Toxicity of free p-cresol: a prospective and cross-sectional analysis.
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 p-cresol 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 micro 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).


CONCLUSIONS
Hypoalbuminemia and total p-cresol increase the free fraction of p-cresol. Patients hospitalized for infections have higher free p-cresol. In vitro, high free p-cresol has a negative impact on leukocyte chemiluminescence production. These data demonstrate the toxicity of free p-cresol.
De Smet
Rita
R
University Hospital Gent, Department of Internal Medicine, Renal Division, Belgium. rita.desmet@rug.ac.be
Van Kaer
Jacqueline
J
Van Vlem
Bruno
B
De Cubber
Antoine
A
Brunet
Philippe
P
Lameire
Norbert
N
Vanholder
Raymond
R
D001798:Blood Proteins / Q000378:metabolism*; D003408:Cresols / Q000097:blood* / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000628:therapy; D007962:Leukocytes / Q000737:chemistry; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011446:Prospective Studies; D012044:Regression Analysis; D006435:Renal Dialysis
D001798:Blood Proteins; D003408:Cresols; C032538:4-cresol