The urea-creatinine ratio as a novel biomarker of critical illness-associated catabolism
Despite advances in intensive care medicine, a considerable number of patients evolve into a stage of persistent critical illness, with prolonged dependency on intensive care, which is associated with poor prognosis [1, 2]. Effectuated by persistent inflammation, neurohumoral alterations, and prolonged immobilization, such patients enter a catabolic state that is often not suppressed by feeding [3, 4]. Ongoing catabolism ultimately leads to severe muscle wasting and associated weakness, which impairs outcome [3, 5]. Currently, monitoring catabolism is cumbersome, since there is no routinely available biomarker with acceptable sensitivity and specificity. Assessment of 3-methylhistidine, released into the circulation during protein degradation, is complex and extends beyond routine measurements . Also, accurate monitoring of nitrogen losses and balances poses multiple challenges in critically ill patients . As catabolism is not accurately measured on a routine basis, its presence and severity often become clear once muscle wasting and weakness are established. The lack of validated and routinely available biomarkers of catabolism to some extent hampers epidemiological and interventional studies on this topic.
In this issue of Intensive Care Medicine, Haines et al. identified the urea over creatinine ratio (UCR) as a potential biomarker of critical illness-associated catabolism . In the absence of a gold standard, the evidence supporting the relationship is mainly indirect. Indeed, to confirm their hypothesis, the investigators focused on the difference between short- and long-stay intensive care unit (ICU) patients, the latter expectedly being more catabolic. In two large trauma ICU cohorts, involving in total > 4000 patients, investigators found a significantly different temporal trend in UCR. Although UCR initially increased in all patients, the rise was substantially greater in patients still in the ICU on day 10 as compared to patients discharged alive earlier. After day 9, when the phenotype of persistent critical illness generally has developed [2, 7], daily UCR discriminated patients with prolonged ICU stay better than baseline illness severity and antecedent patient characteristics, putting forward UCR as a key metabolic signature of persistent critical illness. The increase in UCR coincided with a progressive loss of muscle mass, as assessed by L4 psoas and L3 muscle cross-sectional area (CSA) in 107 patients who had serial CT scans available. Based on CSA, patients with persistent critical illness lost muscle mass more profoundly than surviving short stayers. In a small subgroup of patients with persistent critical illness, CSA negatively correlated with UCR at the time of the second scan. Hence, UCR could be a surrogate for muscle mass at that time.
Although the evidence is circumstantial, the physiological base for UCR, as a catabolic biomarker, is quite strong. Indeed, as catabolism likely increases ureagenesis, whereas progressive loss of muscle mass leads to decreased creatinine generation, the trajectories of urea and creatinine in catabolic state expectedly evolve in opposite directions. Hence, elevated UCR could be a physiologically plausible indicator of ongoing catabolism, and as such, be used as a signature for the catabolic state of persistent critical illness. Previous research showed similar time profiles of urea, creatinine, and UCR in mixed ICU patients , suggesting that current findings are not specific to trauma patients.
The identification of UCR as a potential marker of critical illness-associated catabolism is highly relevant for future studies. Indeed, instead of merely investigating the end-product of catabolism (i.e., sarcopenia), future metabolic studies should consider monitoring UCR as a biomarker of the catabolic process itself. This may assist in identifying early effects of an intervention, before impact on muscle mass and function has become clear. Moreover, large observational studies could use UCR to gain insights into risk factors and potential therapeutic targets of critical illness-associated catabolism. In nutritional studies, however, it is important to consider that elevated UCR can result from metabolism of exogenous amino acids on top of endogenous catabolism [8, 9].
The use of renal function markers as indicators of low muscle mass, as the catabolic end-product, is not unprecedented. Previously, the sarcopenia index, calculated as the serum creatinine-to-cystatin C ratio, was described as a biomarker of decreased muscle mass in critically ill patients [12, 13]. Unlike urea and creatinine, however, cystatin C is usually not routinely measured. Hence, the use of UCR for estimating muscle mass may be more evident. However, caution is needed since urea is a product of active proteolysis, hence low UCR may not necessarily exclude low muscle mass. This contrasts with creatinine and cystatin C, of which production rate is directly related to muscle mass and the number of nucleated cells, respectively. Moreover, the correlation between UCR and muscle CSA was only observed in a small subset of patients at one time point, which requires confirmation.
Finally, another interesting finding is the progressive decrease of creatinine during critical illness, which is corroborated by other investigators . This questions the accuracy of detecting AKI when solely relying on serum creatinine. Indeed, these data may indicate that during critical illness, such an approach may considerably underestimate the incidence of AKI .
In conclusion, Haines et al. identified UCR as a metabolic signature for the ongoing catabolic state characterizing persistent critical illness. Clinical usability of UCR appears to be limited by potential confounders that may increase UCR independent of catabolism. Whether UCR can act as marker of decreased muscle mass in persistent critical illness requires confirmation. Nevertheless, UCR could be a novel, readily available, and promising biomarker of catabolism in future epidemiological and clinical studies.
JG holds a postdoctoral research fellowship from the Clinical Research and Education Council of the University Hospitals Leuven. GH holds a Fundamental Clinical Research fellowship from the Research Foundation—Flanders (1805116N).
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Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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