Abstract
IntroductionThe 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.MethodsThis 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.ResultsTwenty 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.ConclusionsIn 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.
Highlights
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
Recent research has highlighted that renal antibacterial drug elimination can be significantly elevated in the critically ill [1], such that drug exposure is often suboptimal [1,2,3], and may lead to adverse clinical outcomes [4]
This phenomenon has been termed augmented renal clearance (ARC) [1], and is seen in association with an elevated urinary creatinine clearance (CLCR) [5]. Such measures have been advocated as a useful tool to identify ARC in the critically ill [6,7], the assumption being that elevated glomerular filtration is a key mechanism in this process
Summary
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. In terms of drug disposition, renal excretion of parent compounds or active metabolites represents a key route of drug elimination for many agents Recent research has highlighted that renal antibacterial drug elimination ( renally cleared β-lactams) can be significantly elevated in the critically ill [1], such that drug exposure is often suboptimal [1,2,3], and may lead to adverse clinical outcomes [4] This phenomenon has been termed augmented renal clearance (ARC) [1], and is seen in association with an elevated urinary creatinine clearance (CLCR) [5]. Using such a ‘cocktail,’ Gross and colleagues applied this approach in 12 healthy male subjects [9], establishing useful baseline values for comparison
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