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\begin{document}

\title{The role of venous capacity in fluid retention with Endothelin A
antagonism: Mathematical modeling of the RADAR trial}



\author[1]{Hongtao Yu}%
\author[2]{Peter Greasley}%
\author[3]{Hiddo Lambers Heerspink}%
\author[2]{Philip Ambery}%
\author[2]{Christine Ahlstrom}%
\author[2]{Bengt Hamren}%
\author[1]{Anis Khan}%
\author[1]{David Boulton}%
\author[4]{Melissa  Hallow}%
\affil[1]{AstraZeneca US}%
\affil[2]{AstraZeneca R\&D}%
\affil[3]{University of Groningen}%
\affil[4]{University of Georgia}%


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  \date{May 17, 2024}


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\begin{abstract}
Background and Purpose: Endothelin-1 (ET1) receptor A (ETA) antagonists
reduce proteinuria and prevent renal outcomes in patients with chronic
kidney disease (CKD), but their utility has been limited because of
associated fluid retention and increased heart failure risk in patients
with left ventricular dysfunction. Understanding mechanisms of fluid
retention could result in solutions that preserve their 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 antagonism, kidney function, and sodium and
water homeostasis to evaluate mechanistic hypotheses 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 model's ability to predict observed decreases in hematocrit, urine
albumin creatinine ratio (UACR), mean arterial pressure (MAP) and
estimated glomerular filtration rate (eGFR). 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 hematocrit observed in RADAR.
Conclusions and impact: These findings indicate that fluid retention
with ETA antagonism may not be caused by a direct anti-diuresis effect
within the kidney, but may 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.%
\end{abstract}%



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\textbf{Hosted file}

\verb`RADAR manuscript_Final.docx`  available at \url{https://authorea.com/users/696478/articles/684818-the-role-of-venous-capacity-in-fluid-retention-with-endothelin-a-antagonism-mathematical-modeling-of-the-radar-trial}

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