Can augmented renal clearance be detected using estimators of glomerular filtration rate?

Estimators of glomerular filtration rate (GFR) have been shown to be flawed in critically ill patients, especially for augmented renal clearance (ARC), commonly defined as a measured urinary creatinine clearance (CrCl) ≥ 130ml/ min/1.73 m [1]. Therefore, measuring CrCl should be performed in daily practice on the intensive care unit (ICU). However, many ICUs still rely on estimating formulae to monitor GFR [1, 2]. As estimators underestimate measured CrCl in ARC patients, ARC might remain unrecognized and lead to subtherapeutic plasma levels of drugs with predominant renal clearance [3]. Therefore, the aim of this study is to define the most precise GFR estimator, which can then be used to detect ARC when measured CrCl is unavailable. We performed a multicenter retrospective registrybased [4] cohort study in adult ICUs from 3 tertiary university-affiliated hospitals in Belgium (Leuven, Ghent, Antwerp). All consecutive patients admitted between January 2013 and December 2015 were screened for eligibility. All patients ≥ 18 years old and having at least one measured 24-h urinary CrCl (CrCl24h) were included. Agreement between CrCl24h and formulae estimating renal function, i.e., Cockcroft–Gault (CG), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Modification of Diet in Renal Disease Study (MDRD), was evaluated on all included ICU days. For the estimator with the best precision, a cut-off for ARC with optimal specificity and sensitivity was identified, by calculating the Youden index [5]. Predictions for ARC using the cut-off value were compared to the actual presence of ARC based on the CrCl24h. Cut-off values with either very high sensitivity (> 95%) or specificity (> 95%) were also identified. Finally, the performance of these cut-offs was evaluated in an external single-center (Leuven, January 2016–December 2016) validation set by receiver-operating characteristics (ROC) curve ana-

January 2013 and December 2015 were screened for eligibility. All patients ≥ 18 years old and having at least one measured 24-h urinary CrCl (CrCl 24h ) were included. Agreement between CrCl 24h and formulae estimating renal function, i.e., Cockcroft-Gault (CG), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Modification of Diet in Renal Disease Study (MDRD), was evaluated on all included ICU days. For the estimator with the best precision, a cut-off for ARC with optimal specificity and sensitivity was identified, by calculating the Youden index [5]. Predictions for ARC using the cut-off value were compared to the actual presence of ARC based on the CrCl 24h . Cut-off values with either very high sensitivity (> 95%) or specificity (> 95%) were also identified. Finally, the performance of these cut-offs was evaluated in an external single-center (Leuven, January 2016-December 2016) validation set by receiver-operating characteristics (ROC) curve analysis, using 2000 bootstrap replicates. The same inclusion and exclusion criteria as described above were applied.
A total of 51,604 ICU days were included to define a cut-off. Agreement analysis between CrCl 24h , the clinical reference, and the formulae estimating renal function is shown in Table 1. None of the estimators were precise (i.e., standard deviation of the mean bias was large for all estimators), with the CKD-EPI formula performing best over the whole CrCl 24h range, and for ARC specifically, as illustrated in Fig. 1a. Hence, the CKD-EPI formula was selected for further analysis. In the validation set, 10,503 ICU days were included. For the CKD-EPI formula, the optimal cut-off for ARC was 96. 5 Fig. 1b. Evaluating the optimal cut-off in the validation set, we found that the proportion of accurate predictions for ARC decreased during the first 2 weeks of ICU stay. The is due to an increased false positive rate (Day-1, 16%; Day-14, 49%).
Overall, there was poor agreement between CrCl 24h and GFR estimators, confirming previous literature [1]. However, the CKD-EPI formula, which is the "least worse" alternative to CrCl 24h , provided a cut-off with reasonable performance to detect ARC. Depending on the clinical context, this cut-off can be adapted to increase sensitivity or specificity. When applying this cutoff, the user should note that the accuracy decreases over time during the first 2 weeks of ICU stay. Hence, its largest benefit lies in the beginning of ICU stay. The presented CKP-EPI cut-off can be used to guide upfront increased antimicrobial dosing in patients presenting with ARC early upon ICU admission, when CrCl 24h is not available.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate M@tric data-collection has ethical committee approval from the University Hospitals Ghent, where the database is being hosted (PA 2009/006). Research on the M@tric database requires ethical committee approval of the ethical committee of one of the contributing centers which then independently acts as central ethical committee. Approval for the present study was obtained from the ethical committee of the University Hospitals Leuven (S61364) for the use of the M@tric dataset, as well as the retrospective Leuven dataset. This research has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent for publication
Not applicable.