Fractional Excretion of Sodium and Urea are Useful Tools in the Evaluation of AKI: COMMENTARY

AKI is a common condition, occurring in approximately 20% of hospitalized adult patients in high-resource settings¹ and 57% of those in intensive care units.² In a study of 13 tertiary care hospitals,³ the most frequent etiologies of AKI were acute tubular necrosis (ATN) in 41%, prerenal failure in 26%, AKI with CKD in 13%, and obstructive uropathy in 10%. Differentiating prerenal failure from ATN or other intrinsic kidney disorders is of considerable importance as it usually determines the aggressiveness of remedial therapy, mainly volume repletion, to lessen the chance that prerenal failure will convert to ATN with its increased morbidity and mortality. Whether an oliguric patient will respond to volume expansion with increased urine output is not without risk as volume overload has been shown to be independently associated with progressive renal dysfunction, lower odds of renal recovery, and increased mortality.²

The fractional excretion of sodium (FENa) or, to a lesser extent, fractional excretion of urea (FEUrea), in a “spot” urine sample from patients with AKI, has been used to help make this crucial distinction between prerenal failure and ATN or other intrinsic kidney diseases. However, recently, the value of FENa⁴ and FEUrea⁵ in many settings has been questioned. The arguments for their continued use⁶ or not⁷ are presented in the accompanying articles, and I have been asked to offer my perspective on this controversy.

Hamadah and Gharaibeh⁶ promoting the use of FENa and FEUrea cite a large meta-analysis⁸ of 1287 patients. In this study, a FENa of <1% differentiated prerenal failure from intrinsic AKI with a pooled sensitivity of 90% and specificity of 82%.⁸ In oliguric patients without CKD or diuretic use, the pooled sensitivity and specificity increased to 95% and 91%, respectively. However, in patients with CKD or on diuretics, the pooled sensitivity and specificity dropped to 83% and 66%, respectively.⁸ Since loop diuretics or thiazides are presumed not to greatly affect proximal tubular absorption where urea is reabsorbed, in a study⁹ of patients with AKI on diuretics, of those who had prerenal failure, 89% had a FEUrea <35%, with only 4% of those with ATN having a FEUrea <35%. This yielded a positive predictive value of 98% for prerenal failure, whereas only 48% of prerenal failure patients on diuretics had a FENa <1%.⁹

Aron and Amatruda⁷ in their counter argument note that various disease states and conditions affect FENa and FEUrea as presented in their Table 1. They note that patients with acute GN or obstruction may have FENa's <1%, and to further confuse the issue, those with ATN from liver failure, congestive heart failure, radiocontrast, and early sepsis may have FENa's <1%.¹⁰ In addition, FEUrea may not be reliably <35% in congestive heart failure patients with prerenal failure receiving diuretics.¹¹ Instead, they propose using the findings of casts and renal tubular epithelial cells on urine microscopy now, and novel biomarkers, such as kidney injury molecule-1 (KIM-1) soon, to diagnose ATN rather than FENa and FEUrea results that may mislead the clinician.

So what are my thoughts? First, laboratory tests are not performed in a vacuum and need not be performed in every patient with AKI, as they are in the prospective studies cited. The interpretation of all tests, and in this case, FENa or FEUrea, usually depends on the clinical scenario. The history, physical examination, and urinalysis with sediment microscopy will be performed before FENa or FEUrea results become known. Those findings may already point to a likely diagnosis. For example, the urine sediment may document muddy brown casts of ATN or red blood cell casts or acanthocytes suggesting an acute GN or vasculitis. In current medical practice, ultrasonography (including point-of-care ultrasonography) is often available as well, helping to evaluate whether an obstructive uropathy is present. However, when no evidence of an etiology is found and the differential remains largely between prerenal failure and ATN, as it is in 75%–80% of patients with AKI, I would request a FENa in all such patients and a FEUrea in those on diuretics. The results of these tests are particularly useful in patients with oliguria in whom the accuracy is higher and the risk of volume overload is greater.

I should add that urine osmolality (UOsm) seems to be a forgotten test as a potentially useful marker in oliguric patients without GN. If the UOsm is >500 mOsm/kg, as was seen in 62% of patients with prerenal AKI, <10% of those had ATN.¹² Conversely, if the UOsm is <350 mOsm/kg, as was seen in two thirds of ATN patients, <10% of those had prerenal failure.¹²

The findings of these studies have important limitations. In addition to the differences among individual patients and their concomitant illnesses, medications, etc., the urine specimens may be taken initially or only after volume expansion and other treatments have been started. The latter conditions may weaken the sensitivity and specificity of the FENa and FEUrea findings, but that will be known to the managing clinician. Moreover, another shortcoming cited has been that a low FENa or FEUrea might indicate prerenal failure in a subset of nephrons, whereas other nephrons may have ATN indicated by casts in heterogeneous kidney injury.¹³ This so-called “intermediate syndrome” is seen frequently in AKI in older patients¹⁴ and those with sepsis.¹⁵ I would argue that a low FENa in these circumstances is still helpful as rapid, but controlled, volume repletion despite the finding of muddy brown casts may preserve those hypoperfused nephrons to yield better kidney function. As with any test with variable accuracy, even kidney biopsies, an experienced clinician must know which patient will benefit, when to order the test, and how to interpret its results. With that in mind, a FENa of <1% will be supportive of prerenal failure or a FENa of >2%–3% supportive of ATN in the appropriate settings. Similarly, a FEUrea of <35% or >35% may be helpful in diagnosing those with AKI on diuretics.

I would be less than candid if I did not include the results of a straw poll that I conducted among my colleagues, the clinical faculty, and senior fellows in my Nephrology Division at the Beth Israel Deaconess Medical Center. Only two thirds of these 12 nephrologists ordered a FENa in undiagnosed AKI patients all or most of the time, and only one-third ordered a FEUrea in those on diuretics all or most of the time. Now, I must attempt to convince our nephrologists that these tests have not outlived their usefulness.

Novel biomarkers may replace the FENa and FEUrea in the future but are not yet useful for the management of patients with acute AKI. Neutrophil gelatinase-associated lipocalin is commercially available, but turn-around time is approximately 2 days, rather than the 1–2 hours for FENa and FEUrea. Moreover, the test is expensive. Hence, until biomarkers become clinically tested, affordable, and have rapid turn-around times, FENa and FEUrea will continue to serve a helpful diagnostic purpose in AKI.

Disclosures

R.S. Brown reports the following: Employer: Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Boston, MA; Ownership Interest: Shares of Innovative Wellness Systems, Inc. (privately held), Publicly traded: Apple, AT&T, Brookfield Infrastructure Corp, Costco, CVS, Disney, Emergent Solutions, Jabil Circuit, Nextera Energy, Nokia Corp, Pepsico, Proctor and Gamble, Raytheon Technologies, Rocket Cos, Scotts Miracle Gro Co, Starbucks, and Volkswagen Warner Bros Discovery; Research Funding: Vertex Pharmaceuticals; Honoraria: Beth Israel Deaconess Medical Center and Harvard Medical School Department of Continuing Education; Advisory or Leadership Role: Board of Directors and President of The Organization for Renal Care in Haiti, TORCH, Inc, a nonprofit, charitable Massachusetts corporations and Member of the Medical Advisory Board of the National Kidney Foundation of New England. No income is received from any of these entities; and Other Interests or Relationships: Börm Bruckmeier Publishing LLC, DaVita Dialysis Center, Brookline, MA, Elsevier, Inc, and Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center (HMFP).

Funding

None.

Author Contributions

Data curation: Robert S. Brown.

Formal analysis: Robert S. Brown.

Writing – original draft: Robert S. Brown.

Writing – review & editing: Robert S. Brown.