Estimation of creatinine clearance using plasma creatinine or cystatin C: a secondary analysis of two pharmacokinetic studies in surgical ICU patients

Abstract

Background: In ICU patients, glomerular filtration is often impaired, but also supraphysiological values are observed ("augmented renal clearance", >130 mL/min/1.73 m(2)). Renally eliminated drugs (e.g. many antibiotics) must be adjusted accordingly, which requires a quantitative measure of renal function throughout all the range of clinically encountered values. Estimation from plasma creatinine is standard, but cystatin C may be a valuable alternative.

Methods: This was a secondary analysis of renal function parameters in 100 ICU patients from two pharmacokinetic studies on vancomycin and betalactam antibiotics. Estimated clearance values obtained by the Cockcroft-Gault formula (eCLCG), the CKD-EPI formula (eCLCKD-EPI) or the cystatin C based Hoek formula (eCLHoek) were compared with the measured endogenous creatinine clearance (CLCR). Agreement of values was assessed by modified Bland-Altman plots and by calculating bias (median error) and precision (median absolute error). Sensitivity and specificity of estimates to identify patients with reduced (<60 mL/min/1.73 m(2)) or augmented (>130 mL/min/1.73 m(2)) CLCR were calculated.

Results: The CLCR was well distributed from highly compromised to supraphysiological values (median 73.2, range 16.8-234 mL/min/1.73 m(2)), even when plasma creatinine was not elevated (≤0.8 mg/dL for women, ≤1.1 mg/dL for men). Bias and precision were +13.5 mL/min/1.73 m(2) and ±18.5 mL/min/1.73 m(2) for eCLCG, +7.59 and ±16.8 mL/min/1.73 m(2) for eCLCKD-EPI, and -4.15 and ±12.9 mL/min/1.73 m(2) for eCLHoek, respectively, with eCLHoek being more precise than the other two (p < 0.05). The central 95% of observed errors fell between -59.8 and +250 mL/min/1.73 m(2) for eCLCG, -83.9 and +79.8 mL/min/1.73 m(2) for eCLCKD-EPI, and -103 and +27.9 mL/min/1.73 m(2) for eCLHoek. Augmented renal clearance was underestimated by eCLCKD-EPI and eCLHoek. Patients with reduced CLCR were identified with good specificity by eCLCG, eCLCKD-EPI and eCLHoek (0.95, 0.97 and 0.91, respectively), but with less sensitivity (0.55, 0.55 and 0.83). For augmented renal clearance, specificity was 0.81, 0.96 and 0.96, but sensitivity only 0.69, 0.25 and 0.38.

Conclusions: Normal plasma creatinine concentrations can be highly misleading in ICU patients. Agreement of the cystatin C based eCLHoek with CLCR is better than that of the creatinine based eCLCG or eCLCKD-EPI. Detection and quantification of augmented renal clearance by estimates is problematic, and should rather rely on CLCR.

Figure 1

Measured creatinine clearance (CL_CR) vs. plasma creatinine. Data were obtained from 100 ICU patients participating in pharmacokinetic studies on antibiotics. The inlet shows the distribution of the 63 patients with a plasma creatinine concentration below the upper reference limit (0.8 mg/dL for women, 1.1 mg/dL for men; vertical dotted lines).

Figure 2

Agreement of estimated with measured creatinine clearance (CL_CR) in 100 ICU patients. Estimation was done by (A) the Cockcroft-Gault formula (eCL_CG), (B) the CKD-EPI formula (eCL_CKD-EPI), or (C) the Hoek formula (eCL_Hoek). Bold line: LOWESS curve. Horizontal solid line: median; dashed lines: 25th/75th percentile; dotted lines: 2.5th/97.5th percentile of observations. Note the larger scale of the y-axis in figure A.

Figure 3

Receiver-operator characteristic curves for detection of reduced (A; CL_CR < 60 mL/min/1.73 m²) or augmented renal clearance (B; CL_CR > 130 mL/min/1.73 m²). AUC area under the curve (95%-confidence interval).