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.

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

“…OAT3 was reported to contribute to the elimination of creatinine in mice. 37,38 There are also two publications showing that human OAT3 takes up creatinine. 39,40 In contrast to the previous studies, Lepist et al reported that creatinine was not transported by human OAT1 or OAT3.…”

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…Adapted with permission from Toyohara et al 15 controversial. Eisner et al 74 investigated the creatinine secretion in mouse and compared renal handling between males and females as well as in mice deficient in Oct1/2. Their data showed a role of organic anion transporters in creatinine excretion rather than organic cation transporters because administration of the inhibitor of organic anion transport, para-aminohippuric acid, significantly reduced the secretion fraction in male and female mice and significantly increased the plasma creatinine level.…”

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

“…However, reduction of AER is not always correlated with complete reversal of all phenotypic and in situ changes observed in preclinical mouse models of DN 13 . Moreover, while routinely performed in humans, eGFR assessment in mice is of little comparative value, because in mice 35-50% of the creatinine is secreted and not attributable to the glomerular filtration 15 . Although methods for GFR measurement, based on fluorescent inulin clearance, have been developed for mice, these are still invasive (and cannot be repeated frequently, 16 ) and will not detect small changes in renal function.…”