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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

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 (CrCL) 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 CrCL 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 CrCL 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 CrCL ≥ 130 mL/min/1.73 m2. 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 CrCL values = 124 [83–170] ml/min/1.73 m2) and the incidence of piperacillin underdosing was 51% (median piperacillin concentrations = 32 [22–47] μg/ml). The diagnostic agreement between KeGFR and CrCL was only moderate (κ = 0.48 [95% confidence interval 0.4–0.55]) (Fig. 1). Comparison between KeGFR and CrCL showed a mean bias of − 8.7 ml/min/1.73 m2 and limit of agreement from − 99 ml/min/1.73 m2 to 82 ml/min/1.73 m2. Finally, the area under the ROC curve generated for KeGFR was significantly lower than the one generated for measured CrCL for prediction of piperacillin underdosing (0.76 [0.68–0.83] vs 0.85 [0.79–0.91], p = 0.03; Fig. 2).

Fig. 1
figure1

Correlation between measured CrCL and KeGFR (r2 = 0.54, p < 0.0001) and repartition of samples with (white circles) or without (black circles) piperacillin underdosing, defined by an unbound concentration ≤ 32 μg/ml. ARC was defined by a measured CrCL or a KeGFR ≥ 130 ml/min/1.73 m2. Samples in the gray shaded area are considered to be well classified

Fig. 2
figure2

Receiver operating characteristics (ROC) curves evaluating the ability of KeGFR and measured CrCL to predict piperacillin underdosing. Areas under ROC curves between KeGFR and measured CrCL were compared using the Handley approach. Piperacillin underdosing was defined by a free drug concentration ≤ 32 μg/ml

In conclusion, KeGFR is not interchangeable with measured CrCL 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 CLCR should be performed to accurately guide drug dosing. This study emphasizes the need for dosing adjustment and therapeutic drug monitoring in patients with ARC.

Abbreviations

ARC:

Augmented renal clearance

CrCL :

Creatinine clearance

GFR:

Glomerular filtration rate

KeGFR:

Kinetic estimated glomerular filtration rate

MIC:

Minimum inhibitory concentration

ROC:

Receiver operating characteristic

sCr:

Serum creatinine

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Acknowledgements

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

Funding

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

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

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Contributions

CC and SR designed the study. CC and PS recruited patients and collected the data. CC and MB performed statistical analysis and wrote the manuscript. DB was in charge of sample preparation, storage and quantification. SR, DB, and MB have personally reviewed the data and confirmed that the methods are clearly described and that they are a fair way to report the results. All authors read and approved the final manuscript.

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Correspondence to Cédric Carrié.

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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.

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Carrié, C., Rubin, S., Sioniac, P. et al. 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. Crit Care 22, 177 (2018). https://doi.org/10.1186/s13054-018-2117-7

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Keywords

  • Augmented renal clearance
  • Kinetic glomerular filtration rate
  • Piperacillin
  • Critical care