In Search of the “White Whale”: Is Urine Sodium Effective at Guiding Decongestion?

Despite significant advances in both medical and device-based management, acute heart failure persists as a predominant cause of hospitalization in the Unites States, contributing significantly to health care expenditure and imposing a large burden of morbidity and mortality on affected individuals. Treatment of acute decompensated heart failure is primarily focused on relieving congestion, although studies have indicated that a significant proportion of patients are inadequately decongested at the time of discharge, leading to high rates of rehospitalization and mortality. Although loop diuretics remain a cornerstone of therapy, the ability to assess an adequate therapeutic response remains elusive. Traditional metrics such as changes in weight and cumulative fluid balance are often difficult to assess with accuracy, are unreliable, and often lead to delays in care while data are obtained.

More recently, evaluation of natriuresis via a spot or timed urine sample has garnered interest after several studies have demonstrated benefit in monitoring urine sodium (UNa) to gauge a natriuretic response to decongestive therapy (1–4). This has culminated in the European Society of Cardiology Heart Failure Guidelines (5), which adopts UNa assessment in a spot urine sample 2 hours after diuretic therapy as a recommendation. Various thresholds have been suggested to indicate an insufficient diuretic response, necessitating escalation of therapy.

Recently, two pragmatic trials, Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure (ENACT-HF) (6) and Pragmatic Urinary Sodium-Based Treatment Algorithm in Acute Heart Failure (PUSH-AHF) (7), demonstrated efficacy using a natriuresis-guided therapy utilizing spot UNa levels compared with standard of care (SOC). Although prior studies primarily assessed the impact of initial doses of loop diuretics on spot UNa values, the pragmatic nature of these studies allowed for assessment of protocolized natriuresis-guided decongestion in a diverse group of patients. The PUSH-AHF study (7) randomized 310 adult patients with decompensated heart failure (mean age, 74 years; 45% female; mean left ventricular ejection fraction, 35%; and creatinine, 1.2) to natriuresis-guided therapy versus SOC. The trial design allowed for broad inclusion criteria with main exclusions including severe renal impairment requiring dialysis and dyspnea due to other causes. In the intervention group, spot UNa was assessed at various time points, and treatment intensified if values were less than 70 mmol/L. For the SOC group, diuretic management was not mandated and was left to the discretion of the treating physician. The dual primary outcomes were mean total 24-hour natriuresis and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The natriuresis endpoint was met, with natriuresis in the intervention group reported as 409 ± 178 mmol compared with 345 ± 202 mmol in the SOC group. The natriuresis-guided group received a greater cumulative diuretic dose, and a minority of participants received adjunctive agents in response to suboptimal UNa levels. There were no observed differences in all-cause mortality or rehospitalization rates between groups.

In the Journal of the American Heart Association, Oliva-Damaso et al. (8) recognized a need for a validated metric to assess the diuretic response and acknowledge the promise of UNa to tailor diuretic therapy, although they additionally raised valid concerns and limitations with this approach. They expressed concern of the usefulness of UNa as a biomarker beyond day 1 due to the urine becoming more hypotonic in subsequent days in response to hemodynamic, as well as adaptive, changes in the nephron after repeated exposure to loop diuretics. It should be acknowledged that the single center study (9), cited in their article, suffered from a significant degree of missing urinary data after day 2 and was performed in the absence of a diuretic protocol, with treating physicians unblinded to results; therefore, therapy may have been modified.

Oliva-Damaso et al. (8) additionally raised concerns regarding the validity of a UNa-guided approach to therapy in the setting of acute kidney injury (AKI), citing changes to urinary composition due to impact on sodium handling with acute tubular injury, which is the most common cause of AKI in hospitalized patients. A natriuresis-guided approach has not been validated in patients with a reduced estimated glomerular filtration rate (eGFR) in etiologies other than presumed cardiorenal syndrome, although it is worth noting that both aforementioned pragmatic trials (6, 7) enrolled patients with a wide range of eGFRs, including as low as 35 mL/min/1.73 m². Finally, the authors queried the ability to monitor UNa in response to alternative decongestive agents, specifically aquaretics (such as vasopressin 2 receptor antagonists), which dilute urine by increasing water excretion and hence lower UNa measurements. Although this is mechanistically correct, the overall role for aquaretics as part of decongestive therapy is questionable with trials failing to demonstrate the benefit of vasopressin antagonists compared with placebo in acute decompensated heart failure (10).

The impact of sodium-glucose cotransporter-2 (SGLT2) inhibitors is of greater importance. Although their role in acute decompensated heart failure has not been established, with improvement in filling pressures correlating better with metabolic effects rather than reductions in plasma volume, a high prevalence of patients are expected to be treated with these medications due to their role as part of guideline-directed medical therapy. These agents appear to increase urine output primarily using glycosuria, resulting in an osmotic diuresis, which could confound UNa assessments. Importantly, the study by Ter Maaten et al. (7) included additional agents, such as hydrochlorothiazide, acetazolamide, and SGLT2 inhibitors, in their diuretic protocol to address suboptimal UNa levels. A multicenter randomized trial is underway to assess the utility of a UNa-guided approach with combination diuretic therapy (11).

In summary, despite these concerns, UNa is an easily obtainable, inexpensive marker that may provide a tailored approach to decongestion in patients with acute decompensated heart failure. The use of spot UNa analysis to guide diuretic therapy has demonstrable success in both observational and pragmatic randomized trials. Like many protocols in medicine, UNa should not be used in isolation from other markers of decongestion but viewed as a tool to gauge an appropriate threshold response to decongestive therapy with a primary benefit of escalating care more rapidly, potentially leading to decreased length of hospitalization. Future trials to further define the optimal threshold for UNa values as well as the impact of adjunctive diuretics and other interventions to intensify decongestion will further strengthen its utility as a biomarker.