The role of venous capacity in fluid retention with endothelin A antagonism: Mathematical modelling of the RADAR trial.

Autor: Yu H; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA., Greasley PJ; Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Lambers Heerspink HJ; Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, The Netherlands.; The George Institute for Global Health, Sydney, Australia., Ambery P; Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Ahlstrom C; Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Hamren B; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Khan AA; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA., Boulton DW; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA., Hallow KM; School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia, USA.; Department of Epidemiology and Biostatistics, University of Georgia, Athens, Georgia, USA.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Nov; Vol. 181 (22), pp. 4693-4707. Date of Electronic Publication: 2024 Aug 19.
DOI: 10.1111/bph.16504
Abstrakt: Background and Purpose: Endothelin-1 (ET-1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging.
Approach: We utilized a previously developed mathematical model of ET-1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR).
Background and Key Results: An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR.
Conclusions and Impact: These findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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