Author + information
- aCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- bDivision of Nephrology, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Akshay S. Desai, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Despite increasingly effective medical therapy, patients with heart failure (HF) remain at high risk for hospitalization and death. Most hospitalizations are driven by recurrent congestion, which is in turn a consequence of sodium and fluid retention driven by the systemic neurohumoral activation and impaired natriuresis typical of the HF syndrome and often exacerbated by comorbid chronic kidney disease. Because disrupted sodium and fluid homeostasis is a hallmark of HF, urinary sodium (Una) has emerged as a potential biomarker of interest for risk stratification in patients with HF. Although Una excretion is more accurately quantified by timed urine collections (e.g., >24 h), a growing body of evidence suggests that spot Una concentrations, which are considerably easier to obtain, may be useful in predicting the response to loop diuretic therapy (1), as well as the risk of hospitalization and death (2).
As the master regulator of salt and water balance, the kidney plays a central role in the control of extracellular fluid (ECF) volume. Homeostatic control of salt and water, or osmoregulation, represented a critical step in evolution, allowing primitive organisms to move from saline-rich oceans to more dilute freshwater environments. To adapt to these surroundings, the primitive kidney evolved the ability to excrete water, while retaining sodium chloride. Renal sodium excretion is highly regulated through neurohormonal mechanisms, including the natriuretic peptide system, in response to exogenous sodium intake and fluctuation in ECF volume. Under steady-state conditions and normal physiology, therefore, the Una concentration provides a useful clinical window into volume status, with lower Una concentrations typically reflecting enhanced renal sodium retention in the context of a deficit in ECF volume.
In patients with HF, this direct correlation between Una and ECF volume is disrupted, as tissue hypoperfusion drives sustained activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, which, in turn, stimulates renal retention of filtered sodium and continued expansion of plasma volume (as well as diminished responsiveness to endogenous natriuretic peptides). Accordingly, in the acute HF setting, Una concentration is typically lower than when the patient is in a more compensated steady-state and may reflect the severity of decompensation. It is this apparent correlation between Una excretion and HF disease state that makes Una concentration attractive as a potential biomarker of HF severity.
Although Una concentration may correlate with neurohormonal activation and HF severity, it is also potentially confounded by other factors. For spot Una assessments, the timing and volume of samples used to estimate Una concentration is one important consideration. Factors that lower urine volume (e.g., non-osmotic vasopressin release, decreased fluid intake, and acute kidney injury) or increase urine volume (e.g., glycosuria, diuretics, and excess dietary intake of salt and water) may lead to fluctuations in the measured value that undermine the estimation of overall sodium excretion. Longer-term urinary collections may facilitate more accurate quantitation of Una excretion, but even these measures may be highly variable over time (3). Medical therapy, particularly use of diuretics, is another important confounder. Chronic loop diuretic administration may promote metabolic alkalosis and enhanced bicarbonaturia that can enhance Una loss, further confounding the use of Una concentration as physiological marker. Moreover, while the administration of loop diuretic agents may transiently increase Una excretion, depletion of effective circulating volume from rapid volume loss may enhance neurohormonal activation, exacerbating sodium retention. Therefore, to properly interpret the Una concentration on a spot urine assessment, clinicians must understand the dose and type of diuretic agents being administered, the timing of the measurement in relation to diuretic administration, and the change from pre- to post-diuretic administration.
In this issue of JACC: Heart Failure, Martens et al. (4) provide an analysis of weekly, first morning void, pre-diuretic, spot Una measurements in a cohort of 80 ambulatory patients with chronic HF on stable, guideline-directed medical therapy followed up for 30 weeks. The population included principally patients with HF and reduced ejection fraction (86%), 36% of whom were treated with loop diuretic agents and 81% with aldosterone antagonists at baseline. Although Una excretion varied widely between patients, levels of spot Una concentration remained relatively consistent over time for individual patients and appeared to correlate with 24-h Una measurements. In post hoc statistical analyses of random effects models, the authors identified distinct populations of individuals with higher (88 mmol/l) and lower (73 mmol/l) Una concentration. Notably, those with lower Una concentrations were not distinguishable from higher Una concentrations based on any of the examined clinical characteristics but did appear to be at higher risk for HF hospitalization. Moreover, Una concentrations appeared to decrease in advance of HF hospitalization and recover to baseline after HF treatment. The authors conclude that the inability to efficiently excrete sodium may be a marker of risk for worsening HF, and that clinical measurement of spot Una concentration might be useful in guiding risk stratification and management of patients with HF.
These data regarding longitudinal trends in Una add important information to the growing body of evidence that spot Una might be a relevant prognostic biomarker in HF patients; however, several caveats are important to consider. First, this is a small, highly selected group of patients from a single center, and it remains unclear whether these results are generalizable to broader populations with HF. Of an initial 100 patients identified for the study, 20 were excluded due to failure to return for follow-up or inadequate sample collection, and it is unclear how these patients differed from the group that was studied. A minority of patients had HF with preserved ejection fraction, and the analysis is heavily underpowered to assess consistency of the results in this subgroup. Second, as noted previously, the regulation of Una excretion is complex, and may be heavily confounded by several factors that are not thoroughly explicated in this analysis. Although uniform dietary guidance was provided to all participants, there is no information provided about dietary sodium intake, an important determinant of Una excretion. Loop and other diuretic use might further confound spot Una assessment, and only one-third of patients in this analysis were loop diuretic–treated at baseline. Curiously, patients treated with loop diuretic agents tended to have lower Una excretion than those not taking loop diuretics, which may reflect the timing of Una measurement, enhanced renin-angiotensin-aldosterone system activation, or other unmeasured factors related to disease severity.
To be of clinical value, a novel biomarker should be easily measured and interpreted, must add incremental information to existing data, and should help the clinician to better manage patients (5). While spot Una can be easily measured at low cost and does appear to be associated with risk for HF hospitalization, the evidence is still limited that measurement of Una helps to meaningfully augment risk assessment in patients with chronic HF beyond existing clinical markers such as natriuretic peptides, serum sodium (related to non-osmotic vasopressin release), or renal function. Moreover, it remains unclear precisely what threshold of Una excretion should raise clinical concern or provide reassurance, and whether this threshold is absolute or varies based on dietary sodium intake, medical treatment, HF severity, or other factors. Serial measurement of Una is unlikely to be possible in clinical practice, and the transient and abrupt decrease in Una prior to HF hospitalization makes it unlikely to be a reliable method for anticipating and preventing HF decompensation.
What can we conclude about Una measurement in stable outpatients with HF? Overall, the work of Martens et al. supports the hypothesis that renal sodium retention may be a marker of HF severity, and that lower Una levels in the face of diuretic therapy may reflect vulnerability to HF decompensation, at least in patients with HF and reduced ejection fraction. Further study is needed to see whether measurement of Una can be leveraged to help to facilitate better triage and management of patients with HF across the spectrum of ejection fraction.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Mc Causland is supported by the NIH grant K23DK102511. Dr. Desai has reported that they have no relationships relevant to the contents of this paper to disclose. Outside of the paper, Dr. Desai reports research grants from Novartis; and consulting fees from Novartis, Abbott, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, Corvidia, DalCor Pharma, Regeneron, Relypsa, and Zogenix.
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