The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment

Abstract

Background: The kidney is the only organ in which adenosine is a paracrine vasoconstrictor. This raises the possibility of using adenosine A1 receptor (AA1R) antagonists to selectively vasodilate the kidney in conditions, such as congestive heart failure, in which a selective decrease in renal vascular resistance would be salutary. The present study was undertaken to test the effectiveness of an AA1R antagonist as a renal vasodilator in patients with reduced kidney function superimposed on congestive heart failure.

Methods and results: A randomized, double-blind, placebo-controlled, two-way crossover study was conducted in 32 outpatients with congestive heart failure and renal impairment (median glomerular filtration rate [GFR] 50 mL/min). Baseline GFR and renal plasma flow were assessed by iothalamate and para-amino-hippurate clearances, respectively, 3 hours before treatment. Subjects then received furosemide administered intravenously along with the AA1R antagonist, KW-3902 (rolofylline), or placebo. Clearance measurements were repeated, at intervals, throughout 8 hours beginning with the administration of the study drug. After a washout period of 3 to 8 days, subjects returned to undergo the crossover portion of the study. After the patients received KW-3902, GFR increased by 32% (P < .05 vs. placebo) and renal plasma flow increased by 48% (P < .005 vs. placebo) averaged over the ensuing 8 hours. Furthermore, those subjects who initially received KW-3902 returned for the crossover phase (median 6 days) with a persistent 10 mL/min increase in GFR more than their previous baseline (P < .05).

Conclusions: AA1R activity contributes substantially to renal vascular tone in ambulatory patients with chronic congestive heart failure and impaired kidney function. Blockade of these receptors vasodilates the kidney and increases GFR. The increase in GFR seems to persist several days longer than predicted by pharmacokinetics, suggesting a resetting of one or more controllers among the complex network of physical and biological processes that interact to determine the kidney function. There may be short- or long-term benefits of using AA1R antagonists to improve kidney function in patients with congestive heart failure.

Trial registration: ClinicalTrials.gov NCT00159614.