Mass spectrometry-based proteomic analysis of proteins adsorbed by hexadecyl-immobilized cellulose bead column for the treatment of dialysis-related amyloidosis.

BACKGROUND: Dialysis-related amyloidosis (DRA) is a severe complication in end-stage kidney disease (ESKD) patients undergoing long-term dialysis treatment, characterized by the deposition of ß2-microglobulin-related amyloids (Aß2M amyloid). To inhibit DRA progression, hexadecyl-immobilized cellulose bead (HICB) columns are employed to adsorb circulating ß2-microglobulin (ß2M). However, it is possible that the HICB also adsorbs other molecules involved in amyloidogenesis. METHODS: We enrolled 14 ESKD patients using HICB columns for DRA treatment; proteins were extracted from HICBs following treatment and identified using liquid chromatography-linked mass spectrometry. We measured the removal rate of these proteins and examined the effect of those molecules on Aß2M amyloid fibril formation in vitro. RESULTS: We identified 200 proteins adsorbed by HICBs. Of these, 21 were also detected in the amyloid deposits in the carpal tunnels of patients with DRA. After passing through the HICB column and hemodialyzer, the serum levels of proteins such as ß2M, lysozyme, angiogenin, complement factor D and matrix Gla protein were reduced. These proteins acted in the Aß2M amyloid fibril formation. CONCLUSIONS: HICBs adsorbed diverse proteins in ESKD patients with DRA, including those detected in amyloid lesions. Direct hemoperfusion utilizing HICBs may play a role in acting Aß2M amyloidogenesis by reducing the amyloid-related proteins.

Difelikefalin for Hemodialysis Patients with Pruritus in Japan.

Difelikefalin for Hemodialysis Patients with PruritusDifelikefalin has been developed for the treatment of pruritus in hemodialysis patients. In this randomized trial of 230 Japanese patients with moderate-to-severe pruritus and undergoing maintenance hemodialysis, difelikefalin (0.5 µg/kg three times per week intravenously for 4 weeks) significantly reduced itching and improved quality of life.

Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis.

Dialysis-related amyloidosis (DRA), a serious complication among long-term hemodialysis patients, is caused by amyloid fibrils of ß2-microglobulin (ß2m). Although high serum ß2m levels and a long dialysis vintage are the primary and secondary risk factors for the onset of DRA, respectively, patients with these do not always develop DRA, indicating that there are additional risk factors. To clarify these unknown factors, we investigate the effects of human sera on ß2m amyloid fibril formation, revealing that sera markedly inhibit amyloid fibril formation. Results from over 100 sera indicate that, although the inhibitory effects of sera deteriorate in long-term dialysis patients, they are ameliorated by maintenance dialysis treatments in the short term. Serum albumin prevents amyloid fibril formation based on macromolecular crowding effects, and decreased serum albumin concentration in dialysis patients is a tertiary risk factor for the onset of DRA. We construct a theoretical model assuming cumulative effects of the three risk factors, suggesting the importance of monitoring temporary and accumulated risks to prevent the development of amyloidosis, which occurs based on supersaturation-limited amyloid fibril formation in a crowded milieu.

Efficacy and Safety of Difelikefalin in Japanese Patients With Moderate to Severe Pruritus Receiving Hemodialysis: A Randomized Clinical Trial.

Importance: Patients with pruritus receiving hemodialysis frequently experience oppressive physical and psychiatric symptoms that directly affect their quality of life and increase mortality. However, treatment options are limited. Objective: To determine the clinically recommended dose of difelikefalin, a κ-opioid receptor agonist, based on the efficacy, dose response, safety, and pharmacokinetics. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, 4-arm phase 2 trial was conducted from February 1, 2019, to October 22, 2019, at 94 sites in Japan. Patients with moderate to severe pruritus receiving hemodialysis were enrolled. Interventions: Difelikefalin (0.25, 0.5, and 1.0 µg/kg) and placebo were intravenously administered 3 times a week at the end of each hemodialysis session for 8 weeks. Main Outcome and Measures: The primary end point was the change from baseline in the weekly mean Worst Itching Intensity Numerical Rating Scale (NRS) score at week 8. Secondary outcomes measured changes in itch-related quality-of-life score using the Skindex-16 and 5-D itch scale. Safety was assessed according to adverse events, laboratory tests, vital signs, body weight, and 12-lead electrocardiogram. Results: A total of 247 Japanese patients (186 male [75%]; mean [SD] age, 64.5 [11.7] years) were randomized to placebo (n = 63), 0.25 µg/kg of difelikefalin (n = 61), 0.5 µg/kg of difelikefalin (n = 61), or 1.0 µg/kg of difelikefalin (n = 62). The changes from baseline in the adjusted mean (SE) of the 24-hour Worst Itching Intensity NRS score at week 8 were -2.86 (0.29) in the placebo group, -2.97 (0.29) in the 0.25 µg/kg of difelikefalin group, -3.65 (0.30) in the 0.5 µg/kg of difelikefalin group, and -3.64 (0.30) in the 1.0 µg/kg of difelikefalin group. Significant differences were found in the 0.5 µg/kg of difelikefalin group (adjusted mean difference, -0.80; 95% CI, -1.55 to -0.04; P = .04) and the 1.0 µg/kg of difelikefalin group (adjusted mean difference, -0.78; 95% CI, -1.54 to -0.03; P = .04) compared with placebo. The Skindex-16 overall score and 5-D itch scale total score indicated an improvement with treatment with 0.5 and 1.0 µg/kg of difelikefalin (adjusted weekly mean [SE] Skindex-16 overall score at week 8, -27.79 [2.05]; 95% CI, -31.83 to -23.74 for 0.5 µg/kg of difelikefalin and -22.69 [2.04]; 95% CI, -26.71 to -18.68 for 1.0 µg/kg of difelikefalin; adjusted weekly mean [SE] 5-D itch scale total score at week 8, -6.5 [0.4]; 95% CI, -7.2 to -5.8 for 0.5 µg/kg of difelikefalin and -6.8 [0.3]; 95% CI, -7.5 to -6.2 for 1.0 µg/kg of difelikefalin). The incidence of adverse events was 67% (42 of 63 patients) in the placebo group, 72% (44 of 61 patients) in the 0.25 µg/kg of difelikefalin group, 77% (47 of 61 patients) in the 0.5 µg/kg of difelikefalin group, and 85% (53 of 62 patients) in the 1.0 µg/kg of difelikefalin group. No dependency was reported. Conclusions and Relevance: The findings of this phase 2 randomized clinical trial of difelikefalin suggest that 0.5 µg/kg of difelikefalin should be the clinically recommended dose as a new option for treating moderate to severe pruritus in patients undergoing hemodialysis because of its efficacy, acceptable tolerability, and manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT03802617.

Adsorption of Protein-Bound Uremic Toxins Using Activated Carbon through Direct Hemoperfusion in vitro.

BACKGROUND/AIMS: Accumulation of protein-bound uremic toxins (PBUTs) is associated with mortality due to various systemic disorders in patients with chronic kidney disease (CKD), especially in those undergoing dialysis treatment. The clinical outcomes of such patients could be improved by removing sufficient amounts of PBUTs; however, conventional dialysis lacks this ability. We examined the efficacy of activated carbon in adsorbing circulating PBUTs through direct hemoperfusion (DHP) in vitro. METHODS: An in vitro blood circulating system was constructed with 8.5 mL blood circulating around a column containing activated carbon (50, 100, or 200 mg). Bovine blood containing a kind of PBUT (at the same concentration as that found in the blood of dialysis patients) and blood from hemodialysis patients (n = 8) were used. After circulation for the designated amount of time, sera were collected and the levels of PBUTs, including indoxyl sulfate (IS), p-cresyl sulfate, indole acetic acid (IAA), phenyl sulfate, and hippuric acid, were analyzed with mass spectrometry. RESULTS: Activated carbon decreased the PBUT level in bovine blood in a dose-dependent manner (e.g., reduction rate of IS: 67.9 ± 3.8, 83.3 ± 1.9, and 94.5 ± 1.1% after 60-min circulation in columns containing 50, 100, and 200 mg activated carbon respectively). IS, PCS, and IAA were dramatically adsorbed by activated carbon from the blood of patients undergoing hemodialysis (pre vs. post 240-min reaction: IS 2.835 ± 0.876 vs. 0.455 ± 0.108 mg/dL [p < 0.01], PCS 3.208 ± 2.876 vs. 0.768 ± 0.632 mg/dL [p < 0.01], IAA 0.082 ± 0.045 vs. 0.016 ± 0.005 mg/dL [p < 0.01]). CONCLUSION: Activated carbon effectively adsorbed blood PBUTs in vitro. DHP with activated carbon could be a promising strategy for removing circulating PBUTs from the blood of patients with CKD.

Indoxyl Sulfate Promotes Macrophage IL-1ß Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated.

In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1ß mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1ß production, which may explain sustained chronic inflammation in CKD patients.

Adsorption of Protein-Bound Uremic Toxins Through Direct Hemoperfusion With Hexadecyl-Immobilized Cellulose Beads in Patients Undergoing Hemodialysis.

An accumulation of protein-bound uremic toxins (PBUTs) is one of major reasons for development of uremia-related complications. We examined the PBUT removal ability of a hexadecyl-immobilized cellulose bead (HICB)-containing column for patients undergoing hemodialysis. Adsorption of indoxyl sulfate (IS), a representative PBUT, to HICBs was examined in vitro. The HICB column was used in patients undergoing hemodialysis for direct hemoperfusion with a regular hemodialyzer. The serum IS, indole acetic acid (IAA), phenyl sulfate (PhS), and p-cresyl sulfate (PCS) levels were measured before and after passing the column. HICBs adsorbed protein-free (free) IS in a dose- and time-dependent manner in vitro (55.4 ± 1.4% adsorption of 1 millimolar, 251 µg/mL, IS for 1 h). In clinical studies, passing the HICB-containing column decreased the serum level of free IS, IAA, PhS, and PCS levels significantly (by 34.4 ± 30.0%, 34.8 ± 25.4%, 28.4 ± 18.0%, and 34.9 ± 22.1%, respectively), but not protein-bound toxins in maintenance hemodialysis patients. HICBs absorbed some amount of free PBUTs, but the clinical trial to use HICB column did not show effect to reduce serum PBUTs level in hemodialysis patients. Adsorption treatment by means of direct hemoperfusion with regular hemodialysis may become an attractive blood purification treatment to increase PBUT removal when more effective materials to adsorb PBUTs selectively will be developed.

Effect of Predialysis Recombinant Human Erythropoietin on Early Survival After Hemodialysis Initiation in Patients With Chronic Kidney Disease: Co-JET Study.

Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open-label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO-treated group (rHuEPO group) and a non-treatment group. The primary endpoint was all-cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non-treatment group). One-year survival was 95.36% in the rHuEPO group and 90.36% in the non-treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42-0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78-0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial.

BACKGROUND: Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 µg/day or 240 µg/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method. RESULTS: Regarding the primary endpoint, statistical superiority of TRK-100STP 240 µg over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 µg, at both doses, and at 240 µg, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated. CONCLUSIONS: Although the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels. TRIAL REGISTRATION: NCT02480751. June 21, 2015.

Depression's influence on the Asthma Control Test, Japanese version.

BACKGROUND: Depression has been linked to poorer asthma control in asthmatic patients. Although the Japanese version of the Asthma Control Test (ACT-J) is frequently used as a simple, practical evaluation tool in clinical care settings in Japan, knowledge regarding its efficacy for assessing asthma control in asthmatic patients with depression is limited. Thus, we retrospectively investigated cut-off values of the ACT-J for well-controlled asthma, and explored depression's influence on the test with a questionnaire survey. METHODS: Data were analyzed on 1,962 adult asthmatic patients who had completed both the ACT-J and the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) in 2008 questionnaire survey conducted by the Niigata Asthma Treatment Study Group. Patients were classified into low (LD: J-PHQ-9 score of 0-4) or high depression (HD: J-PHQ-9 score of 5-27) groups. In both groups, the efficacy of the ACT-J was confirmed. We then compared the optimal cut-off points for uncontrolled asthma in both groups by performing a receiver operating characteristic (ROC) analysis, using the original classification referred to the GINA classification as the "true" classification. RESULTS: Cronbach's alpha in the LD and HD group was 0.808 and 0.740 respectively. In both groups, the sub-group with existence of work absenteeism or frequent attacks during the previous 12 months scored lower on the ACT-J. The area under the curve and optimal cut-off point for patients with LD and HD were 0.821 and 0.846, and 23 and 20 respectively. CONCLUSIONS: The efficacy of the ACT-J was confirmed in depressive patients with asthma. Because asthma control as evaluated with the ACT-J can be worse than actual control under depressive states, physicians should also pay attention to a patient's depressive state at evaluation. Further investigations focus on the association between the ACT-J and depression are required.

Impacts of recombinant human erythropoietin treatment during predialysis periods on the progression of chronic kidney disease in a large-scale cohort study (Co-JET study).

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub-cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability-weighted (IPW) analysis to adjust for time-dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time-dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223-0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53-0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.

Low hemoglobin levels and hypo-responsiveness to erythropoiesis-stimulating agent associated with poor survival in incident Japanese hemodialysis patients.

Although erythropoiesis-stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi-center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10,310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three-year survival rate of patients with <9 g/dL Hb levels after 6 months was 74.1%, which was significantly lower than 89.3% for patients with Hb levels 10 to 11 g/dL; the adjusted hazard ratio (HR) was 2.08 (95% CI, 1.57-2.77; P < 0.0001). Moreover, the 3-year survival rate for poor responders defined by Hb levels <10 g/dL and weekly epoetin beta doses ≥ 9000 IU during the induction phase was 71.6%, which was significantly lower than 89.4% for the group, which had Hb levels 10 to 11 g/dL excluding poor responders and those with excursion; the HR was 1.71 (95% CI, 1.13-2.60; P = 0.0118). Adverse events related to the treatment were reported in 71 of 10,310 patients (0.69%). These findings suggest that the achieved low Hb levels and poor response to ESA therapy are significantly associated with high mortality.

Analysis of the influenza A (H1N1) 2009 pandemic infection in Japanese asthmatic patients: using a questionnaire-based survey.

BACKGROUND: Influenza infection is known to be an exacerbating factor in the control of asthma, therfore its prevention is critical in managing asthma. The aim of this study was to investigate the influenza A H1N1 2009 pandemic virus (H1N1 pdm09) infection in adult asthmatic patients. METHODS: Data were obtained from a questionnaire-based survey of asthmatic patients conducted from September to October 2010 in Niigata Prefecture. Patient background, H1N1 pdm09 infection, vaccination status, and asthma exacerbation due to influenza infection were analyzed. RESULTS: In total, 2,555 cases were analyzed. The incidence of the infection was 6.7% (95% confidence interval [CI]: 5.7-7.6), and the rate of vaccination was 63.9% (95% CI: 62.1-65.8). The odds ratio (OR) for vaccination against the infection among adult patients and younger patients (≤ the median age) were 0.61 (95% CI: 0.45-0.84) and 0.62 (95% CI: 0.42-0.90), respectively. However, OR among the older patient (> median age) were 1.38 (95%CI: 0.66-2.89). The rate of infection-induced asthma exacerbation was 23.2% (95% CI: 18.6-29.6), and the OR for vaccination against the infection-induced asthma exacerbation was 1.42 (95% CI: 0.69-2.92). CONCLUSIONS: The effectiveness of the vaccination against the H1N1 pdm09 virus was confirmed during the first pandemic season, but it was limited. Further investigation on H1N1 pdm09 virus infection in asthmatics will be required.

The Asthma Control Test, Japanese version (ACT-J) as a predictor of Global Initiative for Asthma (GINA) guideline-defined asthma control: analysis of a questionnaire-based survey.

BACKGROUND: The 2006 Global Initiative for Asthma (GINA 2006) guidelines emphasize the importance of evaluating the control rather than the severity of asthma. The Asthma Control Test (ACT) is well known to be an excellent tool for evaluating asthma control in the clinical setting. This study aimed to evaluate the ACT, Japanese version (ACT-J) as a predictor of asthma control as defined by the GINA 2006 guidelines in actual clinical practice. METHODS: A cross-sectional analysis comparing the ACT-J score and GINA classification of asthma control among 419 patients of primary care physicians and specialists was performed using the data from a 2010 questionnaire-based survey conducted by the Niigata Asthma Treatment Study Group. RESULTS: The optimal cut-off point of the ACT-J score for predicting GINA-defined asthma control was 23, with ACT-J scores of ≥23 and ≤22 predicting controlled and uncontrolled asthma with area under the receiver operating characteristics curve values of 0.76 [95% confidence interval (CI): 0.72-0.81] and 0.93 [95% CI: 0.90-0.97], respectively. CONCLUSIONS: ACT scores of ≥23 and ≤22 are useful for identifying patients with controlled and uncontrolled asthma, respectively, as defined by GINA 2006, and the latter is more strongly predictive than the former. The reason for the higher cut-off point of the ACT-J relative to other versions of the ACT is unclear and warrants further investigation.

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.

The Asthma Control Test, Japanese Version (ACT-J) as a Predictor of Global Initiative for Asthma (GINA) Guideline-Defined Asthma Control: Analysis of a Questionnaire-Based Survey.

BACKGROUND: The 2006 Global Initiative for Asthma (GINA 2006) guidelines emphasize the importance of evaluating the control rather than the severity of asthma. The Asthma Control Test (ACT) is well known to be an excellent tool for evaluating asthma control in the clinical setting. This study aimed to evaluate the ACT, Japanese version (ACT-J) as a predictor of asthma control as defined by the GINA 2006 guidelines in actual clinical practice. METHODS: A cross-sectional analysis comparing the ACT-J score and GINA classification of asthma control among 419 patients of primary care physicians and specialists was performed using the data from a 2010 questionnaire-based survey conducted by the Niigata Asthma Treatment Study Group. RESULTS: The optimal cut-off point of the ACT-J score for predicting GINA-defined asthma control was 23, with ACT-J scores of ≥23 and ≤22 predicting controlled and uncontrolled asthma with area under the receiver operating characteristics curve values of 0.76 [95% confidence interval (CI): 0.72-0.81] and 0.93 [95% CI: 0.900.97], respectively. CONCLUSIONS: ACT scores of ≥23 and ≤22 are useful for identifying patients with controlled and uncontrolled asthma, respectively, as defined by GINA 2006, and the latter is more strongly predictive than the former. The reason for the higher cut-off point of the ACT-J relative to other versions of the ACT is unclear and warrants further investigation.

High target hemoglobin with erythropoiesis-stimulating agents has advantages in the renal function of non-dialysis chronic kidney disease patients.

We investigated the long-term effects of maintaining high hemoglobin (Hb) on renal function in patients with chronic kidney disease not on dialysis. Subjects (Hb < 10 g/dL and serum creatinine (Cr) 2-6 mg/dL) were randomized to either a high Hb group (N = 161, 11.0 ≤ Hb < 13.0 g/dL) receiving darbepoetin alfa or to a low Hb group (N = 160, 9.0 ≤ Hb < 11.0 g/dL) with epoetin alfa, stratified according to baseline Hb and serum Cr levels, comorbidity of diabetes, and study centers. Primary endpoints were composites of the following events: doubling of serum Cr, initiation of dialysis, renal transplantation, or death. Three-year cumulative renal survival rates (95% CI) were 39.9% (30.7-49.1%) and 32.4% (24.0-40.8%) in the high and low Hb groups, respectively (log-rank test; P = 0.111). A Cox proportional-hazards model adjusted by age, sex and the randomization factors showed a significantly lower event rate in the high Hb group (P = 0.035). The estimated hazard ratio (95% CI) for the high versus the low Hb group was 0.71 (0.52-0.98), the risk reduction was 29% in the high Hb group. Incidences of serious adverse cardiovascular events did not differ significantly between the high and low Hb groups (3.1% and 4.4%, respectively). No safety issues were noted in either group. Maintaining higher Hb levels with darbepoetin alfa better preserved renal function in patients with chronic kidney disease not on dialysis.

Efficacy of using the Japanese version of the asthma control test for determing the level of asthma control in clinical settings.

BACKGROUND: The Asthma Control Test (ACT) is frequently used for the evaluation of asthma control in clinical care setting because it does not require the use of pulmonary function tests, which can be difficult for general practitioners to use. However, few large-scale studies have investigated the efficacy of the Japanese version ACT (J-ACT) in actual use during clinical care. METHODS: The aim of this study was to analyze the efficacy of the J-ACT in a clinical care setting. Using data from a 2008 questionnaire survey including the J-ACT by the Niigata Asthma Treatment Study Group, we compared the ACT scores of 2233 patients with respect to multiple parameters, including the severity by Japanese Society of Allergology and the attack frequency. Using the definition of asthma control partially referred to Global Initiative for Asthma (GINA) guidelines from the survey data, the accuracy screening and determination of optimal ACT cutpoints were performed by retrospective analysis. RESULTS: Cronbach's α for the J-ACT was 0.785. Patients with more severe asthma and more frequent asthma attacks had lower ACT scores than did patients with less severe, less frequent attacks. The optimal ACT cutpoints were 24 for the controlled asthma and 20 for the uncontrolled asthma. CONCLUSIONS: Our study, the first large-scale investigation of the efficacy of the J-ACT, determined that this evaluation tool is highly efficacious in establishing the level of asthma control. However, the determination of accurate cutpoints for the J-ACT will require more clear definitions of asthma control in future prospective studies.

Analysis of depression in asthmatic patients using the Japanese version of Patient Health Questionnaire-9.

BACKGROUND: Previous studies show that depression plays an important role in asthma. However, the association between asthma control and severity, and depression is inconclusive. METHODS: To investigate the association between asthma control and severity, and depression, we assessed differences in asthma control and asthma severity between groups with various grades of depressive state as defined by the PHQ-9 score using data from the Japanese version of Patient Health Questionnaire-9 (J-PHQ-9) and a questionnaire survey including the Asthma Control Test (ACT). RESULTS: The ACT scores in the symptom-screen positive (SP) and major/other depressive disorder (MDD/ODD) group were significantly lower than those in the symptom-screen negative (SN) and non-MDD/ODD groups, respectively. The rate of step1 and of step 3 and 4 in the SP group were significantly lower and higher than those in the SN group, respectively. When the SP group was divided into three, that is minimal, mild, and more than mild (MTM) depressive state subgroups, the ACT scores in the mild and MTM depressive state subgroups were significantly lower than those in the minimal depressive state subgroup. When the MTM subgroup was divided into moderate, moderate-severe and severe depressive state groups, however, there was no significant variation in ACT score and asthma severity among these three depressive state groups. CONCLUSIONS: This study is the first, large-scale investigation of the use of the J-PHQ-9 in asthma patients. Using the J-PHQ-9 and the questionnaire, there was a clear association between asthma control and severity, and depression. As the depression became more severe, the existence of other depression-associated factors unrelated to asthma control and severity might be assumed, although further investigation will be required.

Influence of underweight on asthma control.

BACKGROUND: Although the association between asthma control and body mass index (BMI) has been thoroughly investigated, most of this work has focused on the influence on asthma incidence or the effect of obesity on asthma control. To date, there have been no published studies on the influence of underweight on asthma control. METHODS: The aim of this study was to investigate the influence of underweight, as defined by the Japan Society for the Study of Obesity (JASSO), on asthma control in Japanese asthmatic patients. Using data from questionnaire surveys administered by the Niigata Asthma Treatment Study Group, we compared asthma control, as measured by the Asthma Control Test (ACT), between a normal weight group (18.5kg/m2 =< BMI < 25kg/m2) and an underweight group (BMI < 18.5kg/m2). RESULTS: Of the asthmatic patients who completed the 2008 and 2010 surveys, 1464 and 1260 cases were classified as being in the normal weight group, and 174 and 155 cases were classified as being in the underweight group. The ACT score (median, [interquartile range]) in the underweight group in 2008 (22, [19-24]) and 2010 (23, [19-25]) was significantly lower than that in the normal group in 2008 (23, [20-25]) and in 2010 (24, [21-25]). CONCLUSIONS: This study is the first, large-scale investigation of the influence of underweight on asthma control, and we have confirmed an adverse influence in a clinical setting. A potential mechanism for this interaction was unknown. Further investigation will be required.