Renal Disposition of a Furan Dicarboxylic Acid and Other Uremic Toxins in the Rat

Tsutsumi, Yasuhiro; Deguchi, Toshio; Takano, Mikihisa; Takadate, Akira; Lindup, W E; Otagiri, Masaki

doi:10.1124/jpet.303.2.880

Cited by 58 publications

(56 citation statements)

References 31 publications

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“…Although HA is a known substrate of organic anion transporters 1 and 3, specific mechanisms of CMG transport are unknown. 21,23 Biologic variability in protein expression of different transporters-such as in diabetes 24 -may contribute to the observed intraindividual variability of different secretory solutes.…”

Section: Discussionmentioning

confidence: 99%

Tubular Secretion in CKD

Suchy‐Dicey¹,

Laha²,

Hoofnagle³

et al. 2015

JASN

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Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

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Section: Discussionmentioning

confidence: 99%

Tubular Secretion in CKD

Suchy‐Dicey¹,

Laha²,

Hoofnagle³

et al. 2015

JASN

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“…Warfarin, dansylsarcosine, IS, hippurate (HA) (Sigma-Aldrich, St. Louis, MO), and indoleacetic acid (IA) (Nacalai Tesque Inc., Kyoto, Japan) were obtained as pure substances from the respective manufacturers. 3-Carboxy-4-methyl-5-propyl-2-furan propionate (CMPF) was synthesized as described previously (Tsutsumi et al, 2002). All reagents from commercial sources were of the highest grade.…”

Section: Methodsmentioning

confidence: 99%

Interaction between Two Sulfate-Conjugated Uremic Toxins,p-Cresyl Sulfate and Indoxyl Sulfate, during Binding with Human Serum Albumin

Watanabe

Noguchi²,

Miyamoto³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Recently, p-cresyl sulfate (PCS) has been identified as a proteinbound uremic toxin. Moreover, the serum-free concentration of PCS, which is associated with its efficacy of hemodialysis, appears to be a good predictor of survival in chronic kidney disease (CKD). We previously found that PCS interacts with indoxyl sulfate (IS), another sulfate-conjugated uremic toxin, during renal excretion via a common transporter. The purpose of this study was to further investigate the interaction between PCS and IS on the binding to human serum albumin (HSA

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“…IS was detected by means of a fluorescence monitor. The excitation/emission wavelengths were 300/400 nm (21).…”

Section: Chromatographic Analysis Of Is In Ratsmentioning

confidence: 99%

An Oral Adsorbent, AST-120 Protects Against the Progression of Oxidative Stress by Reducing the Accumulation of Indoxyl Sulfate in the Systemic Circulation in Renal Failure

Shimoishi

Anraku²,

Kitamura³

et al. 2007

Pharm Res

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103

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Purpose. The effect of AST-120, an oral adsorbent, on oxidative stress in the systemic circulation in chronic renal failure (CRF) was examined and the potential role of indoxyl sulfate (IS), an uremic toxin adsorbed by AST-120, in inducing the formation of reactive oxygen species (ROS) in the vascular system was studied, in vitro and in vivo. Materials and methods. The level of oxidized albumin, a marker for oxidative stress in the systemic circulation was determined by HPLC, as previously reported. The mRNA levels of TGF-b 1 and Oat1 were measured by quantitative RT-PCR. The IS induced ROS generation in cultured human umbilical vein endothelial cells (HUVECs) was estimated using a fluorescence microplate reader.Results. An increase in the ratio of oxidized to unoxidized albumin was determined using 5/6 nephrectomized rats (CRF rats) compared to a control group. The ratio was significantly reduced in the group that received AST-120 of 4 weeks, suggesting that AST-120 inhibits oxidative stress in CRF. An anti-oxidative effect of AST-120 was also observed in CRF rats with a similar renal function. The ratio of oxidized albumin was correlated with serum IS levels in vivo. The same relationship was also observed in CRF rats with the continued administration of IS. In addition, IS dramatically increased the generation of ROS in both a dose-and time-dependent manner in HUVEC, suggesting that accumulated IS may play an important role in enhancing intravascular oxidative stress. Conclusion. We propose that AST-120 reduces IS concentrations in the blood that induces ROS production in endothelial cells, thereby inhibiting the subsequent occurrence of oxidative stress in the systemic circulation in renal failure.

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Renal Disposition of a Furan Dicarboxylic Acid and Other Uremic Toxins in the Rat

Cited by 58 publications

References 31 publications

Tubular Secretion in CKD

Tubular Secretion in CKD

Interaction between Two Sulfate-Conjugated Uremic Toxins,p-Cresyl Sulfate and Indoxyl Sulfate, during Binding with Human Serum Albumin

An Oral Adsorbent, AST-120 Protects Against the Progression of Oxidative Stress by Reducing the Accumulation of Indoxyl Sulfate in the Systemic Circulation in Renal Failure

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