Johanna E Emmens1, Martin H de Borst2, Eva M Boorsma1, Kevin Damman1, Gerjan Navis2, Dirk J van Veldhuisen1, Kenneth Dickstein3,4, Stefan D Anker5,6, Chim C Lang7, Gerasimos Filippatos8, Marco Metra9, Nilesh J Samani10,11, Piotr Ponikowski12,13, Leong L Ng10,11, Adriaan A Voors1, Jozine M Ter Maaten14. 1. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Department of Clinical Sciences, University of Bergen, Bergen, Norway. 4. Stavanger University Hospital, Stavanger, Norway. 5. Department of Cardiology and Berlin-Brandenburg Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany. 6. Department of Cardiology and Pneumology, University Medical Center Goettingen, Goettingen, Germany. 7. School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom. 8. Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. 9. Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 10. Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. 11. National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom. 12. Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland. 13. Cardiology Department, Military Hospital, Wroclaw, Poland. 14. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands j.m.ter.maaten@umcg.nl.
Abstract
BACKGROUND AND OBJECTIVES: The estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance. RESULTS: Low TmP/GFR (<0.80 mmol/L) was observed in 1392 (67%) and 21 (27%) patients. Patients with lower TmP/GFR had more advanced heart failure, lower eGFR, and higher levels of tubular damage markers. The main determinant of lower TmP/GFR was higher fractional excretion of urea (P<0.001). Lower TmP/GFR was independently associated with higher risk of plasma NGAL doubling (odds ratio, 2.20; 95% confidence interval, 1.05 to 4.66; P=0.04) but not with deterioration of kidney function. Lower TmP/GFR was associated with higher risk of all-cause mortality (hazard ratio, 2.80; 95% confidence interval, 1.37 to 5.73; P=0.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P=0.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P=0.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P=0.004) but not after adjustment for eGFR change. CONCLUSIONS: TmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.
BACKGROUND AND OBJECTIVES: The estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance. RESULTS: Low TmP/GFR (<0.80 mmol/L) was observed in 1392 (67%) and 21 (27%) patients. Patients with lower TmP/GFR had more advanced heart failure, lower eGFR, and higher levels of tubular damage markers. The main determinant of lower TmP/GFR was higher fractional excretion of urea (P<0.001). Lower TmP/GFR was independently associated with higher risk of plasma NGAL doubling (odds ratio, 2.20; 95% confidence interval, 1.05 to 4.66; P=0.04) but not with deterioration of kidney function. Lower TmP/GFR was associated with higher risk of all-cause mortality (hazard ratio, 2.80; 95% confidence interval, 1.37 to 5.73; P=0.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P=0.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P=0.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P=0.004) but not after adjustment for eGFR change. CONCLUSIONS: TmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.
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Authors: Adriaan A Voors; Stefan D Anker; John G Cleland; Kenneth Dickstein; Gerasimos Filippatos; Pim van der Harst; Hans L Hillege; Chim C Lang; Jozine M Ter Maaten; Leong Ng; Piotr Ponikowski; Nilesh J Samani; Dirk J van Veldhuisen; Faiz Zannad; Aeilko H Zwinderman; Marco Metra Journal: Eur J Heart Fail Date: 2016-04-29 Impact factor: 15.534
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