Removal of α1-Microglobulin Using Post-Dilution Online Hemodiafiltration with Polymethylmethacrylate Membrane: An Open-Label, Single-Arm Study.

INTRODUCTION: The removal of low- and medium-molecular-weight proteins has been improved with online hemodiafiltration (OL-HDF) and hemodialysis using high-flux membranes; however, the outcomes of patients with end-stage kidney disease (ESKD) undergoing dialysis treatment are still worse than in the general population. α1-Microglobulin (α1-m), with a molecular weight of 33,000 Da, may contribute to dialysis-related disorders and mortality. However, the removal is insufficient even with current OL-HDF using the polysulfone (PS) membrane, which is common in Japan. Polymethylmethacrylate (PMMA) membranes can remove medium- to high-molecular-weight proteins by adsorption. This study aimed to assess the efficacy of removing medium- to high-molecular-weight proteins, such as α1-m and ß2-microglobulin (ß2-m), through post-dilution OL-HDF with PMMA (Post-PMMA). The assessment was conducted in comparison to pre-dilution OL-HDF with PS (Pre-PS), using an open-label, single-arm study. METHODS: Seven patients with ESKD on Pre-PS underwent Post-PMMA with replacement volume of 30 mL/min (low flow) and 50 mL/min (high flow). Clearance and removal rates of α1-m, ß2-m, small molecules, inflammatory cytokines, and albumin were measured at 60 and 240 min of treatment. RESULTS: Clearance rates of α1-m at 60 min were -2.8 ± 5.2 mL/min with Pre-PS, -0.4 ± 2.6 mL/min with Post-PMMA (low), and 0.6 ± 3.4 mL/min with Post-PMMA (high). The removal rate of α1-m was higher in Post-PMMA than that in Pre-HDF-PS (Post-PMMA [high] 17.7 ± 5.9%, Post-PMMA [low] 15.0 ± 5.6%, and Pre-PS 4.1 ± 5.5%). Adsorption clearance of ß2-m was increased with Post-PMMA. Albumin leakage in Post-PMMA was not higher than that in Pre-PS. CONCLUSION: The removal rate of α1-m with Post-PMMA was higher than that with Pre-PS. The PMMA membrane adsorbed ß2-m, suggesting the removal effect of medium- to high-molecular-weight proteins by the adsorption method. Since Post-PMMA effectively removes α1-m without excessive albumin leakage, it will be useful for patients with ESKD, especially those with a poor nutritional status.

The Association between Earlobe Creases and Cardiovascular Events in Japanese Hemodialysis Patients: A Prospective Cohort Study.

Objective The earlobe crease, a wrinkle extending from the tragus to the outer border of the earlobe, is a well-known surrogate marker for a high risk of cardiovascular disease. However, information is lacking about its association with cardiovascular events among hemodialysis patients, who already have an increased risk of cardiovascular disease. We tested the hypothesis that earlobe creases are independently associated with the risk of cardiovascular events among Japanese hemodialysis patients. Methods This prospective cohort study followed 247 adult hemodialysis patients with no history of cardiovascular disease for 4 years. The presence of earlobe creases was defined by two researchers using photos of patients' earlobes on both sides while blinded to one another's assessments and clinical data. The primary outcome was defined as the first fatal or nonfatal cardiovascular event (myocardial infarction, ischemic or hemorrhagic stroke, or peripheral vascular disease requiring aortic or peripheral vascular bypass surgery or below- or above-the-knee amputation). A Fine-Gray competing risks regression model was used to examine the association between earlobe creases and cardiovascular events. Results During the 4-year follow-up period, 43 patients suffered cardiovascular events. After the competing risk of non-cardiovascular death was accounted for, patients with earlobe creases had an increased cumulative incidence of cardiovascular events compared to those without earlobe creases (subhazard ratio =2.04, 95% confidence interval: 1.09 to 3.82). This association was no longer significant after adjusting for age. Conclusion Earlobe creases were not independently associated with cardiovascular events among Japanese hemodialysis patients, suggesting that these marks are simply indicative of advanced age.

Prevention of Intradialytic Hypotension with Intermittent Back-Filtrate Infusion Haemodiafiltration: Insights into the Underlying Mechanism.

BACKGROUND: Intradialytic hypotension (IDH) is a major challenge to safely performing haemodialysis. Blood volume depletion due to fluid removal is a major cause of hypotension, so more emphasis should be placed on finding alternative modalities to traditional constant rate ultrafiltration. SUMMARY: Intermittent back-filtrate infusion haemodiafiltration (I-HDF) utilises purified online quality dialysate with an automated dialysis machine. A bolus of 200 mL of dialysate is repetitively infused at 30-min intervals. A pilot study with 68 hypotension-prone patients revealed that I-HDF can reduce the frequency of IDH interventions, particularly in elderly patients and patients with large interdialytic weight gain (IDWG). This was typically accompanied by an increase in intradialytic blood pressure and decreased tachycardia in the latter half of the session, suggesting reduced sympathetic stimulation during I-HDF. Protective mechanisms involved in the pathophysiology of IDH could be explained in part by the findings obtained in this pilot study. Intermittent increases in blood pressure during I-HDF may prevent venous pooling (i.e., the DeJager-Krogh phenomenon), and reduced sympathetic stimulation may maintain a physiological state less likely to induce the cardio-vagal reflex (i.e., the Bezold-Jarisch reflex). The plasma refilling rate (PRR), evaluated as the refilling fraction (RF), is unexpectedly smaller in I-HDF. However, in patients who respond, the RF is well achieved, which suggests that adequate PRR is the central physiology for preventing IDH. Patients for whom I-HDF is effective are characteristically relatively elderly and show increased IDWG. Blood pressure increment and reduced sympathetic activation in I-HDF may be a mechanism for prevention of IDH. Key Messages: Evaluating relative changes in blood volume during I-HDF will provide a new perspective for exploring appropriate ultrafiltration modification that circumvents IDH.

Prevalence of Earlobe Creases and Their Association With History of Cardiovascular Disease in Patients Undergoing Hemodialysis: A Cross-Sectional Study.

Earlobe creases are surrogate markers for high risk of cardiovascular disease. There is no data concerning earlobe creases among hemodialysis patients, who have an increased risk of cardiovascular disease. A cross-sectional study was conducted to determine the prevalence of earlobe creases and their association with prevalent cardiovascular disease among hemodialysis patients. Patients undergoing hemodialysis were recruited from five outpatient hemodialysis centers. Both earlobes were photographed during a dialysis session with the patient in a supine position and the photos evaluated independently by two experienced nephrologists blinded to the participants' clinical characteristics. Prevalent cardiovascular diseases were defined as a history of myocardial infarction, cerebrovascular accident, or peripheral vascular disease. Sensitivity, specificity, and positive and negative predictive values for detection of prevalent cardiovascular disease were calculated. Logistic analysis was used to examine the association between earlobe creases and prevalent cardiovascular disease. Earlobe creases were identified in 24.5% of 330 hemodialysis patients (200 men; mean age, 67.8 years). The prevalence of earlobe creases increased with age for men (P for trend <0.0001), but not for women (P for trend = 0.07). Sensitivity, specificity, and positive and negative predictive values were 30.9% (95% confidence interval, 21.9-41.6), 77.5% (71.9-82.3), 30.9% (21.9-41.6), and 77.5% (71.9-82.3), respectively. Multivariate logistic analyses indicated the prevalence of earlobe crease was not associated with prevalent cardiovascular diseases. The prevalence is similar to that previously reported for Japanese individuals not undergoing dialysis. No association between earlobe creases and prevalent cardiovascular diseases was identified.

Feasibility of intermittent back-filtrate infusion hemodiafiltration to reduce intradialytic hypotension in patients with cardiovascular instability: a pilot study.

BACKGROUND: Intradialytic hypotension (IDH) is one of the major problems in performing safe hemodialysis (HD). As blood volume depletion by fluid removal is a major cause of hypotension, careful regulation of blood volume change is fundamental. This study examined the effect of intermittent back-filtrate infusion hemodiafiltration (I-HDF), which modifies infusion and ultrafiltration pattern. METHODS: Purified on-line quality dialysate was intermittently infused by back filtration through the dialysis membrane with a programmed dialysis machine. A bolus of 200 ml of dialysate was infused at 30 min intervals. The volume infused was offset by increasing the fluid removal over the next 30 min by an equivalent amount. Seventy-seven hypotension-prone patients with over 20-mmHg reduction of systolic blood pressure during dialysis or intervention-requirement of more than once a week were included in the crossover study of 4 weeks duration for each modality. In a total of 1632 sessions, the frequency of interventions, the blood pressure, and the pulse rate were documented. RESULTS: During I-HDF, interventions for symptomatic hypotension were reduced significantly from 4.5 to 3.0 (per person-month, median) and intradialytic systolic blood pressure was 4 mmHg higher on average. The heart rate was lower during I-HDF than HD in the later session. Older patients and those with greater interdialytic weight gain responded to I-HDF. CONCLUSIONS: I-HDF could reduce interventions for IDH. It is accompanied with the increased intradialytic blood pressure and the less tachycardia, suggesting less sympathetic stimulation occurs. Thus, I-HDF could be beneficial for some hypotension-prone patients. UMIN REGISTRATION NUMBER: 000013816.

Required water quality for the use of high-performance membranes.

The clinical benefits of high-performance membrane (HPM) dialyzers have often been reported since the advent of the synthetic polyacrylonitrile dialysis membrane. HPMs, which have high water permeability, eliminate a wide spectrum of uremic toxins, and offer excellent biocompatibility, are now essential for hemodialysis, hemofiltration, and hemodiafiltration. For HPMs whose mean pore size is enlarged to secure better dialysis membrane performance, however, the dialyzing fluid must be highly purified to prevent contamination. Blood purification therapies using highly purified dialyzing fluid and HPM are expected to improve the prognosis of future patients undergoing dialysis.

Characteristics of central dialysis fluid delivery system and single patient dialysis machine for HDF.

The central dialysis fluid delivery system (CDDS), with which dialysis fluid is prepared at a single location and sent to each patient station, was developed as a unique system of dialysis in Japan and has been widely used. Maintenance hemodialysis using the single patient dialysis machine (SPDM), with which reverse osmosis water is first sent to each dialysis unit, and the dialysis fluid is prepared and used at each patient station, is used in many areas worldwide other than Japan and some Asian regions. Purification of dialysis fluid is essential for online hemodiafiltration, and it is possible to achieve the target purification level with both CDDS and SPDM by keeping the appropriate procedure. It is therefore desirable to understand the characteristics of both systems and make a selection based on the scale of the facility and the concept of treatment.

Clinical significance of protein adsorbable membranes--long-term clinical effects and analysis using a proteomic technique.

Polymethylmethacrylate (PMMA) membranes were first developed in Japan in 1977. Over its 30-year history, use of PMMA has given rise to a new generation of dialysers and continues to evolve. In long-term observation of patients treated with PMMA membranes (BK series), it has been found that serum beta2-microglobulin is maintained at a significantly lower level than in haemodialysis (HD) patients undergoing treatment with conventional cellulosic membranes. Regarding long-term side effects, radiolucent bone cysts (RBC) and carpal tunnel syndrome (CTS) have developed in relatively few patients undergoing HD with PMMA membranes. The profiles of various proteins in the blood of HD patients differ from those in normal subjects. PMMA membranes remove a wide variety of solutes not only via permeation, but also adsorption. Numerous reports have noted that pruritus can be ameliorated with the use of slightly anionic PMMA membranes (BG series). We have been performing proteomic analysis of plasma from HD patients with pruritus. We have confirmed that slightly anionic PMMA membranes can adsorb components with a molecular weight of 160,000 Da, which have stimulatory effect on mast cells from pruritus.

[Serum calcium levels at first renal replacement therapy and patients survival].

In K/DOQI guideline, albumin adjusted serum calcium concentrations between 8.4 to 9.5 mg/dL and serum phosphorus concentrations between 3.5 to 5.5 mg/dL are recommended. But without clinical symptoms relating to hypocalcemia, medication for increasing serum calcium levels is not needed even less than 8.4 mg/dL. To clarify this guideline, we examined the data of 271 patients who started dialysis at Shinrakuen Hospital, their medication before renal replacement therapy and life prognosis. Medication made higher serum calcium concentrations (p< 0.005) at first renal replacement therapy. Concerning serum calcium concentrations, the lower group (<8.4 mg/dL) showed significantly better prognosis than the middle group (8.4 to 9.5 mg/dL) and the higher group (>9.5 mg/dL) (p< 0.05). When serum calcium levels were adjusted for the level of serum albumin, this tendency was stronger (p< 0.0001). We concluded that although serum calcium concentrations might not need control, nutritional states are far more important before starting dialysis.