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The protein-bound uremic toxins para-cresyl sulfate (pCS) and indoxyl sulfate (IS) are associated with cardiovascular disease in chronic renal failure, but the effect of different dialysis procedures on their plasma levels over time is poorly studied. The present prospective, randomized, cross-over trial tested dialysis efficacy and monitored pre-treatment pCS and IS concentrations in 15 patients on low-flux and high-flux hemodialysis and high-convective volume postdilution hemodiafiltration over six weeks each. Although hemodiafiltration achieved by far the highest toxin removal, only the mean total IS level was decreased at week three (16.6 ± 12.1 mg/L) compared to baseline (18.9 ± 13.0 mg/L, p = 0.027) and to low-flux dialysis (20.0 ± 12.7 mg/L, p = 0.021). At week six, the total IS concentration in hemodiafiltration reached the initial values again. Concentrations of free IS and free and total pCS remained unaltered. Highest beta₂-microglobulin elimination in hemodiafiltration ( p < 0.001) led to a persistent decrease of the plasma levels at week three and six (each p < 0.001). In contrast, absent removal in low-flux dialysis resulted in rising beta₂-microglobulin concentrations ( p < 0.001). In conclusion, this trial demonstrated that even large differences in instantaneous protein-bound toxin removal by current extracorporeal dialysis techniques may have only limited impact on IS and pCS plasma levels in the longer term.

Background: In patients undergoing maintenance hemodialysis (HD), increased levels of circulating fibroblast growth factor-23 (FGF-23) are independently associated with cardiovascular events and mortality. Interventional strategies aiming to reduce levels of FGF-23 in HD patients are of particular interest. The purpose of the current study was to compare the impact of high-flux versus low-flux HD on circulating FGF-23 levels., Methods: We conducted a post-hoc analysis of the MINOXIS study, including 127 dialysis patients randomized to low-flux (n = 62) and high-flux (n = 65) HD for 52 weeks. Patients with valid measures for FGF-23 investigated baseline and after 52 weeks were included., Results: Compared to baseline, a significant increase in FGF-23 levels after one year of low-flux HD was observed (Delta plasma FGF-23: +4026 RU/ml; p < 0.001). In contrast, FGF-23 levels remained stable in the high flux group (Delta plasma FGF-23: +373 RU/ml, p = 0.70). The adjusted difference of the absolute change in FGF-23 levels between the two treatment groups was statistically significant (p < 0.01)., Conclusions: Over a period of 12 months, high-flux HD was associated with stable FGF-23 levels, whereas the low-flux HD group showed an increase of FGF-23. However, the implications of the different FGF 23 time-trends in patients on high flux dialysis, as compared to the control group, remain to be explored in specifically designed clinical trials., Trial Registration: German Clinical Trials Register (DRKS) DRKS00007612.

Background: Chronic renal failure patients have a high cardiovascular disease burden, low numbers and impaired function of endothelial progenitor cells (EPCs). We hypothesized that enhanced uraemic toxin removal restores EPCs in haemodialysis patients., Methods: In a prospective, randomized, cross-over trial, 18 patients were subjected to 4 weeks of each low-flux haemodialysis, high-flux haemodialysis and haemodiafiltration differing in uraemic toxin removal. EPCs were determined at baseline and at the end of each 4-week period. A cohort of 16 healthy volunteers served as control. EPCs were studied after culture on fibronectin (CFU-Hill) and collagen-1 (ECFC)., Results: Dialysis patients had a lower number of ECFCs than in healthy controls (P < 0.001) and a reduced fraction of vital ECFCs (P < 0.05), whereas the formation of endothelial cell colonies (ECCs) was increased (P < 0.05). Different middle molecular uraemic toxin removal had no effects on EPC numbers. The number of prototypical EPCs (CD34( +)/VEGFR2-KDR( +)/CD45( -) ECFCs) was similar between patients and controls. Correlations of plasma C-reactive protein with ECC count, CFU-Hill colony count and CD34( +)/VEGFR2-KDR( +)/CD45( -) subpopulation of both ECFC and CFU-Hill cells were observed., Conclusions: Different middle molecule removal has no effect on EPCs. Reduced vitality and enhanced ECC formation suggest growth induction of impaired EPCs in chronic renal failure and are associated with inflammation.

Optimizing solute removal at minimized albumin loss is a major goal of dialyzer engineering. In a prospective, randomized, crossover study on eight patients (age 63 +/- 14 years) on maintenance hemodialysis, the new Baxter Xenium 170 high-flux dialyzer (BX), which contains a 1.7-m(2) PUREMA H dialysis membrane, was compared with two widely used reference high-flux dialyzers currently available for hemodialysis in North America, the Fresenius Optiflux 180 NR (FO) and the Gambro Polyflux 170 H (GP). Solute removal and biocompatibility were assessed in hemodialysis for 240 min at blood and dialysate flow rates of 300 and 500 mL/min, respectively. Additional ex vivo experiments detecting the interleukin-1beta (IL-1b) generation in recirculated donor blood were performed to demonstrate the pyrogen retention properties of the dialyzers. The instantaneous plasma clearances were similar for the three dialyzers except for cystatin c (cysc), for which a lower clearance was measured with FO as compared with BX and GP after 30 and 180 min of hemodialysis. The reduction ratios (RRs) corrected for the hemoconcentration of beta(2)-microglobulin and cysc were lower in FO (44 +/- 9 and 35 +/- 9%, respectively) versus BX (62 +/- 6 and 59 +/- 7%, respectively) and GP (61 +/- 7 and 56 +/- 8%, respectively). The RRs of the cytokine tumor necrosis factor alpha and interleukin-6 were not different between the dialyzers. The albumin loss was <300 mg for all filters. No differences between the dialyzers were found in the biocompatibility parameters showing very low leukocyte and complement activation. The ex vivo recirculation experiments revealed a significantly higher IL-1b generation for GP (710 +/- 585 pg/mL) versus BX (317 +/- 211 pg/mL) and FO (151 +/- 38 pg/mL). BX is characterized by a steep solute sieving profile with high low-molecular weight protein removal at virtually no albumin loss and an excellent biocompatibility. This improved performance may be regarded as a contribution to optimal dialysis therapy.

Background: Improving the sieving characteristics of dialysis membranes enhances the clearance of low-molecular-weight (LMW) proteins and may have an impact on outcome in patients receiving haemodialysis. To approach this goal, a novel polyelectrolyte additive process was applied to a polyethersulphone (PES) membrane., Methods: Polyelectrolyte-modified PES was characterized in vitro by measuring complement activation and sieving coefficients of cytochrome c and serum albumin. In a prospective, randomized, cross-over study, instantaneous plasma water clearances and reduction rates of LMW proteins [beta(2)-microglobulin (b2m), cystatin c, myoglobin, retinol binding protein] were determined in eight patients receiving dialysis treatment with PES in comparison with polysulphone (PSU). Biocompatibility was assessed by determination of transient leucopenia, plasma levels of complement C5a, thrombin-antithrombin III (TAT), myeloperoxidase (MPO) and elastase (ELT)., Results: PES showed a steeper sieving profile and lower complement activation in vitro compared with PSU. Instantaneous clearance (69 +/- 8 vs. 58 +/- 3 ml/min; P < 0.001) and reduction rate (72.3 +/- 1 5% vs 66.2 +/- 6.1%; P < 0.001) of b2m were significantly higher with PES as compared with PSU. With higher molecular weight of proteins, differences in the solute removal between PES and PSU further increased, whereas albumin loss remained low (PES, 0.53 +/- 0.17 vs PSU, <0.22 g/dialysis). MPO, ELT and TAT did not differ between the two membranes. In contrast, leucopenia was less pronounced and C5a generation was significantly lower during dialysis with PES., Conclusions: Polyelectrolyte modification of PES results in a higher LMW protein removal and in optimized biocompatibility. Whether these findings translate into better outcome of patients receiving haemodialysis requires further studies.

Background: Mid-dilution haemodiafiltration (HDF) results in an improved middle molecule removal compared with standard HDF. The OLpur MD 190 haemodiafilter represents a new dialyser design exclusively for mid-dilution on-line HDF. Compared with standard haemodialysers, structural changes in the headers allow the infusion of high replacement fluid volumes after a first post-dilution and before a second pre-dilution stage., Methods: We compared in vitro the new device [blood flow (QB) 400 ml/min, substitution flow (QS) 100 and 200 ml/min, dialysate flow (QD) 800 ml/min] with a conventional high-flux dialyser of the same surface area in haemodialysis (HD) (QD 500 ml/min) and post-dilution HDF (at QS 60, QD = 500 ml/min and at QS 100, QD = 800 ml/min) modes. Subsequently, we performed an initial clinical application of the new device in six mid-dilution HDF treatments of five end-stage renal disease patients (QB 400 ml/min, QS 200 ml/min, QD 800 ml/min, treatment duration 205+/-23 min)., Results: In vitro urea and beta2-microglobulin clearances in mid-dilution HDF were, respectively, 309.2+/-5.5 and 144.4+/-15.2 ml/min (QS 100) and 321.6+/-4.1 and 204.9+/-4.1 ml/min (QS 200), compared with 278.6+/- 17.2 and 94.0+/-7.6 ml/min in HD, and 310.8+/-10.2 and 123.0+/-6.5 ml/min (QS 60) and 323.6+/-11.2 and 158.0+/-10.3 ml/min (QS 100) in post-dilution HDF. The in vivo trials showed the clinical utility of the device and confirmed the in vitro data: urea and beta2-microglobulin clearances were, respectively, 324.6+/- 10.9 and 207.9+/-29.3 ml/min, while reduction ratios were 75.0+/-5.5 and 83.6+/-4.7%., Conclusion: Our preliminary results need confirmation in a prospective cross-over study. However, the Nephros MD 190 haemodiafilter promises to be a true technological step ahead in terms of improved beta2-microglobulin removal.

Background: Several studies have indicated that the improved elimination of middle molecules by convective renal replacement procedures might be associated with a better outcome in end-stage renal disease (ESRD). On-line mid-dilution hemodiafiltration (HDF) with the Nephros OLpur MD 190 hemodiafilter represents a novel extracorporeal renal replacement therapy concept to increase the removal of middle molecules., Methods: In a prospective cross-over study in 10 ESRD patients, this technique was compared to on-line post-dilution HDF with a conventional synthetic high-flux dialyzer, operated at its technical limit, concerning small and middle molecular solute removal. Each patient was treated 3 times for 4.0 +/- 0.4 hours with both filters. Blood flow was 400 mL/min, substitution flow (Q(S)) during mid-dilution HDF 200 mL/min, and during post-dilution HDF 100 mL/min, and effective dialysate flow of 700 - Q(S) mL/min. Instantaneous clearances, reduction ratios (RR), and middle molecule mass transfer in continuously collected dialysate were determined., Results: While urea and creatinine clearances were significantly lower (6.4% and 3.9%, respectively), middle molecule removal was much more efficient in mid-dilution HDF over the whole range of investigated proteins: compared to post-dilution HDF, beta(2)-microglobulin (11.8 kD) clearance (165.8 +/- 26.59 vs. 201.9 +/- 20.63 mL/min; P < 0.001), RR (80.0 +/- 5.4% vs. 82.2 +/- 5.7%; P < 0.001), and dialysate mass transfer (53% higher; P < 0.001) were significantly higher. For the larger middle molecules, cystatin C (13.4 kD) and retinol-binding protein (21.2 kD), mid-dilution HDF resulted in an even more superior performance, indicated by significantly higher values of all investigated parameters., Conclusion: On-line mid-dilution HDF with the Nephros OLpur MD 190 hemodiafilter appears to be a true technologic step ahead in terms of improved middle molecule removal. This efficient procedure gives hope to play a role in preventing or at least retarding dialysis-related long-term complications, such as beta(2)m amyloidosis, in ESRD patients, and may contribute to a more adequate dialysis therapy.

Hemodiafiltration (HDF) is a well-recognized treatment modality that offers a way of optimizing renal replacement therapy efficacy of end-stage renal disease (ESRD) patients. On-line production of substitution fluid by the 'cold sterilization' process (ultrafiltration) gives access to an unlimited amount of sterile and non-pyrogenic IV grade solution. This advantageous low-cost solution may therefore be employed to develop various forms of high-flux HDF modalities (ol-HDF). High-flux post-dilutional HDF (post-HDF) has mainly been used in clinical practice since it offers the most efficient and best compromise between diffusive and convective clearances. Nowadays, the new targets in anemia correction have created hemorheological conditions that render high filtration rate more difficult to achieve and/or at the expense of higher transmembrane pressure. To overcome this new challenging condition and keeping the same concept, it has been proposed to develop alternative modalities with various sites of fluid substitution (predilution, mixed pre-post with various percentages) in HDF. In this presentation we discuss the benefits of using pre-HDF and show how to match performances with post-HDF. Potential advantages of new ol-HDF options (pre-, mixed and mid-dilution) that are advocated have to be demonstrated in clinical trials. On-line HDF is a multipurpose treatment method that is employed to improve care and outcomes of ESRD patients. Due to its versatility, ol-HDF should be considered as a technical platform permitting to personalize and tailor treatment to patients' needs. The mode of substitution (post-, pre-, mixed or mid-dilution) should be established according to hemorheological conditions of the individual patient., (Copyright (c) 2004 S. Karger AG, Basel.)