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1 University Hospital Gent, Department of Internal Medicine, Renal Division, De Pintelaan 185, B-9000 Ghent, Belgium.
2 Institut National de la Santé et de la Recherche Médicale, EMI 0019, Faculté de Pharmacie, Université de la Méditerranée, 13005 Marseille, France.
aAuthor for correspondence. Fax 32-9-2404599; e-mail rita.desmet{at}rug.ac.be.
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Abstract |
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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 µmol/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.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Similar to protein-bound drugs, it can be expected that the biological activity of the protein-bound solutes is in most cases exerted by the free, non-protein-bound fraction (2)(3)(4)(5). Because most of these solutes compete with each other and with drugs for protein binding, the cumulative biological impact of these multiple free solutes might substantially enhance the toxic effect of uremia (6)(7). The possibility should be considered that decreases in serum albumin further contribute to the release of ligands from their binding sites and to their toxicity. However, to our knowledge, this hypothesis has never been tested in clinical and/or experimental conditions. This hypothesis becomes more interesting in view of the recent suggestion of a link between malnutrition and hypoalbuminemia on one hand and survival of hemodialysis patients on the other (8).
One of the protein-bound compounds that has been shown to exert a substantial impact on biological systems in uremia is p-cresol (9)(10)(11). In the present study, we evaluated the impact of several factors on the free concentration of p-cresol. In addition, we considered the relationship between free p-cresol and hospitalization for infectious disease. In vitro experiments were undertaken to evaluate the influence of high and low free p-cresol concentrations on the response capacity of granulocytic leukocytes, one of the biological functions significantly affected by p-cresol. The results showed that the release of p-cresol from its protein binding sites is influenced by hypoalbuminemia together with total p-cresol concentrations. The additional release of p-cresol from its binding sites may have a negative biochemical and clinical impact.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Conventional hemodialysis was performed for 4 h three times per week with low-flux polysulfone [F8 (Fresenius Medical Care) and Rapido BLS 646 (Sorin Biomedica, Bellco)], Hemophan (FS PLUS 1.6; Gambro), or cellulose diacetate (Nipro Nissho). The composition of the dialysate was 38.5 mmol/L bicarbonate, 138 mmol/L sodium, 104 mmol/L chloride, 4 mmol/L acetate, 1.25 mmol/L calcium, and 0.5 mmol/L magnesium. The dialysate potassium concentration was adapted to the needs of the patients and ranged from 1 to 3 mmol/L. A blood flow (QB) of at least 250 mL/min and a dialysate flow (QD) of 500 mL/min were maintained. Kt/V was targeted at >1.2 (single pool).
Blood was collected before hemodialysis from the inlet bloodline before heparinization to avoid the enzymatic hydrolysis that occurs in plasma of heparinized patients and that produces an artifactual increase of the free fraction of protein-bound compounds (12).
For the determination of urea kinetics, additional blood samples were collected according to standard methods. The blood samples were collected on ice (Venoject II; Terumo Europe) and centrifuged immediately at 1900g (CR 412; Jouan). The serum was stored at -20 °C until analysis. We collected 30 mL of blood from 10 healthy individuals in heparinized tubes (Becton Dickinson) to isolate healthy granulocytes for the in vitro experiments.
reagents
HPLC-grade water, HPLC-grade methanol, and isopropyl ether were purchased from Acros Organics; 25% ammonia solution was obtained from BDH Laboratory Supplies, dextran was from Amersham Pharmacia, and phenol red-free Hanks’ balanced salt solution was from Life Technologies. Creatinine reagent was from Analis. The methanolic p-cresol standard solution (46.2 mmol/L), bovine serum albumin (BSA;1
essentially fatty acid free; 
97%), luminol, zymosan, the reagents for the determination of blood urea nitrogen (BUN), and the reagents for the determination of serum albumin were purchased from Sigma Chemical.
biochemical assays
BUN was measured photometrically by the coupled enzyme reactions involving urease and glutamate dehydrogenase. The total dialyzer urea clearance normalized for urea distribution volume (Kt/V) and the normalized protein catabolic rate (nPCR) were calculated by the iterative calculation method of Sargent and Gotch (13).
Creatinine concentrations were analyzed by the Jaffe reaction with the Creatinine Analyzer 2 (Beckman Instruments). Albumin was measured photometrically based on the bromcresol green reaction. p-Cresol did not affect the measurement of albumin (data not shown).
The p-cresol analyses were performed as described previously (14). In brief, for the determination of total p-cresol, serum was deproteinized by acidification with HCl and NaCl. For the determination of free p-cresol, after acidification serum was ultrafiltered with a Centrifree® Micropartition Device (molecular cutoff of Mr 30 000; Amicon Inc.), and 2,6-dimethylphenol was added as internal standard. p-Cresol was then extracted with isopropyl ether. After the addition of NaOH to the organic layer, the isopropyl ether was evaporated. The dry residue was redissolved in HCl and analyzed by HPLC on a reversed-phase column [C18, Ultrasphere ODS; 15 cm x 4.6 mm (i.d.); Beckman Instruments]. A linear gradient of methanol (40–75% over 13 min) in 50 mmol/L formic acid buffer, pH 3.0, was programmed on the chromatographic controller at a flow rate of 1 mL/min (Pharmacia). p-Cresol was detected by fluorescence with excitation at 280 nm and emission at 340 nm (RF530; Shimadzu). p-Cresol was quantified based on peak height, and the concentrations of total and free p-cresol in the unknown samples were calculated from calibration curves.
chemiluminescence production
Granulocyte isolation for in vitro experiments.
Granulocytes were isolated from the blood of healthy individuals with a dextran gradient (15); plasma was separated from the normal blood by centrifugation at 1900g for 10 min. The pellet was removed from the red blood cells and placed in a mixture of dextran (500 g/L in saline) and Hanks’ balanced salt solution (1:2 by volume) and kept for 20 min at 37 °C. The upper layer was transferred into another test tube and centrifuged at 450g for 5 min, after which the supernatant was removed. The remaining red blood cells in the sediment were hemolyzed with 0.5 mL of hemolysis buffer for 10 min at 4 °C. The hemolysis buffer consisted of (per liter) 9.3 g of ammonium chloride, 0.3 g of potassium hydrogen carbonate, and 0.3 mL of EDTA (0.1 mol/L) and was adjusted to pH 7.4 with sodium hydroxide. The white blood cells were washed twice with Hanks’ balanced salt solution and divided into equal portions; the tubes were centrifuged at 150g for 10 min, after which the supernatant was removed.
The number of isolated cells was counted (M5 30; Coulter Counter Electronics Ltd.), and the cells were differentiated according to their light microscopy properties.
Chemiluminescence measurement.
The production of reactive oxygen species by granulocytes was monitored by luminol-amplified chemiluminescence at 425 nm (Lumicon). Luminol was added to enhance the chemiluminescence of the generated photons. Luminol was dissolved in dimethyl sulfoxide (0.13 mol/L;10 g/L) and kept at -20 °C. A working solution of luminol [1:1000 dilution in Hanks’ balanced salt solution (0.1 mL of luminol in 100 mL of Hanks’)] was prepared immediately before testing, and 500 µL was added to 50 µL of the cell suspension. Light emission was monitored over 60 min in 30-s intervals. The maximum number of photons during any 30-s interval and the total number of photons detected during the 60-min period were recorded.
In vitro estimation of granulocyte functional capacity.
The chemiluminescence produced by the isolated cells was measured in the resting state after the addition of 100 µL of Hanks’ balanced salt solution and after stimulation with zymosan as an index of the capacity of granulocytes to produce free radicals, which is a measure of the activity of the cells in the killing of bacteria after phagocytosis (16). Zymosan (5 g) was suspended in 100 mL of saline, and 100 µL of the suspension was added to the isolated cells.
To evaluate the stimulated response, the counts in the resting state were subtracted from the number of counts produced by the stimulated cells. The counts were normalized per 1000 granulocytes.
in vivo transsectional study
In the first part of the study, prehemodialysis serum albumin, creatinine, BUN, and total (T) and free (F) p-cresol concentrations were measured in 44 hemodialysis patients. In addition, free p-cresol was also normalized for total p-cresol to exclude the potential impact of total p-cresol on free p-cresol by calculating the ratio (F:T) (17). Together with blood analyses, time on hemodialysis and body weight were noted. Finally, urea kinetics were obtained simultaneously, and nPCR and Kt/V were calculated. All of these variables were evaluated statistically to define the variables with the most significant relationship with free p-cresol.
in vivo prospective longitudinal studies
Influence of change of serum albumin on free p-cresol in the same patients.
In a population of 12 patients, total and free p-cresol and the other above-mentioned variables were evaluated again when serum albumin had changed by more than 5 g/L from the original value. The two evaluations occurred with an interval of 11 ± 8 months. Five patients had an increase in serum albumin over time, whereas in the remaining seven patients serum albumin decreased.
The above-mentioned variables were also evaluated in the remaining patients in whom serum albumin was unaltered. The absolute difference between the free p-cresol concentrations at two time points, one at the start of study and one 
12 months thereafter, was calculated for all of the patients.
Free p-cresol in relation to hospitalization days for infection per year.
Blood was collected before hemodialysis from the inlet bloodline twice a year at the start and the end of the 1-year follow-up period. For each of the 44 patients, prehemodialysis values for total p-cresol, free p-cresol, albumin, BUN, creatinine, body weight, nPCR, and Kt/V were obtained, and the two values were averaged. For each patient, the total number of hospitalization days with and without infections during an entire year was counted.
in vitro experiments
Influence of change in BSA on free p-cresol.
We prepared 25 and 50 g/L BSA solutions in Hanks’ balanced salt solution to determine free p-cresol and to measure the chemiluminescence production. To 10 mL of each BSA solution, we added 10 µL of increasing concentrations of p-cresol. The test tubes were incubated at room temperature for 15 min, and the free p-cresol concentrations in the solutions were determined as described above.
Free p-cresol in relation to chemiluminescence production.
The effect of modifying total p-cresol concentrations between 70 and 370 µmol/L (7.5 and 40.0 mg/L) on chemiluminescence production was evaluated in 25 g/L (n = 13) and 50 g/L (n = 13) BSA solutions. The BSA solutions were added to 500 µL of isolated normal granulocytes and incubated at 37 °C for 10 min. Simultaneously, the same procedure was performed with BSA solutions containing no p-cresol. The chemiluminescence production of the cells was measured in the resting state and after stimulation with zymosan. The final results were expressed as the percentage difference between the chemiluminescence production of cells with and without the addition of p-cresol.
statistical analysis
Statistical analyses were performed with Statistica for Windows, Ver. 4.5 (Statsoft Inc.). All data are expressed as the mean ± SD. For univariate analyses of groups of variables, the Kruskal-Wallis nonparametric ANOVA was performed. The Wilcoxon test was applied for paired data, and the Mann-Whitney U-test was used for unpaired data. For bivariate analyses, linear regression was performed. Multivariate analyses were performed with backward stepwise multiple regression analysis to predict the most significant relationship between a dependent variable and independent variables. The difference between two regression coefficients was estimated by calculating the t-value (18). P <0.05 was considered significant. The gaussian distribution of variables was tested with the Kolmogorov-Smirnov test, and normality was accepted when P was >0.20. The Fisher test was performed to test the association between row and column variables.
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Results |
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. Uremic solutes covered a broad range of concentrations; the lowest and highest concentrations differed by factors of 3 and 4 for creatinine and BUN, respectively, and by a factor of 10 for total and free p-cresol. Serum albumin ranged from hypoalbuminemia to normoalbuminemia.
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Linear regression analyses with free p-cresol as dependent variable.
Single linear regression analysis of free p-cresol with the above-mentioned variables revealed a significant correlation with total p-cresol (Fig. 1
). Multiple regression analysis with free p-cresol as dependent variable and the other factors as independent variables demonstrated a significant correlation with total p-cresol, albumin, and creatinine (Table 2A
).
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Calculation of F:T ratio.
Considering that the impact of total p-cresol on free p-cresol could have masked a possible relationship between free p-cresol and the other variables, we then normalized free p-cresol for total p-cresol by calculating the ratio between these two variables (F:T). The overall F:T ratio was 0.12 ± 0.04 (range, 0.05–0.21). F:T had a gaussian distribution (P >0.20; Fig. 2A
).
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In the first quartile of the histogram, the F:T ratio was <0.10 (mean ± SD, 0.07 ± 0.02), and the serum albumin for the patients in that section of the population was 39 ± 3 g/L. For the patients in the fourth quartile of the histogram, the F:T ratio exceeded 0.15 (0.17 ± 0.02) with a serum albumin of 35 ± 3 g/L (P <0.05 vs the first quartile; Fig. 2B
).
Linear regression analyses with F:T as dependent variable.
The single linear regression between F:T and the other variables was analyzed. F:T correlated negatively with serum albumin (r = -0.44; P <0.01; Fig. 3
) and positively with creatinine (r = 0.31; P <0.05; data not shown). We performed multiple regression analysis with the ratio F:T as dependent variable and the other factors, except for free and total p-cresol, as independent variables (Table 2B
). Backward stepwise multiple regression analysis revealed that albumin and creatinine were related to F:T.
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in vivo prospective longitudinal studies
Influence of change of serum albumin on free p-cresol in the same patients.
The patient characteristics and blood chemistries of the 12 patients whose serum albumin changed by >5 g/L during a time interval of 11 ± 8 months were evaluated at two different time points according to their albumin concentrations. The data sets consisted of the values registered when serum albumin was lower (35 ± 3 g/L) and when it was higher (40 ± 3 g/L). No difference between the two time points was found for prehemodialysis serum concentrations of BUN and creatinine or for body weight, nPCR, or Kt/V (data not shown).
A shift from normoalbuminemia to hypoalbumininemia produced a 39.1% increase in free p-cresol, from 5.9 ± 3.2 to 8.2 ± 4.5 µmol/L (0.64 ± 0.35 to 0.89 ± 0.49 mg/L; P <0.05). The total p-cresol concentrations were the same in patients with normal [54.6 ± 21.3 µmol/L (5.9 ± 2.3 mg/L) p-cresol] and low albumin [55.5 ± 21.3 µmol/L (6.0 ± 2.3 mg/L) p-cresol]. Those observations were also reflected in a high F:T ratio in the hypoalbuminemic condition compared with normal serum albumin (0.15 ± 0.07 vs 0.11 ± 0.03; P <0.05).
The patient characteristics and blood chemistries of the remaining patients, in whom serum albumin did not change during the year, were evaluated at two different time points. We found no statistical difference between the mean total and free p-cresol at the two time points.
The mean of the absolute difference between the free p-cresol concentrations at the two time points was 4.2 ± 4.0 µmol/L (0.45 ± 0.43 mg/L).
p-Cresol in relation to hospitalization days for infection.
The patients were divided into two groups according to hospitalization with (n = 16) and without infection (n = 28) over a period of 1 year. We found no differences in body weight, nPCR, Kt/V, creatinine, BUN, albumin, and total p-cresol among the two groups (data not shown). Free p-cresol was higher in patients hospitalized for infectious diseases: 13.9 ± 6.5 vs 9.2 ± 5.5 µmol/L (1.5 ± 0.7 vs 1.0 ± 0.6 mg/L); P <0.05; Fig. 4
).
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in vitro experiments
Influence of change in serum albumin on free p-cresol.
We observed a significant linear regression between total and free p-cresol concentrations in the 25 and 50 g/L BSA solutions (Fig. 5A
). The regression coefficients of the two lines were significantly different (P <0.01) related to higher free p-cresol concentrations in the low-BSA solution.
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Free p-cresol in relation to chemiluminescence production.
The inhibition of chemiluminescence production by stimulated granulocytes in medium containing 25 and 50 g/L BSA in the presence of increasing total p-cresol concentrations produced a significant correlation between the percentage of inhibition and the free p-cresol concentrations, as illustrated in Fig. 5B
. The inhibition was more pronounced in the 25 g/L BSA solution than in the 50 g/L solution although the total p-cresol concentration was the same (28% ± 6% vs 21 ± 8%; P <0.05; Fig. 5C
). The free p-cresol concentration was the highest in the low-BSA solution: 52.7 ± 28.7 vs 23.1 ± 14.8 µmol/L (5.7 ± 3.1 vs 2.5 ± 1.6 mg/L; P <0.01; Fig. 5C
). Chemiluminescence production was not inhibited in the BSA solutions containing no p-cresol.
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Discussion |
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To our knowledge, this is one of the first studies to imply a relationship between the concentration of one of the protein-bound compounds and clinical conditions. Furthermore, free p-cresol correlates negatively with in vitro chemiluminescence production, which is considered as one of the negative pathophysiologic effects attributed to p-cresol. In the absence of differences in total p-cresol, free p-cresol was highest and chemiluminescence inhibition was most pronounced in the experiment using the lowest albumin concentration.
One of the unsolved questions concerning protein-bound uremic solutes is whether the total or the free fraction is responsible for their toxic effect (19). We are not aware of any study that demonstrates the pathophysiologic impact of free uremic solutes. However, data support the biological impact of the free fraction of protein-bound drugs such as phenytoin, mycophenolic acid, valproic acid, and salicylate (2)(3)(4)(5)(6)(7)(20). Among the protein-bound compounds, p-cresol can be considered a prototype because of its high protein binding (90% 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 p-cresol 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).
In the present in vitro study, we studied the relationship between free p-cresol and chemiluminescence production by leukocytes. The concentration of free p-cresol was directly related to chemiluminescence inhibition (Fig. 5B
). In the presence of the same amount of total p-cresol, the chemiluminescence inhibition was more pronounced in the 25 g/L BSA solution with the highest free p-cresol concentration (Fig. 5C
). It is worth noting that in these in vitro experiments, the free p-cresol concentration was higher than the values observed in uremic serum. This could be attributable to a lower binding capacity of BSA compared with human serum albumin. Such an effect has not been demonstrated directly for p-cresol per se, but similar changes have been observed for peroxisomicine (22). To further extrapolate these findings to the clinical condition, we also considered the relationship between free p-cresol and hospitalization. Free p-cresol was higher in patients hospitalized for infectious diseases (Fig. 4
).
The relationship between the concentrations of currently used markers, such as urea and creatinine, and outcome measures, such as the morbidity and mortality of renal failure patients, is a source of confusion. In patients suffering from wasting and malnutrition, BUN and creatinine are low; nevertheless, the outcome is deceiving (23) because of the relationship between these compounds and dietary intake and muscular mass. Indirectly, these data also point to a relatively weak biological impact of the latter compounds. Relatively few studies point to a toxic effect of urea and creatinine at the concentrations found in uremic patients (19). The addition of urea to dialysate, enhancing plasma concentrations to high concentrations over a 3-month period, had no impact on the clinical condition (24). The present data suggest a possible relationship between the concentration of free p-cresol, a prototype of protein-bound solutes, and a biological and clinical effects. We emphasize, however, that renal failure is a multifactorial disease and that the morbidity and mortality associated with this disease are also multifactorial in origin.
The present study also set out to evaluate which factors affect the concentration of free p-cresol. Total p-cresol and serum albumin were identified as the most important influencing factors.
As expected, the total p-cresol concentration had a substantial impact on the concentration of free p-cresol because more ligand is available to binding sites that become saturated more easily. Likewise, for protein-bound drugs, the free concentration increases with increasing total concentration (25). In a multiple backward stepwise regression analysis, free p-cresol was, however, also related to albuminemia (Table 2A
). Subsequently, we normalized free p-cresol to total p-cresol by calculating the F:T ratio, as described previously (17). The application of this ratio confirmed more consistently the impact of albuminemia (Table 2A
and Fig. 2B
).
Albumin is the most important binding protein for many acidic and basic drugs (26)(27). The results of our in vitro study suggest that p-cresol also has an affinity for albumin because the in vitro decrease in the BSA concentration led to a higher free fraction of p-cresol (Fig. 5A
).
In a transsectional approach, multiple known and unknown factors, such as drug intake, nutritional status, and the presence of other protein ligands, might have an impact on the final concentration of free solute. We therefore sought an approach that would in part neutralize these influencing factors. In a prospective study, the same patients were evaluated once at a lower and once at a higher serum albumin; free p-cresol was lower when serum albumin was high. Likewise, in vitro studies in which albumin concentrations differed showed an impact of albumin on the free p-cresol concentration as well as on an important biological effect exerted by p-cresol.
These findings might shed light on the present perception of pathophysiologic events in uremia. An important relationship exists between hypoalbuminemia and morbidity and mortality of uremic patients (28). Traditionally, several factors have been suggested to play a role in the induction of this hypoalbuminemia, such as cardiopulmonary failure with fluid overload, catabolic status, inflammation, and dialyzer membrane bioincompatibility (8)(29)(30)(31)(32). On the basis of the present data, the liberation of protein-bound solutes from their binding sites, which enhances their toxicity, should be considered an additional mechanism. Other protein-bound solutes, such as indoles, free fatty acid derivatives, and phenols, are retained in uremia. It is possible that the presence of p-cresol increases the free fraction of these uremic metabolites or drugs and vice versa when they share the same albumin binding sites. We observed a decrease in theophylline protein binding by uremic solutes, and a similar phenomenon can occur for p-cresol (6). Therefore, albumin should, by its binding capacity for ligands, be seen as a buffer of toxic effects. 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)(41)(42), leptin (43)(44), homocysteine (45)(46), hippuric acid (47)(48), and p-hydroxyhippuric acid (49)(50).
In conclusion, this study demonstrates that the free, rather than the total, concentration of the protein-bound toxin p-cresol is related to "uremic" toxicity. The free concentration of the toxin depends both on the total concentration and on serum albumin. Hypoalbuminemia might therefore affect patient outcome by changing the free fraction of protein-bound solutes.
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Acknowledgments |
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) with the expected gaussian distribution curve (line) and with the four quartiles indicated (arrows). F:T was <0.10 in the first quartile and >0.15 in the fourth quartile. (B), serum albumin concentrations in the four quartiles of the F:T histogram varied from normal (
) to hypoalbuminemia (
). *, P <0.05 vs first quartile. Error bars, SD.
). *, P <0.01 between the regression coefficients of the two lines. (B), linear regression analysis of free p-cresol with percentage inhibition of the chemiluminescence capacity of stimulated granulocytes in 25 and 50 g/L BSA (n = 26; r = 0.82; P <0.001). (C), percentage inhibition of the chemiluminescence capacity of stimulated granulocytes in solutions containing 25 or 50 g/L BSA and p-cresol (n = 13). Error bars, SD. *, P <0.05 vs 25 g/L.