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Original ArticleClinical Nephrology
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Assessment of Proximal Tubular Function by Tubular Maximum Phosphate Reabsorption Capacity in Heart Failure

Johanna E. Emmens, Martin H. de Borst, Eva M. Boorsma, Kevin Damman, Gerjan Navis, Dirk J. van Veldhuisen, Kenneth Dickstein, Stefan D. Anker, Chim C. Lang, Gerasimos Filippatos, Marco Metra, Nilesh J. Samani, Piotr Ponikowski, Leong L. Ng, Adriaan A. Voors and Jozine M. ter Maaten
CJASN February 2022, 17 (2) 228-239; DOI: https://doi.org/10.2215/CJN.03720321
Johanna E. Emmens
1Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Martin H. de Borst
2Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Eva M. Boorsma
1Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Kevin Damman
1Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Gerjan Navis
2Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Dirk J. van Veldhuisen
1Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Kenneth Dickstein
3Department of Clinical Sciences, University of Bergen, Bergen, Norway
4Stavanger University Hospital, Stavanger, Norway
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Stefan D. Anker
5Department of Cardiology and Berlin-Brandenburg Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany
6Department of Cardiology and Pneumology, University Medical Center Goettingen, Goettingen, Germany
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Chim C. Lang
7School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Dundee, United Kingdom
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Gerasimos Filippatos
8Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Marco Metra
9Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
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Nilesh J. Samani
10Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
11National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
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Piotr Ponikowski
12Department of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
13Cardiology Department, Military Hospital, Wroclaw, Poland
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Leong L. Ng
10Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
11National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
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Adriaan A. Voors
1Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Jozine M. ter Maaten
1Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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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.

  • proximal tubule
  • heart failure
  • outcomes
  • renal dysfunction
  • Received March 16, 2021.
  • Accepted November 23, 2021.
  • Copyright © 2022 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 17 (2)
Clinical Journal of the American Society of Nephrology
Vol. 17, Issue 2
February 2022
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Assessment of Proximal Tubular Function by Tubular Maximum Phosphate Reabsorption Capacity in Heart Failure
Johanna E. Emmens, Martin H. de Borst, Eva M. Boorsma, Kevin Damman, Gerjan Navis, Dirk J. van Veldhuisen, Kenneth Dickstein, Stefan D. Anker, Chim C. Lang, Gerasimos Filippatos, Marco Metra, Nilesh J. Samani, Piotr Ponikowski, Leong L. Ng, Adriaan A. Voors, Jozine M. ter Maaten
CJASN Feb 2022, 17 (2) 228-239; DOI: 10.2215/CJN.03720321

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Assessment of Proximal Tubular Function by Tubular Maximum Phosphate Reabsorption Capacity in Heart Failure
Johanna E. Emmens, Martin H. de Borst, Eva M. Boorsma, Kevin Damman, Gerjan Navis, Dirk J. van Veldhuisen, Kenneth Dickstein, Stefan D. Anker, Chim C. Lang, Gerasimos Filippatos, Marco Metra, Nilesh J. Samani, Piotr Ponikowski, Leong L. Ng, Adriaan A. Voors, Jozine M. ter Maaten
CJASN Feb 2022, 17 (2) 228-239; DOI: 10.2215/CJN.03720321
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