Fractional Excretion of Sodium (FENa)

Simple to obtain yet complex to interpret, the fractional excretion of sodium (FENa) is frequently quoted when a nephrology consult is placed. FENa, calculated by measuring creatinine and sodium levels in the blood and urine simultaneously [(urinary sodium × serum creatinine)/(urinary creatinine × serum sodium)×100), has been described as an uncomplicated method to determine tubular handling of sodium because it can be calculated at any moment without the measurement of urine volume. A cutoff of <1% has been used to define the sodium-avid state of prerenal azotemia, whereas a FENa >1% indicates tubular damage and intrinsic kidney injury, sometimes referred to as acute tubular necrosis. Since its inception in 1976 when Espinel described its use in oliguric patients with AKI, the test has been widely used in hospitals to differentiate prerenal azotemia from acute tubular necrosis. Over the years, many studies, case reports, and reviews have been published on this particular method, with variable opinions about its effectiveness (1–3). In this issue of CJASN, to provide an update to the contemporary performance of this test, Abdelhafez et al. (4) have conducted a comprehensive literature search for worthwhile studies examining the sensitivity and specificity of this method in differentiating intrinsic from prerenal AKI using the 1% inflection point, with true positives denoted as those with intrinsic AKI and FENa >1%.The pooled sensitivity and specificity for FENa were 95% and 91%, respectively, in studies of oliguric patients that did not include patients with CKD or those on diuretic therapy, whereas the sensitivity and specificity dropped to 83% and 66%, respectively, if such patients were included. They concluded that FENa has the most utility in oliguric patients without CKD and not on diuretic therapy, as originally envisioned by the early propagators of FENa. Although this result is not at all surprising, it is still rewarding to see the validation of a method frequently used in clinical practice.

Understanding the pitfalls of FENa requires a deeper look into the mathematics of the equation and the underlying pathophysiology. An individual on an average Western diet who takes in approximately 3.4 g of sodium (∼150 mEq) per day has a FENa of <0.1% when getting rid of that sodium load considering a normal eGFR of 180 L/d (27,000 mEq of Na filtered). Yet, this does not indicate a sodium-avid state; it merely denotes normal sodium excretion. This is a reflection of the limitation of FENa in nonoliguric states or in states where GFR is relatively well preserved. In fact, the mathematics computes to a FENa of <1% in a prerenal state when the GFR is reduced to at least 10%–20% of normal. The severity of AKI required for FENa to have utility may not be immediately apparent unless urine output is minimal (<30 ml/h) and/or there is a rapid rise in creatinine. FENa cannot be used in individuals with CKD due to a similar reason, where low GFR (and hence, low sodium filtered per day) leads to a higher FENa to excrete an ingested sodium load and maintain a steady state.

FENa has traditionally been considered as lacking validity in patients on diuretics. In this study, FENa (>1%) had a specificity of just 54% in detecting intrinsic kidney injury. However, it is important to note that an FENa of <1% may still provide value in patients on diuretics, as noted by the high negative predictive value of 82% in this study (table 3 in the work by Abdelhafez et al. [4]). This is likely because diuretics may not have full effectiveness at the time of FENa calculation, and an FENa of <1% in such situations may indicate higher reversibility of renal perfusion with volume resuscitation. Fractional excretion of urea, an alternative to FENa with urea reabsorbed in the proximal tubule and less affected by diuretics, is not widely used in clinical settings. Other caveats for FENa use involve kidney injuries that spare tubular function, such as GN, interstitial nephritis, or vasculitis, and those that produce more vasoconstriction than tubular dysfunction, such as intravenous contrast administration (5). In addition, pigment-induced injuries, like rhabdomyolysis or hemoglobinopathies, can also mimic a prerenal state, yet there is indeed intrinsic AKI present (6). Such patients are excluded from all of the studies included in the systematic review. In practice, it is important to keep in mind that FENa is purely a marker for evaluating renal perfusion and tubular sodium handling and cannot fundamentally differentiate between “prerenal” and “renal” causes of AKI.

We need to explore the purpose of FENa with nuance. We should examine whether the intention to dichotomize perfusion-related AKI into prerenal azotemia versus intrinsic kidney injury serves a clinical or prognostic purpose (7). The same causes propagate both injuries, and they both lie on a spectrum of kidney insult that varies from mild to the most severe forms of AKI. Additionally, there are no specific markers or signs that indicate a transition point of severity from prerenal azotemia to intrinsic kidney injury. Clinically, although it seems prudent to try and identify earlier forms of disease in an attempt to mitigate damage, the “reversibility” of AKI depends more on the cause of low renal perfusion than on the fact that the patient presents at a less severe stage. Although milder, reversible forms of kidney injury may indicate favorable prognosis, it must be remembered that we do not possess great tools to treat early tubular injury and continue to rely on fluid resuscitation, which in itself may have adverse effects if too little or too much is given (8). A plethora of biomarkers (such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver fatty acid-binding protein) have shown promise as potential candidates for the early detection of kidney injury, but none have received widespread consensus for use in AKI risk assessment (9). The authors in this study suggest combining urine microscopy with FENa in future studies. This is a notable endeavor, however, combining a test limited by many caveats (FENa) with another (microscopy) that requires a concurrent urine sample drawn at the same point in time may make this less practical in clinical practice.

At this time, although newer methods are unproven, a comprehensive bedside clinical assessment in concert with accessories, such as FENa and urine microscopy, should be used to formulate a nuanced and expert opinion in these clinical scenarios. FENa is an attractive, physiology-based tool that may be used with knowledge as long as its caveats and limitations are recognized.

Disclosures

A.Z. Fenves reports consultancy agreements with Weber Gallagher & Associates Law Firm; royalties from UpToDate; honoraria from Advance-Medical for teledoc expert opinion; and expert review of records from the law firm Shook, Hardy and Bacon. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

A.Z. Fenves and H. Seethapathy conceptualized the study; A.Z. Fenves and H. Seethapathy were responsible for project administration; A.Z. Fenves provided supervision; A.Z. Fenves and H. Seethapathy wrote the original draft; and A.Z. Fenves and H. Seethapathy reviewed and edited the manuscript.