revealed that the complex of FGF23 and FGFR1, the physiologic FGF23 receptor in the kidney, includes soluble α-klotho (klotho) and heparin, which both act as co-factors for FGF23/FGFR1 signaling. Here, we investigated whether soluble klotho, a circulating protein with cardio-protective properties, and heparin, a factor that is routinely infused into patients with kidney failure during the hemodialysis procedure, regulate FGF23/FGFR4 signaling and effects in cardiac myocytes. We developed a plate-based binding assay to quantify affinities of specific FGF23/FGFR interactions, and found that soluble klotho and heparin mediate FGF23 binding to distinct FGFR isoforms. Heparin specifically mediated FGF23 binding to FGFR4, and increased FGF23 stimulatory effects on hypertrophic growth and contractility in isolated cardiac myocytes. When repetitively injected into two different mouse models with elevated serum FGF23 levels, heparin aggravated cardiac hypertrophy. We also developed a novel procedure for the synthesis and purification of recombinant soluble klotho, which showed anti-hypertrophic effects in FGF23-treated cardiac myocytes. Thus, soluble klotho and heparin act as independent FGF23 coreceptors with opposite effects on the pathologic actions of FGF23, with soluble klotho reducing and heparin increasing FGF23-induced cardiac hypertrophy. Hence, whether heparin injections during hemodialysis in patients with extremely high serum FGF23 levels contribute to their high rates of cardiovascular events and mortality remains to be studied.