Membranes for dialysis: can we do without them?

Over the past five decades, membranes used for the treatment of chronic kidney disease have continuously evolved. In the course of this evolution, the use of classical non-modified cellulose membranes has declined in favor of cellulose-based membranes in which the basic structure has been modified to improve the biocompatibility profile of the material as well as membranes based on synthetic polymers. In addition to providing improved biocompatibility, manufacturing methods have been innovatively adapted to produce membranes with optimized pore size and pore size distribution. This has led to the more effective removal of molecules involved in the development of complications associated with dialysis treatment. More recently, the approach has been move membranes beyond being just selective barriers with a high performance and to incorporate biological function. Despite these advances, membranes in current clinical use represent a compromise: while efficient in their removal of water soluble compounds, they are non selective, retain some bioreactivity and differ in their ability to adsorb endotoxins or bacterial fragments that may be present in the dialysis fluid. In this paper, an overview of the membranes used in current clinical practice and their limitations are discussed, together with approaches to solute transport in which no membranes are used.

The role of improved water quality on inflammatory markers in patients undergoing regular dialysis.

Hemodialysis utilizes large quantities of water for the preparation of dialysis fluid. Such water meets national standards and international standards but a considerable disparity exists between such standards with respect to microbiological purity. This study collated and retrospectively analyzed the impact of upgrading water systems from that specified in the US standards to those specified in European standards on clinical measures associated with inflammation in four metropolitan dialysis units for two periods. Two periods were compared, three months prior to and six months post upgrading the water treatment systems. The monthly total erythropoietin dosage and intravenous iron supplementation for each patient were also compared over these periods. Variables with significant pre-post differences were assessed using multivariate models to control for confounding factors. The results indicated significant increases in hemoglobin, ferritin and TSat (all p < 0.0001) and albumin (p = 0.0001) were associated with improvement in water quality. Decreases in CRP and creatinine (both p < 0.0001) were also noted. These findings suggest that the current regulations in the United States set the microbiological limits of water and dialysis fluid inappropriately high, and the limits should be revised downwards, since such an approach is reflected in improvement in markers of inflammation.

Preparation of novel mesoporous carbons for the adsorption of an inflammatory cytokine (IL-1 beta).

Mesoporous carbons derived from two types of sulphonated styrene divinylbenzene copolymers (Macronet MN500HS and CT275, Purolite International Ltd) were produced and their adsorptive capacity for the proinflammatory cytokine IL-1 beta (MW 14.4 kDa) determined. The carbons produced had surface areas from 400 to 1200 m(2)g(-1) and pore volume between 0.2 and 1.4 cm(3)g(-1). The mechanical strength of the carbon beads with surface area values up to 800 m(2)g(-1) were robust. The highest adsorption value of IL-1 beta was 150 ng g(-1) for a mesoporous carbon with surface area around 900 m(2)g(-1) and pore volume around 1.3 cm(3)g(-1). However, there was a trade-off between adsorptive capacity and mechanical strength. When used in conjunction with existing treatment modalities, the materials produced have the potential to enhance the removal of uraemic toxins.

Technological advances in renal care.

The first systems for treating kidney failure were developed in the 1940's, when it was found that blood could be successfully cleared of toxins and returned to the body using a relatively simple device based on artificial sausage skin wrapped around a wooden frame. This process was used to replace the function of the kidney, allowing patients to recover from conditions such as poisoning or crush injuries that temporarily stop the kidneys working. In the 1960's, advances in technology made long-term replacement of renal function using haemodialysis machines possible and allowed surgeons to carry out kidney transplants between people who were not identical twins. Long-term peritoneal dialysis became a viable treatment option two decades later. There are now over 1.1 million people world-wide receiving regular dialysis treatment and around 340,000 people living with a donated kidney. This paper reviews the pioneering work in the treatment of kidney failure and looks at some of the recent advances in equipment design, materials science, immunosuppression and information technology that aim to improve the quality of life and the life expectancy for patients living on renal replacement therapy.

Is decreased treatment time in hemodialysis patients harmful if solute clearance is maintained?

An association between decreased duration of hemodialysis and increased morbidity and mortality in patients has been suggested. Whether this is due only to decreased solute clearance is unclear. In this prospective randomised study the effect of reducing treatment time whilst maintaining constant solute clearance was examined in fourteen patients. The study lasted for a period of 36 weeks (3x12 week study periods) and used a crossover design. The patients dialysis prescription (KW) was not changed on entering the study and was maintained during short (150 minutes) and long dialysis (240 minutes) by varying blood flow, dialysate flow and dialyzer surface area. The delivered KW was kinetically assessed. Fractional urea clearance was also measured during each treatment period by measurement of urea concentration in spent dialysate and total body water using 3H2O. At the end of each treatment period a full biochemical and hematological profile, nutritional intake and status, 24 h ambulatory blood pressure, nerve conduction studies, and quality of life questionnaire were performed. Within patients the delivered single pool KW was uniform throughout the 3 treatment periods and fractional urea clearance did not vary. However, Kt/W assessed using equilibrated models (Daugardis and Smye) was significantly lower in the short dialysis period. No differences between short and long dialysis sessions were noted in any of the measured variables. Thus, over a 36 week period there is no evidence to suggest that hemodialysis patients are adversely affected by decreased duration of treatment provided that solute clearance is maintained.

Accuracy and clinical utility of dialysis dose measurement using online ionic dialysance.

BACKGROUND: Statistical associations between urea removal and survival have been described in a number of publications. Urea removal during treatment may be quantified by the delivered dose of dialysis. Methods in clinical use to measure delivered dose are retrospective and reliant on accurate blood sampling. The new generation of single patient proportionating systems incorporate the facility to automatically measure ionic dialysance throughout dialysis. METHODS: In a prospective study on 9 anuric patients with a stable dialysis prescription, we have compared the agreement of the dose of dialysis determined from ionic dialysance (Dt/V) with that derived from equilibriated Kt/V (eKt/V) and Kt/V measured by direct dialysis quantification (Kt/V(DDQ)) using 2 types of hemodialysis membrane (hemophan and low-flux polysulfone). The variability of the delivered dose over a 1-month period was also determined. RESULTS: Ionic dialysance was independent of membrane type. It was comparable to that established for plasma urea water clearance for hemophan but lower for polysulfone (p < 0.001). The mean (+/- SD) delivered dose of dialysis (Dt/V) was similar for both membranes (1.18 +/- 0.15 (hemophan) and 1.18 +/- 0.11 (low-flux polysulfone)). Bland Altman comparisons showed the limits of agreement between Dt/V and Kt/V(DDQ) were +/- 0.17 and for Dt/V compared with eKt/V +/- 0.15. A 1-month measurement of Dt/V demonstrated considerable treatment to treatment variability indicating that delivered dose cannot be considered stable. CONCLUSION: The availability of online measurement of ionic dialysance provides a step towards monitoring dialysis more closely at the time of delivery, and its clinical application will ensure that a more constant dialysis dose is delivered.

Oxidative stress and inflammation in hemodialysis patients.

Dialysis is associated with an increased generation of oxidants, which play an important part in the development of endothelial dysfunction and atherogenesis. Markers of oxidative stress include F2-isoprostanes and ethane. Measurements in dialysis patients before dialysis showed higher levels of esterified plasma F2-isoprostanes (1.62 +/- 0.73 ng/mL) than in control subjects (0.27 +/- 0.10 ng/mL) (P < 0.001). Furthermore, levels also correlated with high plasma C-reactive protein (CRP) levels (r =.48, P = 0.015). Breath ethane levels for dialysis patients (N = 19) were 6.32 +/- 3.16 pmol/kg-min, in contrast to 3.08 +/- 1.50 pmol/kg-min in control subjects (N = 11, P < 0.005). Analysis to investigate the relationship between CRP levels and outcome indicated that there was a significant difference in mortality rate over a 3-year period between patients with low and high CRP values (P < 0.001). Patients with high CRP (> 16.8 mg/L) levels were more than twice as likely to die as patients with low CRP levels (relative risk [RR] = 2.16; 95% confidence interval [CI], 1.50-3.09). CRP values were a significant predictor of mortality even after controlling for diabetes, albumin, ferritin, and age at commencement of dialysis. The RR for CRP after adjustment was 1.58 (95% CI, 1.06-2.34, P = 0.024). There were no significant interactions between CRP and other predictors of mortality, indicating that high CRP levels have an additive effect on the mortality risk. These findings show that hemodialysis patients are exposed to both oxidative stress and inflammation.

Consequences of hyperphosphatemia and elevated levels of the calcium-phosphorus product in dialysis patients.

Control of serum phosphorus levels is a central goal in the management of patients with chronic renal failure. Inadequate control of serum phosphorus leads to elevated levels of the calcium-phosphorus product. This plays a pivotal role in vascular calcification, cardiovascular disease, calciphylaxis, and death. Elevated phosphorus and elevated levels of the calcium-phosphorus product are both significant predictors of cardiovascular mortality, at phosphorus and calcium-phosphorus product levels that were considered safe until recently. A lowering of levels such that phosphorus is maintained between 2.2 and 5.5 mg/dl, calcium-phosphorus product is below 55 mg(2)/dl(2), and serum calcium is at 9.2-9.6 mg/dl, respectively, might well be the goal of therapeutic management strategies.

Pre and interdialytic acid-base balance in hemodialysis patients.

In an observational study, nine hemodialysis patients using 35 mmol/l bicarbonate dialysate were studied over a 44-hour interdialytic interval. Serum bicarbonate was measured at regular intervals at home and the mean time averaged concentration was 27.0+/-1.2 mmol/l. Seven of the nine patients showed a slow linear decline in bicarbonate whilst in two patients levels were unchanged. In 8 of 9 patients the average of the post and predialysis bicarbonate accurately predicted the time-averaged (area under the curve) bicarbonate concentration. In addition, predialysis serum bicarbonate was measured in 46 patients after both a 2 and 3-day interdialytic interval. The serum bicarbonate was significantly lower after the 3-day interdialytic interval (3-day, 22.1+/-0.6 vs 2-day, 23.0+/-0.5 mmol/l, p<0.05). The results from this study emphasize the importance of standardization of bicarbonate measurement in order to avoid spurious acidosis.

Clinical characterisation of polysulfone LS membrane for renal replacement therapy.

The solute transport characteristics and biocompatibility of a new polysulfone membrane (Polysulfone LS, Fresenius Medical Care, Bad Homburg, Germany) has been established and compared for two different sizes of dialyser (1.3 and 1.8 m2). The in vivo small molecular clearance of the two sizes of dialyser showed an overlap in performance. Neutropenia was slight and independent of the membrane area as were changes in C5adesArg. The membrane induced neutrophil degranulation characterised by the release of elestase alpha1 inhibitor complex with time averaged values over 180 minutes related to membrane area (p=0.010). Heparin activity during dialysis with the membrane was within the therapeutic range necessary for anticoagulation (0.3-1.0 IU/ml), but despite this an increase in thrombin antithrombin 111 levels during treatment was noted. Polysulfone LS extends the range of polysulfone membranes available for clinical use and its performance is such that it may be considered as a membrane for the treatment of patients awaiting a transplant, or in whom use of the high flux therapies may be inappropriate.

Clinical performance of a new high-flux synthetic membrane.

The clinical performance during first use of a new membrane manufactured from a blend of polyarylethersulfone and polyvinylpyrrolidone (Arylane; Hospal Renal Care, Lyon, France), in which the microstructure of the membrane has been tailored by the manufacturing process and polymer blend, has been compared with Fresenius Polysulfone (Fresenius Medical Care, Bad Homburg, Germany) in a prospective, randomized, crossover study. Small-molecular clearances were similar. A reduction in plasma beta(2)-microglobulin levels was present using both membranes, with a significantly greater removal by Arylane such that the mean postdialysis plasma level difference between the membranes at the end of dialysis was 8. 7 mg/L (95% confidence interval, 3.9 to 13.5; P = 0.004). Recovery of beta(2)-microglobulin from the dialysis fluid was similar: 170 +/- 70 mg for Arylane and 110 +/- 60 mg for Fresenius Polysulfone (P = 0.04). Both membranes were impermeable to albumin but allowed the passage of low-molecular-weight proteins, with 10,046 +/- 3,239 mg for Arylane and 7,285 +/- 2,353 mg for Fresenius Polysulfone recovered from the dialysis fluid (P = 0.07). Neutropenia and platelet adhesion to the membrane were minimal, and time-averaged complement levels during dialysis for C3a and C5b-9 were 207 +/- 92 and 62 +/- 24 ng/mL for Arylane and 223 +/- 68 and 45 +/- 24 ng/mL for Fresenius Polysulfone, respectively, and were membrane independent. This study indicates that the membrane using polyarylethersulfone in conjunction with PVP has complement-activation potential and neutropenia similar to Fresenius Polysulfone but has an enhanced capacity to remove beta(2)-microglobulin. This enhanced removal arises from transmembrane transport augmented by adsorption within the membrane matrix.

A microdomain-structured synthetic high-flux hollow-fiber membrane for renal replacement therapy.

A prospective crossover clinical study evaluated solute removal and biocompatibility of a tailored, hydrophobic-hydrophilic microdomain structure produced from a blend of polyamide, polyarylethersulfone, and polyvinylpyrrolidone (Polyflux) compared with Fresenius Polysulfone in dialyzers of similar surface area. The clearance of small molecules (urea, creatinine, and phosphate) for both membranes was comparable. Plasma levels of beta2 microglobulin were reduced at the end of treatment with both membranes (49.8% of pretreatment values for Polyflux; 45.9%, Fresenius Polysulfone) and was associated with the recovery of 207 +/- 84 mg of beta2 microglobulin from the dialyzing fluid for Polyflux compared with 147 +/- 29 for Fresenius Polysulfone (p = 0.12). The dialyzing fluid also contained 7,758 mg of protein when using Polyflux compared with 7,793 mg using Fresenius Polysulfone (standard error of difference for any pair was 511 mg). No albumin was present in the dialysis fluid for either membrane. Neutropenia, platelet adhesion to the membrane, and complement activation characterized by C3a, C5a, and SC5b-9 generation were slight and independent of membrane type. Membrane thrombus generating potential measured by thrombin:antithrombin III were also similar. These results indicate that the tailored, hydrophobic-hydrophilic microdomain structure of the membrane results in a favorable biocompatibility profile and clinically acceptable solute removal similar to the widely used Fresenius Polysulfone membrane.