A Heartwarming Role of the Proximal Tubules

Kidney function plays a central role in the evaluation and management of heart failure. Accurate and timely monitoring of kidney function is necessary for selecting and titrating appropriate therapies to relieve congestion and optimize cardiac function. Yet, current markers of kidney function have major limitations that impede the clinical monitoring and treatment of heart failure. Serum creatinine concentrations do not provide real-time assessment of the GFR, but rather change in consequence to changes in GFR, confounding the timing and intensity of treatments. More importantly, glomerular filtration is primarily a passive process governed by kidney hemodynamics, which may be insensitive to evolving patterns of injury and recovery in heart failure.

The kidney tubules regulate sodium and water balance, actively secrete medications including diuretics, and are exquisitely sensitive to ischemic injury. Markers of tubular function and health, ranging historically from urine sodium and urea to modern biomarkers of tubular injury, such as kidney injury molecule-1 and neutrophil gelatinase–associated lipocalin, have demonstrated clinical relevance in the setting of heart failure (1). Treatment with sodium-glucose cotransporter 2 inhibitors, which target the proximal tubules, improve symptoms of heart failure and reduce hospitalization and death among persons with reduced and preserved ejection fraction (2,3). Consequently, broadening the assessment of kidney functions to include measures of tubular health could bolster clinical judgment, reveal previously unrecognized patterns of disease, and suggest new approaches to therapy.

In this issue of CJASN, Emmens and colleagues investigate a salient kidney tubular function in heart failure: reabsorption (4). They focused specifically on the kidney handling of phosphate, which is freely filtered, reabsorbed to a variable degree in the proximal tubules, and not secreted. As with secretory solute clearance, tubular reabsorption involves a series of linked transport steps that require energy (either directly or indirectly) and maintenance of cell polarity, suggesting functional relevance as a measure of kidney health. To estimate phosphate reabsorption, Emmens et al. calculated the tubular maximum phosphate reabsorption capacity (TmP/GFR) (5). Higher TmP/GFR values indicate relatively greater tubular phosphate reabsorption, whereas lower values suggest potential kidney phosphate wasting.

Among 2085 participants in a prospective cohort study of heart failure (ejection fraction ≤40% or elevated brain natriuretic peptide, plus treatment with a loop diuretic), TmP/GFR was associated with hormonally and clinically distinct patient subgroups. Persons with lower TmP/GFR values had higher circulating concentrations of fibroblast growth factor 23 (FGF-23), inflammatory biomarkers (growth/differential factor-15, IL-6), urine concentrations of kidney injury molecule 1 and neutrophil gelatinase–associated lipocalin, and were receiving the highest dosages of loop diuretics. Over a median of 21 months follow-up, lower TmP/GFR was associated with greater risks of heart failure hospitalization and all-cause mortality. These associations persisted after adjustment for estimated GFR, serum phosphate, and other clinical characteristics.

There are several commendable aspects of this study. Conceptually, adding measurements of a biologically active kidney tubular mechanism to existing measures of glomerular filtration should provide a more informative assessment of kidney function. Although glomerular and tubular functions are physiologically linked via tubuloglomerular feedback (6), variation in this regulatory process across individuals and disease processes suggest that separate measurements could improve classification in heterogeneous conditions, such as heart failure. The focus on phosphate handling is innovative because phosphate reabsorption is restricted to the proximal tubules without secretion or distal regulation, providing a potentially more focused assessment. The well-characterized cohort of persons with heart failure, standardized data collection methods, and prospective evaluation of clinical outcomes are additional strengths.

An important limitation is uncertainty as to whether the calculated TmP/GFR values solely reflect tubular phosphate reabsorption. TmP/GFR was originally derived using inulin clearance, intravenous phosphate infusions, and timed urine collections in 77 persons without heart failure, but prevalent in hyperparathyroidism and thyrotoxicosis. The validity of TmP/GFR calculated using spot blood and urine measurements in patients with heart failure and concurrent loop diuretic use is uncertain. The TmP/GFR values calculated in this study showed residual dependence on estimated GFR. Moreover, individual components of the TmP/GFR equation—serum creatinine, urine creatinine, and serum phosphate—are themselves associated with the outcomes under investigation (7). Combining these characteristics as ratios or multiplicative terms could yield associations with the study outcomes, even after adjustment for the individual linear terms.

Further work investigating the specificity of TmP/GFR, or related measures, for tubular phosphate reabsorption in persons with heart failure will be needed to ensure confidence in interpretation. The association of low TmP/GFR values with hospitalizations and death may be confounded by characteristics that influence phosphate reabsorption, including FGF-23, parathyroid hormone, calcitriol, and dietary phosphate. FGF-23 potently inhibits phosphate reabsorption in the proximal tubules and is associated with heart failure and left ventricular hypertrophy (8). The absence of a statistical association of TmP/GFR with a single measurement of FGF-23 does not dismiss the possibility of confounding. The possibility of confounding due to parathyroid hormone or vitamin D metabolism is also not explored because these were not measured in this study.

What are the implications of the study findings? If TmP/GFR can reliably capture tubular phosphate reabsorption in heart failure, then this kidney function may reveal biologically and clinically relevant subgroups of patients, suggesting a more individualized approach to evaluation and treatment. As with other emerging markers of kidney tubular functions, demonstration of associations with clinical outcomes independent of GFR represents an important initial step. However, clinical assimilation of these measures will require studies investigating their role in diagnosis and treatment, and demonstration of specificity for the physiologic processes of interest, intra-individual precision, low cost, and ease of application. These barriers are challenging, but a worthwhile focus of research. The study by Emmens et al. provides another step toward more comprehensive assessments of kidney functions in clinical medicine.

Disclosures

B. Kestenbaum reports receiving consulting fees and honoraria from Reata Pharmaceuticals. The remaining author has nothing to disclose.

Funding

None.