Fractional excretion of urea (FEUrea)

Clinical background

In acute renal failure the first diagnostic step is to distinguish prerenal (functional, potentially reversible) from intrinsic (structural, tubular injury) renal failure. The traditional method, the fractional excretion of sodium (FENa), rests on the fact that sodium reabsorption increases in prerenal hypoperfusion. But loop and thiazide diuretics increase sodium excretion independently of the underlying mechanism and thereby invalidate FENa. FEUrea fills precisely this gap: urea is reabsorbed mainly in the proximal tubule by passive forces governed by vasopressin and the renin–angiotensin–aldosterone system, and is therefore considerably less affected by diuretics acting more distally [1]. The decision the tool serves is whether the patient should receive volume expansion (prerenal) or whether the investigation should be directed towards intrinsic kidney injury and its causes.

Calculating the fractional excretion of urea (FEUrea)

$$\text{FEUrea} = \frac{U_{\text{urea}} \times S_{\text{creatinine}}}{S_{\text{urea}} \times U_{\text{creatinine}}} \times 100,$$

where $U_{\text{urea}}$ is the urea nitrogen in urine, $S_{\text{urea}}$ is the urea nitrogen in serum (BUN), $S_{\text{creatinine}}$ is the serum creatinine and $U_{\text{creatinine}}$ is the urine creatinine. The units cancel, so any consistent units may be used for each pair.

The derivation cohort consisted of 102 episodes of acute renal failure at a single American university hospital [1]. The patients were divided into three groups: prerenal azotaemia without diuretics ($n = 50$), prerenal azotaemia on diuretic treatment ($n = 27$) and acute tubular necrosis (ATN) ($n = 25$). The outcome modelled was the clinical differential diagnosis of prerenal azotaemia versus ATN. A threshold of $\leq 35,$ was established as the dividing line between prerenal and intrinsic renal failure.

Interpretation in practice

A low value confirms prerenal azotaemia and warrants aggressive volume treatment. A high value shifts the focus to structural injury and its causes. In patients on diuretics, in whom FENa is raised whatever the mechanism, a FEUrea $\leq 35,$ can confirm a prerenal cause when FENa is no longer interpretable [1].

Validation and performance

In the derivation cohort, FEUrea was essentially identical between prerenal patients with and without diuretics (27.9 and 24.5 percentage points respectively), and clearly lower than in ATN (58.6 percentage points, $p < 0{.}0001$) [1]. Of the patients with prerenal azotaemia on diuretics, 89 per cent had a FEUrea below 35 per cent, compared with only 48 per cent who had a FENa below 1 per cent, which was the study's main argument for FEUrea in patients on diuretics.

A systematic review and meta-analysis from 2024, including 11 studies with a total of 1,108 hospitalised patients, nonetheless found moderate performance for FEUrea at the 35 per cent threshold: pooled sensitivity 66 per cent (95 per cent CI 49–79) and specificity 75 per cent (95 per cent CI 60–85) for distinguishing intrinsic from prerenal AKI [2]. In the subgroup of patients given diuretics, FEUrea had lower sensitivity but higher specificity than FENa (sensitivity 52 and 92 per cent respectively; specificity 82 and 44 per cent respectively) [2]. This means that in the setting of diuretic treatment FEUrea gives fewer false positives (prerenal cases wrongly classified as ATN) but more false negatives (ATN missed).

In patients with decompensated cirrhosis the results have been contradictory. Patidar et al. studied 50 patients in a derivation cohort and 50 in a validation cohort, all with cirrhosis and ascites [3]. The AUC for FEUrea was 0.96 (cut-off 33.4 per cent, sensitivity 85 per cent, specificity 100 per cent) for ATN versus non-ATN in the derivation cohort, and performance was maintained in the validation cohort (sensitivity 93 per cent, specificity 97 per cent) [3]. Gowda et al., by contrast, could not reproduce this in a prospective study with 200 patients in a derivation cohort and 50 in a validation cohort: the AUC for FEUrea was only 0.603 (cut-off 34.7 per cent, sensitivity 70 per cent, specificity 58 per cent) for ATN versus non-ATN, and FEUrea could not distinguish the hepatorenal syndrome from other phenotypes (AUC 0.604) [4].

Limitations

FEUrea applies to the prerenal versus intrinsic AKI distinction in generally non-cirrhotic practice. In cirrhosis the evidence is contradictory: two studies of similar design gave AUCs from 0.96 to 0.60, so that FEUrea cannot be recommended unequivocally in this population [3, 4]. In patients with cirrhosis the hepatorenal syndrome is an additional separate phenotype, and FEUrea has not been shown to distinguish this reliably from prerenal azotaemia [4].

The pooled performance in the meta-analysis was considerably poorer than in the original derivation cohort, which is explained in part by the heterogeneity of the studies and their small patient groups, but also by the fact that the clinical diagnosis of prerenal versus ATN is itself uncertain and has no independent gold standard [2]. Sepsis can affect urea handling and hence FEUrea independently of the mechanism, so caution is recommended in septic patients.

A common mistake is to interpret FEUrea as an absolute measure rather than as support for the differential diagnosis. A value just below or just above 35 per cent should not drive the decision on its own; the overall clinical picture, the urinary sediment, the response to volume expansion and the search for nephrotoxic factors must all be weighed in. Nor is FEUrea dynamic: when the clinical picture changes or treatment has begun, the value should not be interpreted retrospectively.

References

1. Carvounis CP, Nisar S, Guro-Razuman S. Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure. Kidney Int. 2002;62(6):2223–9. PMID: 12427149
2. Abdelhafez MO, Alhroob AA, Abu Hawilla MO et al. Utility of fractional excretion of urea in acute kidney injury with comparison to fractional excretion of sodium: A systematic review and meta-analysis. Am J Med Sci. 2024;368(3):224–234. PMID: 38768779
3. Patidar KR, Kang L, Bajaj JS et al. Fractional excretion of urea: A simple tool for the differential diagnosis of acute kidney injury in cirrhosis. Hepatology. 2018;68(1):316–25. PMID: 29315697
4. Gowda YHS, Jagtap N, Karyampudi A et al. Fractional excretion of sodium and urea in differentiating acute kidney injury phenotypes in decompensated cirrhosis. J Clin Exp Hepatol. 2022;12(3):899–907. PMID: 35677524