Novel substitution technique in intermittent infusion hemodiafiltration (I-HDF) therapy using back filtration as substitution.

An infusion of dialysate into the blood compartment across the membrane using back filtration in dialysis therapy provides a stabilizing blood pressure and a membrane flushing during treatment. We devised a method to flush the membrane effectively and tried to find the optimum infusion patterns for intermittent infusion hemodiafiltration (I-HDF) from the aspect of solute removal by computing the pressure distribution in a diafilter. Bovine blood experiments were performed under following three modes: control HD in which no intentional filtration was involved, and two I-HDF in which back filtration was made either under counter current or under parallel flow. The inner surface of the hollow fiber before and after the experiment was observed using FE-SEM. According to the computation of the pressure distribution, a large amount of normal filtration occurs near the blood inlet in control HD. In addition, when the back filtration is performed under parallel flow, the amount of backfiltration near the blood inlet is 3.43 times higher than that in the case of counter current. Clearance (CL) of inulin remained at the highest level when the back filtration was performed under parallel flow. Near the blood inlet where the fouling was significantly formed, many macropores remained on the membrane when the backfiltration was performed under parallel flow. The degree of fouling showed a distribution along with the blood flow and the pressure distribution. Furthermore, the more effective recovery of CL can be expected by introducing the backfiltration under parallel flow to which fouling was significantly formed.

Replication of fouling in vitro in hollow fiber dialyzers by albumin immobilization.

For designing and evaluating the dialyzer and investigating the optimal therapeutic conditions, in vitro studies bring us many useful findings. In hemodialysis, however, the membrane fouling due to protein molecules reduces solute removal performance. Therefore, we investigated a method for replicating the fouling in dialyzers in aqueous experiments. After the albumin solution was circulated in the test circuit with a dialyzer, a glutaraldehyde solution was pumped into the dialyzer to immobilize albumin on the hollow fiber membrane. Under various immobilization conditions, the permeability of creatinine and vitamin B12 was evaluated by dialysis experiments. The creatinine clearance after immobilization of albumin was decreased, suggesting pore plugging by our fouling replication method. The glutaraldehyde crosslinked albumin molecules that adhered them to the membrane firmly. Moreover, the degree of fouling may be controlled by changing the concentration of albumin solution and the volume of glutaraldehyde solution used for immobilization. Our fouling replication method was applied to three types of polyester polymer alloy (PEPA) dialyzers and one polysulfone (PSf) dialyzer. This method enables to evaluate the permeability of various dialyzers with fouling in vitro that will be of great help in collecting data for designing dialyzers.

Electrophysiological insights into the relationship between calcium dynamics and cardiomyocyte beating function in chronic hemodialysis treatment.

For patients in which the Ca2+ concentration of dialysis fluid is lower than that in plasma, chronic hemodialysis treatment often leads to cardiac beating dysfunction. By applying these conditions to an electrophysiological mathematical model, we evaluated the impact of body fluid Ca2+ dynamics during treatment on cardiomyocyte beating and, moreover, explored measures that may prevent cardiomyocyte beating dysfunction. First, Ca2+ concentrations in both plasma and interstitial fluid were decreased with treatment time, which induced both a slight decline in beating rhythm on a sinoatrial nodal cell and a wane in contraction force on a ventricular cell. These simulated results were in agreement with clinical observations. Next, a relationship between the intracellular Ca2+ concentration and ion current dynamics of ion transporters were examined to elucidate the mechanism underlying cardiomyocyte beating dysfunction. The inward current of the Na/Ca exchanger (NCX) increased with a decrease in Ca2+ concentration in interstitial fluid and induced a reduction in intracellular Ca2+ concentration during treatment. Furthermore, the decline in intracellular Ca2+ concentration reduced the contraction force. These findings implied that ion transport through the NCX is a dominant factor that induces cardiomyocyte beating dysfunction during hemodialysis. Finally, the replenishment of Ca2+ or application of an NCX inhibitor during treatment suppressed the decrease in intracellular Ca2+ concentration and contributed to the stabilization of cardiomyocyte beating function. In summary, the clinical implementation of hepatically cleared NCX inhibitor may be a suitable approach to improving the quality of life for patients on chronic hemodialysis.

Support for Dialysis Therapy in Vietnam, Cambodia, and Myanmar by Japanese Societies in the Field of Blood Purification.

With recent economic development in Southeast Asia, there have been improvements in medical services and healthcare provision. This has led to increased numbers of dialysis patients and increased numbers of dialysis facilities in the region. To assist economically developing countries in managing this change, support projects from Japan have been conducted in the region since around 2007. This article summarizes and discusses Japan's support activities, in which some of the authors were directly involved, in Vietnam, Cambodia, and Myanmar. Initial support was mainly organized by the non-governmental organization Ubiquitous Blood Purification International (NGO UBPI), and currently several organizations in the field of blood purification work together to offer ongoing support in the region. Many positive changes have resulted from these activities in Southeast Asia, but challenges remaining for the future are to establish an educational system for each dialysis specialty and develop dialysis techniques ensuring high treatment quality and safety.

The Impact of Potassium Dynamics on Cardiomyocyte Beating in Hemodialysis Treatment.

Background: Observational studies of intermittent hemodialysis therapy have reported that the excess decrease in K+ concentration in plasma (KP) during treatment is associated with the destabilization of cardiac function. Elucidating the mechanism by which the decrease in KP impairs myocardial excitation is indispensable for a deeper understanding of prescription design. Methods: In this study, by using an electrophysiological mathematical model, we investigated the relationship between KP dynamics and cardiomyocyte excitability for the first time. Results: The excess decrease in KP during treatment destabilized cardiomyocyte excitability through the following events: (1) a decrease in KP led to the prolongation of the depolarization phase of ventricular cells due to the reduced potassium efflux rate of the Kr channel, temporarily enhancing contraction force; (2) an excess decrease in KP activated the transport of K+ and Na+ through the funny channel in sinoatrial nodal cells, disrupting automaticity; (3) the excess decrease in KP also resulted in a significant decrease in the resting membrane potential of ventricular cells, causing contractile dysfunction. Avoiding an excess decrease in KP during treatment contributed to the maintenance of cardiomyocyte excitability. Conclusions: The results of these mathematical analyses showed that it is necessary to implement personal prescription or optimal control of K+ concentration in dialysis fluid based on predialysis KP from the perspective of regulatory science in dialysis treatment.

Diafilters for predilution and postdilution on-line hemodiafiltration.

When hemodiafiltration (HDF) is performed, we can choose the point on the blood circuit where the substitution fluid goes in, i.e. before the diafilter (predilution) or after the diafilter (postdilution). We must avoid unexpected loss of albumin; however, we should remove a certain amount of albumin in order to remove much larger solutes than ß2-microglobulin and obtain better clinical outcomes. Previously, ultrafiltration experiments were performed in vitro using aqueous albumin solution and commercial diafilters. The results showed a high sieving coefficient for albumin right after starting the experiment that is identical to several clinical reports. Based on these results, a novel design of the diafilter was attempted for predilution and postdilution HDF. Diafilters for predilution HDF do not require much change in design specifications, employing hollow fibers with a slightly larger diameter in order to reduce high blood pressure caused by the high blood flow rate. Diafilters for postdilution HDF may require much change, including shortening the length in order to reduce the amount of internal filtration. Diafilters specifically designed for predilution or postdilution may be necessary to assure future success of clinical HDF treatment.

Effects of hollow fiber packing density and housing shape on the albumin filtration performance of CRRT filters.

Continuous renal replacement therapy (CRRT) has become the most commonly used acute blood purification therapy for critically ill patients. As a key point of extracorporeal blood circulation, the CRRT filter plays a decisive role in therapeutic efficacy. However, few in vitro studies have been conducted on CRRT filters, particularly concerning the effects of design factors on filter effectiveness and safety profile; no comprehensive evaluation system has been established. Here, we designed nine CRRT filters with various combinations of hollow fiber packing density (PD) and housing shape (effective hollow fiber length (L) and inner housing diameter (D) ratio (L/D ratio)) and introduced a high-frequency sampling pressure monitor to accurately monitor small changes in transmembrane pressure (TMP) and ultrafiltration rate (UFR) over time. We also used concentration polarization mass transfer resistance (Rc), change in sieving coefficient (S) of albumin over time, and amount of albumin removed (Mfld) to investigate the effects of two design factors on albumin filtration performance and analyze the mechanism of protein filtration performance over time, thereby establishing a comprehensive in vitro evaluation system to explore the safety profile of CRRT filters. Our results showed that the nine CRRT filters designed with different combinations of PD (50%, 55%, and 60%) and L/D ratio (2.9, 5.3, and 9.3) were able to maintain stability in terms of hemodynamics and water permeability; the lowest Mfld was PD = 60% and L/D ratio = 9.3, which indicates that design factor optimization can effectively control albumin filtration, thereby improving the safety profile of CRRT filters.

A practical design equation for accurate quantification of CRRT filter design factors and convection effects.

Considering the increasing clinical need for continuous renal replacement therapy (CRRT), further improvement in therapeutic efficacy has become an important focus for researchers. Here, we designed nine CRRT filters with various combinations of hollow fiber packing density (PD) and housing shape (effective hollow fiber length (L) and inner housing diameter (D) ratio (L/D ratio)) to evaluate the clearance of middle molecular uremic toxins (MMs) via simulation of an in vitro continuous veno-venous hemodialysis treatment model. We also used Doppler ultrasonography to measure the maximum internal filtration flow rate (QIF-Max) as an aid; this approach facilitated an exploration of the impacts of various design factors on convection effects, while revealing the mechanisms influencing MM removal performance. Furthermore, we constructed a multiple linear regression model of design factors and QIF-Max, then conducted experimental verification. Finally, we proposed an accurate and practical design equation to quantify the design factors influencing CRRT filters and convection effects: QIF-Max=4.749×ND2+2.293×LD-34.775, where N/D2 and L/D affect QIF-Max by 15.0% and 85.0%, respectively. This design equation was able to effectively quantify the convection effects of CRRT filters with different design factors, thereby predicting MM removal performance; this convenient design equation can support the development of CRRT-related products.

Effect of hollow fiber packing density and housing shape on the solute removal performance of CRRT filters for acute blood purification.

Continuous renal replacement therapy (CRRT) has a good therapeutic effect in a variety of diseases, such as acute kidney injury. CRRT filters should feature small membrane surface area, excellent water permeability and solute removal performance for long-term use. Solute removal performance depends on the physicochemical structure of the dialysis membrane as well as on the housing design. On the basis of the same hollow fiber membrane, optimizing the housing design can maximize the performance of the dialysis membrane. In this article, we experimentally demonstrated the influence of hollow fiber packing density (PD) and housing shape (effective hollow fiber length (L) and inner housing diameter (D) ratio (L/D ratio)) on the performance of CRRT filters. In each continuous hemodialysis mode and post-diluted continuous hemodiafiltration mode, we tested nine CRRT filters with the same high-flux membrane but with different PDs (50%, 55%, and 60%) and L/D ratios (2.9, 5.3, and 9.3), and we evaluated the effect of different combinations of the two design factors on solute clearance. Our results showed that unlike with the clearance of small molecular weight solutes, the clearance of medium molecular weight solute was obviously affected by PD and L/D ratio, and the design providing the best removal of medium molecular solutes among the nine experiments was PD = 60% and L/D ratio = 9.3. This article will help address the lack of research on CRRT filter housing design as well as lead to the development of higher performance filters for acute blood purification.

Effect of Membrane Surface Area on Solute Removal Performance of Dialyzers with Fouling.

In a clinical situation, since membrane fouling often causes the reduction of solute removal performance of the dialyzer, it is necessary to evaluate the performance of the dialyzer, considering the effects of fouling even in aqueous in vitro experiments that are useful for the better design of dialyzers. We replicated the membrane fouling by immobilizing albumin on the membrane in a dialyzer using glutaraldehyde as a stabilizer. The modules of various membrane surface areas with and without replication of the fouling were used for performance evaluation of solute (creatinine, vitamin B12, and inulin) removal in dialysis experiments in vitro. Clearances for these solutes in the modules with fouling were lower than those without fouling. Furthermore, the smaller the surface area, the larger the fouling effect was observed in all solutes. Calculated pressure distribution in a module by using a mathematical model showed that the solute removal performance might be greatly affected by the rate of internal filtration that enhances the solute removal, especially for larger solutes. The increase in the rate of internal filtration should contribute to improving the solute removal performance of the dialyzer, with a higher effect in modules with a larger membrane surface area.

Particulates formed in online prepared substitution fluid-Effect of acetic acid cleaning on endotoxin retentive filters.

INTRODUCTION: There is no standard for insoluble particulate matters in dialysate. We evaluated the insoluble particulate matters in online prepared substitution fluid. METHODS: We evaluated particle diameters and constituent elements of particles in online prepared substitution fluid and the final endotoxin retentive filter (ETRF). RESULTS: The measurement results with particles in the online prepared substitution fluid and particles attached to the final ETRF revealed that Ca-containing particles accounted for 11 particles and Si-containing particles accounted for 19 particles of 30 particles detected in the online prepared substitution fluid and the final ETRF. CONCLUSION: We presume that insoluble particulates in online prepared substitution fluid were Ca and Mg precipitated from dialysate and Si precipitated from dialysis water. Even if two ETRFs were connected in series, these particles were formed in the final ETRF.

Present status of renal replacement therapy in lower-middle-income Asian countries: Cambodia, Myanmar, Laos, Vietnam, Mongolia, and Bhutan as of June 2019 (before COVID-19), from the interviews of leading doctors in every country: (duplicated English publication from "the special Japanese edition of educational lectures in the 64th annual meeting of the Japanese Society for Dialysis Therapy").

The present status of Cambodia, Myanmar, Laos, Vietnam, Mongolia, and Bhutan as of June 2019 was reviewed from the interviews of leading doctors in every country. The timing was until just 6 months before the COVID-19 pandemic broke out. The cost per hemodialysis session was 25-70 US dollar and expensive if it is compared with average monthly income of every country. In Cambodia and Laos, patients must cover 100% of expenses for maintenance hemodialysis, in Myanmar, the government covers the cost of once-weekly dialysis sessions, in Vietnam, the government covers 80% of the cost, and in Mongolia and Bhutan, the cost is fully covered by the government. Continuous ambulatory peritoneal dialysis was widely available in Vietnam and Mongolia, which have achieved a relative standard of social infrastructure, but is far from common in any of the other countries. The number of patients on dialysis is increasing with economic development in all countries. Diabetic nephropathy is a common primary reason for dialysis. None of the countries discussed in this article had clinical engineers who could maintain hemodialysis equipment and carry out clinical tasks in dialysis centers. Hospitals were not maintaining their equipment, and damaged units were kept in storage to be used for spare parts. None of the countries had dieticians to provide patients with dietary guidance. Establishment and training of both clinical engineers and registered dietitians are major projects that must be undertaken.

Semi-Quantitative Evaluation of Asymmetricity of Dialysis Membrane Using Forward and Backward Ultrafiltration.

Performance of the dialysis membrane is strongly dependent upon the physicochemical structure of the membrane. The objective of this study is to devise a new in vitro evaluation technique to quantify the physicochemical structures of the membrane. Three commercial dialyzers with cellulose triacetate (CTA), asymmetric CTA (termed ATA®), and polyether sulfone (PES) membranes (Nipro Co., Osaka, Japan) were employed for investigation. Forward and backward ultrafiltration experiments were performed separately with aqueous vitamin B12 (MW 1355), α-chymotrypsin (MW 25,000), albumin (MW 66,000) and dextran solutions, introducing the test solution inside or outside the hollow fiber (HF), respectively. Sieving coefficients (s.c.) for these solutes were measured under the test solution flow rate of 200 mL/min and the ultrafiltration rate of 10 mL/min at 310 K, according to the guidelines provided by Japanese academic societies. We defined the ratio of s.c. in the backward ultrafiltration to that in the forward ultrafiltration and termed it the index for asymmetricity (IA). The IA values were unity for vitamin B12 and α-chymotrypsin in all three of the dialyzers. The IA values for albumin, however, were 1.0 in CTA, 1.9 in ATA®, and 3.9 in PES membranes, respectively, which corresponded well with the fact that CTA is homogeneous, whereas ATA® and PES are asymmetrical in structure. Moreover, the asymmetricity of ATA® and PES may be different by twofold. This fact was verified in continuous basis by employing dextran solution before and after being fouled with albumin. These findings may contribute to the development of a novel membrane for improved success of dialysis therapy.

Comparison of Blood Compatibility in Various Membrane Materials for Continuous Renal Replacement Therapy.

Because hemofilters used for continuous renal replacement therapy contact with blood over a prolonged period during treatments, platelet activation may occur stronger. The purpose of this study is to clarify the blood compatibility in three hemofilters mostly used in Japan. We compared the blood compatibility of the two polysulfone (AEF: Asahi Kasei Medical Co., Tokyo, Japan and SHG: Toray Medical Co., Ltd., Tokyo, Japan) and one polymethylmethacrylate membranes (CH: Toray Medical Co., Ltd.). First, test blood was collected from healthy volunteers. Subsequently, the blood was circulated by a roller pump at the rate of 100 mL/min. We measured the platelet counts and platelet factor 4 (PF4). The platelet counts at 48 h in polymethylmethacrylate membrane were significantly less than that in polysulfone membranes. Levels of the PF4 after the circulation were 978.5 ± 200.0 ng/dL with AEF, 863.0 ± 233.9 ng/dL with SHG and 1780.0 ± 465.1 ng/dL with CH, respectively. Hemofilters with polysulfone membranes showed less platelet activation. It was inferred that the amount of PVP, the smoothness of the membrane surface, and the inner diameter of the hollow fiber affect the blood compatibility in the hemofilter.

Importance of membrane materials for blood purification devices in critical care.

Choosing dialyzers is more important in blood purification in critical care because therapeutic conditions (especially the amount of dialysate) are usually limited. Then, adsorption is the third major mechanism of removing toxic substances from patients in these treatments. Several commercial dialyzers designed for acute blood purification therapy were investigated by performing aqueous ultrafiltration experiments to demonstrate the importance of the membrane materials. Polymethylmethacrylate (PMMA) showed strong adsorptive characteristics to alpha-chymotripsinogen A (MW 25,000) but showed much less adsorptive characteristics to cytochrome C (MW 12,400). On the contrary, polyacrylonitrile (PAN) showed relatively lower affinity and polysulfone (PS) showed essentially no affinity to these proteins. Time and concentration dependent characteristics of clearance for these solutes were also demonstrated in PMMA. These facts were also verified in other dialyzers with another PMMA and polyester polymer alloy (PEPA) designed for chronic hemodialysis, which concluded that adsorption found in PMMA may be due to the occlusion of protein molecules into pores of the membrane. Choosing membrane materials is, therefore, important not only in removing inflammatory cytokines but also considering the loss of albumin in acute and chronic treatments.

Central online hemodiafiltration in Japan: management of water quality and practice.

Hemodiafiltration (HDF) includes a variety of technologies and preparation of ultrapure dialysis fluid has made it possible to perform online HDF and its extensive alternatives. According to current statistics, 5.8% of ESRD patients are treated with HDF in Japan. The majority of these HDF treatments are performed using the central dialysis fluid delivery system (CDDS), this is because most Japanese clinicians and researchers consider that with CDDS it is easier to prepare substitution fluid; moreover, CDDS has economical advantages against single-patient dialysis machine (SPDM)-based counterparts. The water quality at each patient station (dialysis console) is regularly validated by bacterial culture (colony-forming units) and by measuring endotoxin concentration (ET). Since ET measurement takes much less time than bacterial culture, ET is often used as an indicator to verify the water quality for online use. Dialysis fluid with ET below the detection level (usually <0.001 EU/ml) is used for online substitution. In CDDS online HDF, since dialysis clinics must prepare not only the dialysis fluid but also the substitution fluid, they need to satisfy almost the same requirements as pharmaceutical water treatment factories do. The Japanese Society for Dialysis Therapy (JSDT) together with the Japanese Society for Hemodiafiltration (JS-HDF) is now preparing guidelines to meet all these necessary requirements on a worldwide basis.

Amount of adsorbed albumin loss by dialysis membranes with protein adsorption.

Polymethylmethacrylate (PMMA) membrane is the first synthetic polymeric hollow fiber used in dialyzers that is known to adsorb beta(2)-microglobulin. Polyester polymer alloy (PEPA), a blend of two polymers, i.e., polyarylate and polyethersulfone, is another dialysis membrane material with adsorption characteristics. In this study, the adsorption and permeation characteristics of BG-1.6PQ (PMMA) and FLX-15GW (PEPA) dialyzers were investigated by performing ultrafiltration experiments using chymotrypsinogen (molecular weight 25,000) and albumin (molecular weight 66,000) as test solutes. Although PMMA and PEPA had the same sieving coefficient for chymotrypsinogen at steady state, PMMA showed approximately 20% higher fractional adsorption than PEPA under the same initial concentrations. The fractional adsorption for albumin was approximately 20% in PEPA regardless of the ultrafiltration flow rate. The fractional adsorption for albumin in PMMA, however, increased as the ultrafiltration flow rate increased and reached 50%-60% after 10 h. Since PEPA has two skins, one inside and one outside the hollow fiber, proteins may have been adsorbed mainly by these two layers. However, since PMMA is a uniform membrane and since the higher the ultrafiltration flow rate, the higher the fractional adsorption found in PMMA, adsorption may be the result of the occlusion of the dense structure of the membrane. The amount of albumin loss is often clinically evaluated by measuring the amount of permeated albumin in the dialysate. However, when dialyzers with adsorption characteristics are examined, the loss by adsorption should also be taken into account.

Quantification of peritoneal transport.

Kinetic models have been used in both hemodialysis (HD) and peritoneal dialysis (PD) therapies. Because many different theoretical models are available, users should choose a model that suits the purpose of their studies. In general, simple models are useful for clinical investigations and research; rigorous models may be available with the use of computers. Several commercial software packages with rigorous models specifically designed for PD are also useful for analyzing patient data and for constructing prescriptions. Although the overall mass transfer area coefficient (MTAC) is a parameter for diffusion transport, it may become a useful tool for predicting peritoneal ultrafiltration by defining a new "index for peritoneal diffusive selectivity" (IPDS), the ratio of the MTACs for urea and creatinine. Kinetic models are especially useful in treatments with relatively complex prescriptions such as combined PD and HD ("complementary") therapy, sample calculations of which are discussed.

Influence of blood corpuscles on the ultrafiltration of various proteins.

The ultrafiltration characteristics of a commercial dialyzer were examined by measuring the sieving coefficient (s.c.) for three proteins, i.e., cytochrome c, chymotrypsinogen, and albumin, in a bovine blood system. Test blood was passed through a filter at a blood flow rate of 200 ml/min and filtrate was collected at an ultrafiltration flow rate of 10 ml/min from a port located near the blood inlet. The s.c. for cytochrome c and chymotrypsinogen in bovine blood sharply increased at the beginning of the experiment and reached a steady value that was about 60% of that obtained in an aqueous solution system. This may have been caused by the masking effect of the erythrocytes. The s.c. for albumin at steady state in bovine blood that contained added albumin only was almost the same as that obtained in the aqueous solution system. When all three proteins were added to bovine blood, however, the s.c. for albumin showed a steady value (after a slight decrease at the beginning of the experiment) the absolute value of which was higher than that found in the aqueous solution system. This phenomenon may have been caused by the stirring effect of erythrocytes that would disturb the concentration polarization of albumin formed near the membrane.