Highly permeable membranes in dialysis: Optimal therapy design

Summary: Considering the removal potential of diffusion and convection in relation to the size of uraemic toxins, it is evident that we should not rely solely on diffusion to purify the blood, as is the case in the most common form of dialysis, haemodialysis with low-flux membranes. In order to remove more of the larger uraemic toxins, we need to use more convective transport in dialysis therapy. the use of high-flux membranes is increasing and approximately 25% of all dialysis treatments are performed with these membranes. They are characterized by high permeability to water, but for good convective transport they should also have generous and stable sieving properties. the convective transport provided by these membranes when used in a haemodialysis set-up is limited to the desired weight loss and the uncontrolled ultrafiltration which is compensated by backfiltration. to better use the potential of a high-flux membrane, the ultrafiltration should be greatly increased, as in haemodiafiltration (HDF) and haemofiltration (HF). the large volumes of fluid, free from bacteria and pyrogen, which are required for these therapies can be provided by special multi purpose treatment systems. On-line preparation of bicarbonate-containing fluid that can be used for substitution is a safe, practical and cost-effective method. In addition to high clearance of solutes over a wide molecular weight range, the convective therapies provide good haemodynamic stability in response to fluid removal during dialysis.     

β2-Microglobulin and Low-Flux SyntheticDialyzers

Abstract: The aim of this study was to compare the effect on β₂-microglobulin (β₂-M) plasma levels of dialyzers with 3 low-flux synthetic membranes and regenerated cellulose (Cuprophan) in 12 chronic dialysis patients. The synthetic membrane materials chosen were low-flux polymethylmethacrylate (PMMA), low-flux polysulfone (PS 400), and polycarbonate-polyether (Gambrane). Adequate and comparable removal of small solutes was provided by dialyzers with all 4 membrane materials used under similar conditions. A significant reduction of β₂-M plasma levels was seen only with Gambrane while the other 2 synthetic membrane materials gave rise to increases similar to those known to occur with Cuprophan. After correction for the hemoconcentration caused by ultrafiltration, dialysis with Gambrane showed a 24% lower plasma β₂-M level while the β₂-M concentrations with the other 3 membrane materials were practically unchanged. In addition, the efficiency of Gambrane dialyzers in β₂-M removal was able to significantly lower the predialysis plasma β₂-M levels after only 5 dialysis sessions. The hemocompatibility of the 3 synthetic low-flux membranes as judged by the white blood cell (WBC) count and complement activation was similar and therefore cannot be used to explain the different β₂-M plasma levels. In anticipation of gaining further insight into the mechanisms of accumulation and deposition of β₂-M in dialysis patients, a worthwhile approach may be to use a low-flux membrane such as Gambrane which combines removal with protection against potential activating factors in the dialysis fluid.     

Hemodiafiltration in Two Chambers Without Replacement Fluid: A Clinical Study

Abstract: Paired filtration dialysis (PFD) is the only hemodiafiltration (HDF) technique in which ultrafiltrate (Uf) is obtained continuously with a similar composition to plasma. It has been proved that Uf is regenerated when it passes through an uncoated adsorbent charcoal cartridge: this one removes medium-to-large solutes and small toxines (except for urea and phosphates), but not the electrolytes and bicarbonate. This regenerated Uf can be used like replacement fluid, using the same Uf pump as the infusion pump; this makes the HDF technique easier and more reliable. During 12 months (3 h/3 sessions/ week), we treated 13 patients with this PFD-Charcoal technique. These patients were previously on conventional PFD for at least 6 months. The biochemical results were excellent with a stabilization of all parameters (urea, creatinine, uric acid, Na, K, Cl, Ca, phosphates, β₂-microglobulin, β₂M, etc.) and a better control of acidosis (statistically significative after 6 months). The clinical tolerance was also excellent, and the technique was greatly simplified. We conclude that PFD-Charcoal is a good HDF technique that avoids the use of exogenous replacement fluid by using the regenerated Uf itself as an endogenous substitution fluid with bicarbonate.     

Hemodiafiltration history, technology, and clinical results

Hemodiafiltration (HDF) is an extracorporeal renal-replacement technique using a highly permeable membrane, in which diffusion and convection are conveniently combined to enhance solute removal in a wide spectrum of molecular weights. In this modality, ultrafiltration exceeds the desired fluid loss in the patient, and replacement fluid must be administered to achieve the target fluid balance. Over the years, various HDF variants have emerged, including acetate-free biofiltration, high-volume HDF, internal HDF, paired-filtration dialysis, middilution HDF, double high-flux HDF, push-pull HDF, and online HDF. Recent technology has allowed online production of large volumes of microbiologically ultrapure fluid for reinfusion, greatly simplifying the practice of HDF. Several advantages of HDF over purely diffusive hemodialysis techniques have been described in the literature, including a greater clearance of urea, phosphate, beta(2)-microglobulin and other larger solutes, reduction in dialysis hypotension, and improved anemia management. Although randomized controlled trials have failed to show a survival benefit of HDF, recent data from large observational studies suggest a positive effect of HDF on survival. This article provides a brief review of the history of HDF, the various HDF techniques, and summary of their clinical effects.     

Convective Mass Transfer in Hemodialysis

Abstract: Convective mass transfer in hemodialysis is associated with ultrafiltration (UF). In the absence of diffusion as in hemofiltration, the convective clearance is equal to S Q _F where S is the apparent solute sieving coefficient and Q _F the UF flow rate, but the convective contribution significantly decreases when diffusion is present. A rigorous calculation of the combined diffusion–convection mass transfer for partially rejected solutes is very complex. In this paper we review various models of mass fluxes found in the literature. Since all these models express the mass flux through the membrane as a linear function of blood and dialysate concentrations with different coefficients, we present a general expression for the hemodiafiltration clearance combining diffusion and convection which can be adapted to each model of mass flux. A surprising result is that the convective contribution to the clearance is, in the limit of dominant ultrafiltration, independent of the solute sieving coefficient, in contrast to the model of Villaroel et al. This is due to the effect of increased solute concentration at the membrane which compensates exactly for the effect of the sieving coefficient. This effect is overlooked in the Villaroel et al. model which assumes well mixed blood and dialysate compartments. Comparison with in vitro clearance measurements for urea, creatinin, vitamin B₁₂, and myoglobin (16,000 daltons) supports this observation even when diffusion dominates as in the case of clinical conditions for hemodiafiltration. An empirical correlation for the overall clearance valid for all solutes and blood flows between 200 and 500 ml/min is found to be K = K_D + 0.43 Q _F+ 8.3 times 10^-3 Q ²_Fwhen clearances and Q _Fare in ml/min.     

Protein Adsorption by Artificial Membrane Materials Under Filtration Conditions

Abstract: Elevated plasma levels of numerous low molecular weight proteins (LMWP) in renal insufficiency are likely to contribute to the uremic syndrome. Dialysis-related amyloidosis, caused by the accumulation of β₂-microglobulin (β₂M), has highlighted the need for a renal replacement therapy that allows the elimination of LMWP in addition to small solutes. Synthetic membrane materials employed under hemofiltration conditions proved to be most effective in lowering elevated β₂M plasma levels. In addition to convection, protein adsorption to artificial membrane materials is an important mechanism for β₂M removal. Using an in vitro setup, 12 commercially available hemofilters representing 11 different membrane materials were perfused with human blood containing ¹²⁵I-labeled plasma proteins. Under filtration conditions, total protein adsorption ranged from 338–2,098 mg/m² of membrane surface, and the fraction of adsorbed LMWP varied between 14–70% of total protein adsorption and was negatively correlated to total protein adsorption. β₂M adsorption showed up to an 8-fold difference between membranes, and was negatively correlated with total protein adsorption and positively correlated with the adsorption of LMWPs.     

Comparative analysis of procoagulatory activity of haemodialysis, haemofiltration and haemodiafiltration with a polysulfone membrane (APS) and with different modes of enoxaparin anticoagulation.

BACKGROUND: Treatment modalities of renal replacement therapy differ in their diffusive and convective mass transfer characteristics. It was the goal of this study to clarify whether an increase in convective mass transfer as performed with haemofiltration (HF) and haemodiafiltration (HDF) in comparison with high-flux haemodialysis (HD) is associated with an alteration in procoagulatory activity or with complement activation. METHODS: Ten stable chronic HD patients were monitored during 120 treatments in a randomized cross over design. A high-flux polysulfone dialyser (APS 900) was used for high-flux HD, pre-dilution HF and pre-dilution HDF. Constant flow of on-line substitution fluid for HF and HDF was 200 ml/min. The low molecular weight heparin (LMWH) enoxaparin was used for anticoagulation (i) as single bolus (50 IU/kg body weight, median 3700 IU) and (ii) as bolus of 1200 IU followed by a median continuous dose of 400 IU/h. Blood samples were collected before the LMWH bolus, after 10 min, 60 min, 120 min and at the end of treatment in venous and arterial blood lines to determine antiXa activity, thrombin-antithrombin-III complex (TAT), D-dimer and C5a generation. RESULTS: Net ultrafiltration did not significantly differ between HD, HF and HDF but total ultrafiltration in HF and HDF far exceeded total ultrafiltration in HD. With conditions of single bolus, or bolus and continuous anticoagulation with enoxaparin, after comparable treatment times (median duration 4.25 h), TAT and D-dimer generation at identical anti-Xa levels revealed significantly higher coagulation activity during HF and HDF, compared with high-flux HD as assessed by comparative area under the curve (AUC) analysis. Plasma concentration of C5a in venous bloodlines did not significantly differ during HD, HF and HDF. CONCLUSION: A higher convective mass transfer during HF and HDF, in comparison with high-flux HD caused by a greater total ultrafiltration volume was associated with increased procoagulatory activity in the extracorporeal circuit. Molecular markers assessing the activation of coagulation are appropriate to adjust the anticoagulation regime to high UF volumes in order to minimize bleeding risk and optimize patency of the extracorporeal circuit.     

Centralized On-Line Hemodiafiltration System Utilizing Purified Dialysate as Substitution Fluid

We followed the guidelines of the Kyushu Society for Hemodiafiltration (HDF) Therapy on the purification of dialysate used as substitution fluid and clinically applied HDF using only 20 L or 15 L of substitution fluid in the pre- or postdilution mode, respectively. We used a centralized on-line HDF system consisting of a novel multi-patient dialysate delivery system applying 3 endotoxin (ET) removal filters in series, maintaining the ET level within the criteria limit below 1.0 IU/L (measured at the first filter outlet to be 0.1 IU/L and after the third filter to be below the sensitivity limit) irrespective of the fluctuation in the ET level of the tap water. Low molecular weight proteins (β₂-microglobulin, prolactin, α₁ -micro-globulin, and α1-acid glycoprotein) were more effectively removed in this HDF system than in conventional hemodialysis (HD) using the same dialyzer as that in the HDF system, and the removal of these proteins in the HDF system was enhanced as their molecular weights increased. The clinical effect of the HDF system was demonstrated by a decrease in joint pain accompanied by improvement in joint motion in 6 dialysis patients followed over the long term (100 weeks).     

Clinical Experience and Model Analysis on Beta-2-Microglobulin Kinetics in High-Flux Hemodialysis

Abstract: Beta-2-microglobulin (β₂M) is associated with amyloidosis. The study of β₂M kinetics can provide information on the elimination of this uremic toxin. A β₂M kinetic model modified from Gotch, considering the volume changes between intracellular, interstitial, and intravascular compartments and the generation stimulation and inhibition during hemodialysis is proposed. The clinical experiments on 8 stable hemodialysis patients treated with polysulfone (F80) and polymethyl methacrylate (PMMA, BK2.1p) 3 times a week were conducted. There was an 18% decrease of β₂M clearance in the period from 30 to 180 min with a time-averaged β₂M clearance of 48 ml/min using polysulfone dialyzers (F80). In PMMA dialyzers, there was a 64% decrease of β₂M clearance from 30 to 180 min with a time-averaged clearance of 56.3 ml/min. During hemodialysis, the generation rate was 0.379 mg/min in polysulfone and 0.828 mg/min in PMMA dialyzers. There was a stimulation generation of 0.309 mg/min in polysulfone and 0.749 mg/min in PMMA during hemodialysis. In conclusion, we provide a β₂M kinetic model including volume changes, polymerization, generation stimulation, and inhibition that is similar to the human physiological condition. This model can be used for further clinical study.     

Online hemodiafiltration

Online hemodiafiltration (HDF) is an extracorporeal technique for solute removal in renal failure, which takes advantage of an enhancement of convective treatment by the large amount of ultrapure nonpyrogen dialysate being used for substitution of the ultrafiltered volume. It offers many advantages aside from its safe inflammatory profile, which is attributable to the use of ultrapure dialysate and highly biocompatible dialysis membranes. Due to an improved convective clearance, significantly increased removal of large or protein-bound uremic retention solutes can be achieved, with a potential benefit on cardiovascular morbidity and mortality. Recent observational data indicate that online HDF offers a survival advantage even after adjustment for comorbidity and dialysis efficiency. Research has been ongoing to maximize further the effectiveness of the technique by new technical innovations such as transmembrane-pressure feedback control or mid-dilution online HDF.     

On-line hemodiafiltration. Gold standard or top therapy?

In summary, on-line HDF is an extracorporeal blood purification therapy with increased convective removal of uremic toxins as compared to the most frequently used low- or high-flux HD therapy. The clinical advantages of on-line HDF have shown to be dose dependent, which makes on-line HDF superior to other therapies with less convective solute removal. Among the therapies with high convective solute removal, i.e. on-line HDF, on-line HF and double high-flux dialysis, it is difficult to finally decide on the best therapy, as direct comparisons of these therapies are not performed. Theoretical considerations like the relative to on-line HDF lower achievable Kt/Vurea with on-line HF, allow to state that on-line HDF is the top therapy now available for patients with ESRD. A gold standard may be defined as something with which everything else is compared if one tries to establish it in the respective field. In order to declare on-line HDF as the gold standard in renal replacement therapy, we need more direct comparisons of on-line HDF with other therapies, including mortality as an outcome parameter. However, based on our current knowledge, it does not seem to be too speculative that high-quality clinical studies will establish on-line HDF in the next years as the new gold standard in renal replacement therapy.     

A New Therapeutic Approach to Dialysis Amyloidosis: Intensive Removal of β2-Microglobulin with Adsorbent Column

Abstract: Amyloidosis, in which amyloid protein consists of β₂-microglobulin (β₂-M), is both a common and a serious complication of long-term hemodialysis. The mechanism of its development is not completely understood. Since (β₂-M is an amyloid protein, it is essential to try to remove as much of it as possible. A specific adsorbent of β₂-M has been developed for use in direct hemoperfusion. The adsorbent is a porous cellulose bead to which hydrophobic organic compound is bound covalently. A combination of a high-flux membrane dialyzer and an adsorption column (BM-01) would make it possible to efficiently eliminate β₂-M. Dialysis with a combination of direct hemoperfusion (DHP) and an adsorption column led to the elimination of more than 200–300 mg of β₂-M. We observed 5 patients who received treatment with this column (BM-01) in combination with high-flux dialysis 3 times a week for periods of 1 week (3 patients), 6 months (I patient), or 14 months (1 patient). It is demonstrated that the adsorbent column (BM-01) provides an intensive method to eliminate β₂-M from the blood with no serious adverse effect. It thus has the potential to suppress the progression of dialysis amyloidosis. The use of this adsorbent column (BM-01) in combination with a high-flux dialyzer may present an improved approach to removing β₂-M from the body.     

Dialysis-related amyloidosis: Pathogenetic aspects and therapeutic considerations

Summary: Beyond renal transplantation and the provision of symptomatic relief, approaches to treat dialysis-related amyloidosis (DRA), an important long-term complication in patients on regular dialysis, must be based on the knowledge of the underlying pathogenetic process. Retention of beta₂-microglobulin (β₂m) is the prerequisite; biochemical alterations of β₃₂m increasing its amyloidogenicity, and local predisposing tissue factors together with age appear to be relevant. A growing body of evidence points toward the importance of pro-inflammatory effects of dialysis (blood-membrane interactions, pyrogen-related priming of cytokine producing mononuclear cells) in the development of DRA. Advanced glycation endproduct formation (AGE-β₂m) may represent a central element in the pathogenesis of DRA. For non-transplant therapy of DRA, the main goals must be the optimization of β₂m removal (high-flux haemodialysis, haemofiltration, especially pre-dilution haemofiltration) and reduction of pro-inflammatory effects of dialysis (use of non-complement activating biocompatible membranes, pyrogen free dialysate). At least patients at high risk for DRA should be treated according to these guidelines.     

End-stage renal failure in New Zealand Maori: an analysis of circulating transforming growth factor-β1

SUMMARY: There is a high incidence of end-stage renal disease in New Zealand Maori. Reasons for this have not been established. Transforming growth factor-β, (TGF-β₁) is a profibrogenic cytokine, which stimulates the secretion of extracellular matrix components, and has been implicated in the pathogenesis of kidney failure. the aim of this study was to examine TGF-β₁ in the serum of haemodialysis patients at our institution, in order to determine whether there was an upregulation of TGF-β₁ in Maori. A TGF-Prspecific sandwich enzyme-linked immunosorbant assay was used to measure active TGF-β from the sera of 74 haemodialysis patients, and 19 healthy Maori without renal disease, diabetes or hypertension. In addition, clinical and laboratory markers were examined in the haemodialysis patients studied. There was no association between TGF-β₁ and ethnicity in the groups studied. Transforming growth factor-β₁ protein appeared to be inversely related to age. but was not associated with parameters of survival on dialysis such as serum albumin or measures of dialysis adequacy. Although there was a significantly higher incidence of type II diabetes mellitus in the Maori ( P < 0.001) in comparison to European patients, the glycaemic control was comparable between the groups, as were all other laboratory and clinical parameters studied. This is the first study to examine the fibrogenic growth factor TGF-β₁ in New Zealand Maori. Thus, an endogenous increase in TGF-β₁ in Maori does not appear to be implicated in the increased incidence of end-stage renal disease in this population.     

On-line hemodiafiltration: technique and therapy

On-line hemodiafiltration (HDF) provides the largest amount of blood purification over a wide molecular weight spectrum achievable with present renal replacement therapies. When used with state of the art dialysis membranes and treatment systems, the biocompatibility of on-line HDF is as high as can presently be defined. From an economic perspective, the added cost of the ultrafilters used to prepare the substitution solution is balanced by the therapeutic benefits of HDF. For optimal HDF, the ultrafiltration rate must be maximized with respect to the blood flow rate. In on-line HDF systems, the excess volume ultrafiltered, approximately 20 to 30 liters per treatment, is automatically replaced, preferably in postdilution mode, by a substitution solution that is continuously generated by stepwise ultrafiltration of dialysate. When properly prepared, this fluid fulfills the quality demands of commercially available infusion solutions; that is, it can be referred to as sterile and pyrogen-free. The most important factors in preparing substitution solution are the quality of the water, of the concentrates, of the ultrafilters, and the microbiological status of the entire flow path. The clinical safety of substitution solution prepared on-line has been documented by long-term users of on-line systems. Results from clinical studies with on-line HDF confirm the overall increased clearance of solutes in relation to high-flux dialysis using the same membrane.     

Hemodiafiltration: the addition of convective flow to hemodialysis

Hemodiafiltration (HDF) combines both hemofiltration (HF) and hemodialysis in the same procedure. It was initially performed in adults in 1977, and later used in children in the early 1980s. The use of HDF allows a determined convective dialysis dose to be combined with the conventional urea dialysis dose. The dialysis session is better tolerated as a result of the effects of hemofiltration. On-line HDF, i.e., substitution fluid prepared from ultrafiltration of the ultrapure dialysate, can be performed safely due to recent advances in modern technology. However, despite interest and feasibility in children, the majority of pediatric dialysis units across the world still perform hemodialysis using highly permeable membranes, allowing back filtration in the filter and therefore a degree of convective flow, i.e., internal hemodiafiltration. In some countries, government restrictions prohibit the use of on-line hemodiafiltration, (such as the FDA recommendations in North America), and therefore it should not be used in these circumstances.     

Clinical Evaluation of a New Dialyzer, FLX-12 GW, with a Polyester-Polymer Alloy Membrane

Abstract: The performance of a membrane in renal failure therapy is determined by its structure, its overall mass transfer properties, and its blood compatibility. In this regard. removal of β₂-microglobulin (β2M) has become a major objective of dialysis therapy. In the present study, a newly developed high-flux membrane composed of a polyester-polymer alloy (PEPA) with the components of polyarylate and polyethersulfone (dialyzer FLX-12 GW; Nikkiso Co., Japan) has been evaluated with regard to both hiocompatibility and elimination capacity for β2M during hemodialysis of 8 stable chronic uremic patients. The clearance values of low molecular weight solutes were in the same range as those reported for high-flux dialyzers of comparable surface area. There was no drop in leukocyte counts and only a minimal fall in platelet counts nearly in the same range as has been observed by other investigators using polyamide membrane. C3a Des Arg generation was low, and C5a Des Arg formation was not significantly influenced. There was a sharp drop in the serum β2M level (-35%) during dialysis with a clearance between 59.7 ± 5.6 ml/min ( Q_B 200 ml/min) and 70.1 ± 9.7 ml/min ( Q_B 300 ml/min), respectively. Accordingly, the sieving coefficient was calculated to be 0.2 at 30 min after start of dialysis and 0.6 1 h later. The membrane was able to remove 184.0 ± 22.3 mg/4 h due to an apparent rate of adsorption during the first hour of treatment in combination with high transmembrane transfer in the following time.     

Impact of Ultrafiltration on Back-Diffusion in Hemodialyzer

Abstract: Ultrafiltration of water from blood to dialysate decreases the rate of back–diffusion of solutes from dialysate to blood. Therefore, back–clearance ( bK ) of hemodialyzers may be expressed as bK = bK _o – bTrQ _u, where bK _o is the diffusive back–clearance, bTr is the "back–"transmittance coefficient, and Qu is the net ultrafiltration rate. A formula for bK was derived from the one–dimensional theory of hemodialyzer, and bTr was described as a function of bK _o and the Staverman reflection coefficient. The transport parameters, bK _o and bTr , for creatinine and vitamin B₁₂ were measured in two types of hemodialyzers with negligible back–filtration, using water solutions, and compared with the transport parameters, K _o and Tr , for the case of both diffusion and ultrafiltration from blood to dialysate. bK _o was in general equal to K_o. bTr was not different from Tr for creatinine whereas bTr was lower than Tr for vitamin B₁₂. Experimental values of bTr for vitamin B₁₂ were in general agreement with theoretical predictions. However, experimental values of bTr for creatinine were lower than predicted values. We conclude that the impact of ultrafiltration on back–clearance for slowly diffusing solutes is weaker than on their clearance.     

Lixelle Adsorbent to Remove Inflammatory Cytokines

It is the goal of this section to publish material that provides information regarding specific issues, aspects of artificial organ application, approach, philosophy, suggestions, and/or thoughts for the future.
A β₂-microglobulin (β₂M) selective adsorbent (Lixelle) for direct hemoperfusion has been used for the treatment of hemodialysis patients with the long-term complication of dialysis related amyloidosis (DRA), but there is no significant correlation between the serum level of β₂M and the occurrence of DRA. Inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNFα) are related to the development of DRA. We studied the adsorptive rates of cytokines in vitro using the Lixelle adsorbent. The adsorptive rates were 98. 5% for IL-1β, 98.0% for interleukin-1 receptor antagonist (IL-1RA), 82.9% for IL-6, 99.9% for IL-8, 31.2% for TNF α, and 46.1% for soluble TNF receptor (sTNFr), respectively. As the molecular weights of cytokines increase, the adsorptive rates decrease. The Lixelle column adsorbed β₂M and various inflammatory cytokines as well. Therefore, the removal of both β₂M and inflammatory cytokines may play an important role in the treatment of DRA.