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 S. Filippatos, Marco Metra, Nilesh J. Samani, Piotr Ponikowski, Leong L. Ng, Adriaan A. Voors, Jozine M. ter Maaten (Lead / Corresponding author)

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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; P50.04) 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; P50.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P50.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P50.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P50.004) 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.

Original languageEnglish
Pages (from-to)228-239
Number of pages12
JournalClinical Journal of the American Society of Nephrology
Volume17
Issue number2
Early online date7 Feb 2022
DOIs
Publication statusPublished - Feb 2022

Keywords

  • proximal tubule
  • heart failure
  • TmP/GFR
  • tubular damage
  • outcome
  • outcomes
  • renal dysfunction

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