Role of Organic Anion Transporters in the Tubular Transport of Indoxyl Sulfate and the Induction of its Nephrotoxicity

Enomoto, Atsushi; Takeda, Michio; Tojo, Akihiro; Sekine, Takashi; Ho, Seok; Khamdang, Suparat; Takayama, Fumio; Aoyama, Isao; Nakamura, Sho; Endou, Hitoshi; Niwa, Toshimitsu

doi:10.1097/01.asn.0000022017.96399.b2

Cited by 272 publications

(216 citation statements)

References 38 publications

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“…1b). These phenomena were also in agreement with the previous reports (9,24). Figure 2 shows the ratio of oxidized albumin as an index of oxidative stress in the systemic circulation in each group.…”

Section: Biochemical Parameters In Vivosupporting

confidence: 92%

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

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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Section: Biochemical Parameters In Vivosupporting

confidence: 92%

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

103

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“…Table 3 shows the serum concentration and total mass removal of proteinbound URMs at month 24 for anuric and non-anuric PD (19). Renal clearance of PCS and IndS occurs mainly through tubular secretion (20). The dialytic clearance of protein-bound URMs is limited (6,21) because only the free fraction is available for diffusion across the dialysis membrane (22).…”

Section: Calculations and Definitionsmentioning

confidence: 99%

Serum Concentrations of p-Cresyl Sulfate and Indoxyl Sulfate, But Not Inflammatory Markers, Increase in Incident Peritoneal Dialysis Patients in Parallel with Loss of Residual Renal Function

et al. 2014

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♦ Background: High serum concentrations of the proteinbound uremic retention solutes p-cresyl sulfate (PCS) and indoxyl sulfate (IndS) and inflammation are associated with increased cardiovascular morbidity and mortality in chronic kidney disease. Renal clearance contributes to up to 80% of the total clearance of PCS and IndS in peritoneal dialysis (PD) patients. Cross-sectional studies evaluating the impact of residual renal function (RRF) on serum concentrations of PCS, IndS, and circulating inflammatory markers have yielded conflicting results. ♦ Methods: To clarify this issue, we carried out a prospective observational cohort study in incident PD patients (n = 35; 19 men; mean age: 55 ± 17 years). Midday blood samples were collected and analyzed for total serum PCS, IndS, C-reactive protein, and high-sensitivity interleukin 6. Peritoneal and renal clearances were calculated from urine and dialysate collections, and RRF was calculated as the mean of renal urea nitrogen and creatinine clearances. Patients were assessed 1, 6, 12, and 24 months after PD start. Differences between time points were analyzed using linear mixed models (LMMs). ♦ Results: Residual renal function declined significantly over time (LMM p < 0.0001). Peritoneal clearances of both toxins tended to increase, but did not compensate for the declining renal clearances. Serum concentrations of PCS and IndS increased significantly over time (LMM p = 0.01; p = 0.0009). In contrast, total mass removal of both toxins remained stable. Circulating inflammatory markers did not change over time. ♦ Conclusions: Our data indicate that serum concentrations of PCS and IndS, but not inflammatory markers, increase in incident PD patients in parallel with loss of RRF.

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“…In healthy kidneys, circulating IS is excreted by renal tubules via organic anion transporters (OATs) 1 and 3, 118 at a rate of ≈170 μmol per day. 119 IS accumulates whenever renal tubular excretory function is impaired, initially in the kidney as well as in the circulation (Figure 3).…”

Section: Is Indoxyl Sulfate a Culprit Inmentioning

confidence: 99%

Cardiorenal Syndrome

Lekawanvijit

Kompa

Wang

et al. 2012

Circulation Research

149

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Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate−induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.

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Role of Organic Anion Transporters in the Tubular Transport of Indoxyl Sulfate and the Induction of its Nephrotoxicity

Cited by 272 publications

References 38 publications

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

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

Serum Concentrations of p-Cresyl Sulfate and Indoxyl Sulfate, But Not Inflammatory Markers, Increase in Incident Peritoneal Dialysis Patients in Parallel with Loss of Residual Renal Function

Cardiorenal Syndrome

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