Plasma Indoxyl Sulfate Concentration Research Articles

Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms

ObjectiveOur study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome.DesignWe recruited 358 patients...

Evaluation of effects of indoxyl sulfate and parathyroid hormone on CYP3A activity considering the influence of CYP3A5 gene polymorphisms.

Indoxyl sulfate and parathyroid hormone (PTH), which accumulate in chronic kidney disease (CKD), have been reported to reduce cytochrome P450(CYP)3A activity. Homozygotes of the CYP3A5*3 allele have reduced CYP3A5 activity compared to carriers of at least one CYP3A5*1 allele. 4β-Hydroxycholesterol (4β-OHC) has been established as an endogenous substrate reflecting CYP3A activity. 4β-OHC is produced through hydroxylation by CYP3A4 and CYP3A5 and by autoxidation of cholesterol, whereas 4α-hydroxycholesterol (4α-OHC) is produced solely by autoxidation of cholesterol. This study focused on CKD patients and evaluated the effects of plasma indoxyl sulfate and intact-PTH concentrations on plasma 4β-OHC concentration, 4β-OHC/total cholesterol ratio and 4β-OHC-4α-OHC, with consideration of the influence of CYP3A5 polymorphism. Sixty-three CKD patients were analysed and divided into CYP3A5 carrier group (n = 26) and non-carrier group (n = 37). Plasma indoxyl sulfate significantly correlated inversely with 4β-OHC concentration and with 4β-OHC-4α-OHC in both the CYP3A5*1 carrier group (r = -0.42, P = .034; r = -0.39, P = .050, respectively) and the non-carrier group (r = -0.45, P = .0054; r = -0.39, P = .019, respectively). However, multiple regression analysis did not identify plasma indoxyl sulfate concentration as a significant independent factor associated with any of the CYP3A activity indices. There was no significant correlation between plasma intact-PTH concentration and any of the CYP3A activity indices. The present results suggest that plasma indoxyl sulfate and intact-PTH concentrations do not have clinically significant effects on CYP3A activity in patients with CKD.

Effect of hyperphosphatemia on impairment of vascular function in adenine-induced renal injury in rats

We reported that vascular function in adenine-induced renal injury rats was impaired mediated by increase in plasma indoxyl sulfate concentration. It is known that hyperphosphatemia leads to calcification and atherosclerosis. In the present study, we examined effect of hyperphosphatemia on vascular dysfunction in adenine-induced renal injury in anesthetized rats. Renal injury was induced by feeding 0.75% adenine diet for 4 weeks. Lanthanum carbonate was treated with gavage after 2 weeks induced adenine. Treatment with lanthanum carbonate significantly decreased in plasma phosphorus concentration in adenine rats. N-nitro-L-arginine (L-NA) potentiated the ACh-induced depressor response in normal-diet. However, L-NA failed to potentiate the response in adenine rats or lanthanum-treated rats. Sodium nitroprusside (SNP)-induced depressor response in adenine rats was significantly smaller than that in normal rats. Lanthanum carbonate tended to recover impairment of SNP-induced depressor responses in adenine rats. These findings suggest that hyperphosphatemia is partially related to impairment of smooth muscle function rather than that of endothelial function in adenine rats.

Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and ABCG2

Indoxyl sulfate (IS) accumulates in the body in chronic kidney disease (CKD). In the renal proximal tubules, IS excretion is mediated by OAT1/3 and ABCG2. These transporters are inhibited by some hypouricemic agents; OATs by probenecid and benzbromarone, ABCG2 by febuxostat and benzbromarone. Thus, we evaluated whether hypouricemic agents including dotinurad, a novel selective urate reabsorption inhibitor with minimal effect on OATs or ABCG2, affect IS clearance in rats. Intact and adenine-induced acute renal failure rats were orally administered hypouricemic agents, and both endogenous IS and exogenously administered stable isotope-labeled d4-IS in the plasma and kidney were measured. Our results demonstrated that OATs inhibitors, such as probenecid, suppress IS uptake into the kidney, leading to increased plasma IS concentration, whereas ABCG2 inhibitors, such as febuxostat, cause renal IS accumulation remarkably by suppressing its excretion in intact rats. The effects of these agents were reduced in adenine-induced acute renal failure rats, presumably due to substantial decrease in renal OAT1/3 and ABCG2 expression. Dotinurad did not significantly affected the clearance of IS under both conditions. Therefore, we suggest that hypouricemic agents that do not affect OATs and ABCG2 are effective therapeutic options for the treatment of hyperuricemia complicated by CKD.

Factors involved in phenoconversion of CYP3A using 4β-hydroxycholesterol in stable kidney transplant recipients.

Phenoconversion is a phenomenon whereby some genotypic extensive metabolizers transiently exhibit drug metabolizing enzyme activity at similar level as that of poor metabolizers. Renal failure is known to decrease CYP3A activity in humans. Indoxyl sulfate, parathyroid hormone (PTH), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have been reported to cause CYP3A downregulation in renal failure. We measured plasma concentrations of the above compounds in stable kidney transplant recipients, and evaluated their relations with phenoconversion of CYP3A evaluated by plasma concentration of 4β-hydroxycholesterol, a biomarker of CYP3A activity. Phenoconversion was defined as a genotypic extensive/intermediate metabolizer exhibiting CYP3A activity below the cutoff value that discriminates extensive/intermediate from poor metabolizers. Sixty-three Japanese kidney transplant recipients who underwent transplantation more than 180 days prior to the study were included. Morning blood samples were collected, and CYP3A5 polymorphism as well as plasma concentrations of 4β-hydroxycholesterol, indoxyl sulfate, intact-PTH, IL-6 and TNF-α were determined. Significantly higher plasma 4β-hydroxycholesterol concentration was observed in recipients with CYP3A5*1 allele (n = 23) compared to those without the allele (n = 40), and the cut-off value was 40.0 ng/mL. Ten recipients with CYP3A5*1 allele exhibited CYP3A activity below 40.0 ng/mL (phenoconversion). Only plasma indoxyl sulfate concentration was significantly higher in recipients with CYP3A phenoconversion compared to those without phenoconversion. These findings suggest that higher plasma indoxyl sulfate concentration may be involved in CYP3A phenoconversion. Dose adjustment of drugs metabolized by CYP3A may be needed in patients with CYP3A5*1 allele and high blood indoxyl sulfate.

Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H₂S) level. Nevertheless, the role of H₂S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H₂S in patients with different stages of CKD, and to identify the role of H₂S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H₂S was measured with spectrophotometry. Sulfhemoglobin, the integration of H₂S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H₂S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H₂S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H₂S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H₂S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H₂S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative ­correlation between plasma H₂S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H₂S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H₂S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD ­patients.

Plasma indoxyl sulfate concentration predicts progression of chronic kidney disease in dogs and cats

Indoxyl sulfate is a protein-bound uremic toxin that increases as the severity of impaired renal function increases in humans, laboratory animals, dogs and cats. An elevation of indoxyl sulfate is related to prognosis among people with chronic kidney disease. However, whether indoxyl sulfate is able to predict the progression of chronic kidney disease in dogs and cats has not been previously studied. In the present study, 58 cats and 36 dogs with chronic kidney disease were enrolled. Plasma indoxyl sulfate was measured by high performance liquid chromatography. Renal progression was defined as an increase by one International Renal Interest Society (IRIS) stage and/or a rise in serum creatinine concentration of 0.5mg/dL during the same stage within a 3-month period.Compared with the non-progression groups, across different stages of renal failure, the baseline plasma indoxyl sulfate concentration was increased in the renal progression group (P<0.05), especially for IRIS stages 2 and 3 animals. The area under the receiver operator characteristic curves of indoxyl sulfate, when predicting renal progression, was above 0.75 for both dogs and cats. Indoxyl sulfate concentrations were also correlated with the increase of blood urea nitrogen, serum creatinine, and phosphate and the decrease of hematocrit among cats; while in dogs, concentrations were only correlated with the increase of phosphate concentrations. Indoxyl sulfate served as a biomarker of progression risk in dogs and cats with chronic kidney disease.

Detection of indoxyl sulfate levels in dogs and cats suffering from naturally occurring kidney diseases

Indoxyl sulfate (IS), a protein-bound uraemic toxin, has been found to accumulate in the serum of people with renal diseases and is associated with free radical induction, nephrotoxicity cardiovascular toxicity, and osteoblast cytotoxicity. Although IS has been studied in humans and in experimental models, the role of IS in dogs and cats with kidney disease has not been investigated. A high performance liquid chromatography system was applied to detect plasma IS concentrations in non-azotaemic animals (63 dogs, 16 cats) and in animals with renal azotaemia (66 dogs, 69 cats).The IS levels of azotaemic animals were significantly higher (P < 0.01) than those of non-azotaemic animals (median [IQR] 20.4 (9.5) mg/L vs. 7.2 (8.8) mg/L for dogs; median [IQR] 21 (18.9) mg/L vs. 14.8 (12.3) mg/L for cats). The IS level was significantly correlated with blood urea nitrogen, serum creatinine and phosphate concentrations. Dogs with acute kidney injury had significantly higher IS levels (P < 0.01) than those with chronic kidney diseases (CKD) (median [IQR] 57.7 (40.8) mg/L vs. 17.7 (25.1) mg/L). When CKD was graded using the International Renal Interest Society (IRIS) staging system, IS levels were correlated with CKD severity in both dogs and cats. The IS concentration is directly related to loss of renal function. Further studies are necessary to determine whether measurement of IS provides any additional diagnostic or prognostic information in dogs and cats with kidney disease.

血液透析患者におけるアニオン性尿毒症物質の血漿中濃度とプラバスタチンのタンパク結合に対する影響

Uremic toxins (UTs) accumulate in the body of hemodialysis patients. UTs often exert unfavorable effects on patients and cause significant interactions with clinically relevant drugs. In this study, we assayed plasma concentrations of three typical anionic UTs, indoxyl sulfate (IS), 3-indoleacetic acid (IA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), in 20 hemodialysis patients and 5 healthy volunteers. Moreover, the effects of these anionic UTs on the binding of pravastatin to human serum albumin (HSA) were also evaluated. CMPF concentrations in the plasma of patients were unchanged before and after dialysis (63.0 ± 6.3 μM and 65.1 ± 6.7 μM, respectively), and these values were about 5-fold greater compared with those in healthy volunteers. Although dialysis decreased the plasma IS concentration from 157.9 ± 19.9 μM to 103.8 ± 13.3 μM, the value after hemodialysis was still ca. 27-fold greater than that in healthy volunteers. IA concentrations before and after hemodialysis were almost identical to those in healthy volunteers. There were no significant differences in the plasma concentrations of the three anionic UTs between male and female patients. The magnitude of protein binding was in the order CMPF>IS>IA, indicating that hemodialysis clearance of these anionic UTs was dependent on their protein binding capacities. The ability of IS to reduce pravastatin binding to HSA was much greater than that of CMPF. The present results suggest that statins bind to site II on HSA, and that their binding is modulated by IS when elevated in hemodialysis patients.

Exploration of novel predictive markers in rat plasma of the early stages of chronic renal failure

To identify blood markers for early stages of chronic kidney disease (CKD), blood samples were collected from rats with adenine-induced CKD over 28 days. Plasma samples were subjected to metabolomic profiling by liquid chromatography-mass spectrometry, followed by multivariate analyses. In addition to already-identified uremic toxins, we found that plasma concentrations of N6-succinyl adenosine, lysophosphatidylethanolamine 20:4, and glycocholic acid were altered, and that these changes during early CKD were more sensitive markers than creatinine concentration, a universal indicator of renal dysfunction. Moreover, the increase in plasma indoxyl sulfate concentration occurred earlier than increases in phenyl sulfate and p-cresol sulfate. These novel metabolites may serve as biomarkers in identifying early stage CKD.