Maarten Wester

Mixed matrix hollow fiber membranes for removal of protein-bound toxins from human plasma

In end stage renal disease (ESRD) waste solutes accumulate in body fluid. Removal of protein bound solutes using conventional renal replacement therapies is currently very poor while their accumulation is associated with adverse outcomes in ESRD. Here we investigate the application of a hollow fiber mixed matrix membrane (MMM) for removal of these toxins. The MMM hollow fiber consists of porous macro-void free polymeric inner membrane layer well attached to the activated carbon containing outer MMM layer. The new membranes have permeation properties in the ultrafiltration range. Under static conditions, they adsorb 57% p-cresylsulfate, 82% indoxyl sulfate and 94% of hippuric acid from spiked human plasma in 4 h. Under dynamic conditions, they adsorb on average 2.27 mg PCS/g membrane and 3.58 mg IS/g membrane in 4 h in diffusion experiments and 2.68 mg/g membrane PCS and 12.85 mg/g membrane IS in convection experiments. Based on the dynamic experiments we estimate that our membranes would suffice to remove the daily production of these protein bound solutes.

A novel approach for blood purification: Mixed-matrix membranes combining diffusion and adsorption in one step

Hemodialysis is a commonly used blood purification technique in patients requiring kidney replacement therapy. Sorbents could increase uremic retention solute removal efficiency but, because of poor biocompatibility, their use is often limited to the treatment of patients with acute poisoning. This paper proposes a novel membrane concept for combining diffusion and adsorption of uremic retention solutes in one step: the so-called mixed-matrix membrane (MMM). In this concept, adsorptive particles are incorporated in a macro-porous membrane layer whereas an extra particle-free membrane layer is introduced on the blood-contacting side of the membrane to improve hemocompatibility and prevent particle release. These dual-layer mixed-matrix membranes have high clean-water permeance and high creatinine adsorption from creatinine model solutions. In human plasma, the removal of creatinine and of the protein-bound solute para-aminohippuric acid (PAH) by single and dual-layer membranes is in agreement with the removal achieved by the activated carbon particles alone, showing that under these experimental conditions the accessibility of the particles in the MMM is excellent. This study proves that the combination of diffusion and adsorption in a single step is possible and paves the way for the development of more efficient blood purification devices, excellently combining the advantages of both techniques.

Removal of urea in a wearable dialysis device: a reappraisal of electro-oxidation

A major challenge for a wearable dialysis device is removal of urea, as urea is difficult to adsorb while daily production is very high. Electro-oxidation (EO) seems attractive because electrodes are durable, small, and inexpensive. We studied the efficacy of urea oxidation, generation of chlorine by-products, and their removal by activated carbon (AC). EO units were designed. Three electrode materials (platinum, ruthenium oxide, and graphite) were compared in single pass experiments using urea in saline solution. Chlorine removal by AC in series with EO by graphite electrodes was tested. Finally, urea-spiked bovine blood was dialyzed and dialysate was recirculated in a dialysate circuit with AC in series with an EO unit containing graphite electrodes. Platinum electrodes degraded more urea (21 ± 2 mmol/h) than ruthenium oxide (13 ± 2 mmol/h) or graphite electrodes (13 ± 1 mmol/h). Chlorine generation was much lower with graphite (13 ± 4 mg/h) than with platinum (231 ± 22 mg/h) or ruthenium oxide electrodes (129 ± 12 mg/h). Platinum and ruthenium oxide electrodes released platinum (4.1 [3.9-8.1] umol/h) and ruthenium (83 [77-107] nmol/h), respectively. AC potently reduced dialysate chlorine levels to < 0.10 mg/L. Urea was removed from blood by EO at constant rate (9.5 ± 1.0 mmol/h). EO by graphite electrodes combined with AC shows promising urea removal and chlorine release complying with Association for the Advancement of Medical Instrumentation standards, and may be worth further exploring for dialysate regeneration in a wearable system.

Mixed Matrix Membranes: A New Asset for Blood Purification Therapies

a Institute for Biomedical Technology and Technical Medicine MIRA, Biomaterials Science and Technology, and b Membrane Technology Group, Faculty of Science and Technology, University of Twente, Enschede , c Department of Internal Medicine, University Hospital Maastricht, Maastricht , and d Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht , The Netherlands; e State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Material Science and Engineering, Donghua University, Shanghai , PR China

A regenerable potassium and phosphate sorbent system to enhance dialysis efficacy and device portability: an in vitro study

BACKGROUND Continuous dialysis could provide benefit by constant removal of potassium and phosphate. This study investigates the suitability of specific potassium and phosphate sorbents for incorporation in an extracorporeal device by capacity and regenerability testing. METHODS Capacity testing was performed in uraemic plasma. Regenerability was tested for potassium sorbents, with adsorption based on cationic exchange for sodium, with 0.1 M and 1.0 M NaCl. To regenerate phosphate sorbents, with adsorption based on anionic exchange, 0.1 M and 1.0 M NaHCO3 and NaOH were used. Subsequently, sodium polystyrene divinylbenzene sulphonate (RES-A) and iron oxide hydroxide (FeOOH) beads were incorporated in a cartridge for testing in bovine blood using a recirculating blood circuit and a dialysis circuit separated by a high-flux dialyzer (dynamic setup). Preloading was tested to assess whether this could limit calcium and magnesium adsorption. RESULTS In the batch-binding assays, zirconium phosphate most potently adsorbed potassium (0.44 ± 0.05 mmol/g) and RES-A was the best regenerable potassium sorbent (92.9 ± 5.7% with 0.1 M NaCl). Zirconium oxide hydroxide (ZIR-hydr) most potently adsorbed phosphate (0.23 ± 0.05 mmol/g) and the polymeric amine sevelamer carbonate was the best regenerable sorbent (85.7 ± 5.2% with 0.1 M NaHCO3). In the dynamic setup, a potassium adsorption of 10.72 ± 2.06 mmol in 3 h was achieved using 111 g of RES-A and a phosphate adsorption of 4.73 ± 0.53 mmol in 3 h using 55 g of FeOOH. Calcium and magnesium preloading was shown to reduce the net adsorption in 3 h from 3.57 ± 0.91 to -0.29 ± 1.85 and 1.02 ± 0.05 to -0.31 ± 0.18 mmol, respectively. CONCLUSION RES-A and FeOOH are suitable, regenerizable sorbents for potassium and phosphate removal in dialysate regeneration. Use of zirconium carbonate and ZIR-hydr may further increase phosphate adsorption, but may compromise sorbent regenerability. Use of polymeric amines for phosphate adsorption may enhance sorbent regenerability. Calcium and magnesium preloading considerably reduced net adsorption of these ions.

Model-based physiological data stream evaluation for dialysis therapy

Conventional dialysis therapy ofpatients with end-stage renal disease is time-consuming and its discontinuous nature induces physiological stress to the patient. Therefore new emerging approaches facilitate prolonged treatment by using portable devices in home-settings. Such unsupervised treatment calls for continuous automated monitoring of various physiological parameters. This paper highlights the challenges of autonomous personalized renal treatment and presents a leap towards contextaware monitoring in data streams by a physiological modelbased approach. The algorithmic principle is employed to propagate urea concentration, which is measured to assess dialysis efficacy. Simulation results validate the algorithm for the application in a mobile dialysis therapy currently under development. The presented method enables the estimation of medically significant, but technically inaccessible physiological parameters from data stream propagation.

Integrated Monitoring for Personalized Renal Replacement Therapy

Introduction: Emerging renal support devices tend towards automated physiological monitoring and treatment adaptation. In the patient-centred development of the mobile NEPHRON+ system decisive physiological aspects and their mutual affections were identified and methods of measurement were incorporated into a wearable system enabling a personalized and un-supervised auto-adaptive treatment. Methods: Nephrologists determined the physiological variables to be monitored in dialysis patients. The experts’ opinions were confirmed by extensive literature survey to find formalized relationships between the physiological parameters. As a basis for the embedded device control, suitable means of monitoring were integrated into the prototype of NEPHRON+, a networked mobile dialysis system. Results: To monitor the principal function of the blood cleansing device, ion selective and enzymatic electrodes tailored towards the miniaturized device are integrated in the mobile blood treatment system. Weight measurements are transmitted via Bluetooth to gauge the hydration surplus to be removed. Both, fluidic and chemical dynamics in the body are described based on the measurements using compartment models. Hemodynamic instabilities frequently arise during blood cleansing treatment due to homeostatic imbalance. Thus an electric sphygmomanometer and heart rate acquisition are likewise connected for intermittent measurements. To interpret these context sensitive parameters an accelerometer is embodied into the wearable system enabling to estimate the influence of the treated patient’s physical activity on aforementioned vital parameters. This allows differentiating between the vital parameter dynamics arising from activity and the negative influence of homeostatic imbalance. Conclusion: A prototypic architecture for a defined treatment scenario has been realized to demonstrate the technical feasibility, enabling comprehensive physiological monitoring of dialysis treatments. Mathematical models of the monitored variables were gleaned for context aware evaluation of the mutually dependent parameters.

From portable dialysis to a bioengineered kidney

ABSTRACT Introduction: Since the advent of peritoneal dialysis (PD) in the 1970s, the principles of dialysis have changed little. In the coming decades, several major breakthroughs are expected. Areas covered: Novel wearable and portable dialysis devices for both hemodialysis (HD) and PD are expected first. The HD devices could facilitate more frequent and longer dialysis outside of the hospital, while improving patient’s mobility and autonomy. The PD devices could enhance blood purification and increase technique survival of PD. Further away from clinical application is the bioartificial kidney, containing renal cells. Initially, the bioartificial kidney could be applied for extracorporeal treatment, to partly replace renal tubular endocrine, metabolic, immunoregulatory and secretory functions. Subsequently, intracorporeal treatment may become possible. Expert commentary: Key factors for successful implementation of miniature dialysis devices are patient attitudes and cost-effectiveness. A well-functioning and safe extracorporeal blood circuit is required for HD. For PD, a double lumen PD catheter would optimize performance. Future research should focus on further miniaturization of the urea removal strategy. For the bio-artificial kidney (BAK), cost effectiveness should be determined and a general set of functional requirements should be defined for future studies. For intracorporeal application, water reabsorption will become a major challenge.

A regenerable potassium and phosphate sorbent system to enhance dialysis efficacy and device portability: a study in awake goats

Background Patients on standard intermittent haemodialysis suffer from strong fluctuations in plasma potassium and phosphate. Prolonged dialysis with a wearable device, based on continuous regeneration of a small volume of dialysate using ion exchangers, could moderate these fluctuations and offer increased clearance of these electrolytes. We report in vivo results on the efficacy of potassium and phosphate adsorption from a wearable dialysis device. We explore whether equilibration of ion exchangers at physiological Ca 2+ , Mg 2+ and hypotonic NaCl can prevent calcium/magnesium adsorption and net sodium release, respectively. Effects on pH and HCO3- were studied. Methods Healthy goats were instrumented with a central venous catheter and dialysed. Potassium and phosphate were infused to achieve plasma concentrations commonly observed in dialysis patients. An adsorption cartridge containing 80 g sodium poly(styrene-divinylbenzene) sulphonate and 40 g iron oxide hydroxide beads for potassium and phosphate removal, respectively, was incorporated in a dialysate circuit. Sorbents were equilibrated and regenerated with a solution containing NaCl, CaCl 2 and MgCl 2 . Blood was pumped over a dialyser and dialysate was recirculated over the adsorption cartridge in a countercurrent direction. Results Potassium and phosphate adsorption was 7.7 ± 2.7 and 4.9 ± 1.3 mmol in 3 h, respectively. Adsorption capacity remained constant during consecutive dialysis sessions and increased with increasing K + and PO43-. Equilibration at physiological Ca 2+ and Mg 2+ prevented net adsorption, eliminating the need for post-cartridge calcium and magnesium infusion. Equilibration at hypotonic NaCl prevented net sodium release Fe 2+ and arterial pH did not change. Bicarbonate was adsorbed, which could be prevented by equilibrating at HCO3- 15 mM. Conclusion We demonstrate clinically relevant, concentration-dependent, pH-neutral potassium and phosphate removal in vivo with small volumes of regenerable ion exchangers in our prototype wearable dialysis device. Application of the selected ion exchangers for potassium and phosphate removal in a wearable dialysis device appears to be effective with a low-risk profile.