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01.12.2018 | Letter | Ausgabe 1/2018 Open Access

Critical Care 1/2018

The kinetic glomerular filtration rate is not interchangeable with measured creatinine clearance for prediction of piperacillin underexposure in critically ill patients with augmented renal clearance

Critical Care > Ausgabe 1/2018
Cédric Carrié, Sébastien Rubin, Pierre Sioniac, Dominique Breilh, Matthieu Biais
Augmented renal clearance
Creatinine clearance
Glomerular filtration rate
Kinetic estimated glomerular filtration rate
Minimum inhibitory concentration
Receiver operating characteristic
Serum creatinine
In the critical care setting, augmented renal clearance (ARC) is increasingly recognized as one of the leading causes of subtherapeutic antibiotic exposure [ 1]. However, commonly used formulas for estimating glomerular filtration rate (GFR) are inaccurate in patients with ARC and the 24-h urinary creatinine clearance (Cr CL) remains the best available approach for optimizing empirical antimicrobial therapy [ 2]. On the other hand, no study has evaluated the clinical and prognostic value of the kinetic estimated GFR (KeGFR) in this context. We thus aimed to determine whether KeGFR could be a reliable alternative to measured Cr CL in critically ill patients needing early initiation of an appropriate piperacillin dosing regimen.
For this purpose, we retrospectively analyzed 60 consecutive patients who underwent 24-h urinary Cr CL measurements and therapeutic drug monitoring during the first 3 days of antimicrobial therapy of piperacillin administered 16 g/day continuously. The protocol pertaining to this substudy has been published elsewhere [ 3]. As previously described, the corresponding KeGFR was calculated as follows: \( \frac{\mathrm{Baseline}\ \mathrm{sCr}\ \mathrm{x}\ \mathrm{eGFR}}{\mathrm{Mean}\ \mathrm{sCr}}\times \left(1-\frac{24\ \mathrm{x}\ \Delta \mathrm{sCr}}{\Delta \mathrm{t}\ \mathrm{x}\ \mathrm{Max}\Delta \mathrm{sCr}/\mathrm{Day}}\right) \) with eGFR derived from the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation using serum creatinine (sCr) before admission, Δt fixed at 24 h between two sCr measurements, and maximal sCr increase per day approximated to 133 μmol/L [ 4]. ARC was defined by a measured Cr CL ≥ 130 mL/min/1.73 m 2. Piperacillin underdosing was arbitrarily defined by a free drug concentration ≤ 32 μg/ml at steady state.
Among the 180 samples analyzed, the incidence of ARC was 48% (median Cr CL values = 124 [83–170] ml/min/1.73 m 2) and the incidence of piperacillin underdosing was 51% (median piperacillin concentrations = 32 [22–47] μg/ml). The diagnostic agreement between KeGFR and Cr CL was only moderate (κ = 0.48 [95% confidence interval 0.4–0.55]) (Fig.  1). Comparison between KeGFR and Cr CL showed a mean bias of − 8.7 ml/min/1.73 m 2 and limit of agreement from − 99 ml/min/1.73 m 2 to 82 ml/min/1.73 m 2. Finally, the area under the ROC curve generated for KeGFR was significantly lower than the one generated for measured Cr CL for prediction of piperacillin underdosing (0.76 [0.68–0.83] vs 0.85 [0.79–0.91], p = 0.03; Fig.  2).
In conclusion, KeGFR is not interchangeable with measured Cr CL for prediction of piperacillin underexposure in critically ill patients with ARC. Also, scarce data may suggest a better predictive value of Cockcroft-Gault compared to MDRD (Modification of Diet in Renal Disease Study) or CKD-EPI for identifying patients with ARC [ 5]; a measured CL CR should be performed to accurately guide drug dosing. This study emphasizes the need for dosing adjustment and therapeutic drug monitoring in patients with ARC.


The authors thank Nicolas d’Houdain for his contribution to sample storage, preparation, and quantification.


Only departmental funds were used for this study. No external funds were obtained.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Ethics approval was obtained from the Institutional Review Board (Comite de Protection des Personnes Sud-Ouest et Outre Mer III, Bordeaux, France; protocol number DC 2016/147), which waived the need for written consent. Patients or next of kin were orally informed of the goal and design of the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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