Mechanisms of uremic inhibition of phagocyte reactive species production: Characterization of the role of p-cresol

Vanholder, Raymond; Smet, Rita De; Waterloos, Marjan; Landschoot, N. Van; Vogeleere, P; Hoste, Eric; Ringoir, S

doi:10.1038/ki.1995.64

Cited by 141 publications

(84 citation statements)

References 40 publications

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“…Sulfation may also decrease toxicity. In this regard, Vanholder et al (12) have found that the respiratory burst activity of phagocytes is inhibited by p-cresol but not by PCS. It may be necessary to re-evaluate other reported in vitro toxicities of p-cresol in light of the current findings.…”

Section: Discussionmentioning

confidence: 99%

“…Many phenols accumulate in uremia and there has been longstanding interest in their contribution to uremic toxicity (7)(8)(9)(10). Interest has focused on p-cresol because its plasma levels are higher than those of most uremic solutes and because in vitro studies have shown that it has toxic effects (11)(12)(13)(14). Recent studies have confirmed that protein binding limits the removal of p-cresol by dialysis and associated high p-cresol levels with poor outcomes in dialysis patients (15)(16)(17).…”

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confidence: 99%

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Removal of P-Cresol Sulfate by Hemodialysis

Martinez

Recht

Hostetter

et al. 2005

Journal of the American Society of Nephrology

238

178

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Protein-bound solutes are poorly cleared by dialysis. Among the most extensively studied of these solutes is p-cresol, which has been shown to be toxic in vitro. This study examined the form in which p-cresol circulates and quantified its removal by hemodialysis. HPLC analysis of plasma from hemodialysis patients contained a peak whose mobility corresponded to synthetic p-cresol sulfate (PCS) but no detectable unconjugated p-cresol. Treatment with sulfatase resulted in recovery of this peak as p-cresol, confirming its identity. Subsequent studies compared the removal of PCS and another protein-bound solute, indican, to the removal of urea during clinical hemodialysis treatments. PCS and indican were 94 ؎ 1% and 93 ؎ 2% bound to plasma protein, respectively. Protein-binding caused a predictable decrease in measured dialytic clearance, which averaged 20 ؎ 4 ml/min for PCS and 25 ؎ 5 ml/min for indican as compared with 260 ؎ 20 ml/min for urea. Volumes of distribution for the protein-bound solutes were greater than the plasma volume, averaging 15 ؎ 7 L for PCS and 14 ؎ 3 L for indican as compared with 37 ؎ 7 for urea. Solute reduction ratios were 20 ؎ 9% for PCS, 30 ؎ 7% for indican, and 69 ؎ 5% for urea. We conclude that p-cresol circulates in the form of its sulfate conjugate, PCS. PCS is poorly removed by hemodialysis because its clearance is limited by protein binding and the ratio of its volume of distribution to its clearance is high.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Removal of P-Cresol Sulfate by Hemodialysis

Martinez

Recht

Hostetter

et al. 2005

Journal of the American Society of Nephrology

238

178

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“…48 All studies evaluating indoxyl sulfate showed a negative (toxic) effect (Table 3), except the study by Odamaki et al, 52 which showed an increase of hepatocyte albumin production in the presence of indoxyl sulfate. Four studies on p-cresyl sulfate [53][54][55][56] and one study on indoxyl sulfate 55 showed no significant changes (data not shown).…”

Section: Resultsmentioning

confidence: 99%

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

Journal of the American Society of Nephrology

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575

463

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A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

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“…Among the protein-bound compounds, p-cresol can be considered a prototype because of its high protein binding (Ϸ90% in patients with chronic renal failure) (14 ) and its interaction with multiple biological and biochemical functions (10,11 ). One of the most relevant characteristics of pcresol is its capacity to suppress the production by leukocytes of reactive products such as free oxygen radicals (9 ), which play a role in the elimination of infective agents. As a consequence, p-cresol retention has been considered one of the elements playing a role in the susceptibility of the uremic patients to infection (21 ).…”

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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Mechanisms of uremic inhibition of phagocyte reactive species production: Characterization of the role of p-cresol

Cited by 141 publications

References 40 publications

Removal of P-Cresol Sulfate by Hemodialysis

Removal of P-Cresol Sulfate by Hemodialysis

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

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

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