ABSTRACT
INTRODUCTION: Diuretic resistance is a common complication impairing decongestion during hospitalization for acute decompensated heart failure (ADHF). The current understanding of diuretic resistance mechanisms in ADHF is based upon extrapolations from other disease states and healthy volunteers. However, accumulating evidence suggests that the dominant mechanisms in other populations have limited influence on diuretic response in ADHF. Additionally, the ability to rapidly and reliably diagnose diuretic resistance is inadequate using currently available tools. AIMS: The Mechanisms of Diuretic Resistance (MDR) Study is designed to rigorously investigate the mechanisms of diuretic resistance and develop tools to rapidly predict diuretic response in a prospective cohort hospitalized with ADHF. METHODS: Study assessments occur serially during the ADHF hospitalization and after discharge. Each assessment includes a supervised 6-hour urine collection with baseline blood and timed spot urine collections following loop diuretic administration. Patient characteristics, medications, physical exam findings, and both in-hospital and post-discharge HF outcomes are collected. Patients with diuretic resistance are eligible for a randomized sub-study comparing an increased loop diuretic dose with combination diuretic therapy of loop diuretic plus chlorothiazide. CONCLUSIONS: The Mechanisms of Diuretic Resistance Study will establish a prospective patient cohort and biorepository to investigate the mechanisms of diuretic resistance and urine biomarkers to rapidly predict loop diuretic resistance.
ABSTRACT
BACKGROUND: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-ß-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. METHODS: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. RESULTS: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-ß-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-ß-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-ß-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001). CONCLUSIONS: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.
