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

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ABSTRACTThe fractional excretion of urea (FEU) is a useful index for differentiating the main categories of causes of acute kidney injury, ie, prerenal causes and intrinsic causes. It may be used in preference to the more widely used fractional excretion of sodium (FENa) in situations in which the validity of the latter is limited, such as in patients taking a diuretic.

KEY POINTS

  • Finding the cause of acute kidney injury is important, as management strategies differ.
  • Although cutoff values differ among studies, in a patient with acute kidney injury, an FENa lower than 1% suggests a prerenal cause, whereas a value higher than 3% suggests an intrinsic cause.
  • Similarly, an FEU less than 35% suggests a prerenal cause of acute kidney injury, whereas a value higher than 50% suggests an intrinsic one.
  • The FENa can be falsely high in patients taking a diuretic; it can be falsely low in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis.


 

References

An acute kidney injury can result from a myriad of causes and pathogenic pathways. Of these, the two main categories are prerenal causes (eg, heart failure, volume depletion) and causes that are intrinsic to the kidney (eg, acute tubular necrosis). Together, these categories account for more than 70% of all cases.1–3

While early intervention improves outcomes in both of these categories, the physician in the acute care setting must quickly distinguish between them, as their treatments differ. Similar clinical presentations along with confounding laboratory values make this distinction difficult. Furthermore, prolonged prerenal azotemia can eventually lead to acute tubular necrosis.

Therefore, several methods for distinguishing prerenal from intrinsic causes of acute kidney injury have been developed, including urinalysis, response to fluid challenge, the blood urea nitrogen-to-plasma creatinine ratio, levels of various urine electrolytes and biomarkers, and, the topics of our discussion here, the fractional excretion of sodium (FENa) and the fractional excretion of urea (FEU).4 While each method offers a unique picture of renal function, the validity of each may be affected by specific clinical factors.

Of note, the FENa has been shown to be inaccurate in patients with myoglobinuria,5 sepsis,6 or contrast-induced nephropathy,7 and in those taking a diuretic8 (Table 1). The FEU, which is not affected by concomitant diuretic use, has been proposed as an alternative. However, its utility has been debated.

In light of the frequent use of diuretics in inpatients and outpatients, a review of the utility of the FEU test is warranted. We will therefore present the theory behind the use of the FENa and the FEU for distinguishing intrinsic from prerenal causes of acute kidney injury, the relevant literature comparing the utility of these investigations, and our suggestions for clinical practice.

ACUTE KIDNEY INJURY DEFINED

Acute kidney injury (formerly called acute renal failure) describes an abrupt decline in renal function. Consensus definitions of it have been published and are gaining more widespread acceptance and use.9,10 The current definition is10:

  • An absolute increase in serum creatinine ≥ 0.3 mg/dL (26.4 μmol/L) in 48 hours, or
  • A percentage increase in serum creatinine ≥ 50% in 48 hours, or
  • Urine output < 0.5 mL/kg/hour for > 6 hours.

These clear criteria allow for earlier recognition and treatment of this condition.

Acute kidney injury is fairly common in hospitalized patients, with 172 to 620 cases per million patients per year.11–14 Furthermore, hospitalized patients with acute kidney injury continue to have high rates of morbidity and death, especially those with more severe cases, in which the mortality rate remains as high as 40%.15

FRACTIONAL EXCRETION OF SODIUM

The FENa is a measure of the extraction of sodium and water from the glomerular filtrate. It is the ratio of the rate of sodium filtration (the urinary sodium concentration times the urinary flow rate, divided by the plasma sodium concentration) to the overall glomerular filtration rate, estimated by the renal filtration of creatinine. It can be calculated as the ratio of plasma creatinine to urine creatinine divided by the ratio of plasma sodium to urine sodium:

A euvolemic person with normal renal function and moderate salt intake in a steady state will have an FENa of approximately 1%.16

In 1976, Espinel17 originally showed that the FENa could be used during the oliguric phase in patients in acute renal failure to differentiate between prerenal acute kidney injury and acute tubular necrosis. Given the kidney’s ability to reabsorb more sodium during times of volume depletion, Espinel suggested that an FENa of less than 1% reflected normal sodium retention, indicating a prerenal cause, ie, diminished effective circulating volume. A value greater than 3% likely represented tubular damage, indicating that the nephrons were unable to properly reabsorb sodium.

The clinical utility of this index was apparent, as the management of prerenal azotemia and acute tubular necrosis differ.18 While both require fluid repletion, the risk of volume overload in acute tubular necrosis is high. Furthermore, acute tubular necrosis secondary to nephrotoxins could require hemodialysis to facilitate clearance of the offending agent.

The FENa test was subsequently validated in a number of studies in different populations and is still widely used.19–21

Limitations to the use of the FENa have been noted in various clinical settings. Notably, it can be falsely depressed in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis. Conversely, patients with prerenal acute kidney injury who take diuretics can have a falsely elevated value due to the pharmacologically induced renal excretion of sodium independent of volume status. This is commonly seen in patients on diuretic therapy with baseline low effective circulating volumes, such those with congestive heart failure and hepatic cirrhosis.

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