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.
Methods:
This prospective, observational pharmacokinetic (PK) study was performed in a university affiliated, tertiary level, adult intensive care unit (ICU). Patients aged more 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??mol/L), and no history of chronic kidney disease or renal replacement therapy, were eligible for inclusion. The following study markers were administered concurrently; sinistrin 2500?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, NSW, Australia) and fluconazole 100?mg (Diflucan?, Pfizer Australia Pty Ltd, NSW, Australia). Plasma concentrations were then measured at 5, 10, 15, 30, 60, 120?min, 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 95% CI ? 180 (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 (428 (306 to 550) mL/min), as was net tubular reabsorption of fluconazole (135 (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.