Serum Concentrations Of Indoxyl Sulfate Research Articles

Inhibition of thyroxine transport into cultured rat hepatocytes by serum of nonuremic critically ill patients: effects of bilirubin and nonesterified fatty acids.

We investigated bilirubin and oleic acid as causes of low plasma T3 in nonuremic critically ill patients with gross changes in serum thyroid hormone levels (T4, < or = 60; T3, < or = 1.1; rT3, > or = 0.45 nmol/L) and elevated bilirubin concentrations (> or = 33 mumol/L). Iodide production from [125I]T4 was inhibited by 42% when rat hepatocytes in primary cultures were incubated with 10% serum from these patients. The mean serum concentration of albumin was reduced by 41%, while the concentrations of bilirubin and nonesterified fatty acids (NEFA) were increased by 2022% and 115%, respectively, in the patients. The molar ratios of bilirubin/albumin and NEFA/albumin in the patients were 0.42 and 3.18, respectively. Addition of oleic acid (50-400 mumol/L) and bilirubin (3-130 mumol/L) to 10% normal human serum (albumin, 70 mumol/L; NEFA, 54 mumol/L; bilirubin, 1.1 mumol/L) progressively inhibited the production of iodide by rat hepatocytes. The decreased iodide production was presumed to be caused by inhibition of T4 transport into hepatocytes. The deiodination of rT3 by rat liver microsomes was unaltered by free bilirubin and free oleic acid concentrations up to 0.1 mumol/L. These free concentrations are at least 1 order of magnitude higher than that attained in nonthyroidal illness. The inhibition of iodide production by the sera of critically ill patients (n = 12) was significantly correlated with the molar ratios of bilirubin/albumin (r = 0.72; P < 0.01) and NEFA/albumin (r = 0.58; P < 0.05). Extensive dialysis or treatment of the sera with charcoal did not completely remove the inhibitory activity on iodide production. Serum concentrations of indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid, and hippuric acid in the critically ill patients (other known T4 transport inhibitors into hepatocytes) were similar to those in the normal subjects. This study together with the well known effects of carbohydrate on T3 neogenesis suggest that elevated bilirubin and NEFA and the low albumin level in non-uremic critical illness may be at least partly responsible for the T4 transport inhibition in T3-producing tissues (e.g. the liver) and, thus, the low plasma T3 levels in these critically ill patients. The question of whether inhibitors of T4 transport into the hepatocytes are also present in other patients with nonthyroidal illness who show only mild changes in thyroid hormone levels and have low concentrations of bilirubin and NEFA remains to be determined.

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.

Inhibitory Effect of Oral Sorbent on Accumulation of Albumin-Bound Indoxyl Sulfate in Serum of Experimental Uremic Rats

Serum indoxyl sulfate, which is markedly accumulated in uremic patients, cannot be removed efficiently by hemodialysis due to its albumin binding. To determine if oral adsorbent (AST-120) can decrease its serum concentration in uremic state, oral adsorbent was administered to experimental nephrectomized uremic rats. Uremic rats fed with oral adsorbent showed a significantly lower serum concentration of indoxyl sulfate compared to control uremic rats, even when serum concentrations of urea nitrogen and creatinine were not significantly decreased in the uremic rats fed with oral adsorbent. Indoxyl sulfate was detected only at a lower concentration in bile as compared with the serum of uremic rats. These results suggest that oral adsorbent adsorbs indole, a precursor of indoxyl sulfate, in the intestine and prevents the accumulation of indoxyl sulfate in uremic rats.

Effect of oral sorbent, AST-120, on serum concentration of indoxyl sulfate in uremic rats

Indoxyl sulfate is a metabolite of tryptophan. Indole is synthesized in intestine from tryptophan by intestinal bacteria. The absorbed indole is converted to indoxyl sulfate through indoxyl in liver. Serum concentration of indoxyl sulfate is markedly increased as an inhibitor of drug-binding in uremic patients as compared with healthy subjects. Since indoxyl sulfate is bound to serum albumin, it cannot be removed efficiently by hemodialysis, and it tends to accumulate in uremic serum. To determine if oral sorbent, AST-120, could adsorb indole in intestine and then decrease serum concentration of indoxyl sulfate, it was administered to nephrectomized uremic rats. Serum concentration of indoxyl sulfate was markedly decreased in uremic rats fed with oral sorbent as compared with control uremic rats. However, serum concentrations of creatinine and urea nitrogen were not significantly decreased in the uremic rats fed with oral sorbent as compared with the control uremic rats. Serum concentration of tryptophan was not decreased but rather increased in the uremic rats fed with oral sorbent as compared with the control uremic rats. Concentration of indoxyl sulfate in bile of a uremic rat was much lower than that in the uremic serum, suggesting that the adsorption of indoxyl sulfate in intestine is not a major mechanism of decreasing the serum concentration of indoxyl sulfate. These results demonstrate that oral sorbent, AST-120, can decrease serum concentration of indoxyl sulfate in uremia due to adsorption of indole in intestine.