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At least 271 records · Page 15Linked to original sources
PubMed1976

Diverticular disease: three studies. Part III - Metabolic effect of bran in patients with diverticular disease.

Patients with diverticular disease were given about 24 g bran daily for at least six months. After treatment the oral glucose tolerance curve fell, faecal fat excretion increased, the serum lipoprotein pattern was altered, urinary calcium excretion was reduced, and the serum folate level fell. These changes were not considered to contraindicate the use of bran in the treatment of diverticular disease.

Adult↗
PubMed1970

Dermatogenic enteropathy.

Steatorrhoea has been found in a large proportion of patients with inflammatory dermatoses, especially eczema and psoriasis. It is due to the rash itself and disappears rapidly after topical treatment of the skin. This particular enteropathy, unlike that associated with dermatitis herpetiformis, is not accompanied by an alteration in the stereomicroscopic appearance of the small bowel mucosa. The mechanism is not known. It is important to differentiate dermatogenic enteropathy from gluten sensitivity which has produced a rash, as in the former condition a gluten-free diet is not indicated.

Biopsy↗
PubMed1995

Effects of a furan fatty acid and indoxyl sulfate on thyroid hormone uptake in cultured anterior pituitary cells.

A furan fatty acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and indoxyl sulfate (Indox) accumulate in serum of uremic patients and inhibit the active uptake of thyroxine (T4) into hepatocytes. We tested the effects of CMPF and Indox on the uptake of [125I]triiodothyronine (T3) and [125I]T4 and thyroid-stimulating hormone (TSH) release in anterior pituitary cells. Pituitary cells (500,000/well) were cultured for 3 days in medium with 10% fetal calf serum. Experiments were performed at 37 degrees C in the same medium with 0.5% bovine serum albumin (BSA; [125I]T3 uptake and TSH secretion) or 0.1% BSA ([125I]T4 uptake). The 15-min uptake of [125I]T3 amounted to 0.074 +/- 0.003 fmol/pM free T3 (n = 23) and that of [125I]T4 to 0.033 +/- 0.002 fmol/pM free T4 (n = 32). Preincubation (30 min) and incubation (15 min) with CMPF (20-200 microM) did not alter the uptake of [125I]T3 but reduced [125I]T4 uptake by 27% (P < 0.05) at the highest concentration tested. Indox (40-400 microM) did not affect the uptake of [125I]T3 or [125I]T4. CMPF (40 microM) and Indox (80 microM) did not directly affect the basal or thyrotropin-releasing hormone (TRH)-induced TSH release nor interfere with the effect of 10 nM T3 on TRH-induced TSH release. In conclusion, the absence of inhibitory effects of CMPF or Indox on thyroid hormone uptake by pituitary cells suggests that the transport mechanism is regulated differently compared with that in hepatocytes and underscores the significance of the thyroid hormone carriers for the intracellular availability of T3.

Animals↗
PubMed2006

Indoxyl sulfate induces complex redox alterations in mesangial cells.

Indoxyl sulfate is a protein metabolite that is concentrated in the serum of patients with chronic renal insufficiency. It also is a uremic toxin that has been implicated in the progression of chronic renal disease in rodent models. We have shown previously that mesangial cell redox status is related to activation of mitogen-activated protein kinases and cell proliferation, which are factors related to glomerular damage. We used three methods to examine the ability of indoxyl sulfate to alter mesangial cell redox as a possible mechanism for its toxicity. Indoxyl sulfate increases mesangial cell reduction rate in a concentration-dependent manner as demonstrated by redox microphysiometry. Alterations occurred at concentrations as low as 100 microM, with more marked alterations occurring at higher concentrations associated with human renal failure. We demonstrated that indoxyl sulfate induces the production of intracellular reactive oxygen species (ROS) in mesangial cells (EC50 = 550 microM) by using the ROS-sensitive fluorescent dye CM-DCF. ROS generation was only partially (approximately 50%) inhibited by the NADPH oxidase inhibitor diphenylene iodinium at low (< or = 300 microM) indoxyl sulfate concentrations. Diphenylene iodinium was without effect at higher concentrations of indoxyl sulfate. We also used electron paramagnetic spin resonance spectroscopy with extracellular and intracellular spin traps to show that indoxyl sulfate increases extracellular SOD-sensitive O2-* production and intracellular hydroxyl radical production that may derive from an initial O2-* burst. These results document that indoxyl sulfate, when applied to renal mesangial cells at pathological concentrations, induces rapid and complex changes in mesangial cell redox.

Animals↗
PubMed2000

Decreased bilirubin-binding capacity in uremic serum caused by an accumulation of furan dicarboxylic acid.

In chronic renal failure, substances that are effectively excreted in healthy subjects accumulate in serum. These substances, uremic toxins, include a variety of organic acids. It has been reported that a decrease in the bilirubin (BR) binding capacity occurs in the serum of renal failure patients. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) has a high affinity for human serum albumin (HSA) and is a potent inhibitor of the serum protein binding of many drugs. We recently reported that CMPF and BR share the binding site for dicarboxylate molecules on the HSA molecule [Pharm Res 1999;16:916-923]. In this study, in order to confirm whether CMPF is involved in the decrease of BR serum binding capacity in chronic renal failure patients, the total concentrations of uremic toxins, CMPF, and indoxyl sulfate (IS) and the free BR concentration in serum from healthy volunteers and renal failure patients were determined. Both total CMPF and IS concentrations correlate with the free BR concentration. However, results from the peroxidase method reveal that IS cannot displace BR under the physiological condition [IS]/[HSA] <1. We, therefore, conclude that CMPF is one of the substances which contribute to the decreased binding capacity of BR in uremic serum.

Adult↗
PubMed2002

Combination therapy with benazepril and oral adsorbent ameliorates progressive renal fibrosis in uremic rats.

BACKGROUND/AIMS: The administration of an angiotensin-converting enzyme (ACE) inhibitor or an oral adsorbent, AST-120 (Kremezin), prevents the progression of renal failure. This study was designed to determine the additional effects of AST-120 combined with an ACE inhibitor, benazepril, on the progression of renal fibrosis in uremic rats. METHODS: 5/6-nephrectomized uremic rats were divided into control uremic rats (CRF group), benazepril-treated uremic rats (CRF+B group) and uremic rats receiving benazepril and AST-120 (CRF+BK group). After 14 weeks of treatment renal function and pathological changes were investigated. RESULTS: The progression of renal dysfunction was delayed in both the CRF+B and CRF+BK groups as compared with the CRF group. In the CRF+BK group, the level of serum and urinary indoxyl sulfate and the tubular accumulation of indoxyl sulfate decreased. Both the CRF+B and CRF+BK groups showed lower glomerular sclerosis indices than the CRF group. In the CRF+BK group, but not the CRF+B group, the interstitial fibrosis area and the expression of transforming growth factor (TGF) beta1 and tissue inhibitor of metalloproteinases (TIMP) 1 were decreased as compared with the CRF group. Furthermore, the CRF+BK group showed a smaller interstitial fibrosis area and a lower renal osteopontin expression than the CRF+B group. CONCLUSION: Combination therapy of benazepril and AST-120 is more effective than benazepril alone in retarding the progression of interstitial fibrosis by reducing the expression of TGF-beta 1, TIMP-1 and osteopontin.

Adsorption↗
PubMedDate not supplied

Urinary indoxyl sulfate is a clinical factor that affects the progression of renal failure.

We recently demonstrated that indoxyl sulfate is a stimulating factor for the progression of chronic renal failure (CRF). In this study we determined whether the urine or serum levels of indoxyl sulfate are related to the progression rate of CRF in undialyzed uremic patients. Fifty-five CRF patients with a serum creatinine of >2 mg/dl who had not been treated with an oral sorbent (AST-120) were randomly enrolled in the study. We measured the serum and urine levels of indoxyl sulfate, and estimated the recent progression rate of CRF as the slope of the reciprocal serum creatinine versus time (1/S-Cr-time) plot. The mean urinary amount of indoxyl sulfate in the patients was 60 mg/day. Those with indoxyl sulfate urine levels of >60 mg/day had a significantly faster progression rate of CRF than those with <60 mg/day. Especially, those patients with indoxyl sulfate urine levels of >90 mg/day had the highest CRF progression rate and those with indoxyl sulfate urine levels of <30 mg/day had the slowest CRF progression rate. Urinary indoxyl sulfate had a significantly negative correlation with the slope of the 1/S-Cr-time plot. However, the serum level of indoxyl sulfate or the ratio of serum indoxyl sulfate to creatinine was not significantly correlated with the slope of the 1/S-Cr-time plot. In conclusion, high urine levels of indoxyl sulfate are related with a rapid progression of CRF in undialyzed uremic patients. Thus, urinary indoxyl sulfate is one of the clinical factors that affect CRF progression.

Adult↗
PubMedDate not supplied

Preventive effects of an oral sorbent on nephropathy in rats.

Circulating uremic substances are thought to be involved in the progression of chronic renal failure (CRF). An oral adsorbent AST-120 (Kremezin) is effective in removing circulating uremic toxins from the gastrointestinal tract, and retards the progression of CRF. AST-120 is widely used as an approved drug in Japan for the treatment of undialyzed uremic patients to delay the progression of CRF. AST-120 attenuates the progression of glomerular sclerosis and interstitial fibrosis in a variety of experimental rat models of CRF. However, the mechanism by which AST-120 delays the progression of CRF had not been clear. We have demonstrated that indoxyl sulfate, a dietary protein metabolite, is a circulating uremic toxin stimulating glomerular sclerosis and interstitial fibrosis, and that AST-120 decreases the serum and urine levels of indoxyl sulfate by adsorbing its precursor, indole, in the intestine. The administration of indoxyl sulfate to uremic rats stimulated the expression of transforming growth factor (TGF)-beta1, tissue inhibitor of metalloproteinase (TIMP)-1 and pro-alpha1(I)collagen in the kidneys. Further, the administration of AST-120 to uremic rats reduced the extent of glomerular sclerosis and interstitial fibrosis as well as the renal expression of TGF-beta1 and TIMP-1, by reducing the serum and urine levels of indoxyl sulfate. We propose the protein metabolite hypothesis that endogenous protein metabolites such as indoxyl sulfate play an important role in the progression of CRF, and that AST-120 is effective in retarding the progression of CRF by removing these protein metabolites through intestinal absorption.

Adsorption↗
PubMed2002

An oral adsorbent downregulates renal expression of genes that promote interstitial inflammation and fibrosis in diabetic rats.

BACKGROUND/AIMS: An oral adsorbent, AST-120, removes uremic toxins such as indoxyl sulfate, and delays the progression of renal failure. This study was designed to investigate the effects of AST-120 on the molecular basis of interstitial inflammation and fibrosis, using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus. METHODS: Four weeks after unilateral nephrectomy, the uninephrectomized OLETF (1/2NxOLETF) rats were divided into two groups: AST-120-administered and control 1/2NxOLETF rats. After the administration of AST-120 for 48 weeks, we examined the effects of AST-120 on renal functional, pathological, and gene expressional changes. RESULTS: The administration of AST-120 to the 1/2NxOLETF rats attenuated the progression of renal dysfunction, proteinuria, glomerular sclerosis, tubular injury, and interstitial inflammation and fibrosis. AST-120 significantly reduced renal expression of intercellular adhesion molecule (ICAM)-1, osteopontin, monocyte chemotactic protein (MCP)-1, and transforming growth factor (TGF)-beta1, as well as clusterin. All the five molecules were expressed mainly in tubular cells. AST-120 also decreased serum and urinary levels of indoxyl sulfate and the overload of indoxyl sulfate in tubular cells. CONCLUSIONS: AST-120 ameliorates tubulointerstitial injury by reducing renal expression of ICAM-1, osteopontin, MCP-1, TGF-beta1 and clusterin in 1/2NxOLETF rats.

Administration, Oral↗
PubMed2002

Effects of oral adsorbent AST-120 (Kremezin) on renal function and glomerular injury in early-stage renal failure of subtotal nephrectomized rats.

The aim of the present study was to determine if treatment with an oral adsorbent (AST-120, Kremezin) might decrease the urinary albumin excretion and serum indoxyl sulfate (s-IS), and prevent glomerular sclerosis in early-stage renal failure, i.e. 0.9-1.2 mg/dl of serum creatinine (s-Cr) and 60-95 mg/dl of blood urea nitrogen (BUN), in subtotal (3/4) nephrectomized rats. Levels of s-Cr and s-IS in the AST-120-treated rats were significantly lower than those in the untreated control rats. The AST-120-treated rats showed an increase of creatinine clearance. Urinary protein and indoxyl sulfate excretion in the AST-120-treated rats were also significantly lower than those in the untreated control rats. The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the AST-120-treated rats was significantly lower than that in the untreated control rats. The degree of glomerular sclerosis and tubulointerstitial fibrosis in the AST-120-treated rats was significantly lower than that in the untreated control rats. Furthermore, there was a significant relationship among the degree of GT/BC, glomerular sclerosis, tubulointerstitial fibrosis and the levels of urinary protein excretion. It appears that AST-120 might decrease the accumulation of s-Cr and s-IS, and prevent glomerular sclerosis in early stage renal failure in the subtotal nephrectomized rats.

Adsorption↗
PubMed2006

A nexus of progression of chronic kidney disease: charcoal, tryptophan and profibrotic cytokines.

Fibrosis plays a role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. A novel charcoal compound, AST-120, has been used for over a decade in Japan to prevent progression of CKD. It is thought that the oral administration of AST-120 blocks the intestinal absorption of tryptophan-derived indole. This prevents the hepatic conversion of indole to indoxyl sulfate (IS). IS has been shown to stimulate the production of profibrotic cytokines such as transforming growth factor-beta. AST-120 lowers IS in a dose dependent fashion and does not change the creatinine appearance rate in the urine. Enteric capsules containing Bifidobacterium longum have been shown to prevent progression of CKD in a preliminary study. These findings suggest that prospective clinical trials be undertaken to determine if these other potential methods of inhibiting fibrosis are useful in slowing progressive CKD.

Administration, Oral↗
PubMed2006

Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes.

BACKGROUND: Alterations of hepatic drug metabolism in patients with renal failure are poorly understood. In this study, the effects of uremic substances that can be removed by hemodialysis on in vitrohepatic drug metabolism were studied using human liver microsomes and hepatocytes. METHODS: The metabolism of various compounds that undergo oxidation and glucuronidation in the liver was studied using human liver microsomes and hepatocytes in the presence of 11 uremic substances removable by hemodialysis. RESULTS: The formation of resorufin from ethoxyresorufin was inhibited by 3-indoxylsulfate and 3-indoleacetic acid. The formation of 6beta-hydroxytestosterone from testosterone was inhibited only by 3-indoxylsulfate. These uremic substances reduced the maximum metabolic rate but not the affinity, suggesting that the inhibitory mechanism was noncompetitive. The inhibition of formation of resorufin and 6beta-hydroxytestosterone by 3-indoxylsulfate was also observed in human hepatocytes. The elimination of nicardipine in liver microsomes was decreased significantly in the presence of 3-indoxylsulfate and 3-indoleacetic acid. CONCLUSION: The hepatic metabolism of certain drugs may be inhibited directly by uremic substances such as 3-indoxylsulfate that accumulate in the plasma in patients with chronic renal failure.

Biomarkers↗
PubMed2007

Indoxyl sulfate and atherosclerotic risk factors in hemodialysis patients.

BACKGROUND: Indoxyl sulfate is a uremic toxin that accelerates the progression of chronic kidney disease (CKD). Serum levels of indoxyl sulfate are increased in dialysis patients. It was reported that indoxyl sulfate plays a role in endothelial dysfunction in uremic patients, and stimulates proliferation of rat vascular smooth muscle cells (VSMC). We examined associations between indoxyl sulfate and several markers related to atherosclerosis. METHODS: The association between indoxyl sulfate and atherosclerotic risk factors was studied in 224 hemodialysis (HD) patients (123 male, 101 female). Serum levels of indoxyl sulfate were measured by using high-performance liquid chromatography (HPLC). RESULTS: There were significant differences in serum levels of creatinine, calcium x phosphate and pentosidine between high- and low-indoxyl sulfate level groups. Indoxyl sulfate showed significant positive correlations with pentosidine, creatinine, and protein catabolic rate, and a significant negative correlation with high-density lipoprotein (HDL) cholesterol. Further, pentosidine, creatinine, and HDL-cholesterol were independently associated with indoxyl sulfate by multiple linear regression analysis. CONCLUSION: In addition to creatinine, pentosidine and HDL-cholesterol, the risk factors of atherosclerosis, were associated with indoxyl sulfate in HD patients. Indoxyl sulfate may be involved in the pathogenesis of atherosclerosis.

Adolescent↗
PubMed1992

Suppressed serum and urine levels of indoxyl sulfate by oral sorbent in experimental uremic rats.

In uremic patients, the serum concentration of indoxyl sulfate is markedly increased. To determine if oral sorbent (AST-120) suppresses the endogenous synthesis of indoxyl sulfate, it was administered to experimental uremic rats, and the serum concentration and urinary excretion of indoxyl sulfate were quantified by high-performance liquid chromatography. Oral sorbent decreased both the serum concentration and urinary excretion of indoxyl sulfate, suggesting that there was suppression of the endogenous synthesis of indoxyl sulfate by the oral sorbent. Oral sorbent did not decrease the serum concentration and urinary excretion of hippuric acid, but it did alleviate the deterioration of renal function in the experimental uremic rats.

Adsorption↗
PubMed1994

Fast atom bombardment mass spectrometric determination of the molecular weight range of uremic compounds that displace phenytoin from protein binding: absence of midmolecular uremic toxins.

Uremic compounds are known to displace phenytoin from protein binding, resulting in a higher concentration of the pharmacologically active free fraction of phenytoin. The true chemical identities and molecular weight range of all these compounds are still unknown. We demonstrated that indoxyl sulfate and hippuric acid, which are found at high concentrations in uremic patients, can only partially explain the elevated free phenytoin concentration. Other known uremic compounds, guanidine, methylguanidine, and guanidinosuccinic acid, do not displace phenytoin from the protein-binding sites. Uremic compounds from sera of patients on maintenance hemodialysis were removed using activated charcoal. These compounds were then backextracted from activated charcoal using methanol and analyzed by fast atom bombardment mass spectroscopy. Mass spectra of uremic sera showed no peak over m/z 450, indicating that midmolecular uremic toxins are not involved in displacing phenytoin from protein binding. We also observed additional peaks in the mass spectrum of uremic compounds when compared with the normal serum extract, indicating the presence of several endogenous compounds in uremic sera, as expected.

Drug Interactions↗