Abstract
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. 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. 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. 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.
Highlights
The glomerular filtration rate is a crucial parameter in heart failure
Lower tubular maximum phosphate reabsorption capacity (TmP/glomerular filtration rate (GFR)) was independently associated with higher risk of plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) doubling (OR 2.20(1.05–4.66), P=0.038), but not with deterioration of kidney function
Lower TmP/GFR is associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function
Summary
The glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the impact of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure. Many studies have addressed the cardiorenal syndrome, but almost exclusively focused on glomerular filtration rate (GFR). Much less is known about prevalence, predictors, and clinical outcome of tubular function in patients with heart failure.[3,4]. Since proximal tubular function is of vital importance for sodium handling of the kidney, sodium retention, and diuretic response, it is of great relevance to patients with heart failure.[4,5]. Recent studies have drawn attention to the proximal tubule by showing that sodium-glucose cotransporter 2(SGLT2)-inhibitors improve outcomes in patients with heart failure with reduced ejection fraction.[6,7]. The tubular maximum phosphate reabsorption capacity (TmP/GFR) indicates the maximum capacity of the kidney to reabsorb phosphate in the proximal tubule independent of GFR and net inflow of phosphate.[8,9]. We aimed to study the clinical value of TmP/GFR and investigate effects of SGLT2-inhibition on TmP/GFR in heart failure
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