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.

Keywords: Critical illness; Intensive care unit; Nutrition; Protein catabolism; UCR; Urea-to-creatinine ratio.

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

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

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