The urea-to-creatinine ratio as an emerging biomarker in critical care: a scoping review and meta-analysis

Abstract

Background

Severe protein catabolism is a major aspect of critical illness and leads to pronounced muscle wasting and, consequently, extended intensive care unit (ICU) stay and increased mortality. The urea-to-creatinine ratio (UCR) has emerged as a promising biomarker for assessing protein catabolism in critical illness, which is currently lacking. This review aims to elucidate the role of UCR in the context of critical illness.

Methods

This scoping review adhered to the PRISMA Extension for Scoping Reviews guidelines. A comprehensive literature search was conducted on the 3rd of September 2024, across Embase, PubMed, ScienceDirect, and Cochrane Library to identify studies related to (1) critically ill adult patients and (2) reporting at least a single UCR value. A meta-analysis was conducted for ≥ 5 studies with identical outcome parameters.

Results

Out of 1,450 studies retrieved, 47 were included in this review, focusing on UCR's relation to protein catabolism and persistent critical illness (10 studies), mortality (16 studies), dietary protein interventions (2 studies), and other outcomes (19 studies), such as delirium, and neurological and cardiac adverse events. UCR is inversely correlated to muscle cross-sectional area over time and associated to length of ICU stay, emphasising its potential role in identifying patients with ongoing protein catabolism. A UCR (BUN-to-creatinine in mg/dL) of ≥ 20 (equivalent to a urea-to-creatinine in mmol/L of approximately 80) upon ICU admission, in comparison with a value < 20, was associated with a relative risk of 1.60 (95% CI 1.27–2.00) and an adjusted hazard ratio of 1.29 (95% CI 0.89–1.86) for in-hospital mortality.

Discussion

UCR elevations during critical illness potentially indicate muscle protein catabolism and the progression to persistent critical illness, and high levels at ICU admission could be associated with mortality. UCR increments during ICU stay may also indicate excessive exogenous dietary protein intake, overwhelming the body's ability to use it for whole-body or muscle protein synthesis. Dehydration, gastrointestinal bleeding, kidney and liver dysfunction, and renal replacement therapy may also influence UCR and are considered potential pitfalls when assessing catabolic phases of critical illness by UCR. Patient group-specific cut-off values are warranted to ensure its validity and application in clinical practice.

Introduction

Critically ill patients are in a catabolic state due to extensive inflammation, neurohumoral changes, and prolonged immobilisation. When ongoing, protein catabolism may lead to significant muscle wasting and consequent weakness [1,2,3], resulting in prolonged ICU stay [4, 5] and increased risk of long-term disability or death [3, 5,6,7]. Existing biomarkers to monitor muscle wasting during critical illness are often complex and expensive, and more diagnostic accuracy is needed to accurately capture the full extent of catabolic activity [8, 9]. Therefore, identifying a reliable and standardised biomarker that can be easily measured and monitored is essential to detect and monitor ongoing catabolism in critically ill patients.

The urea-to-creatinine ratio (UCR), the quotient of (blood) plasma urea (nitrogen) over creatinine, may be a useful biomarker of overall protein catabolism in critically ill patients [10, 11]. Urea, produced in the liver as a by-product of protein breakdown, rises in the blood during catabolic states due to heightened proteolysis [8]. Although elevated plasma urea reflects overall protein breakdown, skeletal muscle represents the largest protein reservoir in the body [12, 13] and ICU patients undergo extensive skeletal muscle wasting during periods of severe illness [1]. Therefore, increments in plasma urea are likely to be related to the extent of muscle atrophy during critical illness, in addition to exogenous protein provision. Simultaneously, creatinine production decreases primarily due to the reduction in absolute skeletal muscle mass, as serum creatinine is mainly a breakdown product of muscle creatine phosphate. The combination of increased urea and decreased creatinine results in a rise in UCR. As such, this may indicate significant protein catabolism, often seen in stress, infection, or corticosteroid use [8]. Accordingly, an elevated UCR may serve as a potential indicator of muscle wasting, reflecting both the increased breakdown of muscle proteins and the reduction in muscle mass [8, 14].

Although urea and creatinine are frequently monitored in ICUs, the clinical potential of UCR is frequently under-recognised, and its broader utility in managing critical illness remains largely unexplored. In addition to its role as a marker for the end products of protein catabolism, Gunst et al. proposed that the UCR could be used to monitor the catabolic process of muscle proteins during critical illness [8]. This may enable the modification of dietary regimens and the introduction of therapeutic measures before the discernment of alterations in muscle mass and functionality. Prior research has demonstrated that a high UCR may be indicative of an excess of exogenous amino acids, in addition to endogenous catabolism [15, 16], suggesting that the supply of dietary protein may exceed the body's capacity for utilisation at that moment. This phenomenon is known as anabolic resistance, the reduced ability of muscle tissue to synthesize protein in response to anabolic stimuli like dietary protein or exercise [17]. This condition is driven by inflammation, insulin resistance, and physical inactivity [17]. These mechanisms reduce the effectiveness of key pathways like mTOR signalling, contributing to muscle loss and functional decline, particularly in aging, chronic disease, and critical illness [17, 18].

The finding that UCR may reflect anabolic resistance and even harm by high protein dosing is also corroborated by the reanalysis of the EFFORT protein trial, indicating that the elevated risk of mortality observed in critically ill patients randomised to a higher protein dose may be attributed to extensive ureagenesis [19]. Conversely, a low or declining UCR could serve as a marker for protein-responsive ICU patients [20].

There is an increasing need for personalised nutrition to provide optimal nutrition dose and timing for critically ill patients [21], a necessity that experts in a consensus paper have also acknowledged [22]. In this context, the bedside biomarker UCR could prove useful in determining the extent, timing, and variability of anabolic responses, particularly as anabolic resistance resolves and the state shifts toward improved metabolic responsiveness to feeding.

This scoping review elucidates the roles of UCR in the context of critical illness. It aims to investigate the role of UCR as a potential biomarker of muscle wasting and indicator for persistent critical illness, the association of UCR and mortality in critically ill patients, the potential of UCR as a biomarker in response to nutrition interventions, and understand any other roles of UCR in critical illness. Furthermore, this scoping review highlights the pitfalls of interpreting UCR values, delineates areas of current knowledge deficiency, and offers recommendations for enhancing critical care.

Methods

This scoping review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) Extension for Scoping Reviews guidelines [9], with the study protocol registered on the 28 th of August 2024, on the Open Science Framework (https://doi.org/10.17605/OSF.IO/M365Q). A literature search was conducted on the 3rd of September 2024, across multiple databases, including Embase, PubMed, ScienceDirect, and the Cochrane Library, to identify relevant studies on UCR in critically ill patients. The primary search terms included'critical illness,''UCR,'and related variations (Additional file 1: Table S1). No restrictions were applied regarding publication year and status.

Articles were included if they focused on (1) critically ill adult patients (age ≥ 18 years) and 2() UCR in any context (as descriptive or outcome measure). No restrictions were placed on geographical location, patient race, sex, or the type of critical care facility. All identified articles were imported into Rayyan, an online tool for conducting systematic reviews, where duplicates and triplicates were manually identified and removed [23]. Two authors (MCP & AvE) independently screened the remaining articles based on their titles and abstracts. Full texts of the selected articles were then obtained for further review. If full texts were unavailable, authors were contacted for access. Studies were excluded if (1) they did not include data specifically related to critically ill patients, (2) only a case report, symposium abstract, or editorial was available, and 3) the study was in a foreign language with no available translation. Additional articles were identified using the included studies'relevant search terms and reference lists. The full-text screening was conducted independently by two authors (MCP & AvE). In cases of disagreement, they discussed the issue to reach a consensus. In cases where consensus could not be reached, an adjudicator made the final decision (AvZ). Data was extracted independently by two authors (MCP & AvE), abstracted data including year of publication, country of origin, population and sample size, sex distribution, inclusion/exclusion criteria, methodology, outcome measures, and key findings are summarised in Table 1, 2, 3 and Additional file 1: Table S3. Only studies that met the criteria of comparing two UCR groups were included in the post-hoc meta-analysis. When possible, two groups were constructed based on the available data, with the classification of these groups being determined by the cut-off value as reported in the article. In instances where multiple groups were presented and their integration into two groups was possible, the cut-off value that corresponded most closely to a BUN/Cr ratio of 20 was selected to ensure the comparability of the results with those of other studies. The quality of the included studies was evaluated using the JBI Critical Appraisal Tools [24], with higher scores indicating a higher study quality.

Table 1 Role of UCR as a catabolic marker and indicator for persistent critical Illness

Table 2 Summary of included articles assessing the impact of UCR on mortality risk in critically Ill patients

Table 3 Summary of included articles assessing the relation between UCR and protein intake in critically Ill patients

In this review, the term UCR is used to refer to both the blood urea nitrogen (BUN)-to-creatinine ratio and the urea-to-creatinine ratio due to both measurements being reported as UCR in the studies under review. If values are referenced in the review, they pertain to the BUN-to-creatinine ratio in mg/dL:mg/dL, unless otherwise indicated. In instances where five or more studies employed the same outcome measure and sufficient event data were available to calculate risk ratios, post-hoc meta-analyses were conducted with a random effects model using R Studio version 2023.06.1 and R version 4.4.1 and presented in forest plots. Heterogeneity was quantified using the I² measure, and a P-value < 0.05 was considered statistically significant. The established cut-off values for UCR were maintained, as presented in the original studies, with the UCR cut-off value illustrated in the meta-analysis. In cases where multiple cut-off values were reported, the one most consistent with the other studies was used.

Results

A total of 1,450 studies were initially identified in the search, with 140 selected after title and abstract screening (Additional file 1: Table S1). Additional file 1: Fig. S1 and Table S4 present the exclusion criteria for full-text articles. After a comprehensive review with 94% initial consensus during the independent review process, 47 articles investigating UCR in critically ill patients were included. These studies focused primarily on the following areas: 10 on muscle wasting and persistent critical illness (Table 1), 17 on mortality (Table 2), two on protein interventions (Table 3), and 19 on other roles (Additional file 1: Table S3). A critical appraisal checklist for the included studies is provided in Additional file 1: Table S2.

UCR as indicator of catabolism

Two studies have been conducted to determine the relationship between UCR and muscle mass (Table 1). A study by Haines et al. among 1173 ICU patients after major trauma found no correlation between muscle cross sectional area (CSA) measured on L3 and L4 level on Computed Tomography (CT) and UCR at ICU admission. However, it was observed that the group with an ICU stay ≥ 10 days had increased UCR from ICU admission to discharge compared to those discharged from the ICU before day 10 (133% vs. 59%, p < 0.001) [14]. In patients with persistent critical illness, a negative correlation was observed between UCR and muscle CSA after day 10 (L4 psoas and L3 muscle CSA R² 0.39 and 0.44, respectively, both p < 0.001). This correlation consisted of a median decrease of 34% in the L4 psoas CSA and a 21% decrease in the L3 muscle CSA, with a concomitant 221% increase in UCR (from urea-creatinine-ratio 51 mmol/L: mmol/L [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67] to 164 mmol/L: mmol/L [109–200], p < 0.001). Additionally, in a single centre retrospective investigation in mixed medical-surgical ICU patients it was observed that UCR during the first three days of ICU admission was higher in medical patients with persistent critical illness (n = 250) compared to those without (n = 862), but no difference was found in UCR trajectory in the trauma subpopulation [25]. However, Araújo et al. found no statistically significant association between UCR and reduced calf circumference in 208 Coronavirus disease 2019 (COVID-19) ICU patients (OR 1.01, 95% CI 0.99–1.03, p = 0.194), but the dynamics of UCR and calf circumference during or after ICU stay was not followed up on [26].

A study in 1388 ICU patients observed that patients with overweight (BMI ≥ 25 kg/m²) exhibited lower net protein catabolism (reduced net nitrogen loss and reduced UCR on ICU day 5) than matched lean patients (BMI < 25 kg/m²)[27]. Furthermore, sex differences may play a role, with a study in 73 critically ill burn patients showing a significant correlation between UCR and duration of ICU stay in female patients only [28]. A study by Zijlstra et al. in ICU patients with an ICU stay of ≥ 28 days also observed that the UCR is consistently higher in women than in men [12]. In line with the study by Haines et al. [14], studies indicate that UCR possibly increases during ICU stay, with patients having a prolonged ICU stay showing a greater increase in UCR compared to those with a shorter ICU duration [10, 12, 14, 29]. Notably, Zijlstra et al. also observed that the increase in UCR appears to be most pronounced 7–10 days after ICU admission, after which it gradually increases further [12]. This study showed that both plasma and urinary UCR increased throughout the entire ICU stay, exhibiting a comparable trajectory.

Rousseau et al. observed in ICU survivors (n = 64) a significant decrease in UCR values at three months post-ICU discharge compared to ICU discharge (p = 0.008), paralleling serum short chain acylcarnitine levels that are indicative of impaired protein metabolism [30]. An increase in the sarcopenia index, an index of skeletal muscle mass (ratio between serum creatinine and serum cystatin C), accompanied this observation. Moreover, in a study of long-term mechanically ventilated patients, UCR was related to long-term clinical outcomes. Patients who successfully weaned from invasive mechanical ventilation (n = 205) exhibited a lower UCR at 6 weeks of ventilator dependency compared to those who remained ventilator-dependent or had died (n = 190; 28.7 vs 35.9, p = 0.001)[31].

UCR and ICU admission

In addition to the UCR-related observations during ICU stay and post-ICU recovery, several studies have assessed the predictive value of UCR to become admitted to the ICU. A retrospective study demonstrated that UCR exhibits moderate predictive performance for the likelihood of ICU admission in emergency department patients (n = 914), with an AUC of 0.61 [95% CI: 0.58–0.64] and an optimal predictive value of 23.64 [32]. A tendency for UCR to predict the likelihood of ICU admission by 6% for each 5-unit UCR increase was observed (HR 1.06, 95% CI: 0.99–1.12, p = 0.085)[33]. Furthermore, a single-centre, retrospective case–control study among 95 adult COVID-19 patients also demonstrated that UCR was an independent predictor of admission to an ICU (Odds Ratio = 1.72, 95% CI 1.20–2.66)[34]. However, this was not applicable to hospitalised patients with chronic kidney disease [35]. Additionally, UCR has been linked to disease severity, as demonstrated by a retrospective Indian study of hospitalised COVID-19 patients (n = 996), which found higher UCR levels in severe cases compared with mild cases (clinical severity classified according to peripheral oxygen saturation; AUC 0.62, 95% CI 0.56–0.67, optimal cut-off 14.5)[36].

UCR and mortality in critically Ill patients

Seventeen studies have examined the association between UCR and mortality (see Table 2). Forest plots were generated to summarise the association between UCR and in-hospital mortality across studies included in the meta-analysis (Figs. 1 and 2). The forest plots for unadjusted relative risks (RR) exhibited higher in-hospital mortality in the higher UCR group (RR = 1.53, 95% CI: 1.16, 2.03). However, this trend diminished with adjusted hazard ratios (HR), where UCR was incorporated in multivariable Cox regression models (adjusted HR = 1.25, 95% CI: 0.77, 2.01). Additionally, several studies have indicated that the relationship between UCR and in-hospital mortality may not be linear. Both low and high UCR have been observed to be associated with an elevated risk of in-hospital mortality, indicating a U-shaped association [37,38,39].

Fig. 1

Forest plot of relative risk for in-hospital mortality. The illustration depicts forest plots derived from a meta-analysis conducted with a random-effects model. The degree of heterogeneity was evaluated using the I² statistic. The UCR cut-off values were retained as reported in the original studies, with the value closest to 20 (BUN:C, mg/dL:mg/dL) chosen for comparison with other studies. This figure illustrates unadjusted relative risks based on the number of in-hospital mortality events in the low and high UCR groups

Fig. 2

Forest plot of hazard risk for in-hospital mortality. The illustration depicts forest plots derived from a meta-analysis conducted with a random-effects model. The degree of heterogeneity was evaluated using the I.² statistic. The UCR cut-off values were retained as reported in the original studies, with the value closest to 20 (BUN:C, mg/dL:mg/dL) chosen for comparison with other studies. This figure illustrated adjusted hazard ratios based on multivariable Cox regression models. Covariates adjusted for in the multivariable models are presented in Table 2

Furthermore, an association between UCR and long-term all-cause mortality is described in two studies. A high UCR (≥ 20.4) on hospital admission in cardiac ICU patients (n = 557) was associated with an increased likelihood of long-term mortality (HR 1.81, 95% CI 1.16–2.80, p = 0.009) in a retrospective analysis [40]. A single-centre retrospective study also demonstrated that an elevated UCR at ICU admission was associated with an increased mortality risk within one year after ICU admission in 2098 patients that survived until at least the 10 th day of ICU and did not require renal replacement therapy (RRT). This association was observed consistently across increasing quintiles, with progressively lower survival rates [25].

UCR and Protein Intake during critical illness

Multiple studies indicate that UCR could be responsive to nutritional interventions in critically ill patients (Table 3). A secondary analysis of the EFFORT protein trial revealed that high protein doses (> 2.2 vs 1.2 g/kg/day) were harmful in patients with high sequential organ failure (SOFA)-scores and renal impairment [41], and were associated with elevated urea levels [19]. More profound ureagenesis was related to increased mortality at 30 days, even after adjustment for organ dysfunction and acute kidney injury (AKI)[19]. A comparable urea-mediated correlation was also identified in a reanalysis of the multicentre randomised trial to investigate the efficacy of glutamine supplementation during critical illness (REDOXS trial) [42]. The findings indicated that an elevated UCR trajectory was particularly prominent in patients randomized to glutamine and linked to poorer survival. The UCR, measured around day 7, was associated with an increased risk of death while no longer a direct impact of glutamine supplementation on mortality was identified after adjustment. These findings indicate that an elevated UCR may be indicative of harm from high protein doses or amino acid supplementations during critical illness.

The UCR was also included in secondary analyses of other feeding interventions. A pre-specified analysis of the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study showed that early parenteral nutrition (PN) compared to late supplemental PN (initiation after 1 week) resulted in a notable elevation in UCR levels and higher nitrogen loss from day 4 to day 11 of ICU stay [15]. The additional nitrogen loss net wasted in ureagenesis attributable to early parenteral nutrition was estimated to be 30% after one week and 63% by day 14. A less negative nitrogen balance was observed with late PN, suggesting that delayed PN was more effectively utilised when provided in the later days of ICU stay. UCR was thereby indicative of ‘feeding responsiveness’. Another study demonstrated that continuous feeding resulted in a steeper positive gradient of UCR compared to bolus feeding over 10 days of nutrition after adjusting for several covariates, including RRT and protein amount delivered (p = 0.016)[43]. This finding could indicate that bolus feeding induces a more pronounced anabolic response than continuous feeding, a phenomenon referred to as ‘the muscle full effect’, which posits that the body has an upper limit for the amount of amino acids used for muscle protein synthesis. In this case, bolus feeding was suggested to prevent protein catabolism compared to continuous feeding, with the UCR being reflective of excess amino acids entering the urea cycle that can no longer be utilised for protein tissue building [44,45,46].

UCR and other outcomes during critical illness

In addition to its role in catabolism and persistent critical illness, the literature describes other functions of UCR (see Additional file 1: Table S3). For example, an elevated UCR at the time of ICU admission (18 and 24.9 as the cut-off value) has been associated with the onset of delirium in critically ill patients and a longer duration of ICU stay [47, 48]. In critically ill patients with aneurysmal subarachnoid haemorrhage, an elevated UCR in the acute phase (days 5–7 after ictus) has been linked to an increased risk of delayed cerebral ischemia (DCI) (UCR > 29), DCI-related infarction (UCR > 30.8), and unfavourable clinical outcomes at 12 months [49].

Discussion

This scoping review and meta-analysis sought to ascertain the significance of the UCR in critically ill patients in relation to mortality and clinical outcomes, as well as to determine whether UCR may serve as a potentially useful marker to reflect protein catabolism during critical illness. UCR was found to substantially increase over time during persistent critical illness among patients with prolonged ICU stays. There is a potential association between admission UCR and in-hospital mortality, although there is considerable heterogeneity across studies. Additionally, it may rather be a biomarker for illness than the cause of mortality. Secondary analyses of two large intervention studies (EFFORT protein and REDOXS) indicate that elevated UCR associates with increased mortality in ICU patients receiving high protein doses or amino acid supplementation, suggesting that the UCR represents a promising catabolic signature and a potential biomarker to monitor the response to nutritional interventions aiming to reduce muscle wasting. Furthermore, additional links between clinical outcomes and UCR were found, including the correlation between elevated UCR and the incidence of delirium and cerebral ischemia in specific patient groups.

Application of UCR in clinical practice

In patients with critical illness, UCR is higher at ICU admission than in healthy controls [50] and increases further during admission [10, 14, 29, 43, 49, 51], with the most pronounced elevation occurring during the initial 7–10 days [12, 43, 51]. This observed increase in ureagenesis during critical illness could be attributed to a decline in amino acid utilisation and an increase in protein breakdown in the body (anabolic resistance), which results in a greater influx of amino acids into the urea cycle [12, 52,53,54]. After the first 7–10 days, a gradual yet sustained rise of UCR was noted throughout the remainder of the ICU stay [12]. It is conceivable that the lack of further elevation in the UCR can be attributed to the urea cycle's optimal efficacy being reached. The study by Zijlstra et al. demonstrated that both plasma urea and urinary urea excretion rise during the initial ten to fourteen days of ICU stay, potentially indicating an upregulation of the urea cycle in the first week before maximum capacity is reached [12]. Following this interval, a modest decline in both plasma urea and urinary urea excretion was noted, amounting to 1% per day for the remainder of the ICU stay. Consequently, UCR continues to exhibit an upward trend [12], attributed to a more pronounced decrease in creatinine levels in conjunction with a reduction in muscle mass [8, 55]. In this context, an elevated UCR could serve as an indicator of skeletal muscle wasting during persistent critical illness. This finding was also identified by Haines et al., observing a weak converse correlation between dynamics of UCR and muscle CSA on CT scans in trauma patients [13]. Considering the available literature, we recommend UCR to be measured upon ICU admission (as a baseline value) and subsequently at regular intervals, rather than a solitary measurement at admission as has been conducted in the majority of available studies [27, 28, 38, 56,57,58,59]. The latter approach may also reflect other causes of UCR elevation beyond catabolism (Fig. 3), while assessing UCR dynamics may be particularly helpful in critically ill patients with prolonged anticipated ICU stays, as a continued rise in UCR may indicate a protein catabolic state and progressive muscle wasting [14, 19, 25].

Fig. 3

Urea-to-creatinine ratio during critical illness. The illustration depicts the production and processing of urea and creatinine within the human body. The figure illustrates the potential causes of increased UCR during critical illness and other factors that may contribute to this phenomenon. Abbreviations: ICU = Intensive Care Unit; GI = Gastro-intestinal. Created with Biorender.com

Furthermore, it is important to consider the potential influence of age and sex differences, with evidence suggesting that the UCR increases with age [60] and may be higher in female than in male ICU patients [12, 28]. This discrepancy could be attributed to differences in muscle mass proportion, resulting, on the one hand, in less creatinine release, and on the other hand, in a higher risk of protein overfeeding since the current guidelines advise to dose protein irrespective of sex or age (i.e. in grams/kg actual body weight in case of BMI ≤ 25 kg/m² instead of measured fat-free mass or sex-adjusted) [61, 62]. The recently conducted PRECISe trial revealed a lower EuroQoL 5-Dimension 5-Level (EQ-5D-5L) health utility score with higher enteral protein provision (2.0 g/kg/day) compared to standard protein provision (1.3 g/kg/day), which was most pronounced in female patients [63]. The authors hypothesise that this may be due to women's lower lean body mass. It is conceivable that protein dosing based on lean body mass rather than actual body weight might result in less overfeeding and, thus, a less pronounced UCR increase. However, this hypothesis remains to be tested.

A recent review has advocated for further investigation into UCR as a potential marker in response to nutrition provision [64]. Secondary analyses of the EFFORT Protein study [65] and the REDOXS trial [42] demonstrated poor outcomes when patients were provided with high protein and glutamine provision, respectively, which was reflected by an elevated UCR trajectory in the high protein/amino acid intervention. However, it is currently unknown if ureagenesis itself or other toxic metabolites are responsible for impaired outcome associated with protein overfeeding during acute catabolism. It is postulated that if the urea cycle is overloaded through both endogenous (from protein degradation) and exogenous (from protein provision) sources, toxic intermediate metabolites, such as ammonia, cannot be converted and will accumulate, particularly in the critically ill [66]. Hyperammonaemia may present in adult ICU patients independently of liver dysfunction, possibly as a result of redundant protein feeding stressing the urea cycle [67]. Intracellular hyperammonaemia harms several metabolic processes, including skeletal muscle metabolic derangements, impaired skeletal muscle protein synthesis, and increased autophagy, resulting in muscle loss and weakness [68]. Furthermore, hyperammonaemia has been demonstrated to induce alterations in pH, membrane potential, and cell metabolism, which can result in damage to multiple organs [68]. Whether elevations in UCR parallel hyperammonaemia in the critically ill seems logical but remains to be elucidated.

The EAT-ICU study demonstrated that patients who were randomized to receive individualized early goal-directed nutrition exhibited a reduced negative protein balance in comparison to those who received standard nutritional care [69]. However, the group with early goal-directed nutrition exhibited augmented plasma urea and 24-h urinary urea, with the rise in plasma urea closely aligning with the enhanced protein balance [69]. It is recognised that the capacity of critically ill patients to utilise ingested protein for muscle protein synthesis is impaired despite the presence of normal protein digestion and amino acid absorption [17]. This phenomenon is indicative of anabolic resistance. These mechanisms, alongside suppressed autophagy, likely explain why recent large trials observed harmful effects of high protein provision during acute critical illness [16, 20].

Conversely, three studies have indicated a U-shaped relationship between UCR and in-hospital mortality [37,38,39]. While UCR was assessed in one of these studies at ICU admission and in the remaining the timing was not reported, it is plausible that very low UCR levels may be indicative of inadequate protein intake, which aligns with evidence suggesting that protein intake and mortality exhibit a U-shaped relationship [70]. Consequently, a low or decreasing UCR could indicate an improved response to dietary protein [20], a crucial tipping point from which nutrition or protein provision may be increased. However, nutrition intervention studies incorporating UCR as a biomarker are required to test the hypothesis that UCR is responsive to nutrient provision in order to advance personalised nutrition therapies in the ICU. Furthermore, studies investigating the relationship between UCR and protein metabolism pathways during critical illness are warranted to elucidate the magnitude to which UCR may be related to ‘protein-feeding responsiveness’[20].

Pitfalls of UCR as a catabolic biomarker in critical illness

It is important to note that there are certain pitfalls when using UCR as a catabolic biomarker in critical illness in clinical practice (Fig. 3). Firstly, since UCR is a ratio, it is essential to take into account variations in both urea and creatinine when assessing it as a metabolic signature. Furthermore, factors other than pronounced protein catabolism may also increase UCR. These include conditions that enhance urea reabsorption, such as activation the renin-angiotensin activating system (i.e., hypovolemia or heart failure), as well as factors that elevate urea production, such as high dietary protein intake and blood absorption in the gastrointestinal tract [8, 71, 72]. Conversely, the level of UCR can be reduced by liver dysfunction that affects the urea cycle metabolism [73]. Similarly, renal factors, such as medications (e.g. loop diuretics) [74] or damage to the renal tubules [75], may decrease urea reabsorption and lead to a decrease in UCR. The study by Haines et al. found that major trauma patients with severe AKI tended to have a lower UCR [14], while a single-centre retrospective study of ICU patients revealed no significant difference in UCR between patients with disparate AKI stages [25]. Differences in AKI aetiology may explain discrepancies in these findings. One study observed an UCR > 20 at ICU admission, indicative of prerenal insufficiency, to reduce the risk of requiring RRT [72]. In addition to this, evaluating UCR trajectory as a metabolic signature during RRT may be challenging since RRT removes both urea and creatinine from the blood, with a therapy-specific relationship between solute removal and clearance [43, 76]. Future studies are required to determine suitable catabolism biomarkers for AKI and RRT patients in the ICU, as they represent a challenging population.

Lastly, recognising that the UCR is reported in disparate units is also crucial. In Europe, the urea/creatinine ratio is frequently used, whereas in the United States, the blood urea nitrogen (BUN)/creatinine ratio is commonly reported. Conversion factors are available for calculating BUN, which is approximately one-half (28/60 or 0.446) of blood urea [77]. It is essential to ensure that both BUN or urea and creatinine are reported in the same units to ensure the accuracy of the ratio calculation (Fig. 4). Standardisation in reporting facilitates comparison between studies and provides a uniform approach to assessing patient outcomes and formulating clinical decision-making.

Fig. 4

Conversion factors BUN and urea. The chemical formula of urea is CO(NH₂)₂, with a molecular weight of approximately 60 [78]. Each of the two nitrogen molecules has a weight of approximately 14 g/mol. The ratio 60/28 can be expressed as follows: To convert from BUN to urea, one must multiply by 2.14. Similarly, to convert from urea to BUN, one must divide by 2.14. To convert from mg/dL to mmol/L for BUN and urea, the value should be multiplied by the weight in mol and then multiplied by 10 to convert L to dL. For BUN, this is 2 × nitrogen (2 × 14 = 10/28 = 0.357), while for urea it is CO(NH₂)₂ (10/60 = 0.166). Both BUN and urea in mmol/L are molecular weight units and can be converted without the use of a conversion factor. All of these values are approximations and have been rounded for simplicity. Created with Biorender.com

Limitations and strengths

A strength of this review is its comprehensive examination of UCR in the context of critical illness. It offers insights into its potential as a biomarker for muscle wasting, persistent critical illness, and response to nutritional interventions. The review also addresses interpretation challenges and identifies knowledge gaps in critical care. However, several limitations should be noted. First, selective reporting bias is a potential limitation due to the post-hoc nature of our meta-analyses. In addition, the substantial heterogeneity between studies and their study populations, the absence of cut-off values for UCR, and the paucity of studies directly comparing UCR with tracer methodologies or measurements of absolute muscle mass loss impede the ability to derive precise and uniform conclusions. Additionally, there is a risk of publication bias, as unpublished or non-English studies may not be captured in the search, and the majority of included studies are observational and retrospective in nature. Another limitation is the geographical concentration of the included studies, with multiple articles originating from China. This predominance may introduce a regional bias, as healthcare practices and patient demographics may differ between regions. Consequently, this may hamper the generalizability of the findings to other healthcare systems. Lastly,, most of the discussed studies are from single centres, which could further limit the external validity of the results.

Implications for future research

Future studies should focus on refining UCR’s clinical applications and tailoring its use to specific critically ill patient groups, as its interpretation must always be context specific. Additional research is warranted to establish optimal cut-offs for rises in UCR related to protein catabolic processes, such as severe muscle wasting, along with consequent investigations exploring its role in guiding nutritional interventions. However, since a strict cut-off approach may fail to accurately capture dynamic changes in UCR over time, future studies should consider incorporating repeated measurements or utilizing a continuous ordinal modelling approach. The development of valuable markers to tailor protein provision throughout critical illness remains an unmet need [21]. UCR may represent a promising marker to guide this process, but prospective studies are required to substantiate this hypothesis.

Summary

UCR is potentially reflective of muscle wasting and may be an indicator of persistent critical illness and in-hospital mortality in critically ill patients. A high UCR may indicate an excess of exogenous amino acids provided in addition to endogenous protein catabolism, suggesting that the protein supply may temporarily exceed the body's capacity for utilisation. It is crucial to acknowledge that a multitude of factors can elevate UCR levels beyond the mere phenomenon of protein catabolism. The necessity for valuable markers to tailor protein provision is evident, and the dynamics of UCR in critically ill patients may play an important role in this in the future. However, this approach needs further evidence-based research and warrants confirmation in prospective studies. To ensure the effective application of UCR in clinical practice and to facilitate the guidance of nutritional interventions, it is essential to establish age and sex-specific cut-off values explicitly tailored for critical illness.