Decreased Bilirubin-Binding Capacity in Uremic Serum Caused by an Accumulation of Furan Dicarboxylic Acid

Tsutsumi, Yasuhiro; Maruyama, Toru; Takadate, Akira; Shimada, Hirokazu; Otagiri, Masaki

doi:10.1159/000045631

Cited by 30 publications

(18 citation statements)

References 9 publications

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“…A clinical illustration of this effect is seen in renal failure patients on dialysis. In such patients, the total plasma UB concentration was only one-quarter of the normal value,72 and the free fraction was four- to eightfold greater than normal,73,74 as predicted from the above relation. This increase in free fraction (decrease in albumin affinity) in chronic renal failure has been attributed to plasma accumulation of organic acid “uremic toxins” such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid.…”

Section: Bilirubin Glucuronidation and Ub Excretionmentioning

confidence: 60%

Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease

Levitt¹,

Levitt²

2014

CEG

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Serum bilirubin measurements are commonly obtained for the evaluation of ill patients and to screen for liver disease in routine physical exams. An enormous research effort has identified the multiple mechanisms involved in the production and metabolism of conjugated (CB) and unconjugated bilirubin (UB). While the qualitative effects of these mechanisms are well understood, their expected quantitative influence on serum bilirubin homeostasis has received less attention. In this review, each of the steps involved in bilirubin production, metabolism, hepatic cell uptake, and excretion is quantitatively examined. We then attempt to predict the expected effect of normal and defective function on serum UB and CB levels in health and disease states including hemolysis, extra- and intrahepatic cholestasis, hepatocellular diseases (eg, cirrhosis, hepatitis), and various congenital defects in bilirubin conjugation and secretion (eg, Gilbert’s, Dubin–Johnson, Crigler–Najjar, Rotor syndromes). Novel aspects of this review include: 1) quantitative estimates of the free and total UB and CB in the plasma, hepatocyte, and bile; 2) detailed discussion of the important implications of the recently recognized role of the hepatic OATP transporters in the maintenance of CB homeostasis; 3) discussion of the differences between the standard diazo assay versus chromatographic measurement of CB and UB; 4) pharmacokinetic implications of the extremely high-affinity albumin binding of UB; 5) role of the enterohepatic circulation in physiologic jaundice of newborn and fasting hyperbilirubinemia; and 6) insights concerning the clinical interpretation of bilirubin measurements.

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Section: Bilirubin Glucuronidation and Ub Excretionmentioning

confidence: 60%

Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease

Levitt¹,

Levitt²

2014

CEG

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“…It should be stressed that many protein-bound uremic solutes have important pathophysiologic actions and might be subject to a similar enhancement of toxicity in the case of hypoalbuminemia. Candidate molecules are indoxyl sulfate (6,33,34 ), indole 3-acetic acid (35,36 ), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (37,38 ), phenol (39 ), advanced glycation end products (40 -42 ), leptin (43,44 ), homocysteine (45,46 ), hippuric acid (47,48 ), and p-hydroxyhippuric acid (49,50 ).…”

Section: Discussionmentioning

confidence: 99%

Toxicity of Free p-Cresol: A Prospective and Cross-Sectional Analysis

et al. 2003

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Background: Uremic syndrome is the consequence of the retention of solutes usually cleared by the healthy kidneys. p-Cresol can be considered a prototypic protein-bound uremic toxin. It is conceivable, analogous with drugs, that the non-protein-bound fraction of pcresol exerts toxicity. This aspect had never been evaluated, nor have the factors influencing the free fraction of p-cresol. Methods: In a transsectional study we evaluated the relationship between prehemodialysis free p-cresol and the ratio of free to total p-cresol (F:T) to clinical and biological factors in 44 chronic renal failure patients. The evolution of free p-cresol was assessed prospectively in 12 patients showing a change in serum albumin of at least 5 g/L over time. Hospitalization days attributable to infection and the free p-cresol concentrations were noted over a 1-year period. The impact of free p-cresol in vitro on leukocyte functional capacity was evaluated by chemiluminescence. Results: We observed a correlation between total and free p-cresol (r ‫؍‬ 0.84; P <0.001). In the multivariate analyses, free p-cresol and F:T showed a negative correlation with albumin. A shift from normal serum albumin to hypoalbumininemia in 12 patients led to an increase in free p-cresol from 5.9 ؎ 3.2 to 8.2 ؎ 4.5 mol/L (P <0.05; 0.64 ؎ 0.35 to 0.89 ؎ 0.49 mg/L). Free p-cresol (P <0.05) was higher in the patients hospitalized for infectious disease. In vitro, free p-cresol was higher in a 25 g/L than in a 50 g/L albumin solution (P <0.05). Leukocyte chemiluminescence production was more inhibited in the low albumin (high free p-cresol) solution (28% ؎ 6% vs 21% ؎ 8%; P <0.05).

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“…On the basis of observations from binding displacement and a molecular docking model, we concluded that CMPF contributed to the binding defect of BR in uremia because CMPF and BR partially share the binding site for dicarboxylate molecules on HSA. 32,33 In the case of PCS, its binding characteristics are not fully understood and some controversial observations have been reported. Meijers et al 34 conducted in vitro spiking experiments using serum from hemodialysis patients and found that the addition of IS significantly increased the free concentration of PCS and vice versa, suggesting that both sulfateconjugated uremic toxins share the same binding site on HSA.…”

Section: The Binding Of Uremic Toxins To Serum Albuminmentioning

confidence: 99%

Update on the Pharmacokinetics and Redox Properties of Protein-Bound Uremic Toxins

Watanabe

Miyamoto

Otagiri

et al. 2011

Journal of Pharmaceutical Sciences

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100

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Decreased Bilirubin-Binding Capacity in Uremic Serum Caused by an Accumulation of Furan Dicarboxylic Acid

Cited by 30 publications

References 9 publications

Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease

Quantitative assessment of the multiple processes responsible for bilirubin homeostasis in health and disease

Toxicity of Free p-Cresol: A Prospective and Cross-Sectional Analysis

Update on the Pharmacokinetics and Redox Properties of Protein-Bound Uremic Toxins

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