Zachary L Cox1,2, Veena S Rao3, Juan B Ivey-Miranda3,4, Julieta Moreno-Villagomez3,5, Devin Mahoney3, Piotr Ponikowski6, Jan Biegus7, Jeffrey M Turner8, Christopher Maulion3, Lavanya Bellumkonda3, Jennifer L Asher9, Helen Parise3, Perry F Wilson10, David H Ellison11, Christopher S Wilcox12, Jeffrey M Testani3. 1. Department of Pharmacy Practice, Lipscomb University College of Pharmacy, 1 University Park Drive, Nashville, TN 37204, USA. 2. Department of Pharmacy, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA. 3. Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, 135 College Street, Suite 230, New Haven, CT 06510, USA. 4. Hospital de Cardiologia, Instituto Mexicano del Seguro Social, 330 Cuauhtemoc Avenue. Cuauhtemoc, Mexico City 06720, Mexico. 5. Universidad Nacional Autónoma de México, Avenida Insurgentes Sur, Mexico City 3000, Mexico. 6. Department of Heart Diseases, Wrocław Medical University, Rektorat, wybrzeże Ludwika Pasteura 1, Wroclaw 50-367, Poland. 7. Clinical Military Hospital, Weigla 5, Wroclaw 50-981, Poland. 8. Department of Medicine, Division of Nephrology, Yale University School of Medicine, 135 College Street, Suite 230, New Haven, CT 06510, USA. 9. Department of Comparative Medicine, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, USA. 10. Clinical and Translational Research Accelerator, Yale University School of Medicine, 60 Temple Street, New Haven, CT 06520, USA. 11. Oregon Clinical and Translational Research Institute, Oregon Health and Science University and the Veterans Affairs Portland Health Care System, 3181 S.W. Sam Jackson Park Road Portland, OR 97239, USA. 12. Division of Nephrology and Hypertension and Hypertension Center, Georgetown University, 3800 Reservoir Road, N.W., Washington, DC 20007, USA.
Abstract
AIMS: In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. METHODS AND RESULTS: Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13-17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47). CONCLUSION: On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. METHODS AND RESULTS: Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13-17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47). CONCLUSION: On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF. Published on behalf of the European Society of Cardiology. All rights reserved.
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