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University Hospital Gent, Departments of
1
Internal Medicine, Nephrology Division, and
2
Clinical Biology, B 9000 Gent, Belgium.
3
Medizinische Universitätsklinik, D 7400
Tübingen, Germany.
aAddress correspondence to this author at: University Hospital Gent, Department of Internal Medicine, Nephrology Division, De Pintelaan 185, B 9000 Gent, Belgium. Fax 32-09-240-4599; e-mail rita.desmet{at}rug.ac.be.
Background: Several studies have pointed to a release of drugs or protein-bound solutes from their binding sites during heparinization. The effect is attributed to the metabolism of triglycerides to free fatty acids (FFAs), which compete with drugs for protein binding sites. This study evaluated the impact of intradialytic heparin on the free concentration of the uremic toxin p-cresol and on FFAs.
Methods: Blood samples from hemodialysis (HD) patients, before and during HD, were collected with selected anticoagulation strategies. We assessed the effects of standing time, temperature, pH, and the addition of a lipase inhibitor, tetrahydrolipstatin (THL) to blood samples on the free p-cresol concentration. p-Cresol was analyzed by HPLC with fluorescence detection. We measured FFAs by gas chromatography, and the free fractions of added valproic acid and phenytoin were evaluated by fluorescence polarization immunoassay.
Results: In blood samples (n = 22) not submitted to a specific treatment, free p-cresol increased from 9.9 ± 5.1 to 31.9 ± 22.3 µmol/L after 30 min of heparin HD (P <0.001) and correlated significantly with FFAs (r = 0.80; P = 0.002; n = 12). There was no increase in free p-cresol during heparin-free HD (n = 6) and trisodium citrate HD (n = 9). In addition, p-cresol in ultrafiltrates (n = 3) did not correspond to the free p-cresol in heparinized blood, suggesting that the increase in free p-cresol was artifactual. The release of p-cresol in the test tube was enhanced by standing time (n = 6), sample temperature (n = 6), and alkaline pH (n = 6). Inhibition of lipase activity with THL prevented the increase of FFAs (n = 6) and the release of free p-cresol during HD (n = 22). These results were corroborated by the study of the free fraction of valproic acid (n = 6) and phenytoin (n = 6).
Conclusions: The free concentrations of protein-bound solutes in plasma of heparinized patients are influenced by external factors that alter the lipase activity in the test tube. The free fraction does not increase during HD when lipase activity is neutralized at the time of blood sampling, so that previously reported increases are probably artifacts.
The following articles in journals at HighWire Press have cited this article:
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  T. Nishio, N. Takamura, R. Nishii, J. Tokunaga, M. Yoshimoto, and K. Kawai Influences of haemodialysis on the binding sites of human serum albumin: possibility of an efficacious administration plan using binding inhibition Nephrol. Dial. Transplant., July 1, 2008; 23(7): 2304 - 2310. [Abstract] [Full Text] [PDF]
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 R. De Smet, J. Van Kaer, B. Van Vlem, A. De Cubber, P. Brunet, N. Lameire, and R. Vanholder Toxicity of Free p-Cresol: A Prospective and Cross-Sectional Analysis Clin. Chem., March 1, 2003; 49(3): 470 - 478. [Abstract] [Full Text] [PDF]
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