LAUSR

AIMS Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness. METHODS AND RESULTS We conducted a prospective, observational study of fifty patients with acute heart failure patients divided into two groups based on previous furosemide use: furosemide naïve n=28 (56%) and chronic furosemide users n=22 (44%). Each patient received a protocol-derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints, all p<0.05. Urine furosemide delivery was similar in furosemide naïve vs. chronic users after accounting for differences in eGFR: 28.02 [21.03-35.89] vs 29.70 [18.19-34.71] mg, respectively, p=0.87. However, the tubular response to delivered diuretic was dramatically higher in naïve vs. chronic users, i.e.: the urine volume per 1μg/ml of urine furosemide at 2h was: 148.6±136.1 vs 50.6±56.1 ml, p=0.005. CONCLUSIONS Patients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery.