Finding the cause of acute kidney injury: Which index of fractional excretion is better?

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Urea is continuously produced in the liver as the end product of protein metabolism. It is a small, water-soluble molecule that freely passes across cell membranes and is therefore continuously filtered and excreted by the kidneys. Not merely a waste product, urea is also important in water balance and constitutes approximately half of the normal solute content of urine.22

Urea’s excretion mechanisms are well characterized.22,23 It is absorbed in the proximal tubule, the medullary loop of Henle, and the medullary collecting ducts via facilitated diffusion through specific urea transporters.24 After being absorbed in the loop of Henle, urea is resecreted, a process that creates an osmotic gradient along the medulla that ultimately regulates urea excretion and reabsorption in the medullary collecting duct. Low-volume states are associated with decreased urea excretion due to a physiologic increase in antidiuretic hormone secretion, and the reverse is true for high-volume states.

The FEU has been recognized as a clinically useful tool. The correlation between serum and urine urea concentrations was investigated as early as 1904.25 However, most studies during the ensuing century focused on the serum urea concentration or the creatinine-to-urea ratio as a measure of glomerular failure.26–28 In 1992, Kaplan and Kohn29 proposed that the FEU could be a useful measure for assessing renal dysfunction in acute kidney injury. Conceptually similar to the FENa, the FEU is calculated as:

An FEU less than 35% suggests a prerenal cause of acute kidney injury, while a value greater than 50% suggests an intrinsic one.


Kaplan and Kohn (1992)

Kaplan and Kohn,29 in their 1992 study, retrospectively analyzed 87 urine samples from 40 patients with renal dysfunction (not specifically acute kidney injury) thought to be secondary to volume depletion in which the FENa was discordant with the FEU.

Findings. Thirty-nine of the 40 patients treated with diuretics had a high FENa value. However, the FEU was low in all of these patients, leading the authors to conclude that the latter may be the more useful of the two indices in evaluating patients receiving diuretics who present with symptoms that suggest prerenal azotemia.

Limitations of the study. On closer inspection, these findings were not generalizable, for several reasons. First, the time that elapsed between administration of diuretics and evaluation of urinary electrolytes varied widely. Additionally, the study was a retrospective analysis of isolated urine specimens without clear correlation to a clinical patient or context. For these reasons, prospective analyses to investigate the utility of the fractional excretion of urea needed to be conducted.

Carvounis et al (2002)

Carvounis et al30 prospectively evaluated the FENa and the FEU in 102 consecutive intensive care patients with acute kidney injury (defined as a serum creatinine concentration > 1.5 mg/dL or an increase of more than 0.5 mg/dL in less than 48 hours). Oliguria was not an inclusion criterion for the study, but patients with acute glomerulonephritis and obstructive nephropathy were excluded. The study grouped subjects into those with prerenal azotemia, prerenal azotemia plus diuretic use, or acute tubular necrosis on the basis of the clinical diagnosis of the attending nephrologist.

Findings. The FEU was more sensitive than the FENa in detecting prerenal azotemia, especially in those with prerenal azotemia who were receiving diuretics. Overall, the FEU had higher sensitivity and specificity for prerenal azotemia regardless of diuretic usage, and more importantly, the best overall positive and negative predictive value for detecting it (99% and 75% respectively).

These results indicate that, in patients given diuretics, the FENa fails to discriminate between prerenal azotemia and acute tubular necrosis. Conversely, the FEU was excellent in discriminating between all cases of prerenal azotemia and acute tubular necrosis irrespective of the use of diuretics. This has significant practical application, given the frequency of diuretic use in the hospital, particularly in intensive care patients.

Limitations of the study. While the findings supported the utility of the FEU, the study population was limited to intensive care patients. Furthermore, the authors did not report the statistical significance of their findings.30

Pépin et al (2007)

Pépin et al8 performed a similar study, investigating the diagnostic utility of the FENa and the FEU in patients with acute kidney injury, with or without diuretic therapy.

The authors prospectively studied 99 consecutive patients confirmed by an independent nephrologist to have acute kidney injury (defined as an increase in serum creatinine of more than 30% over baseline values within less than 1 week) due to either volume depletion or ischemia. They excluded patients with less common causes of acute kidney injury, such as rhabdomyolysis, obstructive nephropathy, adrenal insufficiency, acute glomerulonephritis, and nephrotoxic acute kidney injury, as well as patients with chronic kidney disease.

Patients were grouped into those with transient acute kidney injury (from decreased kidney perfusion) and persistent acute kidney injury (attributed to acute tubular necrosis), with or without diuretic therapy, according to predefined clinical criteria. They were considered to have diuretic exposure if they had received furosemide (Lasix) within 24 hours or a thiazide within 48 hours of sampling.

Findings. The FENa proved superior to the FEU in patients not taking diuretics and, contrary to the findings of Carvounis et al,30 exhibited diagnostic utility in patients taking diuretics as well. Neither index discriminated between the different etiologies exceptionally well, however.

Of note, the study population was more inclusive than in previous studies, with only 63 intensive care patients, thus making the results more generalizable to all cases of inpatient acute kidney injury. Furthermore, the study included patients with and without oliguria, and the sensitivity and specificity of both the FENa and the FEU were higher in the nonoliguric group (n = 25).

Limitations of the study. The authors admit that a long time may have elapsed between diuretic administration and urine measurements, thereby mitigating the diuretic’s natriuretic effect independent of the patient’s volume status. While this variable may account for the better performance of the FENa than in the other studies, it does not account for the poor performance of the FEU.

Additionally, few of the findings reached statistical significance.

Lastly, a high percentage (30%) of patients had sepsis. The FEU is less effective in patients with infection, as cytokines interfere with the urea transporters in the kidney and colon.31

Lim et al (2009)

Lim et al32 conducted a study similar in design to that of Pépin et al.8

Findings. The FEU was as clinically useful as the FENa at distinguishing transient from persistent acute kidney injury in patients on diuretics. Using a cutoff FEU of less than 30% and a cutoff FENa of less than 1.5% for transient acute kidney injury (based on calculated receiver operating characteristic curves), FENa was more sensitive and specific than FEU in the nondiuretic groups. In patients exposed to diuretics, FEU was more sensitive but less specific than FENa.

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