Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.     

Protein-bound uremic toxins: new insight from clinical studies

The uremic syndrome is attributed to the progressive retention of a large number of compounds which, under normal conditions, are excreted by healthy kidneys. The compounds are called uremic toxins when they interact negatively with biological functions. The present review focuses on a specific class of molecules, namely the family of protein-bound uremic toxins. Recent experimental studies have shown that protein-bound toxins are involved not only in the progression of chronic kidney disease (CKD), but also in the generation and aggravation of cardiovascular disease. Two protein-bound uremic retention solutes, namely indoxyl sulfate and p-cresyl sulfate, have been shown to play a prominent role. However, although these two molecules belong to the same class of molecules, exert toxic effects on the cardiovascular system in experimental animals, and accumulate in the serum of patients with CKD they may have different clinical impacts in terms of cardiovascular disease and other complications. The principal aim of this review is to evaluate the effect of p-cresyl sulfate and indoxyl sulfate retention on CKD patient outcomes, based on recent clinical studies.     

A Metabolomic Approach to Clarifying the Effect of AST-120 on 5/6 Nephrectomized Rats by Capillary Electrophoresis with Mass Spectrometry (CE-MS)

The oral adsorbent AST-120 is composed of spherical carbon particles and has an adsorption ability for certain small-molecular-weight compounds that accumulate in patients with chronic kidney disease (CKD). So far, very few compounds are known to be adsorbed by AST-120 in vivo. To examine the effect of AST-120 in vivo, we comprehensively evaluated the plasma concentrations of 146 compounds (61 anions and 85 cations) in CKD model rats, with or without four weeks of treatment with AST-120. By capillary electrophoresis with mass spectrometry, we identified 6 anions and 17 cations that were significantly decreased by AST-120 treatment. In contrast, we also identified 2 cations that were significantly increased by AST-120. Among them, 4 anions, apart from indoxyl sulfate and hippurate, and 19 cations were newly identified in this study. The plasma levels of N-acetyl-neuraminate, 4-pyridoxate, 4-oxopentanoate, glycine, γ-guanidinobutyrate, N-γ-ethylglutamine, allantoin, cytosine, 5-methylcytosine and imidazole-4-acetate were significantly increased in the CKD model compared with the sham-operated group, and were significantly decreased by AST-120 treatment. Therefore, these 10 compounds could be added as uremic compounds that indicate the effect of AST-120 treatment. This study provides useful information not only for identifying the indicators of AST-120, but also for clarifying changes in the metabolic profile by AST-120 treatment in the clinical setting.     

Protein-Bound Uremic Toxins Lowering Effect of Sevelamer in Pre-Dialysis Chronic Kidney Disease Patients with Hyperphosphatemia: A Randomized Controlled Trial

P-cresyl sulfate and indoxyl sulfate are strongly associated with cardiovascular events and all-cause mortality in chronic kidney disease (CKD). This randomized controlled trial was conducted to compare the effects between sevelamer and calcium carbonate on protein-bound uremic toxins in pre-dialysis CKD patients with hyperphosphatemia. Forty pre-dialysis CKD patients with persistent hyperphosphatemia were randomly assigned to receive either 2400 mg of sevelamer daily or 1500 mg of calcium carbonate daily for 24 weeks. A significant decrease of total serum p-cresyl sulfate was observed in sevelamer therapy compared to calcium carbonate therapy (mean difference between two groups −5.61 mg/L; 95% CI −11.01 to −0.27 mg/L; p = 0.04). There was no significant difference in serum indoxyl sulfate levels (p = 0.36). Sevelamer had effects in terms of lowering fibroblast growth factor 23 (p = 0.01) and low-density lipoprotein cholesterol levels (p = 0.04). Sevelamer showed benefits in terms of retarding CKD progression. Changes in vascular stiffness were not found in this study.     

Protein-Bound Uremic Toxins: New Culprits of Cardiovascular Events in Chronic Kidney Disease Patients

Chronic kidney disease (CKD) has been considered a major risk factor for cardiovascular diseases. Although great advances have recently been made in the pathophysiology and treatment of cardiovascular diseases, CKD remains a major global health problem. Moreover, the occurrence rates of cardiovascular events among CKD patients increase even in cases in which patients undergo hemodialysis, and the mechanisms underlying the so-called “cardiorenal syndrome” are not clearly understood. Recently, small-molecule uremic toxins have been associated with cardiovascular mortality in CKD and/or dialysis patients. These toxins range from small uncharged solutes to large protein-bound structures. In this review, we focused on protein-bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which are poorly removed by current dialysis techniques. Several studies have demonstrated that protein-bound uremic toxins, especially indoxyl sulfate, induce vascular inflammation, endothelial dysfunction, and vascular calcification, which may explain the relatively poor prognosis of CKD and dialysis patients. The aim of this review is to provide novel insights into the effects of indoxyl sulfate and p-cresyl sulfate on the pathogenesis of atherosclerosis.     

Indoxyl Sulfate Elevated Lnc-SLC15A1-1 Upregulating CXCL10/CXCL8 Expression in High-Glucose Endothelial Cells by Sponging MicroRNAs

Cardiovascular disease (CVD) is the leading cause of mortality in diabetes mellitus (DM). Immunomodulatory dysfunction is a primary feature of DM, and the emergence of chronic kidney disease (CKD) in DM abruptly increases CVD mortality compared with DM alone. Endothelial injury and the accumulation of uremic toxins in the blood of DM/CKD patients are known mechanisms for the pathogenesis of CVD. However, the molecular factors that cause this disproportional increase in CVD in the DM/CKD population are still unknown. Since long non-protein-coding RNAs (lncRNAs) play an important role in regulating multiple cellular functions, we used human endothelial cells treated with high glucose to mimic DM and with the uremic toxin indoxyl sulfate (IS) to mimic the endothelial injury associated with CKD. Differentially expressed lncRNAs in these conditions were analyzed by RNA sequencing. We discovered that lnc-SLC15A1-1 expression was significantly increased upon IS treatment in comparison with high glucose alone, and then cascaded the signal of chemokines CXCL10 and CXCL8 via sponging miR-27b, miR-297, and miR-150b. This novel pathway might be responsible for the endothelial inflammation implicated in augmenting CVD in DM/CKD and could be a therapeutic target with future clinical applications.     

Update on the pharmacokinetics and redox properties of protein-bound uremic toxins

Protein-bound uremic toxins, such as indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, p-cresyl sulfate, hippuric acid, and indoleacetic acid, have been the subjects of extensive investigations. In this review, we summarized the recent works providing the new insight on the pharmacokinetics and redox properties of these uremic toxins. They have a common characteristic of being difficult to remove by conventional dialysis because they all bind tightly to serum albumin. They are transported via organic anion transporters to various tissues, and accumulate not only in the kidney but also in other tissues including vascular endothelial cells, smooth muscle cells, osteoblasts, and the central nervous system. Accumulated uremic toxins alter nonrenal drug clearance. Intracellular accumulated uremic toxins have been linked to the induction of oxidative stress and the stimulation of proinflammatory cytokines through the production of reactive oxygen species, which play a role in the progression of chronic kidney disease and the development of complications. Unfortunately, despite the massive amount of information on the undesirable effects of uremic toxins, methods for improving the detoxification of these toxins appear to be lacking.     

Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway

Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial–mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.     

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

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-β 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.     

pH-Dependent Protein Binding Properties of Uremic Toxins In Vitro

Protein-bound uremic toxins (PBUTs) are difficult to remove using conventional dialysis treatment owing to their high protein-binding affinity. As pH changes the conformation of proteins, it may be associated with the binding of uremic toxins. Albumin conformation at pH 2 to 13 was analyzed using circular dichroism. The protein binding behavior between indoxyl sulfate (IS) and albumin was examined using isothermal titration calorimetry. Albumin with IS, and serum with IS, p-cresyl sulfate, indole acetic acid or phenyl sulfate, as well as serum from hemodialysis patients, were adjusted pH of 3 to 11, and the concentration of the free PBUTs was measured using mass spectrometry. Albumin was unfolded at pH < 4 or >12, and weakened interaction with IS occurred at pH < 5 or >10. The concentration of free IS in the albumin solution was increased at pH 4.0 and pH 11.0. Addition of human serum to each toxin resulted in increased free forms at acidic and alkaline pH. The pH values of serums from patients undergoing hemodialysis adjusted to 3.4 and 11.3 resulted in increased concentrations of the free forms of PBUTs. In conclusion, acidic and alkaline pH conditions changed the albumin conformation and weakened the protein binding property of PBUTs in vitro.     

Exploring Protein Binding of Uremic Toxins in Patients with Different Stages of Chronic Kidney Disease and during Hemodialysis

As protein binding of uremic toxins is not well understood, neither in chronic kidney disease (CKD) progression, nor during a hemodialysis (HD) session, we studied protein binding in two cross-sectional studies. Ninety-five CKD 2 to 5 patients and ten stable hemodialysis patients were included. Blood samples were taken either during the routine ambulatory visit (CKD patients) or from blood inlet and outlet line during dialysis (HD patients). Total (C_T) and free concentrations were determined of p-cresylglucuronide (pCG), hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS) and p-cresylsulfate (pCS), and their percentage protein binding (%PB) was calculated. In CKD patients, %PB/C_T resulted in a positive correlation (all p < 0.001) with renal function for all five uremic toxins. In HD patients, %PB was increased after 120 min of dialysis for HA and at the dialysis end for the stronger (IAA) and the highly-bound (IS and pCS) solutes. During one passage through the dialyzer at 120 min, %PB was increased for HA (borderline), IAA, IS and pCS. These findings explain why protein-bound solutes are difficult to remove by dialysis: a combination of the fact that (i) only the free fraction can pass the filter and (ii) the equilibrium, as it was pre-dialysis, cannot be restored during the dialysis session, as it is continuously disturbed.     

靶向肠道菌群调控肠源尿毒素代谢通路干预慢性肾病进展的治疗策略分析

慢性肾病(chronic kidney disease, CKD)是一种发病率高、预后差、并发症复杂的重大慢性疾病,对人类健康造成极大危害。硫酸吲哚酚(indoxyl-sulfate, IS)和硫酸对甲酚(p-cresol sulfate, PCS)是两种典型的肠源尿毒素,由肠道菌群与宿主共代谢生成。随着慢性肾病的进展,慢性肾病患者体内的IS和PCS等肠源尿毒素不断蓄积,并进一步促进CKD进展。肠道菌群与CKD密切相关,靶向肠道菌群调控肠源尿毒素合成及代谢通路很可能是延缓CKD进展的新思路及新策略。本文通过对肠道菌群及肠源尿毒素与慢性肾病进展之间的关系进行分析,提出基于肠源尿毒素代谢调控干预慢性肾病进展的治疗策略。     

An Innovative Synbiotic Formulation Decreases Free Serum Indoxyl Sulfate,Small Intestine Permeability and Ameliorates Gastrointestinal Symptoms in a Randomized Pilot Trial in Stage IIIb-IV CKD Patients

Proteolytic dysbiosis of the gut microbiota has been recognized as both a typical feature of chronic kidney disease (CKD) and a risk factor for its progression. Blood accumulation of gut-derived uremic toxins (UTs) like indoxyl sulfate (IS) and p-cresyl sulfate (PCS), intestinal permeability and constipation are typical features accompanying CKD progression and triggering chronic inflammation. In order to verify the efficacy of the innovative synbiotic formulation NATUREN G^® in modulating the levels of circulating UTs, intestinal permeability and gastrointestinal symptoms, we set up a randomized, single-blind, placebo-controlled, pilot trial in stage IIIb-IV CKD patients and in healthy controls. Two-month administration of the synbiotic resulted in a decrease of free IS, as compared with the placebo-treated arm, only in the CKD group. The other UTs did not significantly change, although different trends in time (increase in the placebo arm and decrease in the synbiotic arm) were observed. Moreover, after supplementation, reduction of small intestinal permeability and amelioration of abdominal pain and constipation syndromes were observed only in the CKD group. The obtained results suggest the specificity of action of NATUREN G^® in CKD and justify further validation in a wider study population.     

Albumin is the main plasma binding protein for indoxyl sulfate and p‐cresyl sulfate

Indoxyl sulfate and p‐cresyl sulfate are two uremic retention solutes implicated in the uremic syndrome. Removal during dialysis is limited, mainly due to protein binding. Binding characteristics to healthy albumin have recently been characterized. Whether uremia alters the binding characteristics of albumin is currently unknown. Moreover, protein binding values previously determined with ultrafiltration are in sharp contrast to recently reported values based on microcalorimetry. In the present study, indoxyl sulfate and p‐cresyl sulfate binding were therefore quantified using both equilibrium dialysis and ultrafiltration. Deming regression demonstrated good agreement between equilibrium dialysis and ultrafiltration. Free serum concentrations of indoxyl sulfate (+26.6%) and p‐cresyl sulfate (+19.7%) were slightly higher at body temperature compared with at room temperature. To investigate binding kinetics, the plasma of healthy individuals or hemodialysis patients was titrated with albumin solutions. Theoretical models of protein binding were fitted to observed titration curves. Binding coefficients of both toxins were highest in purified albumin, and were reduced from healthy to uremic plasma. In conclusion, the ultrafiltration–HPLC technique reliably measures free serum concentrations of indoxyl sulfate and p‐cresyl sulfate. Albumin is the main binding protein, both in health and in advanced stages of chronic kidney disease. Modeling suggests that albumin contains two binding sites for both toxins, a single high affinity binding site and a second low affinity binding site. The high affinity binding site accounts for at least 90% of overall binding. Competition for this binding site could be used to augment free solute concentrations during dialysis, thus improving epuration. Copyright © 2013 John Wiley & Sons, Ltd.     

Intestinal Chelators,Sorbants, and Gut-Derived Uremic Toxins

Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota’s activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins.     

Inhibitory effects of uraemic toxins 3‐indoxyl sulfate and p‐cresol on losartan metabolism in vitro

Objectives The purpose of this study was to clarify the cause of decreased metabolic clearance of losartan in patients with end‐stage renal failure. The influence of serum from haemodialysis patients (uraemic serum) and uraemic toxins on the metabolism of losartan to EXP‐3174 was investigated in vitro. Methods The formation of EXP‐3174 was estimated using pooled human liver microsomes. 3‐Carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid, hippuric acid, indole‐3‐acetic acid, 3‐indoxyl sulfate and p‐cresol were used as uraemic toxins. Key findings Uraemic serum potently decreased the formation of EXP‐3174 in pooled human liver microsomes. In addition, 3‐indoxyl sulfate and p‐cresol significantly decreased the formation of EXP‐3174 in a concentration‐dependent manner. Furthermore, normal serum (10% v/v) with both 3‐indoxyl sulfate and p‐cresol (both 20 μmol/l) significantly decreased the formation of EXP‐3174 by 46%, which was similar to the level of inhibition with uraemic serum (10% v/v). Conclusions These results suggest that decreased the metabolic clearance of losartan in patients with end‐stage renal failure is partly due to high concentrations of 3‐indoxyl sulfate and p‐cresol.     

Increased Proinflammatory Cytokine Production and Decreased Cholesterol Efflux Due to Downregulation of ABCG1 in Macrophages Exposed to Indoxyl Sulfate

One of the possible causes of enhanced atherosclerosis in patients with chronic kidney disease (CKD) is the accumulation of uremic toxins. Since macrophage foam cell formation is a hallmark of atherosclerosis, we examined the direct effect of indoxyl sulfate (IS), a representative uremic toxin, on macrophage function. Macrophages differentiated from THP-1 cells were exposed to IS in vitro. IS decreased the cell viability of THP-1 derived macrophages but promoted the production of inflammatory cytokines (IL-1β, IS 1.0 mM: 101.8 ± 21.8 pg/mL vs. 0 mM: 7.0 ± 0.3 pg/mL, TNF-α, IS 1.0 mM: 96.6 ± 11.0 pg/mL vs. 0 mM: 15.1 ± 3.1 pg/mL) and reactive oxygen species. IS reduced macrophage cholesterol efflux (IS 0.5 mM: 30.3% ± 7.3% vs. 0 mM: 43.5% ± 1.6%) and decreased ATP-binding cassette transporter G1 expression. However, lipid uptake into cells was not enhanced. A liver X receptor (LXR) agonist, T0901317, improved IS-induced production of inflammatory cytokines as well as reduced cholesterol efflux. In conclusion, IS induced inflammatory reactions and reduced cholesterol efflux in macrophages. Both effects of IS were improved with activation of LXR. Direct interactions of uremic toxins with macrophages may be a major cause of atherosclerosis acceleration in patients with CKD.     

Association of Sarcopenia and Gut Microbiota Composition in Older Patients with Advanced Chronic Kidney Disease,Investigation of the Interactions with Uremic Toxins,Inflammation and Oxidative Stress

Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m², not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.     

Regulation of Renal Organic Ion Transporters in Cisplatin-Induced Acute Kidney Injury and Uremia in Rats

Purpose  The purpose of this study was to examine the regulation of renal organic ion transporters in cisplatin-induced acute kidney injury (AKI) and its relation with indoxyl sulfate (IS), a uremic toxin. Methods  The IS concentrations in the serum and kidney were monitored by high-performance liquid chromatography. Uptake of p-aminohippuric acid, estrone-3-sulfate and tetraethylammonium were examined using renal slices. Real-time PCR and immunoblotting were performed to examine the mRNA and protein expression of rOATs, rOCTs and rMATE1 in the kidney, respectively. Results  The serum and renal IS levels were markedly elevated in cisplatin-treated rats. However, this effect was largely reversed by administration of AST-120, an oral charcoal adsorbent. The functions of renal basolateral organic anion and cation transporters were reduced in cisplatin-treated rats. The levels of mRNA and protein corresponding to rOAT1, rOAT3, rOCT2 and rMATE1, but not rOCT1, were depressed in the kidney of cisplatin-treated rats. Administration of AST-120 to cisplatin-treated rats partially restored the function and expression level of these transporters. Conclusions  Cisplatin-induced AKI causes down-regulation of renal organic ion transporters accompanied by accumulation of serum and renal IS. IS could be involved in the mechanism of down-regulation of rOAT1, rOAT3 and rMATE1 under cisplatin-induced AKI.