Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds

Andrew A Udy, Paul Jarrett, Janine Stuart, Melissa Lassig-Smith, Therese Starr, Rachel Dunlop, Steven C Wallis, Jason A Roberts, Jeffrey Lipman, Andrew A Udy, Paul Jarrett, Janine Stuart, Melissa Lassig-Smith, Therese Starr, Rachel Dunlop, Steven C Wallis, Jason A Roberts, Jeffrey Lipman

Abstract

Introduction: The aim of this study was to explore changes in glomerular filtration (GFR) and renal tubular function in critically ill patients at risk of augmented renal clearance (ARC), using exogenous marker compounds.

Methods: This prospective, observational pharmacokinetic (PK) study was performed in a university-affiliated, tertiary-level, adult intensive care unit (ICU). Patients aged less than or equal to 60 years, manifesting a systemic inflammatory response, with an expected ICU length of stay more than 24 hours, no evidence of acute renal impairment (plasma creatinine concentration < 120 μmol/L) and no history of chronic kidney disease or renal replacement therapy were eligible for inclusion. The following study markers were administered concurrently: sinistrin 2,500 mg (Inutest; Laevosan, Linz, Austria), p-aminohippuric acid (PAH) 440 mg (4% p-aminohippuric acid sodium salt; CFM Oskar Tropitzsch, Marktredwitz, Germany), rac-pindolol 5 or 15 mg (Barbloc; Alphapharm, Millers Point, NSW, Australia) and fluconazole 100 mg (Diflucan; Pfizer Australia Pty Ltd, West Ryde, NSW, Australia). Plasma concentrations were then measured at 5, 10, 15, 30, 60 and 120 minutes and 4, 6, 12 and 24 hours post-administration. Non-compartmental PK analysis was used to quantify GFR, tubular secretion and tubular reabsorption.

Results: Twenty patients were included in the study. Marker administration was well tolerated, with no adverse events reported. Sinistrin clearance as a marker of GFR was significantly elevated (mean, 180 (95% confidence interval (CI), 141 to 219) ml/min) and correlated well with creatinine clearance (r = 0.70, P < 0.01). Net tubular secretion of PAH, a marker of tubular anion secretion, was also elevated (mean, 428 (95% CI, 306 to 550) ml/min), as was net tubular reabsorption of fluconazole (mean, 135 (95% CI, 100 to 169) ml/min). Net tubular secretion of (S)- and (R)-pinodolol, a marker of tubular cation secretion, was impaired.

Conclusions: In critically ill patients at risk of ARC, significant alterations in glomerular filtration, renal tubular secretion and tubular reabsorption are apparent. This has implications for accurate dosing of renally eliminated drugs.

Figures

Figure 1
Figure 1
Plot of plasma concentration versus time for intravenous study markers. Mean (95% confidence interval) plasma sinistrin (A) and p-aminohippuric acid (PAH) (B) concentrations (y-axis) versus time (x-axis) are shown.
Figure 2
Figure 2
Bland-Altman plots of sinistrin clearance versus creatinine clearance and Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate. Comparison of the difference between sinistrin clearance (CL) and Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (CKD-EPI eGFR) (A) and creatinine clearance (CLCR) (B) on the y-axis versus the average value on the x-axis. The solid lines represent the bias (mean difference), and the dotted lines represent the 95% limits of agreement.
Figure 3
Figure 3
Graphical correlations between sinistrin clearance, creatinine clearance, p-aminohippuric acid renal clearance and filtration fraction. (A) Sinistrin clearance (CL) (y-axis) versus creatinine clearance (CLCR) (x-axis) (r =0.70, P <0.01). (B) p-Aminohippuric acid renal clearance (PAH CLR) (y-axis) versus CLCR (x-axis) (r =0.65, P <0.01). (C) Filtration fraction (y-axis) versus sinistrin CL (x-axis) (r =0.68, P <0.01). (D) Filtration fraction (y-axis) versus PAH CLR (x-axis) (r = −0.49, P =0.06). (E) Sinistrin CL (y-axis) versus PAH CLR (x-axis) (r =0.27, P =0.32). A linear regression line has been fitted in each case.
Figure 4
Figure 4
Plot of plasma concentration versus time for (S)- and (R)-pindolol. Mean (95% confidence interval) plasma (S)-pindolol (A) and (R)-pindolol (B) concentrations (y-axis) versus time (x-axis) are plotted.
Figure 5
Figure 5
Fluconazole plasma concentration versus time plot. Mean (95% confidence interval) plasma fluconazole concentration (y-axis) versus time (x-axis) values are plotted.

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