Impaired kidney function is common and associated with greater risk of poor outcomes in patients with heart failure (1). 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 (2,3). Because 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 (3,4). 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 (5,6).
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 (7,8). As such, TmP/GFR can be considered a parameter of proximal tubular function. In experimental studies, expression of sodium phosphate cotransporters decreased in response to kidney injury, ranging from injury due to ischemia-reperfusion to hereditary kidney diseases, thereby decreasing tubular phosphate reabsorption (9–14). Because of its high rates of oxygen consumption and relatively sparse endogenous antioxidant defenses, the proximal tubule as a whole is particularly vulnerable to injury (15). TmP/GFR of living kidney donors predicts recipient measured GFR independent of donor measured GFR, confirming TmP/GFR as a functional tubular parameter not primarily driven by GFR (16). As such, TmP/GFR might be useful to detect damage and dysfunction of the proximal tubule and investigate its consequences. We therefore aimed to study the clinical value of TmP/GFR and investigate effects of SGLT2 inhibition on TmP/GFR in heart failure.
Materials and Methods
We used the index cohort of a systems Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF), an investigator-driven, multicenter clinical study consisting of 2516 patients with the aim of identifying patients with a poor outcome despite currently recommended treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and β-blockers (17).
Additionally, we evaluated TmP/GFR in the randomized, double-blind, placebo-controlled, multicenter pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF) cohort. The main outcomes have been published (18). In brief, patients hospitalized for acute heart failure treated with (intravenous) loop diuretics were included. Patients were randomly assigned to empagliflozin 10 mg/d or placebo within 24 hours of presentation and treated for 30 days.
Both studies were conducted in accordance with the Declaration of Helsinki, national ethics and legal requirements, and relevant European Union legislation. All participants provided written informed consent for study participation.
Calculations and Biomarker Measurements
TmP/GFR could be calculated in 2085 patients in BIOSTAT-CHF and 78 patients in EMPA-RESPONSE-AHF using the formula described by Payne (7) and originally devised by Bijvoet (19). The study subset did not differ substantially from patients without available TmP/GFR (Supplemental Table 1). First, fractional tubular reabsorption of phosphate (TRP) was calculated:
When TRP was ≤0.86, indicating maximal phosphate reabsorption and a linear relationship between serum phosphate concentration and excretion, TmP/GFR was calculated by
When TRP was >0.86, indicating a curvilinear relationship between serum phosphate concentration and excretion, TmP/GFR was calculated by
Urinary phosphate and other urinary measurements were measured in nonfasting spot urine using standardized methods in both cohorts. The normal reference range of 0.80–1.35 mmol/L for TmP/GFR was derived from data in healthy individuals 65–75 years old (7).
The association between TmP/GFR, doubling of plasma neutrophil gelatinase–associated lipocalin (NGAL) levels, and deterioration of kidney function (>25% eGFR decrease) was analyzed between baseline and 9 months (20,21). Sensitivity analyses were conducted for >30% and >40% eGFR decrease from baseline. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula (22). Presence of CKD was defined as eGFR<60 ml/min per 1.73 m2. After blood was drawn by venipuncture, samples were stored at −80°C. If possible, analyses were performed directly locally with standardized international methods; otherwise, they were performed in a central laboratory. Urinary kidney injury molecule-1 (KIM-1) and NGAL were measured using an in-house developed and validated multiplex immunoassay (xMAP; Luminex, Austin, TX) (23). Measurement of additional biomarkers was performed as previously described (24–26). Endogenous fractional excretion of lithium was measured prior to empagliflozin administration using inductively coupled plasma mass spectrometry in EMPA-RESPONSE-AHF (Supplemental Methods).
Study End Points
The relation of TmP/GFR with all-cause mortality, heart failure hospitalization, and those combined was evaluated. End points were adjusted for BIOSTAT-CHF risk models created for each specific outcome (27).
Data are presented as means±SD when normally distributed, as medians (quartiles 1 to quartile 3) when skewed, and as frequencies (percentages) when categorical, and statistically tested using ANOVA, the Kruskal–Wallis H test, and the chi-squared test, respectively. Trends were tested with the Cochran–Armitage trend test, the Jonckheere–Terpstra test, or linear regression for categorical, skewed variables, and normally distributed variables, respectively.
Determinants of TmP/GFR were analyzed using linear regression. All variables with P=0.10 univariably were included in multivariable analysis and subjected to backward elimination. Variables with P=0.05 were retained in the final multivariable regression model. Prior to linear regression, normal distribution of residuals was checked as well as the presence of outliers. If necessary, variables were transformed using natural logarithm, including TmP/GFR. The association between log TmP/GFR, risk of plasma NGAL doubling, and deterioration of kidney function was evaluated using logistic regression. Results were adjusted for log plasma and urinary NGAL, eGFR, log urine albumin-creatinine ratio (UACR), log KIM-1, log fractional excretion of sodium (FENa), and log fractional excretion of urea (FEUrea). Results are expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). Cox proportional hazard models were constructed to evaluate the prognostic value of log TmP/GFR and adjusted for BIOSTAT-CHF risk models, phosphate, eGFR, and New York Heart Association class. Results are expressed as hazard ratios (HRs) with 95% CIs. Kaplan–Meier plots were constructed using the survminer package. The dendrogram was constructed using the Hmisc package. Analysis of covariance was used to study the effects of empagliflozin versus placebo on TmP/GFR, controlling for baseline TmP/GFR. A two-tailed P=0.05 was considered statistically significant. Statistical analyses were performed with R (version 1.3.1073).
In BIOSTAT-CHF, median TmP/GFR was 0.67 (0.46–0.88) mmol/L. Low TmP/GFR (<0.80 mmol/L) was observed in 1392 (67%) patients. Patients with lower TmP/GFR were older; had lower levels of serum phosphate and higher fractional excretion of phosphate; had lower eGFR; had higher doses of loop diuretics; and had higher levels of N-terminal probrain natriuretic peptide (NT-proBNP), FENa, FEUrea, plasma and urinary NGAL, and UACR (Table 1). Baseline characteristics by median TmP/GFR and presence/absence of CKD are shown in Supplemental Table 2 and according to low, normal, and high TmP/GFR in Supplemental Table 3, the latter yielding similar trends to Table 1.
Table 1. -
Baseline characteristics of the BIOSTAT-CHF index cohort stratified by quartiles of tubular maximum phosphate reabsorption capacity
||Tubular Maximum Phosphate Reabsorption Capacity, mmol/L
|Quartile 1, n=522, 0.32 (0.19–0.40) [Minimum: −0.38, Maximum: 0.46]
||Quartile 2, n=521, 0.57 (0.52–0.62) [Minimum: 0.46, Maximum: 0.67]
||Quartile 3, n=521, 0.77 (0.72–0.82) [Minimum: 0.67, Maximum: 0.88]
||Quartile 4, n=521, 1.06 (0.95–1.25) [Minimum: 0.88, Maximum: 6.81]
| Age, yr
| Sex (men), n (%)
| BMI, kg/m2
| New York Heart Association classification (III/IV), n (%)
| Systolic BP, mm Hg
| Diastolic BP, mm Hg
| Heart rate, bpm
| Presence of atrial fibrillation/flutter, n (%)
| Left ventricular ejection fraction, %
| Diabetes mellitus, n (%)
| Smoking (past or current), n (%)
Primary heart failure etiology, n (%)
| Ischemic heart disease
Medication, n (%)
| ACE inhibitor/angiotensin receptor blocker
| Loop diuretics
| Loop diuretic dose, mg furosemide equivalent
| Aldosterone antagonist
| Hemoglobin, g/dl
| Sodium, mEq/L
| Potassium, mEq/L
| Phosphate, mg/dl
| NT-proBNP, ng/L
| AST, U/L
| ALT, U/L
| Creatinine, mg/dl
| eGFR, ml/min per 1.73 m2
| Plasma NGAL, ng/ml
| Urea, mg/dl
| Urinary creatinine, mg/dl
| Urinary KIM-1, ng/gCr
| Urinary NGAL, μg/gCr
| UACR, mg/gCr
| FENa, %
| FEUrea, %
| FEPhosphate, %
| Aldosterone, pg/ml
| Renin, µUI/ml
| Aldosterone-renin ratio, ng/dl-ng/ml
| FGF23, RU/ml
| Bio-ADM, pg/ml
| PENK, pmol/L
| Pro-ADM, ng/ml
| Galectin-3, ng/ml
| GDF-15, ng/L
| IL-6, pg/ml
Normally distributed continuous variables are presented as mean±SD, and non-normally distributed continuous variables are presented as median (interquartile range). BMI, body mass index; ACE, angiotensin-converting enzyme; NT-proBNP, N-terminal probrain natriuretic peptide; AST, aspartate aminotransferase; ALT, alanine transaminase; NGAL, neutrophil gelatinase–associated lipocalin; KIM-1, kidney injury molecule-1; gCr, gram of urinary creatinine; UACR, urine albumin-creatinine ratio; FE, fractional excretion; FGF23, fibroblast growth factor 23; Bio-ADM, bioactive adrenomedullin; PENK, proenkephalin; pro-ADM, proadrenomedullin; GDF‐15, growth differentiation factor 15.
Association between Tubular Maximum Phosphate Reabsorption Capacity and Clinical Variables
Multivariable linear regression for log TmP/GFR including serum phosphate is shown in Supplemental Table 4 (adjusted R2=0.83). Upon exclusion of phosphate, the strongest predictors of log TmP/GFR were log FEUrea, log urea, hemoglobin, log urinary creatinine, and log loop diuretic dose (Table 2) (adjusted R2=0.24).
Table 2. -
Multivariable regression analysis for log tubular maximum phosphate reabsorption capacity in BIOSTAT-CHF
|Log urinary creatinine
|Log loop diuretic dose
|Log plasma NGAL
|Log urinary osteopontin
|Log urinary NGAL
Multivariable regression analysis for log tubular maximum phosphate reabsorption capacity after exclusion of serum phosphate. Complete case analysis: n=1318, R2=0.24. FE, fractional excretion; NGAL, neutrophil gelatinase–associated lipocalin; ALT, alanine transaminase.
aIn furosemide equivalent.
Correlation Plots and Hierarchical Cluster Analysis of Tubular Maximum Phosphate Reabsorption Capacity
Correlation plots showing the association between TmP/GFR and eGFR, plasma NGAL, urea, and FEUrea are displayed in Figure 1. In hierarchical cluster analysis (Figure 2), TmP/GFR clustered closely with urinary creatinine, FENa, age, and hemoglobin. TmP/GFR did not directly cluster with serum phosphate or eGFR.
Tubular Maximum Phosphate Reabsorption Capacity Predicts Doubling of Plasma Neutrophil Gelatinase–Associated Lipocalin over Time
Deterioration of kidney function occurred in 221 (19%) of 1168 patients with available measurements. Log decrease of TmP/GFR was neither a significant predictor for deterioration of kidney function overall (OR, 0.53; 95% CI, 0.27 to 1.04; P=0.06) nor a significant predictor in a subgroup of patients without CKD (n=569; OR, 0.65; 95% CI, 0.24 to 1.78; P=0.40). Sensitivity analyses for >30% and >40% decrease in eGFR yielded consistent results.
Doubling of plasma NGAL between baseline and 9 months occurred in 413 (35%) of 1178 patients with available measurements. Log TmP/GFR decrease was a significant predictor for doubling of plasma NGAL after adjustment for baseline plasma and urinary NGAL, eGFR, urinary KIM-1, UACR, FENa, and FEUrea (Table 3) (OR, 2.20; 95% CI, 1.05 to 4.66; P=0.04).
Table 3. -
Logistic regression analysis for incidence of doubling of plasma neutrophil gelatinase–associated lipocalin
||95% Confidence Interval
|Per log baseline TmP/GFR decrease
||1.65 to 4.84
|Per log baseline plasma NGAL decrease
||3.61 to 5.54
|TmP/GFR adjusted for log baseline plasma NGAL
||3.17 to 11.13
|TmP/GFR adjusted for above + baseline eGFR
||1.27 to 4.87
|TmP/GFR adjusted for above + log baseline UACR
||1.20 to 4.66
|TmP/GFR adjusted for above + log baseline KIM-1
||1.23 to 4.77
|TmP/GFR adjusted for above + log baseline urinary NGAL
||1.20 to 4.67
|TmP/GFR adjusted for above + log baseline FENa
||1.06 to 4.69
|TmP/GFR adjusted for above + log baseline FEUrea
||1.05 to 4.66
Logistic regression analysis for incidence of doubling of plasma NGAL was between baseline and 9 months. Complete case analysis: n=1178. TmP/GFR, tubular maximum phosphate reabsorption capacity; NGAL, neutrophil gelatinase–associated lipocalin; UACR, urine albumin-creatinine ratio; KIM-1, kidney injury molecule-1; FE, fractional excretion.
aAt baseline unadjusted.
Lower Tubular Maximum Phosphate Reabsorption Capacity Predicts Poor Clinical Outcomes
Overall, 559 (27%) patients died, and 535 (26%) were hospitalized for heart failure. In 878 (42%), one or both occurred during a median follow-up of 21 (15–27) months. In unadjusted Cox regression, TmP/GFR was significantly associated with all three outcomes and remained so after adjustment for the previously described risk models, serum phosphate, eGFR, and New York Heart Association class (mortality HR per log decrease, 2.80; 95% CI, 1.37 to 5.73; P=0.005; heart failure hospitalization HR per log decrease, 2.29; 95% CI, 1.08 to 4.88; P=0.03; and combined end point HR per log decrease, 1.89; 95% CI, 1.07 to 3.36; P=0.03) (Table 4). Serum phosphate was not associated with any of these outcomes (Supplemental Table 5). Kaplan–Meier curves for the combined end point per quartile of TmP/GFR illustrate increasing risk with lower quartiles of TmP/GFR (Supplemental Figure 1) (log rank P<0.001).
Table 4. -
Cox proportional hazards analysis per log tubular maximum phosphate reabsorption capacity decrease predicting all-cause mortality, hospitalization, or the composite end point
||Event Rates, n (%)
||Adjusted for BIOSTAT Risk Score,
Serum Phosphate, eGFR, and New York Heart Association Class
|Hazard Ratio (95% Confidence Interval)
||Hazard Ratio (95% Confidence Interval)
||3.94 (2.69 to 5.77)
||2.80 (1.37 to 5.73)
|Heart failure hospitalization
||3.20 (2.16 to 4.74)
||2.29 (1.08 to 4.88)
|All-cause mortality or heart failure hospitalization
||3.14 (2.31 to 4.26)
||1.89 (1.07 to 3.36)
aVariables in BIOSTAT-CHF risk score. All-cause mortality: age, log BUN, log N-terminal probrain natriuretic peptide, hemoglobin, and β-blocker use at baseline. Heart failure hospitalization: age, heart failure hospitalization in previous year, peripheral edema, systolic BP, and eGFR. Combined end point: age, heart failure hospitalization in previous year, systolic BP, log N-terminal probrain natriuretic peptide, hemoglobin, HDL, sodium, and β-blocker use at baseline. Complete case analysis in adjusted analyses: n=2021 for all three end points. BIOSTAT-CHF, Biology Study to Tailored Treatment in Chronic Heart Failure.
The combination of low TmP/GFR and CKD was significantly associated with higher risk of poor outcomes after adjustment (Supplemental Tables 6 and 7). Kaplan–Meier curves also revealed worst survival for this combination (Supplemental Figure 2).
Effect of Empagliflozin on Tubular Maximum Phosphate Reabsorption Capacity
Median TmP/GFR in EMPA-RESPONSE-AHF was 0.97 (0.78–1.13) mmol/L. Low TmP/GFR was observed in 21 (27%) patients. Patients with TmP/GFR below the median had higher levels of NT-proBNP, FEUrea, and fractional excretion of phosphate and lower levels of hemoglobin, urinary creatinine, and serum phosphate (Supplemental Table 8) (all P<0.05).
Only 1 day after administration, patients randomized to empagliflozin had higher TmP/GFR compared with placebo (1.17 [1.00–1.33] mmol/L versus 0.92 [0.70–1.10] mmol/L; F=8.983; P=0.004, adjusted for baseline TmP/GFR) as shown in Figure 3. However, after additional adjustment for eGFR change between baseline and day 1, this difference was no longer statistically significant. Urinary phosphate and urinary glucose were not correlated at day 1 in patients allocated to empagliflozin.
Baseline TmP/GFR correlated with fractional excretion of lithium (rho=−0.513; P<0.001), fractional excretion of glucose (rho=−0.325; P=0.005), fractional excretion of uric acid (rho=−0.354; P=0.002), FEUrea (rho=−0.552; P<0.001), and FENa (rho=−0.329; P=0.003) but not with fractional excretion of serum bicarbonate. For all fractional excretions, it should be kept in mind that all incorporated serum/urinary creatinine.
In this study, we showed that TmP/GFR is frequently reduced in patients with heart failure, especially in patients with more advanced heart failure, worse kidney function, and increased signs of tubular damage. TmP/GFR predicted plasma NGAL doubling over time after adjustment for several kidney parameters but not deterioration of kidney function. TmP/GFR was independently associated with both all-cause mortality and heart failure hospitalization. Finally, empagliflozin increased TmP/GFR compared with placebo 1 day after the start of administration but not after adjustment for eGFR change.
Symptoms of heart failure are primarily driven by congestion, for which loop diuretics are the cornerstone of treatment (28). However, a large number of patients with heart failure do not appropriately respond to loop diuretics (28). Because approximately 65% of sodium handling occurs at the proximal tubule, this kidney segment is of particular relevance to patients with heart failure (3). However, the proximal tubule is one of the most vulnerable segments; for this reason, proximal tubule cells are early and central sensors, effectors, and injury recipients (15,29), leading to multiple features of CKD (15,30,31). Proximal tubule cells are as such suggested as a primary player in the progression of acute kidney injury and CKD (15). Following damage, proximal tubules also become evidently less functional due to pathologic changes impairing reabsorption and secretion (32). In heart failure, hypoperfusion of the kidney and congestion (1) might cause proximal tubular dysfunction and damage. This, vice versa, might in theory (counterbalancing natriuretic peptide release) cause congestion through increased sodium and water reabsorption downstream, similar to mechanisms involved in diuretic resistance (28), and lead to progression of heart failure. This has, for example, been shown in a study by Rao et al. (33), which addressed mechanisms of diuretic resistance and showed that compensatory distal tubular sodium reabsorption makes the largest relative contribution (79%) to diuretic-induced increase in FENa. Additionally, sympathetic nervous system activation in heart failure with formation of reactive oxygen species may also have detrimental effects on proximal tubular cells (34).
For all of these reasons, a relevant metric of proximal tubular function that allows heart failure specialists to look beyond eGFR will be highly relevant. Several heart failure studies have focused on tubular damage markers, such as NGAL or KIM-1 (35), yet these do not assess tubular function. As such, TmP/GFR might be a clinically relevant metric of proximal tubular function in heart failure.
Originally, TmP/GFR was invented to help distinguish hypercalcemia due to hyperparathyroidism from other causes (19). We now know that expression of (sodium) phosphate (co-)transporters (i.e., NaPi-IIa, NaPi-IIc, and PiT-2 that determine TmP/GFR) decreases in response to injury (9–14,32). In studies conducted in rats, expression of phosphate (co-)transporters also decreased in the setting of acute hypertension (36). TmP/GFR is thought to be independent of glomerular function but instead represents the functioning of phosphate reabsorption in the proximal tubule (7,16). TmP/GFR thus shows promise as a functional proximal tubular parameter. TmP/GFR was already suggested to be useful for monitoring kidney tubular response to therapy in tubular damage over two decades ago (7), and it has since been reported as a marker of tubular dysfunction (13,14). Additionally, TmP/GFR of living kidney donors was independently associated with recipient measured GFR independent of donor measured GFR but not NGAL or KIM-1 (16).
In this study, we observed that TmP/GFR is frequently reduced in patients with heart failure, more often so in BIOSTAT-CHF (67%) than in EMPA-RESPONSE-AHF (27%). The difference in the proportion of the occurrence of low TmP/GFR between the two cohorts might be explained by EMPA-RESPONSE-AHF including a higher percentage of de novo heart failure compared with BIOSTAT-CHF (47% versus 28%, respectively) and less frequently of an ischemic etiology (29% versus 61%, respectively). Longer existence of heart failure and ischemic injury might result in more proximal tubular dysfunction. Indeed, in patients with heart failure and proven renovascular disease, an ischemic etiology was more often present compared with in patients without renovascular disease (37).
Second, lower TmP/GFR was indeed associated with higher doses of loop diuretics, higher levels of bioactive adrenomedullin (a congestion marker ) and NT-proBNP, and higher fractional excretion of lithium, providing hints toward patients with lower TmP/GFR having more congestion and/or diuretic resistance.
Lower TmP/GFR was also associated with higher levels of tubular damage markers, such as NGAL, but less strongly than with higher FENa and FEUrea, which may also be considered functional parameters (32,39). This seems logical precisely because NGAL levels do not necessarily indicate tubular function, and furthermore originate from multiple tubular segments. The association between TmP/GFR and FEUrea might well be explained by the fact that a large proportion of urea is already absorbed in the proximal tubule and is rather a reflection of proximal peritubular forces than distal forces (39). In addition, TmP/GFR was independently associated with the future doubling of plasma NGAL and poor clinical outcomes, further underlining its clinical relevance, independent of glomerular function. Of course, its association with clinical outcomes might partly be influenced by other forces driving phosphate metabolism, but our findings that (1) TmP/GFR did not cluster with fibroblast growth factor 23 (FGF23; neither was FGF23 a significant determinant of TmP/GFR) and that (2) serum phosphate, by far the largest determinant of TmP/GFR, was not associated with any outcome in this study make it less likely that these effects were of a large magnitude. Lastly, one might postulate that TmP/GFR decline could also be a physiologic compensatory mechanism in preventing hyperphosphatemia, but values below the lower reference limit of serum phosphate (the lowest two quartiles of TmP/GFR) imply an “overshoot” of TmP/GFR decline that is likely attributable to proximal tubular dysfunction.
Finally, SGLT2 inhibition significantly increased TmP/GFR 1 day after administration after adjustment for baseline TmP/GFR but not after additional adjustment for eGFR change (40). This was contrary to our expectation: first because of the anatomic proximity of SGLT2 to NaPi-IIa (believed to be responsible for 70% of phosphate reabsorption), with both primarily located in the S1 segment (41,42). Second, SGLT2 inhibitors have an effect on phosphate homeostasis by increasing serum phosphate in both the short and long terms (43,44). Third, prevention of sodium reabsorption by SGLT2 inhibition causes the sodium gradient to be preserved for, among others, sodium-dependent phosphate transporters (43). Alternatively, changes in urine osmolality induced by empagliflozin (although no correlation between urinary phosphate and urinary glucose was observed) (40) or neurohormonal influences might also influence phosphate transport.
Certain associations of TmP/GFR deserve additional discussion. First, low TmP/GFR was associated with higher albuminuria. This might be explained by the fact that decreased albumin reabsorption in tubules due to tubular damage can contribute to albuminuria (1). Second, FGF23 not clustering with or being a determinant of TmP/GFR was unexpected because FGF23 regulates urinary phosphate excretion (45). Likely, FGF23 is more strongly affiliated with different pathways in heart failure, like development of ventricular hypertrophy (46), sodium homeostasis (47), volume overload, and more pronounced RAAS activation (24,45). Third, low TmP/GFR was not associated with eGFR decline. This might be explained by eGFR changes not necessarily reflecting changes in intrinsic kidney (tubular) damage (2). We showed that low TmP/GFR and low eGFR often occur together and confer a very poor survival and cardiorenal profile if they do, but they might not necessarily determine one another, consistent with regression and cluster analyses.
To our knowledge, this is the first study to pose TmP/GFR as a potentially clinically relevant parameter of proximal tubular function in heart failure (Figure 4). Looking beyond glomerular function with a relevant metric of proximal tubular function will provide valuable cardiorenal insights because it might ultimately contribute to therapies that modulate proximal tubular function and improve sodium homeostasis in heart failure. Further research is warranted to study dynamics of TmP/GFR and its value in prospectively predicting (long-term) future CKD onset. Additionally, because we could only include derivatives of sodium homeostasis and diuretic response and because EMPA-RESPONSE-AHF had a small sample size, extended exploration of the role of TmP/GFR in this sense will be important. Finally, exploration of other parameters reflecting tubular (sodium) transport will also be highly valuable to further increase our knowledge of proximal tubular function in heart failure.
We investigated TmP/GFR in relation to a wide panel of variables in a large, heterogeneous, multinational heart failure population, which is a strength of our study. Furthermore, this study included a good balance of patients with and without CKD, allowing reliable subgroup analyses. Additional insights were provided by studying the effects of empagliflozin on TmP/GFR in a small but very well-defined cohort in patients with acute heart failure. However, we are mainly able to describe associations, not causality. We also realize that this study does not provide definitive proof of the relationship of TmP/GFR with actual proximal tubular damage or overall reduced sodium reabsorption of the proximal tubule, as previous experimental studies in rats have detected upregulation of the NHE3 transporter in response to heart failure (48–50). Necessity for collecting urinary samples is a disadvantage. Also, the formula is quite complex, but this can easily be solved by implementation in electronic patient systems. Furthermore, urinary NGAL would have been preferred over plasma NGAL, but unfortunately, no measurements were available at 9 months. We were only able to show dynamic changes of TmP/GFR in EMPA-RESPONSE-AHF because no repeat measurements were performed in BIOSTAT-CHF. Finally, no true GFR or parathyroid hormone levels were measured, and patients were not fasted and did not have consistent sample collection times, which would have provided more consistency in TmP/GFR readouts.
TmP/GFR, a metric of proximal tubular function, is frequently reduced in patients with heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is associated with plasma NGAL doubling over time and poor outcomes, independent of glomerular function. SGLT2 inhibition increased TmP/GFR but not after adjustment for eGFR change.
S.D. Anker reports consultancy agreements with Abbott Vascular, Bayer, Boehringer Ingelheim, BRAHMS, Cardiac Dimensions, Cordio Novartis, Servier, and Vifor Pharma; receiving fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; receiving research funding from Abbott Vascular and Vifor Pharma; and serving as a scientific advisor or member of Cardiac Dimensions and Novartis. C.C. Lang reports receiving research funding from AstraZeneca, Boehringher Ingelheim, and Novo Nordisk and receiving honoraria from AstraZeneca, Boehringher Ingelheim, MSD, Novartis, and Novo Nordisk. K. Damman reports receiving consultancy fees from AstraZeneca and Boehringer Ingelheim; receiving speaker fees from Abbott, AstraZeneca, and Boehringer Ingelheim; and serving on the editorial board of European Journal of Heart Failure. M.H. de Borst reports consultancy agreements with Astellas, Kyowa Kirin, Pharmacosmos, Sanofi Genzyme, and Vifor Pharma; receiving research funding from Sanofi Genzyme and Vifor Pharma; and serving as an associate editor of Nephrology Dialysis Transplantation. G. Filippatos reports consultancy agreements with Amgen, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor; receiving research funding from the European Union; receiving honoraria from Bayer and Boehringer Ingelheim; lecture fees and/or committee membership in trials and/or registries sponsored by Amgen, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, and Vifor; serving as a scientific advisor or member of European Heart Journal, European Journal of Heart Failure, and JACC: Heart Failure; and speakers bureau for Bayer and Boehringer Ingelheim. M. Metra reports personal fees from Amgen, AstraZeneca, Bayer, and WindTree Therapeutics as a member of trials, committees, or advisory boards; personal fees from Abbott vascular, Actelion, Amgen, AstraZeneca, Bayer, Edwards Therapeutics, Livanova, Servier, Vifor Pharma, and WindTree Therapeutics as a member of trials or committees or for speeches at sponsored meetings; personal fees from Amgen, AstraZeneca, Bayer, Vifor Pharma, and WindTree Therapeutics as a member of trials, committees, or advisory boards; and personal fees from Abbott vascular, Edwards Therapeutics, and Novartis for speakers bureau. G. Navis reports serving as chair of the scientific board of the Dutch Kidney Foundation, a member of the Health Council of The Netherlands, and a member of the permanent advisory board on prevention for the Ministry of Health. P. Ponikowski reports consultancy agreements with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DC Device, Impulse Dynamics, Novartis, Renal Guard Solutions, Respicardia, Servier, and Vifor Pharma; receiving research funding from Vifor Pharma; receiving honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DC Device, Impulse Dynamics, Novartis, Renal Guard Solutions, Respicardia, Servier, and Vifor Pharma; and speakers bureau for Amgen, AstraZeneca, Berlin Chemie, Boehringer Ingelheim, DC Device, Impulse Dynamics, Novartis, Pfizer, Respicardia, Servier, and Vifor Pharma. N.J. Samani reports serving as a scientific advisor or member of the British Heart Foundation and the Novo Nordisk Oxford Research Centre. A.A. Voors received consultancy fees and/or research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novartis, Novo Nordisk, and Roche Diagnostics. The University Medical Center Groningen, which employs several authors, has received research grants and/or fees from Abbott, AstraZeneca, Bristol-Myers Squibb, Novartis, Roche, ThermoFisher GmbH, and Trevena. All remaining authors have nothing to disclose.
BIOSTAT-CHF was funded by European Commission grant FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29.
Prof. M.H. de Borst, Dr. J.E. Emmens, and Dr. J.M. ter Maaten designed the study; Prof. S.D. Anker, Dr. E.M. Boorsma, Prof. C.C. Lang, Dr. K. Damman, Prof. K. Dickstein, Prof. G. Filippatos, Prof. M. Metra, Prof. L.L. Ng, Prof. P. Ponikowski, Prof. N.J. Samani, Prof. D.J. van Veldhuisen, and Prof. A.A. Voors acquired data; Dr. J.E. Emmens analyzed the data and made tables/figures; Dr. J.E. Emmens took primary responsibility for drafting and revising the paper, with assistance from Dr. E.M. Boorsma, Dr. K. Damman, Prof. M.H. de Borst, Prof. G. Navis, Dr. J.M. ter Maaten, and Prof. A.A. Voors (supported by feedback from all authors); and all authors approved the final version of the manuscript.
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.03720321/-/DCSupplemental.
Supplemental Figure 1. Kaplan–Meier curve for the combined end point for quartiles of TmP/GFR.
Supplemental Figure 2. Kaplan–Meier curves according to low/high TmP/GFR and presence of CKD predicting the combined end point.
Supplemental Figure 3. Correlation plot of TmP/GFR with fractional excretion of lithium.
Supplemental Material. Supplemental Methods.
Supplemental Table 1. Baseline characteristics of study subset and patients without TmP/GFR measurements in BIOSTAT-CHF.
Supplemental Table 2. Baseline characteristics according to low/high TmP/GFR and presence of CKD.
Supplemental Table 3. Baseline characteristics according to low, normal, and high TmP/GFR.
Supplemental Table 4. Multivariable regression analysis for log TmP/GFR with phosphate included.
Supplemental Table 5. Cox regression analysis of serum phosphate.
Supplemental Table 6. Cox proportional hazards analysis according to low/high TmP/GFR and presence of CKD predicting all-cause mortality.
Supplemental Table 7. Cox proportional hazards analysis according to low/high TmP/GFR and presence of CKD predicting the combined end point.
Supplemental Table 8. Baseline characteristics of the EMPA-RESPONSE-AHF cohort stratified by above or below median TmP/GFR.
1. Damman K, Testani JM: The kidney in heart failure: An update. Eur Heart J 36: 1437–1444, 2015
2. Metra M, Voors AA: The puzzle of kidney dysfunction in heart failure: An introduction. Heart Fail Rev 17: 129–131, 2012
3. Mullens W, Verbrugge FH, Nijst P, Tang WHW: Renal sodium avidity in heart failure: From pathophysiology to treatment strategies. Eur Heart J 38: 1872–1882, 2017
4. Ter Maaten JM, Rao VS, Hanberg JS, Perry Wilson F, Bellumkonda L, Assefa M, Sam Broughton J, D’Ambrosi J, Wilson Tang WH, Damman K, Voors AA, Ellison DH, Testani JM: Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure. Eur J Heart Fail 19: 1014–1022, 2017
5. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi D-J, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca H-P, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde M-F, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators: Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 383: 1413–1424, 2020
6. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang C-E, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde A-M; DAPA-HF Trial Committees and Investigators: Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381: 1995–2008, 2019
7. Payne RB: Renal tubular reabsorption of phosphate (TmP/GFR): Indications and interpretation. Ann Clin Biochem 35: 201–206, 1998
8. Walton RJ, Bijvoet OL: Nomogram for derivation of renal threshold phosphate concentration. Lancet 2: 309–310, 1975
9. Vogel M, Kränzlin B, Biber J, Murer H, Gretz N, Bachmann S: Altered expression of type II sodium/phosphate cotransporter in polycystic kidney disease. J Am Soc Nephrol 11: 1926–1932, 2000
10. Xiao Y, Desrosiers RR, Beliveau R: Effect of ischemia-reperfusion on the renal brush-border membrane sodium-dependent phosphate cotransporter NaPi-2. Can J Physiol Pharmacol 79: 206–212, 2001
11. Kwon T-H, Frøkiaer J, Han JS, Knepper MA, Nielsen S: Decreased abundance of major Na(+
) transporters in kidneys of rats with ischemia-induced acute renal failure. Am J Physiol Renal Physiol 278: F925–F939, 2000
12. Rubinger D, Wald H, Gimelreich D, Halaihel N, Rogers T, Levi M, Popovtzer MM: Regulation of the renal sodium-dependent phosphate cotransporter NaPi2 (Npt2) in acute renal failure due to ischemia and reperfusion. Nephron, Physiol 100: 1–12, 2005
13. Min HK, Kim EO, Lee SJ, Chang YK, Suh KS, Yang CW, Kim SY, Hwang HS: Rifampin-associated tubulointersititial nephritis and Fanconi syndrome presenting as hypokalemic paralysis. BMC Nephrol 14: 13, 2013
14. Maiorana A, Malamisura M, Emma F, Boenzi S, Di Ciommo VM, Dionisi-Vici C: Early effect of NTBC on renal tubular dysfunction in hereditary tyrosinemia type 1. Mol Genet Metab 113: 188–193, 2014
15. Chevalier RL: The proximal tubule is the primary target of injury and progression of kidney disease: Role of the glomerulotubular junction. Am J Physiol Renal Physiol 311: F145–F161, 2016
16. van Londen M, Aarts BM, Sanders J-SF, Hillebrands J-L, Bakker SJL, Navis G, de Borst MH: Tubular maximum phosphate reabsorption capacity in living kidney donors is independently associated with one-year recipient GFR. Am J Physiol Renal Physiol 314: F196–F202, 2018
17. Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P, Hillege HL, Lang CC, Ter Maaten JM, Ng L, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zannad F, Zwinderman AH, Metra M: A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: Rationale, design, and baseline characteristics of BIOSTAT-CHF. Eur J Heart Fail 18: 716–726, 2016
18. Damman K, Beusekamp JC, Boorsma EM, Swart HP, Smilde TDJ, Elvan A, van Eck JWM, Heerspink HJL, Voors AA: Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail 22: 713–722, 2020
19. Bijvoet OL: Relation of plasma phosphate concentration to renal tubular reabsorption of phosphate. Clin Sci 37: 23–36, 1969
20. Damman K, Tang WHW, Testani JM, McMurray JJV: Terminology and definition of changes renal function in heart failure. Eur Heart J 35: 3413–3416, 2014
21. Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, de Zeeuw D, Cheung AK, Coresh J: GFR decline as an end point for clinical trials in CKD: A scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 64: 821–835, 2014
22. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro 3rd AF, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration): A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612, 2009
23. van Balkom BWM, Gremmels H, Ooms LSS, Toorop RJ, Dor FJMF, de Jong OG, Michielsen LA, de Borst GJ, de Jager W, Abrahams AC, van Zuilen AD, Verhaar MC: Proteins in preservation fluid as predictors of delayed graft function in kidneys from donors after circulatory death. Clin J Am Soc Nephrol 12: 817–824, 2017
24. Ter Maaten JM, Voors AA, Damman K, van der Meer P, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P, Hillege HL, Lang CC, Metra M, Navis G, Ng L, Ouwerkerk W, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zannad F, Zwinderman AH, de Borst MH: Fibroblast growth factor 23 is related to profiles indicating volume overload, poor therapy optimization and prognosis in patients with new-onset and worsening heart failure. Int J Cardiol 253: 84–90, 2018
25. Marino R, Struck J, Maisel AS, Magrini L, Bergmann A, Di Somma S: Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis. Crit Care 18: R34, 2014
26. Ouwerkerk W, Zwinderman AH, Ng LL, Demissei B, Hillege HL, Zannad F, van Veldhuisen DJ, Samani NJ, Ponikowski P, Metra M, Ter Maaten JM, Lang CC, van der Harst P, Filippatos G, Dickstein K, Cleland JG, Anker SD, Voors AA: Biomarker-guided versus guideline-based treatment of patients with heart failure: Results from BIOSTAT-CHF. J Am Coll Cardiol 71: 386–398, 2018
27. Voors AA, Ouwerkerk W, Zannad F, van Veldhuisen DJ, Samani NJ, Ponikowski P, Ng LL, Metra M, Ter Maaten JM, Lang CC, Hillege HL, van der Harst P, Filippatos G, Dickstein K, Cleland JG, Anker SD, Zwinderman AH: Development and validation of multivariable models to predict mortality and hospitalization in patients with heart failure. Eur J Heart Fail 19: 627–634, 2017
28. ter Maaten JM, Valente MAE, Damman K, Hillege HL, Navis G, Voors AA: Diuretic response in acute heart failure-pathophysiology, evaluation, and therapy. Nat Rev Cardiol 12: 184–192, 2015
29. Molitoris BA: Therapeutic translation in acute kidney injury: The epithelial/endothelial axis. J Clin Invest 124: 2355–2363, 2014
30. Takaori K, Nakamura J, Yamamoto S, Nakata H, Sato Y, Takase M, Nameta M, Yamamoto T, Economides AN, Kohno K, Haga H, Sharma K, Yanagita M: Severity and frequency of proximal tubule injury determines renal prognosis. J Am Soc Nephrol 27: 2393–2406, 2016
31. Grgic I, Campanholle G, Bijol V, Wang C, Sabbisetti VS, Ichimura T, Humphreys BD, Bonventre JV: Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. Kidney Int 82: 172–183, 2012
32. Vallon V: Tubular transport in acute kidney injury: Relevance for diagnosis, prognosis and intervention. Nephron 134: 160–166, 2016
33. Rao VS, Planavsky N, Hanberg JS, Ahmad T, Brisco-Bacik MA, Wilson FP, Jacoby D, Chen M, Tang WHW, Cherney DZI, Ellison DH, Testani JM: Compensatory distal reabsorption drives diuretic resistance in human heart failure. J Am Soc Nephrol 28: 3414–3424, 2017
34. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B: The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 26: 11–17, 2005
35. Damman K, Masson S, Hillege HL, Maggioni AP, Voors AA, Opasich C, van Veldhuisen DJ, Montagna L, Cosmi F, Tognoni G, Tavazzi L, Latini R: Clinical outcome of renal tubular damage in chronic heart failure. Eur Heart J 32: 2705–2712, 2011
36. Blaine J, Weinman EJ, Cunningham R: The regulation of renal phosphate transport. Adv Chronic Kidney Dis 18: 77–84, 2011
37. Bourantas CV, Loh HP, Lukaschuk EI, Nicholson A, Mirsadraee S, Alamgir FM, Tweddel AC, Ettles DF, Rigby AS, Nikitin NP, Clark AL, Cleland JGF: Renal artery stenosis: An innocent bystander or an independent predictor of worse outcome in patients with chronic heart failure? A magnetic resonance imaging study. Eur J Heart Fail 14: 764–772, 2012
38. Voors AA, Kremer D, Geven C, Ter Maaten JM, Struck J, Bergmann A, Pickkers P, Metra M, Mebazaa A, Düngen H-D, Butler J: Adrenomedullin in heart failure: Pathophysiology and therapeutic application. Eur J Heart Fail 21: 163–171, 2019
39. Carvounis CP, Nisar S, Guro-Razuman S: Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure. Kidney Int 62: 2223–2229, 2002
40. Boorsma EM, Beusekamp JC, Ter Maaten JM, Figarska SM, Danser AHJ, van Veldhuisen DJ, van der Meer P, Heerspink HJL, Damman K, Voors AA: Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure. Eur J Heart Fail 23: 68–78, 2021
41. Cowie MR, Fisher M: SGLT2 inhibitors: Mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 17: 761–772, 2020
42. Manghat P, Sodi R, Swaminathan R: Phosphate homeostasis and disorders. Ann Clin Biochem 51: 631–656, 2014
43. Vinke JSJ, Heerspink HJL, de Borst MH: Effects of sodium glucose cotransporter 2 inhibitors on mineral metabolism in type 2 diabetes mellitus. Curr Opin Nephrol Hypertens 28: 321–327, 2019
44. de Jong MA, Petrykiv SI, Laverman GD, van Herwaarden AE, de Zeeuw D, Bakker SJL, Heerspink HJL, de Borst MH: Effects of dapagliflozin on circulating markers of phosphate homeostasis. Clin J Am Soc Nephrol 14: 66–73, 2019
45. Kovesdy CP, Quarles LD: Fibroblast growth factor-23: What we know, what we don’t know, and what we need to know. Nephrol Dial Transplant 28: 2228–2236, 2013
46. Faul C, Amaral AP, Oskouei B, Hu M-C, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M: FGF23 induces left ventricular hypertrophy. J Clin Invest 121: 4393–4408, 2011
47. Andrukhova O, Slavic S, Smorodchenko A, Zeitz U, Shalhoub V, Lanske B, Pohl EE, Erben RG: FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med 6: 744–759, 2014
48. Zheng H, Liu X, Katsurada K, Patel KP: Renal denervation improves sodium excretion in rats with chronic heart failure: Effects on expression of renal ENaC and AQP2. Am J Physiol Heart Circ Physiol 317: H958–H968, 2019
49. Borges-Júnior FA, Silva Dos Santos D, Benetti A, Polidoro JZ, Wisnivesky ACT, Crajoinas RO, Antônio EL, Jensen L, Caramelli B, Malnic G, Tucci PJ, Girardi ACC: Empagliflozin inhibits proximal tubule NHE3 activity, preserves GFR, and restores euvolemia in nondiabetic rats with induced heart failure. J Am Soc Nephrol 32: 1616–1629, 2021
50. Lütken SC, Kim SW, Jonassen T, Marples D, Knepper MA, Kwon T-H, Frøkiaer J, Nielsen S: Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: Response to angiotensin II AT1 receptor blockade. Am J Physiol Renal Physiol 297: F1678–F1688, 2009