title: Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Intensive Care and Hyperbaric Medicine, The Alfred, 55 Commercial Road, Prahran, Melbourne, Victoria, 3181, Australia. a.udy@alfred.org.au.|Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Herston, Brisbane, Queensland, 4029, Australia. a.udy@alfred.org.au.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Udy
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia. paul.jarrett@health.qld.gov.au.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarrett
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia. janine.stuart@health.qld.gov.au.
authors.forename: Janine
authors.initials: J
authors.lastname: Stuart
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia. melissa.lassig-smith@health.qld.gov.au.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lassig-Smith
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia. therese.starr@health.qld.gov.au.
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.affiliation: Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia. rachel.dunlop@health.qld.gov.au.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dunlop
authors.affiliation: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Herston, Brisbane, Queensland, 4029, Australia. s.wallis@uq.edu.au.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Herston, Brisbane, Queensland, 4029, Australia. j.roberts2@uq.edu.au.|Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia. j.roberts2@uq.edu.au.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Herston, Brisbane, Queensland, 4029, Australia. j.lipman@uq.edu.au.|Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Brisbane, Queensland, 4029, Australia. j.lipman@uq.edu.au.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000097:blood / Q000652:urine; D016638:Critical Illness / Q000628:therapy*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007677:Kidney Function Tests / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology*; D009844:Oligosaccharides / Q000008:administration & dosage / Q000097:blood* / Q000652:urine*; D011446:Prospective Studies
chemical_list: D015415:Biomarkers; D009844:Oligosaccharides; D003404:Creatinine; C064636:sinistrin