title: Major contribution of tubular secretion to creatinine clearance in mice.
abstract: This study was performed to quantify the fraction of excreted creatinine not attributable to creatinine filtration for accurately determining the glomerular filtration rate in mice. To measure this we compared creatinine filtration with the simultaneous measurement of inulin clearance using both single-bolus fluorescein isothiocyanate (FITC)-inulin elimination kinetics and standard FITC-inulin infusion. During anesthesia, creatinine filtration was found to be systematically higher than inulin clearance in both male and female C57BL/6J mice. The secretion fraction was significantly less in female mice. Administration of either cimetidine or para-aminohippuric acid, competitors of organic cation and anion transport respectively, significantly reduced the secretion fraction in male and female mice and both significantly increased the plasma creatinine level. Creatinine secretion in both genders was not mediated by the organic cation transporters OCT1 or OCT 2 since secretion fraction levels were identical in FVB wild-type and OCT1/2 knockout mice. Thus, secretion accounts for about 50 and 35% of excreted creatinine in male and female mice, respectively. Increasing plasma creatinine threefold by infusion further increased the secretion fraction. Renal organic anion transporter 1 mRNA expression was higher in male than in female mice, reflecting the gender difference in creatinine secretion. Hence we show that there is a major secretory contribution to creatinine excretion mediated through the organic anion transport system. This feature adds to problems associated with measuring endogenous creatinine filtration in mice.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisner
authors.forename: Robert
authors.initials: R
authors.lastname: Faulhaber-Walter
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Wang
authors.forename: Asada
authors.initials: A
authors.lastname: Leelahavanichkul
authors.forename: Peter S T
authors.initials: PS
authors.lastname: Yuen
authors.forename: Diane
authors.initials: D
authors.lastname: Mizel
authors.forename: Robert A
authors.initials: RA
authors.lastname: Star
authors.forename: Josephine P
authors.initials: JP
authors.lastname: Briggs
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
mesh_terms: D000818:Animals; D002412:Cations / Q000378:metabolism; D002927:Cimetidine / Q000378:metabolism; D003404:Creatinine / Q000097:blood / Q000378:metabolism*; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D005919:Glomerular Filtration Rate; D007444:Inulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007677:Kidney Function Tests / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D002412:Cations; D005456:Fluorescent Dyes; D002927:Cimetidine; D007444:Inulin; D003404:Creatinine; D016650:Fluorescein-5-isothiocyanate; D010130:p-Aminohippuric Acid