High-performance dialyzers and mortality in maintenance hemodialysis patients.

Few data are available regarding the association of dialyzer type with prognosis. In Japan, dialyzers are classified as types I, II, III, IV, and V based on ß2-microglobulin clearance rates of < 10, < 30, < 50, < 70, and ≥ 70 mL/min, respectively. We investigated the relationship of the 5 dialyzer types with 1-year mortality. This nationwide cohort study used data collected at the end of 2008 and 2009 by the Japanese Society for Dialysis Therapy Renal Data Registry. We enrolled 203,008 patients on maintenance hemodialysis who underwent hemodialysis for at least 1 year and were managed with any of the 5 dialyzer types. To evaluate the association of dialyzer type with 1-year all-cause mortality, Cox proportional hazards models and propensity score-matched analyses were performed. After adjustment of the data with clinicodemographic factors, the type I, II, and III groups showed significantly higher hazard ratios (HRs) than the type IV dialyzers (reference). After adjustment for Kt/V and ß2-microglobulin levels, the HRs were significantly higher in the type I and II groups. After further adjustment for nutrition- and inflammation-related factors, the HRs were not significantly different between the type IV and type I and II groups. However, type V dialyzers consistently showed a significantly lower HR. With propensity score matching, the HR for the type V dialyzer group was significantly lower than that for the type IV dialyzer group. Additional long-term trials are required to determine whether type V dialyzers, which are high-performance dialyzers, can improve prognosis.

Glycated albumin and hemoglobin A1c levels and cause-specific mortality by patients' conditions among hemodialysis patients with diabetes: a 3-year nationwide cohort study.

INTRODUCTION: Differences in mortality and cause-specific mortality rates according to glycated albumin (GA) and hemoglobin A1c (HbA1c) levels among dialysis patients with diabetes based on hypoglycemic agent use and malnutrition status remain unclear. Here, we examine these associations using a nationwide cohort. RESEARCH DESIGN AND METHODS: We examined 40 417 dialysis patients with diabetes who met our inclusion criteria (female, 30.8%; mean age, 67.3±11.2 years; mean dialysis duration, 5.4±4.6 years). The Global Leadership Initiative on Malnutrition criteria were used to assess malnutrition. Adjusted HRs and 95% confidence limits were calculated for 3-year mortality after adjustment for 18 potential confounders. HRs and subdistribution HRs were used to explore cause-specific mortality. RESULTS: We found a linear association between 3-year mortality and GA levels only in patients with GA ≥18% and not in patients with low GA levels, with a U-shaped association between HbA1c levels and the lowest morality at an HbA1c 6.0%-6.3%. This association differed based on patient conditions and hypoglycemic agent use. If patients using hypoglycemic agents were malnourished, mortality was increased with GA ≥24% and HbA1c ≥8%. In addition, patients with GA ≥22% and HbA1c ≥7.6% had significantly higher infectious or cardiovascular mortality rates. On the other hand, an inverse association was found between GA or HbA1c levels and cancer mortality. Patients with GA ≤15.8% had a higher risk of cancer mortality, especially those not using hypoglycemic agents (HR 1.63 (1.00-2.66)). CONCLUSIONS: Target GA and HbA1c levels in dialysis patients may differ according to hypoglycemic agent use, nutritional status, and the presence of cancer. The levels may be higher in malnourished patients than in other patients, and a very low GA level in dialysis patients not taking hypoglycemic agents may be associated with a risk of cancer. TRIAL REGISTRATION NUMBER: UMIN000018641.

Seasonal variations in cause-specific mortality and transition to renal replacement therapy among patients with end-stage renal disease.

Despite some studies showing seasonal variations in mortality and the transition to renal replacement therapy in patients with end-stage renal disease, detailed evidence is still scarce. We investigated seasonal variations in patients with end-stage renal disease using a large Japanese database for dialysis patients. We compared the fractions of all-cause and cause-specific mortality and the transition to renal replacement therapy among seasons and performed a mixed-effects Poisson regression analysis to compare the mortality among seasons after adjustment for some variables. The initiation of hemodialysis was highest in winter and lowest in summer. Seasonality in the initiation of peritoneal dialysis and transition to kidney transplantation differed from hemodialysis. All-cause mortality was highest in the winter and lowest in the summer. Death from coronary artery disease, heart failure, cerebral hemorrhage, and infectious pneumonia had similar seasonality, but death from cerebral infarction, septicemia, or malignant tumor did not have similar seasonality. In conclusion, the initiation of hemodialysis, all-cause mortality, and mortality from coronary heart disease, heart failure, cerebral hemorrhage, and infectious pneumonia were significantly highest in winter and lowest in summer. However, the initiation of peritoneal dialysis, transition to kidney transplantation, or mortality from cerebral infarction, septicemia, or malignant tumor did not have similar seasonal variations.

Long-Term Safety and Efficacy of JR-131, a Biosimilar of Darbepoetin Alfa, in Japanese Patients With Renal Anemia Undergoing Hemodialysis: Phase 3 Prospective Study.

The objective of this study was to evaluate the safety and efficacy of JR-131, a biosimilar of darbepoetin alfa, for long-term treatment of renal anemia patients undergoing hemodialysis. In this multicenter, single-arm, phase 3 study, 159 patients with renal anemia who had been receiving darbepoetin alfa or recombinant human erythropoietins were treated with intravenous JR-131 for 52 weeks. In patients receiving darbepoetin alfa, JR-131 was administered at the same dose, while in patients receiving recombinant human erythropoietin the dose was determined based on the 1:200 conversion ratio following the Japanese darbepoetin alfa package insert. No notable adverse drug reactions were reported, and no anti-JR-131 antibodies were detected. The hemoglobin levels were maintained in the range of 10.0-12.0 g/dL throughout the study. JR-131 proved to be a useful and lower-cost alternative to darbepoetin alfa in the management of renal anemia in patients undergoing hemodialysis.

JR-131, a Biosimilar of Darbepoetin Alfa, for the Treatment of Hemodialysis Patients With Renal Anemia: A Randomized, Double-Blinded, Parallel-Group Phase 3 Study.

The aim of this study was to compare the efficacy and safety of intravenous JR-131, a darbepoetin alfa biosimilar, to darbepoetin alfa in hemodialysis patients with renal anemia. In this 24-week, multicenter, randomized, double-blinded, parallel-group phase 3 study, 334 hemodialysis patients with renal anemia who had been receiving darbepoetin alfa were randomized to either JR-131 or darbepoetin alfa group. The initial dose was set based on the darbepoetin alfa dose during the observation period. The primary endpoint was change in hemoglobin level from baseline to end of treatment. The 95% confidence interval of the difference in the change in hemoglobin level between the groups was -0.19 to -0.20 g/dL, within the equivalent margin of -0.5 to 0.5 g/dL. No notable treatment-emergent adverse events were observed in either group. JR-131 was therapeutically equivalent to darbepoetin alfa, and the safety profile of JR-131 was similar to that of darbepoetin alfa.

Types of Erythropoietin-Stimulating Agents and Mortality among Patients Undergoing Hemodialysis.

BACKGROUND: Despite the widespread use of erythropoietin-stimulating agents (ESAs) to treat anemia in patients undergoing hemodialysis, the relative mortality risks associated with use of different types of ESAs are unknown. METHODS: To compare the mortality risk associated with use of short-acting ESAs versus long-acting ESAs, we conducted a nationwide cohort study of 194,698 hemodialysis patients in Japan who received either a short-acting (epoetin α/ß or epoetin κ) or a long-acting (darbepoetin or epoetin ß pegol) ESA. Study outcomes were 2-year all-cause and cause-specific mortality. In addition to Cox proportional hazards models, we performed an instrumental variable analysis in which facility-level long-acting ESA prescription rates were taken as the instrumental variable. RESULTS: During the 2-year follow-up period, 31,557 deaths occurred. In a multivariable Cox model, long-acting ESA users had a 13% higher rate of deaths compared with short-acting ESA users, a significant difference (P<0.001). Similar results were obtained in other analyses. This difference in risk was pronounced among patients receiving high doses of ESA (for whom the adjusted 2-year number needed to harm for death was 30.8). Long-acting ESA use was associated with an increased rate of death from cardiovascular diseases, infection, and malignancies. In the instrumental variable analysis, long-acting ESA users remained at a significantly higher risk of death. Compared with anemic (hemoglobin 9.0-9.9 g/dl) short-acting ESA users, long-acting ESA users who achieved more optimal hemoglobin levels (10.0-10.9 g/dl) showed a higher mortality rate. CONCLUSIONS: Among patients undergoing hemodialysis, use of long-acting ESAs might be associated with a higher risk of death than use of short-acting ESAs.

Functional impairment attenuates the association between high serum phosphate and mortality in dialysis patients: a nationwide cohort study.

BACKGROUND: Both functional impairment and abnormalities in mineral and bone disorder (MBD) parameters are well-known predictors of mortality in dialysis patients. However, previous studies have not evaluated whether functional impairment modifies the association between MBD parameters and mortality. METHODS: A nationwide prospective cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry collected at the end of 2009 and 2010. The Eastern Cooperative Oncology Group performance status (PS) was used to assess functional status. Cox proportional hazards models were used to assess the associations of baseline functional status, serum phosphate, albumin-corrected calcium and intact parathyroid hormone (PTH) with 1-year all-cause mortality. RESULTS: By 31 December 2010, 18 447 of 220 054 prevalent dialysis patients (8.4%) had died. Mortality significantly increased with worsening PS grade. PS grade modified the association of serum phosphate levels with mortality (Pinteraction = 0.001). Worsening PS grade attenuated the association of hyperphosphatemia (≥7.4 mg/dL) with mortality, and hyperphosphatemia was no longer significant on mortality among patients with the worst PS grade (hazard ratio = 1.1, 95% confidence interval 0.88-1.39), compared with the level between 3.5 and 4.7 mg/dL. In contrast, hypophosphatemia (<3.5 mg/dL) had a greater adjusted risk of mortality irrespective of PS grade. Serum-corrected calcium (Pinteraction = 0.26) and intact PTH (Pinteraction = 0.17) showed consistent associations with mortality irrespective of PS grade. Findings were robust in several sensitivity analyses. CONCLUSIONS: Functional impairment was significantly associated with 1-year mortality and attenuated the effect of hyperphosphatemia on mortality among prevalent dialysis patients.

Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Glycated albumin versus hemoglobin A1c and mortality in diabetic hemodialysis patients: a cohort study.

Background: For glycemic control in diabetic patients on dialysis it was unclear what level of glycated albumin (GA) was associated with the lowest mortality and GA's utility. Accordingly, we examined the difference in association between GA and hemoglobin A1c (HbA1c) with 1-year mortality in a cohort of the Japanese Society for Dialysis Therapy. Methods: We examined 84 282 patients with prevalent diabetes who were on maintenance hemodialysis (HD) (female 30.3%; mean age 67.3 ± 11.2 years; mean dialysis vintage 6.4 ± 4.5 years). Of them, 22 441 had both GA and HbA1c. We followed these for a year, 2013-14, using Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence limits for 1-year mortality after adjusting for potential confounders such as baseline age, sex, smoking and diabetes type. Results: One-year mortality was lowest in diabetic HD patients who had GA levels of 15.6-18.2% and HbA1c levels of 5.8-6.3%. The associations were linear or J-shaped for GA and U-shaped for HbA1c. Adjusted HRs were significantly higher in patients with GA <12.5% and GA ≥22.9%. This trend flattened in elderly patients, those with higher hemoglobin or those with prior cardiovascular disease. In addition, the C-statistics, Harrell's C and category-free net reclassification improvement to predict 1-year mortality were better when GA was added to the model than when HbA1c was added. Conclusions: There was a linear or J-shaped association between GA and 1-year mortality, with the lowest mortality at GA 15.6-18.2%. Furthermore, our analyses suggest the potential superiority of GA over HbA1c in predicting mortality.

Significance of the decreased risk of dialysis-related amyloidosis now proven by results from Japanese nationwide surveys in 1998 and 2010.

BACKGROUND: Although dialysis technology greatly improved in recent years, it remained unclear whether those improvements helped decrease the incidence of dialysis-related amyloidosis (DRA). Accordingly, we retrospectively compared the incidence of first-time carpal tunnel surgery (CTS)-as proxy for DRA onset-in two cohorts of chronic hemodialysis patients, with the second cohort studied after dialysis methods (especially dialyzate quality control) had greatly improved. METHODS: We used the 1998 and 2010 Japan Renal Data Registries to compare crude risk of first-time CTS the following year. After adjusting for patient background and laboratory data, odds ratios (ORs) for CTS in the whole cohorts and the populations matched by propensity score (PS) for hemodialysis and hemodiafiltration were calculated at a 95% confidence interval. RESULTS: Of note, 2 02 726 patients were analyzed. In the 1998 cohort, 1.77% experienced first-time CTS compared with 1.30% of the 2010 cohort (P < 0.001); with 2010 as referent, the adjusted 1998 OR was 2.22 (1.68-2.95). Both crude risks and adjusted ORs were analyzed by dialysis vintage, age, pre-dialysis ß2-microglobulin (ß2m) and ß2m clearance, risk of CTS trending 1.5-2.0 higher in 1998 than 2010. The reduction was most prominent in patients with longer dialysis vintage, patients who were younger, and those with lower pre-dialysis ß2m levels. Similar results were obtained by PS-matched analysis. We also found that ß2m clearance >80% may reduce risk of CTS. CONCLUSIONS: The incidence of first-time CTS as proxy for DRA decreased significantly from 1998 to 2010. Several factors may have contributed to this decrease, including improved dialysis methods.

A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy.

The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

Carpal tunnel surgery as proxy for dialysis-related amyloidosis: results from the Japanese society for dialysis therapy.

BACKGROUND/AIMS: This study aims to identify current risk factors for developing dialysis-related amyloidosis using carpal tunnel syndrome (CTS) as proxy for general amyloidosis. METHODS: The cohort consisted of 166,237 patients on dialysis (mean age 66.1 ± 12.4 years; mean dialysis vintage 7.2 ± 6.4 years) who could be followed for a year between 2010 and 2011. Of these, 2,157 (1.30%) needed first-time CTS surgery during the study period. Odds ratios (ORs) for CTS were calculated at a 95% confidence interval (95% CI) after adjusting for age, gender, primary kidney disease, history of smoking, history of hypertension vintage, dialysis modality, use of high-flux membrane, body mass index, serum albumin, Kt/V, normalized protein catabolic rate, C-reactive protein, pretreatment ß2-microglobulin (ß2MG), and ß2MG clearance. RESULTS: Adjusted ORs of first-time CTS for vintages 10-15, 15-20, 20-25 (referent), 25-30, and >30 years were, respectively, 0.18 (0.12-0.26), 0.43 (0.31-0.62), 1.00, 2.37 (1.64-3.40), and 3.87 (2.52-5.93). Adjusted ORs for ages 40-50, 50-60 (referent), 60-70, 70-80, and >80 were 0.53 (0.30-0.94), 1.00, 1.89 (1.41-2.52), 1.52 (1.08-2.14), and 1.04 (0.60-1.80). Female gender, low serum albumin, and diabetic nephropathy were also associated with CTS. Pretreatment serum ß2MG and ß2MG clearance <80% were not significant, although ß2MG clearance >80% was negatively associated with CTS [OR 0.34 (0.13-0.90)]. CONCLUSION: ORs of first-time CTS almost doubled with every 5-year increase in dialysis vintage. ORs of CTS were highest for patients aged 60-70. Other factors associated with CTS were gender, serum albumin, and diabetic nephropathy. ß2MG clearance >80% may decrease the incidence of CTS.

Survey of the effects of a column for adsorption of ß2-microglobulin in patients with dialysis-related amyloidosis in Japan.

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of ß2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of ß2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients.

An overview of regular dialysis treatment in Japan (as of 31 December 2010).

A nationwide statistical survey of 4226 dialysis facilities was conducted at the end of 2010, and 4166 facilities (98.6%) responded. The number of new patients introduced into dialysis was 37,512 in 2010. This number has decreased for two consecutive years since it peaked in 2008. The number of patients who died in 2010 was 28,882, which has been increasing every year. The number of patients undergoing dialysis at the end of 2010 was 298,252, which is an increase of 7591 (2.6%) compared with that at the end of 2009. The number of dialysis patients per million at the end of 2010 was 2329.1. The crude death rate of dialysis patients in 2010 was 9.8%, and has been gradually increasing. The mean age of the new patients introduced into dialysis was 67.8 years and the mean age of the entire dialysis patient population was 66.2 years. Regarding the primary disease of the new patients introduced into dialysis, the percentage of patients with diabetic nephropathy was 43.6%, which is a slight decrease from that in the previous year (44.5%). Patients with diabetic nephropathy as the primary disease accounted for 35.9% of the entire dialysis patient population, which approaches the percentage of patients with chronic glomerulonephritis as the primary disease (36.2%). The percentage of patients who had undergone carpal tunnel release surgery (CTx) was 4.3%, which is a slight decrease from that at the end of 1999 (5.5%). The decrease in the percentage of patients who had undergone CTx was significant among the patients with dialysis durations of 20-24 years (1999, 48.0%; 2010, 23.2%). A total weekly Kt/V attributable to peritoneal dialysis and their residual functional kidney was 1.7 or higher for 59.4% of patients who underwent peritoneal dialysis.

Choice of modality with the use of high-performance membrane and evaluation for clinical effects.

The golden target for dialysis therapy should be to guarantee longer survival and to give a higher quality of life without dialysis-related complications. In order to achieve this target, the choice of dialysis modality and membrane is essential but we have not yet established what the best choice for a dialysis modality and membrane are. Generally, we choose a dialysis modality for better solute removal and better biocompatibility. In this issue we would like to propose that the patients' preference for dialysis therapy is a useful parameter in prescribing the dialysis modality. In our recent experience, chronic dialysis patients have had preferences on a dialysis modality and membrane, those being PMMA, EVAL, AN-69 and pre-dilution online HDF. These modalities could relieve them of uncomfortable dialysis-related symptoms such as insomnia, itchiness, irritability, and so on. Other characteristics of these modalities are of a nutritional advantage, a broad removal pattern of uremic toxins including low-molecular-weight protein and protein-bound uremic toxins, and good biocompatibility free from chemical components of dialysis membrane. In conclusion, patients' symptoms could be a useful parameter to choose a dialysis modality and membrane.

Review: Clinical usefulness of ultrapure dialysate--recent evidence and perspectives.

It has generally been accepted that biological contamination of dialysate deteriorates the biocompatibility of dialysis therapy and accelerates dialysis-related complications such as dialysis-related amyloidosis (DRA) and malnutrition-inflammation-atherosclerosis (MIA) syndrome. During the past decade several studies have clarified that very slight amounts of contamination can lead to inflammatory response, and we could not confirm biological dialysate quality only by measuring endotoxin levels despite of measuring viable cell counts or biofilms. To achieve this, the European Renal Association/European Dialysis Transplantation Association and the American National Standardization Institute/Association for the Advancement of Medical Instrumentation published new standards for dialysate, in which very strict control levels were recommended with regard to viable bacterial cell counts. In 2004 JSDT raised the required standard of the levels of endotoxin, and began to develop a standard for bacterial cell counts. In Japan, many chronic kidney disease patients are treated with centralized dialysate supply systems which have weak spots in disinfecting the system. This causes some difficulties in making a standard for viable bacterial cell counts. In the present paper, we summarize evidences of clinical usefulness of ultrapure dialysate and perspectives of the standard for dialysate in Japan.