Nephrol Dial Transplant (2000) 15: 50-57
© 2000 European Renal Association-European Dialysis and Transplant Association
Intradialytic removal of protein-bound uraemic toxins: role of solute characteristics and of dialyser membrane
Renal Division, Department of Internal Medicine, University Hospital, Gent, Belgium
Correspondence and offprint requests to: Gerrit Lesaffer, Renal Division, University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
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Abstract |
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Background. The efficiency of dialysis membranes is generally evaluated by assessing their capacity to remove small, water-soluble and non-protein-bound reference markers such as urea or creatinine. However, recent data suggest that protein-bound and/or lipophilic substances might be responsible for biochemical alterations characterizing the uraemic syndrome.
Methods. In the present study, the total concentrations of four uraemic retention compounds (indoxyl sulphate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) and p-cresol) and of tryptophan, the only protein-bound amino acid and a precursor of indoxyl sulphate, were compared with those of urea and creatinine in pre- and post-dialysis serum and in dialysate of 10 patients; two high-flux (HF) membranes (cellulose triacetate (CTA) and polysulphone (PS)) and a low-flux polysulphone (LFPS) membrane were compared in a crossover design, using HPLC.
Results. Except for hippuric acid (67.3±17.5% decrease), major differences were found in the percentage removal of the classical uraemic markers on one hand (creatinine 66.6±7.0% and urea 75.5±5.8% decrease) and the studied protein-bound and/or lipophilic substances on the other (indoxyl sulphate, 35.4±15.3% and p-cresol 29.0±14.2% decrease; tryptophan, 27.5±40.3%, and CMPF, 22.4±17.5% increase; P<0.01 vs urea and creatinine in all cases). Hippuric acid removal was more pronounced than that of the remaining protein-bound compounds (P<0.01). After correction for haemoconcentration, per cent increase of tryptophan and CMPF was less substantial, while per cent negative changes for the remaining compounds became more important. There was a correlation between creatinine and urea per cent removal at min 240 (r=0.51, P<0.01), but all the other compounds showed no significant correlation with either of these two. The three membranes were similar regarding the changes of total solute concentrations from the start to the end of dialysis.
Conclusions. Urea and creatinine are far more efficiently removed than the other compounds under study, except for hippuric acid. There are no striking differences between the HF membranes. Moreover, compared with the LF membrane these HF membranes do not appear to be superior in removing the studied compounds.
Keywords: cellulose triacetate; dialysis membrane; haemodialysis; polysulphone; protein binding; removal; tryptophan
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Introduction |
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For the removal of uraemic solutes by haemodialysis (HD), different membrane types are available. Efficiency of dialysis therapy will at least in part be determined by the characteristics of these membranes [1–5]. The efficiency of a dialysis procedure can be evaluated by assessing its capacity to remove certain low-molecular-weight (MW) reference markers [2,4,5], which in general are water-soluble and non-protein-bound [5,6]. Recent data, however, suggest that the biochemical alterations in uraemia are not only caused by such small water-soluble toxins [4]. Protein-bound substances (e.g. phenol, p-cresol, indoxyl sulphate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF)), of which some are lipophilic as well (e.g. phenol, p-cresol, CMPF) and larger molecules (e.g.ß2-microglobulin, advanced glycation end-products, several peptides, complement factor D) might also, at least in part, be responsible [2,6].
Although HD membranes are often compared by their removal capacity for classical small water-soluble retention solutes and for middle molecules, this has rarely been the case for protein-bound and lipophilic substances. The aim of this study was to compare the removal of protein-bound and lipophilic substances with that of urea and creatinine. The comparison was performed applying two high-flux (HF) membranes and a low-flux (LF) membrane in a crossover design.
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Subjects and methods |
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Patients
Ten stable chronic HD patients, five men and five women, who had been on HD for 29.8±25.8 months, were included in this study. Their mean age was 72.4±8.9 years (range 51–81). Primary diagnoses were renal vascular disease 2, polycystic kidney disease 2, nephroangiosclerosis 2, diabetic nephropathy 2, analgesic nephropathy 1, and chronic interstitial nephritis 1. None of the patients had residual renal function. Patients were on a thrice-weekly dialysis regimen with a mean dialysis time of 4.3±0.3 h per dialysis and were routinely dialysed with a 1.8 m2 low-flux polysulphone (LFPS) membrane (F8, Fresenius Medical Care, Bad Homburg, Germany), only patients with an AV fistula as vascular access were included; anticoagulation was achieved with low-molecular-weight heparin (LMWH) (Innohep® (Tinzaparin, Leo Pharmaceutical Products, Ballerup, Denmark) or Fragmin® (Dalteparin, Pharmacia, Stockholm, Sweden)). A single dose, equivalent to 4900±568 IU standard heparin for Innohep® or 5450±685 IU standard heparin for Fragmin® was administered at the start of dialysis. All patients were dialysed against standard bicarbonate dialysate (composition: bicarbonate 38.5 mmol/l; Na+ 138 mmol/l; Cl- 104 mmol/l; acetate 4 mmol/l; Ca2+ 1.25 mmol/l, and Mg2+ 0.5 mmol/l) at a temperature of 37°C. A dialyser blood flow (QB) of 250 ml/min and a dialysate flow (QD) of 500 ml/min were applied. Only non-smoking patients without recent infections and without intake of antibiotics or immunosuppressive agents in the last 2 weeks before the study were selected. This study was approved by the Ethics Review Committee of the hospital and written consent was obtained from all patients.
Study protocol
Two HF dialysis membranes, a HF polysulphone membrane (HFPS) (F60, Fresenius Medical Care, Bad Homburg, Germany) with a surface of 1.3 m2 and a HF cellulose triacetate membrane (HFCTA) (Nissho Nipro, Osaka, Japan) with a surface of 1.5 m2 were compared. Additionally, both HF membranes were compared with the LFPS membrane by which the patients were treated routinely. Each dialyser type was used for a period of 2 weeks. All patients were first dialysed with the LFPS membrane, followed then by the two HF filters in a crossover design, whereby the first dialyser was selected in random order. Blood and dialysate flows were maintained at the same level during the entire study period. Mean ultrafiltration rate was 0.011±0.004 l/min with HFPS, 0.011±0.005 l/min with HFCTA, and 0.012±0.005 l/min with LFPS.
All samples (blood and dialysate) were collected during the midweek dialysis of the second week of application. Blood was collected before dialysis and after 240 min. Total dialysate was collected in a 200-litre polyethylene (PE) vessel only when the HF membranes were used. Blood before dialysis was drawn from the AV fistula, immediately after the insertion of the dialysis cannula but before the administration of LMWH. The post-dialysis blood sample was collected from the inlet blood-line of the dialyser. Blood was sampled in 4 cc Venoject II tubes (Terumo Europe, Leuven, Belgium) and centrifuged (10 min, 3000 r.p.m.). Total dialysate was vigorously stirred immediately after dialysis, after which 100 ml was collected in a PE bottle. Serum and dialysate were immediately stored at -20°C until assayed.
Reagents
HPLC water, methanol and isopropyl ether were delivered by Acros Organics (New Jersey, USA), ammonia by BDH Laboratory Supplies (Poole, UK), and reagents for determination of creatinine by Analis (Namur, Belgium). CMPF was a generous gift from G. Spiteller (Bayreuth, Germany). All other reagents were supplied by Sigma Chemical Company (St Louis, MO, USA).
Sample analyses
HPLC analyses. Preparation of the samples.
To establish the total concentrations of indoxyl sulphate, tryptophan, hippuric acid, and CMPF, samples were submitted to heat denaturation as previously reported [7]; subsequently, 100 µl of naphthalene sulphonic acid (NSA) (4 mg/100 ml) was added as internal standard to 300 µl of sample. Fifty microlitres of this solution was analysed by reverse-phase (RP) HPLC.
p-Cresol was determined as recently described [8,9]. In brief, samples were deproteinized by adding HCl 6 M (15 µl in 0.1 ml). Subsequently, NaCl (100 mg) was added and after mixing, p-cresol was extracted with 4 ml isopropyl ether. After adding 0.1 ml NaOH and 2,6-dimethylphenol (25 µg/ml in methanol) as internal standard for HPLC analysis, methanol and isopropyl ether were evaporated in a vacuum centrifuge (RC 10.22, Jouan, Saint-Herblain, France). The dry residue was then redissolved and finally 100 µl was analysed by RP HPLC.
Determination of indoxyl sulphate, tryptophan, hippuric acid, and CMPF.
Indoxyl sulphate, tryptophan, hippuric acid, and CMPF were measured as previously described [10] on a chromatographic unit that consisted of a solvent degassing system (Degasys-DG 1310), two high-pressure pumps (type 2248), a high pressure solvent mixing unit, an autosampler (type 2157), a gradient controller (type 2252) and a variable wavelength UV detector (type 2141) from Pharmacia (Bromma, Sweden). Analyses were carried out at room temperature on a reverse-phase C18 column of 4.6 mmx 15 cm with microparticles of 5 µm (Ultrasphere ODS, Beckman Instruments, San Ramon, USA); a guard column (4.6 mmx5 cm) was used to protect the main column from contaminants. A buffer of methanol and ammonium formate (50 mmol/l, pH 4.0) was used as solvent system in a sequence of different linear gradients in order to obtain an optimal separation of the compounds under study: after initial application of 15% methanol/85% ammonium formate during the first 5 min, the gradient was increased linearly to 60% methanol at 15 min, 80% methanol at 25 min, and finally 100% methanol at 30 min at a flow rate of 1 ml/min. Peaks at 254 and 280 nm were registered using the HPLC manager software from Pharmacia (Bromma, Sweden). For hippuric acid and CMPF, the optimal UV absorption occurred at 254 nm, for indoxyl sulphate, and tryptophan at 280 nm. The nature of the compounds in the peaks was confirmed by spiking experiments.
Determination of p-cresol.
p-Cresol was determined on a chromatographic unit similar to that described above. A fluorescence detector (RF 530, Shimadzu, Tokyo, Japan) was used at excitation/emission wavelengths of 284/310 nm. Eluting peaks were registered on an integrator (type 2221, Pharmacia, Bromma, Sweden). Injection of the sample occurred manually, using a six-way valve (Valco Inc., Houston, USA) provided with a loop of 100 µl. The solvent system consisted of methanol and a 50 mmol/l ammonium formate buffer (pH 3.0); components were separated using a linear gradient (from 45 to 75% methanol in 10 min and then to 100% methanol at 12 min) at a flow rate of 1 ml/min. Spiking experiments, measurements of the UV absorbance in the range of 200–400 nm and capillary gas chromatography-mass spectrometry allowed the identification of the considered compound as p-cresol [9].
Biochemical analyses
Urea, creatinine, and total protein concentrations in serum were determined according to standard methods. The protein content in dialysate was colorimetrically determined with the Micro Protein kit from Sigma Diagnostics (St Louis, MO, USA) at a wavelength of 580 nm on a Vitatron (VEL, Leuven, Belgium).
Calculations
The concentrations of the studied solutes were calculated using relative peak heights with regard to their respective internal standard. For calculations of the concentrations of indoxyl sulphate, tryptophan, hippuric acid, and CMPF, peaks of solute and internal standard were used at the wavelength with the highest absorption. Concentrations at the end of dialysis (C240) were also corrected for ultrafiltration during HD, by multiplying C240 by a correction factor (CF) based on the total protein (TP) concentration at the start and at the end of dialysis (TP0 and TP240):
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Statistics
Results are expressed as means±SD. Concentrations and removal of solutes before dialysis and after 240 min of dialysis were compared by a Wilcoxon test. In order to examine differences between the three membranes, solute concentrations at the start of dialysis and after 240 min of dialysis were subjected to a Friedman test for analysis of variance. A Wilcoxon test was then carried out for paired analysis whenever the Friedman test indicated that a difference existed between the groups. Correlations were analysed with the Spearman rank test. Significance was accepted whenever P values were <0.05.
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Results |
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Elution pattern of compounds
Figures 1 and 2
contain representative analytical chromatograms of uraemic serum. The elution pattern of indoxyl sulphate, tryptophan, hippuric acid, and CMPF is illustrated on the chromatograms in Figure 1. In Figure 2, the elution pattern of p-cresol is given. Each time, an analysis of a sample obtained before dialysis (A) and after 240 min of dialysis (B) is represented. Retention times of indoxyl sulphate, tryptophan, hippuric acid, and CMPF are 11.8, 12.5, 13.9 and 26.0 min (Figure 1A) and 12.0, 12.6, 14.0 and 25.7 min respectively (Figure 1B). A decrease in concentration can be noted for all compounds, except for CMPF and tryptophan (peaks 2 and 4), where a concentration rise can be observed. In Figure 2, p-cresol elutes after 6.5 min (Figure 2A,B). The peaks at 8.6 min (Figure 2A,B) correspond to the internal standard. The concentration of p-cresol after 240 min of dialysis is about 30% lower than at the start.
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Comparison of high-flux cellulose triacetate with high-flux polysulphone
Apart from tryptophan and CMPF, the total serum concentration of solutes decreased during dialysis (Table 1
). Total protein concentration increased significantly at the end of the dialysis session (from 6.8±0.4 to 8.0±1.1 g/100 ml, P<0.01 for HFPS and from 6.8±0.3 to 7.5±0.8 g/100 ml, P<0.05 for HFCTA). HFPS and HFCTA serum concentrations were similar at each of the two time points, except for CMPF at min 240, when higher values were observed for HFPS (Table 1). After correction for haemoconcentration (240c), tryptophan and CMPF concentrations were no longer different from those at the start of dialysis. In Table 2, the per cent change in concentration of the studied solutes before (Figure 2A
) and after (Figure 2B) correction for haemoconcentration is represented per dialyser. Creatinine was more efficiently removed with the HFCTA membrane compared to the HFPS membrane (–66.5±4.4% vs –63.7±4 6% P<0.05) and the tendency for a positive percentage change in CMPF concentration was less pronounced with HFCTA (P<0.05) (Table 2A). After correction for haemoconcentration, both HF membranes had comparable percent changes for all the studied solutes (Table 2B).
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Results of the analysis of total dialysate are represented in Table 3
. Similar volumes of dialysate were collected for the two membranes. Tryptophan content in dialysate of the HFCTA dialysis was higher than that obtained with HFPS dialysis (0.050±0.014 vs 0.039±0.013 mg/100 ml, P<0.05). No differences were registered for other compounds. CMPF could not be detected in total dialysate. Furthermore, the overall protein content of HFCTA dialysate was higher than that of HFPS dialysate (4.42±1.79 vs 1.97±1.37 g, P<0.05)
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Comparison of low-flux and high-flux membranes
As for the HF membranes, solute concentrations at the end of dialysis with the LF membrane were lower than at the start, except for tryptophan, where the concentration did not change significantly and for CMPF, where a rise in concentration was noted (Table 1
). A significant increase was also noticed for the total protein concentration (7.7±0.9 vs 7.1±0.6 g/100 ml, P<0.01). For each of the two time points, solute concentrations for LFPS were comparable with those of the HF membranes (Table 1). After correction for haemoconcentration, CMPF concentration at min 240 was no longer higher than at the start (Table 1, 240c). Corrected concentrations for LFPS remained comparable with the corrected concentrations of the HF membranes (Table 1, 240c).
There were no differences in percent removal between LF and HF membranes (Table 2A,B).
Comparison of removal of solutes
Combining the results of the three membranes, substantial differences were found in percent removal between the classical markers urea and creatinine on one hand and the remaining protein-bound and/or lipophilic solutes on the other (Figure 3A). Urea and creatinine, although essentially different, showed a far more substantial decrease of concentration than the other protein-bound compounds, with the exception of hippuric acid (Figure 3A). Furthermore, removal of hippuric acid was also more substantial compared to the remaining protein-bound solutes (Figure 3A). The differences in percent removal of the classical uraemic markers and of hippuric acid vs the other protein-bound and/or lipophilic solutes remained present after correction of the results for haemoconcentration (Figure 3B).
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Correlation analyses
Percent removal of urea and creatinine were correlated (r=0.51, P<0.01). No correlations were found between the percent change of the remaining solutes at min 240 and that of urea and creatinine (data not shown).
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Discussion |
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The present study was undertaken to compare the removal of protein-bound and/or lipophilic compounds and of standard uraemic markers with two different HF membranes and a LF membrane. A newly developed HFCTA membrane was compared in a crossover design with HFPS, which can be considered as a reference membrane for the group of HF dialysers.
The main conclusions were that: (i) there were substantial differences in per cent removal between classical markers and protein-bound lipophilic solutes, except for hippuric acid; (ii) no correlation could be found between per cent decrease in concentration of the classical markers urea and creatinine and that of the protein-bound lipophilic solutes; (iii) there were no marked differences between the HF membranes; (iv) there were no marked differences between the HF membranes and the LF membrane.
The uraemic syndrome is characterized by the retention of a host of solutes that interfere with various biochemical functions. Roughly, three groups of solutes can be distinguished: (i) small, water-soluble, non-protein-bound molecules such as urea and creatinine; (ii) large molecules with a MW between 300 and 12000 D, classically referred to as middle molecules, and (iii) small protein-bound compounds. The latter solutes show a peculiar behaviour during dialysis, as their protein binding limits their removal. As a consequence, they show a removal pattern similar to that of much larger molecules [11]. Even a rise in serum concentration in parallel with the rise in total protein can then be observed because of ultrafiltration [12]. Such an evolution was observed with all membranes in this study for CMPF (Table 1), which is 98–100% protein-bound [1,6]. After correction for haemoconcentration, this significant rise, however, disappeared.
This study provides comparative data of per cent removal of different uraemic solutes (Table 2, Figure 3). Except for hippuric acid, removal of the classical uraemic markers is substantially greater, compared to the other compounds under study, which can probably be attributed to the protein binding of the latter. The peculiar behaviour of hippuric acid could be related to its lower protein binding, which tends to decrease further during dialysis [13]. Although per cent removal of urea and creatinine was significantly correlated, no such correlation could be found between urea and creatinine on one hand and the remaining compounds on the other. This suggests that urea and creatinine, although classical uraemic markers, might not be representative for a number of other uraemic compounds, at least as far as their intradialytic behaviour is concerned.
Although it is well known that HF membranes are characterized by a more important removal of middle molecules due to their larger pore size, no data are at present available on their removal of the protein-bound and/or lipophilic solutes. The present study was therefore conceived to compare two HF membranes in a crossover design. In addition, the results were compared with those obtained with the LFPS membrane that had been routinely used to treat the patients.
There are at least two theoretical reasons why removal of protein-bound and/or lipophilic solutes by HF membranes might be different from that with LF membranes: (i) due to their capacity to remove proteins, HF membranes might eliminate a substantially more important quantity of protein-bound solutes; (ii) as certain HF membranes are lipophilic or contain lipophilic domains [14], they might remove lipophilic substances through adsorption. However, no higher removal of protein-bound solutes by HF membranes vs LF membranes could be demonstrated in the present study (Table 2).
Only minor quantities of protein crossed the HF membranes into the dialysate (Table 3). However, the protein concentration in the dialysate of HFCTA dialysis was more substantial than in that of HFPS dialysis. Similar results were found by Hoenich et al. [3] in a comparative study between the same HFPS membrane as used in the present study and a different HFCTA membrane. The concentrations of the protein-bound solutes in dialysate of both HF membranes were comparable [3], and so protein losses into the dialysate apparently had no major impact on solute removal. This can at best be interpreted from the data regarding CMPF, because this molecule is virtually 100% protein-bound. CMPF was not detectable in dialysate, pointing to the limited removal of protein-bound solutes from protein losses in the dialysate. For all other solutes, concentration in dialysate was higher, but they are less protein-bound, so that their free fraction is more substantial. This higher free fraction may account for their better removal. In spite of the higher protein content in the HFCTA dialysate, this membrane did not result in a different solute removal.
In general, synthetic membranes are more lipophilic compared to natural (cellulosic) membranes [15]. Due to the strong positive correlation between lipophilicity and protein adsorption as suggested by Schulman and Levin [16], synthetic membranes should have a greater ability to adsorb lipophilic substances and/or proteins as compared to the membranes based on cellulose. The polysulphone membranes used in this study, however, contain polyvinylpyrrolidone (PVP), a compound that introduces more hydrophilic qualities at the membrane surface [14,17]. The F60 HFPS membrane has already been investigated in many studies on its permeability and adsorption capacities [3,17–21]. All authors seem to agree that this membrane is characterized by a considerable secondary membrane formation as a result of protein deposition on the surface. In a study by Röckel et al. [18], the permeability of the F60 membrane for large molecules decreased within 20 min from about 66 kDa at the start of dialysis to less than 30 kDa, an effect largely attributed to protein deposition. Also with CTA, a protein layer is formed upon contact with blood [22], although this modified cellulosic membrane is inert to blood cellular elements [23].
Nevertheless, according to our data, the use of HF membranes has no added value in the removal of lipophilic and/or protein-bound compounds compared to LF membranes. This contrasts with the different effect on middle molecules. Therefore, if removal of protein-bound and/or lipophilic compounds is to be pursued, other solutions should be developed, e.g. specific adsorption systems, or the membrane characteristics of the HF membranes should be modified further, allowing higher adsorption and/or protein clearance.
Finally, the question might be raised as to whether the compounds under study have an impact on biochemical functions. In general, urea only becomes toxic at concentrations that are higher than those found in uraemic patients [1,2]. Johnson et al. [24] describe a population of haemodialysis patients that had no major clinical problems despite maintaining urea concentrations at 200–300 mg/100 ml, because of the addition of urea to the dialysate. Bergström [2] classifies urea as a `mild' uraemic toxin whose role in the pathophysiology of uraemia is not well defined. Creatinine also seems to be relatively non-toxic, apart from being a precursor of methylguanidine [1,2]. In contrast, the protein-bound and/or lipophilic compounds apparently have a more substantial impact on biochemical functions. Indoxyl sulphate is largely albumin bound (90% in haemodialysis patients [6,25]) and inhibits drug protein binding [1,2,6,25,26]. Furthermore, this compound accelerates the progression of glomerulosclerosis in the rat [27,28]. Lim et al. [29] found uraemic concentrations of indoxyl sulphate to inhibit cellular transport and subsequent deiodination of T4. CMPF is a strong inhibitor of drug protein binding [1,29,30] and depresses the ADP-stimulated oxidation of NADH-linked substrate in isolated mitochondria [31] as well as hepatic glutathione S-transferases [30]. Furthermore, CMPF has the potential to inhibit the renal excretion of various drugs, drug conjugates, and other endogenous organic acids [32], and it inhibits erythropoiesis [33] as well as deiodination of T4 [29]. Tryptophan is the only amino acid that binds to plasma protein [2,34,35]. Total serum concentration of tryptophan is often depressed in uraemic patients [11,35–37] and hence this compound cannot be considered as a real uraemic retention solute. However, most authors report protein binding of tryptophan to be decreased in uraemia, [11,34–39], whereby it should be realized that it is probably the free concentration which exerts biological activity and hence toxicity. Tryptophan is the major intestinal source of indole, a precursor for indoxyl sulphate [6]. Some of the indolic metabolites are known to have neuropsychiatric effects [34,36]. Furthermore, the involvement of metabolites in the kynurenine pathway, which accounts for 95% of tryptophan catabolism, has been suggested in several psychiatric disorders [36]. Quinolinic acid is a potent neurotoxin and depends on tryptophan intake for its formation [36]. Hippuric acid inhibits the transport of other organic acids at the cortical tubular level [1] and interferes with the protein binding of drugs [1,6]; it also inhibits the glucose utilization in muscle [6]. Finally, p-cresol inhibits in vitro oxygen uptake in rat brain and liver slices [1,2], enhances the uptake of aluminium in hepatocytes [40] and depresses phagocytic reactive species production [1,6,41]. It is therefore of interest to note the discrepancy in removal of relatively non-toxic markers such as urea and creatinine, vs biochemically active protein-bound solutes such as indoxyl sulphate, CMPF, tryptophan, and p-cresol.
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Acknowledgments |
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This study was partly supported by a scholarship from the Else Kröner Fresenius Stiftung to G. Lesaffer.
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Accepted in revised form: 23. 7.99
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