Abstract 2731: The Effect of KW-3902, an Adenosine A1 Receptor Antagonist, on Renal Function and Renal Plasma Flow in Subjects With Heart Failure and Renal Impairment: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study
Background: Patients with heart failure (HF) typically have coexisting renal impairment that may result in part from activation of tubuloglomerular feedback (TGF), a negative feedback mechanism, mediated by adenosine and the adenosine A1 receptor. TGF results in decreased renal plasma flow (RPF) and glomerular filtration rate (GFR), making HF management more challenging. This study examined whether the adenosine A1 receptor antagonist, KW-3902, would reverse TGF and thereby improve RPF and GFR in patients with HF compared to placebo in the presence of furosemide.
Methods: 23 HF outpatients with estimated GFR of 30 – 80 mL/min, taking ≥ 80 mg/day furosemide, were studied twice at least 3 days apart. Infusions of iothalamate (for GFR) and para-amino-hippurate (for RPF) were administered over 3 hours before and 8 hours after receiving KW-3902 or placebo plus 80 mg IV furosemide. Urine and plasma were collected for GFR and RPF at baseline and 2, 4, and 8 hours.
Results: Mean GFR at baseline was 61 mL/min. Time between study periods was a median of 6 days. Urine volume over 8 hours was greater during the KW-3902 plus furosemide (2995.1 ± 1138.17mL) than placebo plus furosemide (2535.7 ± 1159.35 mL). In the subgroup of patients who received KW-3902 on the first visit, the increase in GFR noted at 8 hours was seen to persist at the time of follow-up baseline (median 6 days).
Conclusions: These results demonstrate that the adenosine A1 antagonist, KW-3902 produces a statistically significant increase in GFR in HF patients with renal impairment treated with diuretics and this increase in GFR is accompanied by a substantial increase in RPF, the likely mechanism whereby GFR is improved. This effect may persist for days after a single dose. Such profound changes in renal function may translate into clinical benefit when renal impairment limits HF therapy.