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Familial hypercholesterolemia (FH) and chronic kidney disease, especially end-stage renal disease (ESRD), are common and put patients at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). ESRD concomitant with FH may further increase the risk of ASCVD. Achieving target levels of low-density lipoprotein cholesterol (LDL-C) is difficult owing to the limitations of statin administration due to its side effects in ESRD. Therefore, some FH patients with ESRD require lipoprotein apheresis for the prevention of secondary ASCVD events. Although proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors may offer a safe and effective option for lowering lipid levels in such patients, no guidelines are available for their use. Here, we report the case of two male siblings with FH in secondary prevention undergoing hemodialysis combined with PCSK9 inhibitor treatment. The siblings, who showed a heterozygous c.1846-1G>A mutation in the LDLR gene, underwent hemodialysis. In combination with the lipoprotein apheresis, siblings were administered evolocumab, a PCSK9 inhibitor. Both the siblings had coronary artery disease, diabetes, and ESRD, and received hemodialysis. Their LDL-C levels did not reach the target values despite administering statin, ezetimibe, and biweekly lipoprotein apheresis. On the introduction of evolocumab treatment, their LDL-C levels were significantly reduced without any adverse effects, resulting in successful withdrawal from lipoprotein apheresis therapy. Although the effects of switching from lipoprotein apheresis to PCSK9 inhibitors for cardiovascular protection remain unclear in FH patients with and without ESRD, our case report will be helpful in guiding future therapeutic decisions.

Xanthine oxidoreductase (XOR) is a critical enzyme in purine metabolism and uric acid production, and its levels are reported to increase during stress, thereby promoting organ damage. Herein, we investigated the activity of XOR in a mouse model of aristolochic acid I (AA)‐induced nephropathy, a type of nephrotoxic chronic kidney disease (CKD). A persistent decrease in renal function was observed in mice up to 4 weeks after 4 weeks of AA (2.5 mg kg−1) administration. Renal histology revealed an increase in tubular interstitial fibrosis over time. Although AA administration did not change XOR activity in the plasma, heart, liver, or muscle, XOR activity was persistently increased in renal tissue. Our results suggest that the renal tissue‐specific increase in XOR activity is involved in the progression of tubulo‐interstitial disorders, specifically fibrosis., We investigated the activity of xanthine oxidoreductase (XOR) in a mouse model of aristolochic acid I (AA)‐induced nephropathy, a type of chronic kidney disease (CKD). After 4 weeks of AA (2.5 mg·kg−1) administration, renal histology revealed an increase in tubular interstitial fibrosis and XOR activity was persistently increased in renal tissue. Our data suggest that XOR activity is involved in the progression of tubulointerstitial disorders.

Background A simpler method for detecting atherosclerosis obliterans is required in the clinical setting. Laser Doppler flowmetry (LDF) is easy to perform and can accurately detect deterioration in skin perfusion. We performed LDF for hemodialysis patients to determine the correlations between blood flow in the lower limbs and peripheral arterial disease (PAD). Methods This retrospective study included 128 hemodialysis patients. Patients were categorized into the non-PAD group (n = 106) and PAD group (n = 22), 14 early stage PAD patients were included in the PAD group. We conducted LDF for the plantar area and dorsal area of the foot and examined skin perfusion pressure (SPP) during dialysis. Results SPP-Dorsal Area values were 82.1 ± 22.0 mmHg in the non-PAD, and 59.1 ± 20.3 mmHg in PAD group, respectively (p p < 0.001). A total of 21 non-PAD patients underwent LDF before and during dialysis. The LDF-Plantar-Qb values were 36.5 ± 17.6 mL/min before dialysis and 29.6 ± 17.7 mL/min after dialysis (p < 0.05). We adjusted SPP and LDF for PAD using logistic regression, SPP-Dorsal-Area and LDF-P were significantly correlated with PAD (p Conclusion LDF is a simple technique for sensitive detection of early-stage PAD. This assessment will help physicians identify early-stage PAD, including Fontaine stage II in clinical practice, thereby allowing prompt treatment.

Purpose The Informing the Pathway of COPD Treatment (IMPACT) study demonstrated that single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduces moderate/severe exacerbation rates and improves lung function and health status versus FF/VI or UMEC/VI dual therapy in patients with symptomatic COPD and a history of exacerbations. This analysis evaluated the efficacy and safety of FF/UMEC/VI in patients enrolled in Japan. Patients and methods IMPACT was a 52-week, randomized, double-blind, multicenter study comparing FF/UMEC/VI 100/62.5/25 µg with FF/VI 100/25 µg or UMEC/VI 62.5/25 µg in patients ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the previous year. Endpoints included annual rate of on-treatment moderate/severe exacerbations (primary endpoint), time-to-first on-treatment moderate/severe exacerbation and change from baseline at Week 52 in trough FEV1, post-bronchodilator FEV1, St. George's Respiratory Questionnaire, and COPD Assessment Test score. Safety was also assessed. Results The Japan subgroup accounted for only 4% (378/10,355) of the overall IMPACT intent-to-treat (ITT) population. In the Japan subgroup, FF/UMEC/VI reduced the annual rate of on-treatment moderate/severe exacerbations by 15% (95% CI: -20, 40) versus FF/VI (compared with 15% [10, 20] in the ITT) and 36% (95% CI: 6, 57) versus UMEC/VI (compared with 25% [19, 30] in the ITT). FF/UMEC/VI reduced moderate/severe exacerbation risk (time-to-first), improved lung function and health status at Week 52 versus both dual therapies. These results were in the same direction and of a generally similar magnitude to those seen in the overall ITT population. No new safety signals were identified in the Japan subgroup compared with the ITT population. Pneumonia incidence was higher with FF/UMEC/VI and FF/VI versus UMEC/VI. Conclusion These results highlight the favorable benefit-risk profile of FF/UMEC/VI single-inhaler triple therapy compared with FF/VI or UMEC/VI dual therapy in patients in Japan with symptomatic COPD and ≥1 exacerbation in the prior year.

Toshihiko Kaise,1 Eishin Sakihara,2 Kentaro Tamaki,3 Hiroaki Miyata,4 Norimichi Hirahara,4 Oksana Kirichek,5 Ryosuke Tawara,1 Shoko Akiyama,1 Masayuki Katsumata,1 Mei Haruya,6 Takeo Ishii,7 Edgar P Simard,8 Bruce E Miller,8 Ruth Tal-Singer8 1Japan Development, GSK, Tokyo, Japan; 2Lifestyle Related Disease Medical Center, Naha Medical Association, Okinawa, Japan; 3Department of Breast Surgery, Nahanishi Clinic, Okinawa, Japan; 4Health Policy and Management, School of Medicine, Keio University, Tokyo, Japan; 5Value Evidence and Outcomes, GSK, Stockley Park, UK; 6Government Affairs and Market Access, GSK, Tokyo, Japan; 7Medical Japan, GSK, Tokyo, Japan; 8Value Evidence and Outcomes, GSK, Collegeville, PA, USACorrespondence: Toshihiko KaiseJapan Development, GSK, Tokyo, JapanTel +81 80 5927 9500Fax +81 3 4231 5993Email toshihiko.kaise@gsk.comPurpose: Many individuals with obstructive airway disease (OAD), including chronic obstructive pulmonary disease (COPD) and asthma, remain undiagnosed, despite the potential for reducing disease burden through early detection and treatment. OCEAN aimed to determine the prevalence of, and characteristics associated with, impaired lung function in a Japanese population, with the goal of improving strategies for early OAD detection.Methods: OCEAN was an observational, cross-sectional study in sequentially recruited Japanese individuals ≥ 40 years of age undergoing routine health examinations. Participants completed screening questionnaires and spirometry testing. Airflow limitation was defined as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.7 by pre-bronchodilator spirometry. Preserved ratio impaired spirometry (PRISm) was defined as FEV1/FVC ≥ 0.7 and FEV1 < 80% predicted. The primary endpoint was prevalence of spirometry-based airflow limitation and PRISm. The characteristics of study participants were reported as secondary endpoints.Results: Overall, 2518 individuals were included; 79% were < 60 years of age (mean 52.0 years). Airflow limitation and PRISm were observed in 52 (2.1%) and 420 (16.7%) participants, respectively. FEV1 in the PRISm group was between that in the no airflow limitation/PRISm and airflow limitation groups, FVC was similar in the PRISm and airflow limitation groups. The PRISm group had higher mean body mass index and a higher proportion of comorbid metabolic disease compared with the airflow limitation group. The prevalence of airflow limitation and PRISm was highest among current smokers (3.9% and 21.3%, respectively) versus former or never smokers.Conclusion: A significant proportion of Japanese individuals < 60 years of age attending their annual health examination had impaired lung function (airflow limitation and PRISm); prevalence was highest among current smokers. These findings support screening of current or former smokers ≥ 40 years of age using patient-reported questionnaires to inform the need for spirometry to confirm an OAD diagnosis.Keywords: CAPTURE, CAAT, PRISm, COPD-Q, Japan, airflow limitation

Nobuyuki Hizawa,1 Koichi Fukunaga,2 Hisatoshi Sugiura,3 Yasutaka Nakano,4 Motokazu Kato,5 Yutaro Sugiyama,6 Tomohiro Hanazawa,6 Toshihiko Kaise,6 Ruth Tal-Singer,7 Paul W Jones,8 Neil Barnes,8,9 Chris Compton,8 Takeo Ishii6 1Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; 2Pulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; 3Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 4Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Shiga, Japan; 5Respiratory Institute, Kamei Hospital, Osaka, Japan; 6Respiratory Medical Affair and Development, GSK K.K., Tokyo, Japan; 7Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 8GSK, Brentford, Middlesex, UK; 9Barts and the London School of Medicine and Dentistry, London, UKCorrespondence: Takeo IshiiRespiratory Medical Affairs and Development, GSK K.K., Akasaka Intercity AIR, 1-8-1 Akasaka, Minato-ku, Tokyo, 107-0052, JapanTel +81342315045Email takeo.x.ishii@gsk.comBackground: Asthma, chronic obstructive pulmonary disease (COPD), and asthma–COPD overlap (ACO) are complex and heterogeneous diseases that share clinical characteristics (phenotypes) and molecular mechanisms (endotypes). Whilst physicians make clinical decisions on diagnostic groups, for some such as ACO there is no commonly accepted criteria. An alternative approach is to evaluate phenotypes and endotypes that are considered to respond well to a specific type of treatment (“treatable traits”) rather than diagnostic labels.Purpose: The prospective, longitudinal, and observational TRAIT study will evaluate disease characteristics, including both phenotypes and endotypes, in relation to the presentation of obstructive respiratory disease characteristics in patients diagnosed with asthma, COPD, or ACO in Japan, with the aim of further understanding the clinical benefit of a treatable traits-based approach.Patients and Methods: A total of 1500 participants will be enrolled into three cohorts according to their treating physician’s diagnosis of asthma, COPD, or ACO at screening. Part 1 of the study will involve cross-sectional phenotyping and endotyping at study enrollment. Part 2 of the study will evaluate the progression of clinical characteristics, biomarker profiles, and treatment over a 3-year follow-up period. The follow-up will involve three annual study visits and three telephone calls scheduled at 6-month intervals. A substudy involving 50 participants from the asthma cohort (in which the ratio will be approximately 1:1 including 25 participants with a smoking history of ≥ 10 pack-years and 25 participants with no smoking history), 100 participants from the ACO cohort, and 100 participants from the COPD cohort will evaluate disease phenotypes using inspiratory and expiratory computed tomography scans.Conclusion: TRAIT will describe clinical characteristics of patients with obstructive respiratory diseases to better understand potential differences and similarities between clinical diagnoses, which will support the improvement of personalized treatment strategies.Keywords: ACO, asthma, COPD, personalized medicine, biomarkers, treatable traits

Introduction There is a paucity of data describing prescribing patterns and adherence to therapy of inhaled corticosteroids (ICS) in combination with long-acting β2-agonists (LABA) in the Japanese population in clinical practice. Methods This was a non-interventional, retrospective, cohort study of patients who were prescribed medication for asthma, using data from the Japan Medical Data Center Claims Database. Data from patients aged ≥ 15 years with a prescription of asthma drugs between December 2014 and October 2015 (Day 0, the index date when asthma medication was initiated) were analysed in 12-month pre-index and post-index periods. Part 1 focused on baseline characteristics and epidemiological outcomes in the pre- and post-index period in the overall asthma population, whereas comparing medication adherence [number of prescribed days per year and proportion of days covered (PDC)] between ICS/LABA-naïve patients treated with once-daily fluticasone furoate/vilanterol (FF/VI) and twice-daily fluticasone propionate/salmeterol (FP/SAL) was the primary endpoint in Part 2. Results Of the available patient data (N = 2,953,652), 28,699 patients were identified as having asthma. ICS/LABA was the main asthma treatment prescribed; 11,167 (38.9%) patients were continuous ICS/LABA users. In ICS/LABA-naïve asthma patients, treatment with once-daily FF/VI was associated with higher medication adherence compared with twice-daily FP/SAL; mean [standard deviation (SD)] number of prescribed days per year was 97.8 (115.9) for FF/VI versus 80.5 (92.7) for FP/SAL (p = 0.04), mean (SD) PDC was 26.7% (31.5) for FF/VI versus 21.9% (24.8) for FP/SAL (p = 0.04). FF/VI was also associated with a lower rate of treatment discontinuation and no difference in use of short-acting beta2-agonists or oral corticosteroids compared with FP/SAL. Conclusions ICS/LABA was the major prescribed asthma treatment in Japan. Medication adherence was greater with FF/VI, which may indicate that patients are more likely to adhere to once-daily FF/VI versus twice-daily FP/SAL. Funding This study was funded by GSK (study sponsor). Study Registration GSK Study No. 207264, GSK Study Register site: https://www.gsk-clinicalstudyregister.com/search/?search_terms=207264. Electronic supplementary material The online version of this article (10.1007/s41030-018-0084-4) contains supplementary material, which is available to authorized users.

Background Iron-based phosphate binders are widely used in hemodialysis, to avoid the increased mortality associated with high serum phosphate in dialysis patients. However, comparative studies on the effects of phosphate binders are currently limited. In the present study, a comparative analysis of ferric citrate (FC), sucroferric oxyhydroxide (SF), and lanthanum carbonate (LC) was performed to assess their primary phosphate-binding and secondary iron uptake capacities. Methods Patients on maintenance hemodialysis visit our group clinics regularly. The FC, SF, and LC groups comprised 101, 82, and 126 patients, respectively. Subjects were observed from December 2015 to April 2016 (5 months). Serum phosphate levels and other markers were measured in the three medication groups, and changes in phosphate levels and other clinical markers were compared. A drug treatment was considered to be effective if the serum phosphate levels of the patient decreased from baseline in each of the drugs. We evaluated the phosphate-binding capacity compared with each drug using a mixed effect model, for adjusted repeated measured analysis. Results SF showed higher phosphate-binding capacity than FC and LC. FC, SF, and LC showed no significant difference in phosphate-binding capacity in the adjusted mixed effect model. However, patients in the FC group exhibited iron accumulation. Conclusion Sucroferric oxyhydroxide possesses better phosphate-binding efficacies than ferric citrate and lanthanum carbonate. In addition, ferric citrate showed a strong iron-cumulative effect.

Background Recently, several new biological drugs targeting severe asthma are on the market, and various studies on severe asthma have been reported worldwide. However, in Japan, the data are still limited regarding epidemiology and burden of disease on severe asthma. This study determined the prevalence, characteristics, and burden of disease of patients with severe asthma. Methods : This retrospective study (HO-16-16484) used a nationwide health care claims database. Severity of asthma was defined according to the treatment during the baseline period (April 1, 2014–March 31, 2015). Eligible patients were >15–65 years of age with asthma during the 12-month baseline period and were followed up for 12 months. End points included the prevalence, characteristics, exacerbation frequency, and patient behavior in patients with severe, moderate, or mild asthma. Risk factors for exacerbations were explored in patients with all levels of asthma severity and in those with severe asthma. Findings Among the 16,107 patients with asthma, 2.4 (95% CI, 2.1–2.6) per 100 patients had severe asthma. During the baseline period, 130 (34.0%) of 382 patients with severe asthma had ≥1 asthma exacerbation. The exacerbation frequency was highest in patients with severe asthma, and most of the comorbidities increased in proportion to the asthma severity. During the follow-up period, exacerbation frequency increased with asthma severity. Approximately 70% of patients with severe asthma were treated at clinics, requiring outpatient visits ~10 times per year. Different exacerbation risk factors were identified between patients with all severity levels of asthma and those with severe asthma. With the severe asthma patients, experiencing exacerbations during the previous year was a risk factor for further exacerbations during the follow-up period. Implications In Japan, 2.4% of patients with asthma have severe asthma, and there is a significant burden of disease in patients with severe asthma undergoing high-intensity treatment.

Objective Although chronic obstructive pulmonary disease (COPD) is characterized by systemic inflammation, the association between the neutrophil to lymphocyte ratio (NLR; an indicator of inflammation) and the clinical status of COPD has not been well studied. We hypothesized that the NLR is associated with disease severity and exacerbation in COPD patients. Methods We performed blood testing, pulmonary function testing, chest computed tomography, a body composition analysis, and a 6-minute walk test and applied the modified Medical Research Council (MMRC) dyspnea scale for 141 stable COPD patients. In addition, we calculated the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index to evaluate the disease severity. Finally, we examined the association between the NLR and clinical parameters in stable COPD patients, and we further investigated changes in the NLR between exacerbation and the stable state. Results The NLR was positively correlated with the BODE index, extent of emphysema, and MMRC score (p

To date, a number of potential biomarkers for lung squamous cell cancer (SCC) have been identified; however, sensitive biomarkers are currently lacking to detect early stage SCC due to low sensitivity and specificity. In the present study, we compared the 7 serum proteomic profiles of 11 SCC patients, 7 chronic obstructive pulmonary disease (COPD) patients and 7 healthy smokers as controls to identify potential serum biomarkers associated with SCC and COPD. Two-dimensional difference gel electrophoresis (2D-DIGE) and mass-spectrometric analysis (MS) using an affinity column revealed two candidate proteins, haptoglobin (HP) and apolipoprotein 4, as biomarkers of SCC, and α-1-antichymotrypsin as a marker of COPD. The iTRAQ technique was also used to identify SCC-specific peptides. HP protein expression was significantly higher in SCC patients than in COPD patients. Furthermore, two HP protein peptides showed significantly higher serum levels in SCC patients than in COPD patients. We established novel polyclonal antibodies for the two HP peptides and subsequently a sandwich enzyme-linked immunosorbent assay (ELISA) for the quantification of these specific peptides in patient and control sera. The sensitivity of detection by ELISA of one HP peptide (HP216) was 70% of SCC patients, 40% of COPDs patients and 13% of healthy controls. We also measured CYFRA, a cytokeratin fragment clinically used as an SCC tumor marker, in all the 28 cases and found CYFRA was detected in only seven SCC cases. However, when the measurement of HP216 was combined with that of CYFRA, 100% (10 of 10 patients) of SCC cases were detected. Our proteomic profiling demonstrates that the SCC-specific HP peptide HP216 may potentially be used as a diagnostic biomarker for SCC.

Background: Supraventricular and ventricular premature complexes (SVPC and VPC, respectively) are associated with chronic obstructive pulmonary disease (COPD) and with increased mortality in COPD patients. However, there are few reports on the causes of arrhythmia in COPD patients. Objectives: This study explores the associations between cardiopulmonary dysfunction and COPD by comparing patients with defined arrhythmias (>100 beats per 24 h) and those without, based on 24-hour electrocardiogram (ECG) recordings. Methods: Patients with arrhythmia underwent a 24-hour ECG and subsequent pulmonary function tests, computed tomography, ECG, 6-min walk test (6MWT), and BODE (body mass index, airflow obstruction, modified Medical Research Council Dyspnoea Scale, exercise capacity) index calculation. Results: Of 103 study patients (71 COPD patients and 32 at-risk patients), 36 had VPC, 45 had SVPC, 20 had both, and 42 had neither. The predicted post-bronchodilator forced expiratory volume in 1 s, the proportion of low-attenuation area on computed tomography, and BODE index values were significantly worse in the SVPC and VPC groups compared with the corresponding reference groups. Patients in the VPC group showed significantly increased right ventricular pressure and increased desaturation in the 6MWT compared with the reference group. In the multivariate analyses, bronchodilator use was a significant risk factor in the SVPC group, whereas in the VPC group, all parameters of the BODE index except for the dyspnoea score were identified as risk factors. Conclusions: Increased SVPC might be caused by bronchodilator use, whereas increased VPC is likely related to the peculiar pathophysiology of COPD.

Neil Barnes,1,2 Takeo Ishii,3,4 Nobuyuki Hizawa,5 Dawn Midwinter,6 Mark James,3 Emma Hilton,1 Paul Jones1,71Respiratory Medicine Franchise, GlaxoSmithKline, Brentford, UK; 2William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK; 3Medical Affairs, GlaxoSmithKline K.K., Tokyo, Japan; 4Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; 5Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; 6Global Respiratory Department, GlaxoSmithKline, Stockley Park, UK; 7Institute of Infection and Immunity, St George’s University of London, London, UK Background: Blood eosinophil measurements may help to guide physicians on the use of inhaled corticosteroids (ICS) for patients with chronic obstructive pulmonary disease (COPD). Emerging data suggest that COPD patients with higher blood eosinophil counts may be at higher risk of exacerbations and more likely to benefit from combined ICS/long-acting beta2-agonist (LABA) treatment than therapy with a LABA alone. This analysis describes the distribution of blood eosinophil count at baseline in Japanese COPD patients in comparison with non-Japanese COPD patients.Methods: A post hoc analysis of eosinophil distribution by percentage and absolute cell count was performed across 12 Phase II–IV COPD clinical studies (seven Japanese studies [N=848 available absolute eosinophil counts] and five global studies [N=5,397 available eosinophil counts] that included 246 Japanese patients resident in Japan with available counts). Blood eosinophil distributions were assessed at baseline, before blinded treatment assignment.Findings: Among Japanese patients, the median (interquartile range) absolute eosinophil count was 170 cells/mm3 (100–280 cells/mm3). Overall, 612/1,094 Japanese patients (56%) had an absolute eosinophil count ≥150cells/mm3 and 902/1,304 Japanese patients (69%) had a percentage eosinophil ≥2%. Among non-Japanese patients, these values were 160 (100–250) cells/mm3, 2,842/5,151 patients (55%), and 2,937/5,155 patients (57%), respectively. The eosinophil distribution among Japanese patients was similar to that among non-Japanese patients. Within multi-country studies with similar inclusion criteria, the eosinophil count was numerically lower in Japanese compared with non-Japanese patients (median 120 vs 160 cells/mm3).Interpretation: The eosinophil distribution in Japanese patients seems comparable to that of non-Japanese patients; although within multi-country studies, there was a slightly lower median eosinophil count for Japanese patients compared with non-Japanese patients. These findings suggest that blood eosinophil data from global studies are of relevance in Japan.Keywords: COPD, blood eosinophil count, percentage blood eosinophil, Japan

A lower serum uric acid (UA) level has been associated with a higher mortality rate in haemodialysis patients. We investigated the long-term confounding factors of UA and mortality, and fitted a marginal structural model (MSM) based on the causal effect of xanthine oxidoreductase inhibitors (XORi). In total, 2429 patients on regular dialysis from April 2013 to March 2016 were included, and divided into quintiles by serum UA with Kaplan Meier (KM) curves and log rank analysis. Baseline characteristics were evaluated for relationships with all-cause mortality and cardiovascular disease (CVD) using the Cox hazard model. The MSM was used to control for time-dependent confounders of the XORi treatment effect. KM curves indicated that patients in the highest UA quintile had better outcomes than those in the lowest UA quintile. UA was not correlated with all-cause mortality or CVD events in the Cox model; however, the hazard ratio (HR) for mortality was 0.96 for the baseline administration of XORi. The MSM analysis for the effect of XORi treatment on all-cause mortality revealed a HR of 0.24 (95% confidence interval: 0.15-0.38) in all cohorts. These results suggest that XORi improved all-cause mortality in end-stage renal disease, irrespective of the serum UA level.

Background and objective Vitamin D supplementation can decrease the vulnerability to pulmonary infections. Therefore, it is speculated that the genes related to vitamin D metabolism are associated with an exacerbation-prone phenotype in chronic obstructive pulmonary disease (COPD). Because genetic variations of group component (GC) affect immunological capacity and serum vitamin D concentration, they could also affect the susceptibility to COPD exacerbation and the disease progression. We investigated the association between GC genetic variations and COPD and its exacerbation frequency in a Japanese population. Methods We performed genotype analysis of 361 COPD patients and 219 controls to identify two coding single nucleotide polymorphisms of GC, rs4588 and rs7041. We examined whether these polymorphisms were associated with the frequency of COPD exacerbation and analysed the correlation between the genotypes, COPD, emphysema severity and COPD progression, namely, the annual decline in airflow obstruction and diffusing capacity. Results Subjects with a C allele at rs4588 exhibited a higher frequency of exacerbations (P = 0.0048), greater susceptibility to chronic obstructive pulmonary disease (P = 0.0003), and emphysema (P = 0.0029), and a tendency for rapid decline of airflow obstruction (P = 0.0927). Conclusions GC variations may affect exacerbation susceptibility, possibly leading to COPD worsening and its progression.

(Objective) Bone metastasis symptoms are complications that greatly reduce the quality of life (QOL) of cancer patients. We report a retrospective study on the efficacy of radiation therapy for patients with bone metastasis in urinary organ cancer. (Subjects and methods) Subjects are comprised of 17 patients; total irradiated areas consist of 25 sites. There are 5 patients diagnosed with renal cell carcinoma, 1 patient with bladder cancer and 11 patients with prostatic cancer. All of them have undergone radiation therapy for bone metastasis in urinary organ cancer between April 2007 and March 2014 in the Department of Urology, Kanazawa Medical University. The mean age of the patients was 66.7 years old. We looked at irradiated areas, exposure dose and changes of symptom in all patients. (Results) Irradiated areas are thoracolumbar vertebrae (14 sites), cranial base (2 sites), pubic bone (1 site), ilium bone (2 sites), sacral bone (1 site), rib bone (1 site) and hip joint (1 site). The mean exposure dose of one area is 37.5 Gy (13.5-60). 19 irradiated sites which were previously reported to have sharp pain have gained improvement at 16 sites. These 16 sites have comparatively lesser pain or no pain. 8 cases in acknowledgment of walk difficulty, it was with 7 cases walking alone possibility again. (Conclusion) This study showed that radiation therapy have significant improvement in terms of symptoms and QOL for the patients with bone metastasis in urinary organ cancer.

Fut8 (α1,6-Fucosyltransferase) heterozygous knock-out (Fut8+/−) mice had an increased influx of inflammatory cells into the lungs, and this was associated with an up-regulation of matrix metalloproteinases, MMP-2 and MMP-9, after treatment with porcine pancreatic elastase (PPE), exhibiting an emphysema-prone phenotype as compared with wild type mice (Fut8+/+). The present data as well as our previous data on cigarette-smoke-induced emphysema [8] led us to hypothesize that reduced Fut8 levels leads to COPD with increased inflammatory response in humans and is associated with disease progression. To test this hypothesis, symptomatic current or ex-smokers with stable COPD or at risk outpatients were recruited. We investigated the association between serum Fut8 activity and disease severity, including the extent of emphysema (percentage of low-attenuation area; LAA%), airflow limitation, and the annual rate of decline in forced expiratory volume in 1 s (FEV1). Association with the exacerbation of COPD was also evaluated over a 3-year period. Serum Fut8 and MMP-9 activity were measured. Fut8 activity significantly increased with age among the at risk patients. In the case of COPD patients, however, the association was not clearly observed. A faster annual decline of FEV1 was significantly associated with lower Fut8 activity. Patients with lower Fut8 activity experienced exacerbations more frequently. These data suggest that reduced Fut8 activity is associated with the progression of COPD and serum Fut8 activity is a non-invasive predictive biomarker candidate for progression and exacerbation of COPD.

Objective Early diagnosis is a key factor in the management of chronic obstructive pulmonary disease (COPD). Although mass screening is widely used, little is known about its accuracy and efficacy. This study investigated whether using spirometry during mass screening to detect COPD among community residents might be ineffective because of variability in the training and experience of examiners. Participants and Methods Both spirometry and a self-written questionnaire-based survey, including questions designed to detect respiratory symptoms, were conducted on community residents. Two separate studies were conducted on islanders living in similar environments. Study I was performed from 2004 to 2007 on Hachijyo Island residents, while study II, with a similar study design, was performed in 2003 on Inno Island residents. Results In study I, 3,592 subjects underwent examination over the 4-year study period; of these, 378 subjects underwent repeated examinations. Approximately 25% of the subjects had respiratory symptoms. Acceptable spirometry recordings were obtained for 62.0% (2004) to 84.1% (2006) of the subjects. In study II, 167 of the 254 subjects (65.7%) had respiratory symptoms. Acceptable assessment recordings were achieved in 254 subjects (95.5%). The suitability of the recordings was influenced by the extent/level of training of the examiners and the accompanying thoracic specialists. Conclusion We concluded that the effectiveness of health check-ups for COPD evaluation using spirometry was greatly influenced by the quality of the examiners, even when the subjects had respiratory symptoms. Thus, we recommend caution when screening for early signs of COPD during health check-ups.

Background Although muscle loss is thought to be a prognostic factor in chronic obstructive pulmonary disease (COPD), its determinants remain unclear. Aim To verify the hypothesis that fat-free mass (FFM) and fat mass (FM) are associated with the extent of emphysema in COPD patients. Patients and Methods A total of 112 stable, male current or ex-smokers with or without COPD attending a secondary care specialist COPD clinic were studied. FFM and FM were measured by bioelectrical impedance analysis. We also assessed the nutrition status, muscle strength by the handgrip test, exercise tolerance by the 6-minute walking test, airflow limitation and diffusion capacity, the extent of emphysema by high-resolution CT scan, systemic inflammation status using C-reactive protein, and a lipid-related hormone (adiponectin). Results The FFM index (FFMI), which was defined as the FFM divided by the square of the body height, was significantly correlated with age, the total number of lymphocytes, handgrip strength, distance on 6-minute walking, airflow limitation, diffusion capacity, extent of emphysema, and C-reactive protein. On multivariate analysis, the FFMI was associated with handgrip strength and inversely correlated with the extent of emphysema. The FM index (FMI) was positively correlated with pack-years, and was inversely correlated with the extent of emphysema and concentrations of adiponectin. Conclusion The extent of emphysema was correlated with skeletal muscle loss and also the FM.

This report describes the case of a 57-year-old man who underwent a repeated renal biopsy 25 years after the first biopsy in which the diagnosis of IgA nephropathy was made. Although the patient exhibited gradually increasing proteinuria and a slowly progressive renal impairment, the histological findings of the repeat biopsy revealed no evidence of either glomerular inflammatory changes or IgA deposition. Instead, a marked decrease in the glomerular density and hypertrophy of the remnant glomeruli were noted. Almost a complete disappearance of urinary protein excretion by a calorie-restricted diet indicated that the patient's obesity and its related factors may have contributed to the present nephropathic development.

Objectives and background : Nocturnal apnea and hypoxia are implicated in the pathogenesis of pulmonary and systemic hypertension in obstructive sleep apnea syndrome (OSAS). We have hypothesized that vasodilating factors including nitric oxide (NO) are affected by nocturnal apnea and hypoxia in patients with OSAS. Method : We examined the serum level of NO production in 24 patients with OSAS (mean age 54.2±7.9 years) and 24 age-matched control subjects (53.4±8.1 years) and tested the effects of oxygen administration on the production of NO in the patients. Results : The serum level of nitrite/nitrates (NO x ), which are stable metabolites of NO, was lower in patients with OSAS than in control subjects. Administration of 1–2 l/min of oxygen during night increased the patients' NO x level from 35.6±7.3 to 57.8±11.6 μM. Compressed air administration did not affect the NO x level in the patients. Conclusion : These results indicate that systemic NO production is impaired in OSAS patients, possibly due to nocturnal hypoxia.

Background The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). Methods Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. Results During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01–8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. Conclusions The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

To the Editors: In a recent issue of the European Respiratory Journal , Coughlin et al. 1 demonstrated that, in Caucasians with untreated obstructive sleep apnoea (OSA), continuous positive airway pressure (CPAP) can improve baroreceptor responsiveness and reduce waking blood pressure within 6 weeks, but that this treatment period was insufficient to modify insulin resistance or change the metabolic profile. This is the first randomised placebo-controlled blinded crossover trial comparing cardiovascular and metabolic outcomes after 6 weeks of therapeutic and sham CPAP in obese symptomatic Caucasians with OSA. We have found similar CPAP effects in obese Japanese OSA patients (table 1⇓). The authors suggested that there is a need to offer multiple modalities of treatment to obese OSA patients if their cardiovascular risk profile is to be successfully modified. We totally agree with their conclusion. However, it may be necessary to address the following unresolved issues. View this table: Table 1— Effect of 6-week continuous positive airway pressure …

We evaluated variations in spirometric indices (i.e., forced vital capacity [FVC], peak expiratory flow [PEF], and forced expiratory volume in 1 sec [FEV1]) and static respiratory muscle pressures (i.e., maximum static inspiratory pressure [PImax] and maximum static expiratory pressure [PEmax]) within a span of 12 hr in 60 healthy elderly subjects, 60 young subjects, and 30 Chronic Obstructive Pulmonary disease (COPD) patients. There were no differences among data of FVC, PEF, FEV1, PImax, and PEmax on three separate occasions within a day in the elderly or the young. The mean coefficient of variation (CV) values of PEF and PImax on three occasions were 3.0 +/- 0.3% and 4.2 +/- 0.4% in the elderly, and 2.4 +/- 0.2% and 3.7 +/- 0.3% in the young, respectively. No subjects had more than 9% CV on each measurement in the study, suggesting that there is nosignificant daytime variation in measurement of expiratory flow and respiratory pressures in young and elderly people. However, FVC, PEF FEV1, and PImax values in the morning were smaller than those measured at the other two occasions in COPD patients. The results indicate that COPD affects diurnal variation in pulmonary function, but age alone has little impact on diurnal variation.

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.

Introduction: There is still insufficient data concerning the clinical effects of eplerenone, a selective aldosterone blocker, in patients with non-diabetic chronic kidney disease (CKD). Methods: This study included non-diabetic CKD patients with urinary protein excretion (UPE) of 1.0 g/gCr or more in spite of long-term treatment with renin–angiotensin system (RAS) inhibitors. The clinical effects of eplerenone (25–50 mg/day) were investigated for 12 months. Results: Eplerenone treatment was associated with a 38% reduction in UPE after 12 months. There was only a slight increase in the serum potassium level. The reduction of proteinuria was observed more prominently in patients with modestly impaired renal function than in those with preserved renal function at baseline. Conclusion: The long-term administration of low-dose eplerenone was effective and safe for the treatment of non-diabetic CKD patients who showed persistent proteinuria in spite of therapy with RAS inhibitors.

A serotonin transporter gene, SLC6A4, is thought to be related to nicotine dependence and depression, one of the comorbidities of chronic obstructive pulmonary disease (COPD). To investigate the association between SLC6A4 variation and tobacco consumption, susceptibility to COPD, and depression status. In all, 247 patients with COPD and 119 control subjects were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) of SLC6A4. We analyzed the correlation between these genotypes and COPD, using the results of a pulmonary function test or chest computed tomography; data on tobacco consumption (pack-years); and the depression score based on the hospital anxiety and depression scale (HADS) after adjusting for age, gender, and smoking status (and pack-years, when appropriate). The rare allele rs2020936 was significantly associated with COPD incidence in the trend model (P = 0.003; odds ratio, 2.20; 95% confidence interval, 1.31-3.74). This allele was also associated with the number of pack-years (P = 0.026). The major allele of another SNP of SLC6A4, namely rs3794808, correlated with the HADS depression score (P = 0.016). We conclude that SLC6A4 variation affects COPD pathogenesis, and this effect depends partly on tobacco consumption. SLC6A4 variation also affects depressive symptoms. SLC6A4 could be modified to prevent COPD and treat the depressive symptoms of COPD.

Background: Limited data are available on the association between the severity of emphysema or airway narrowing, and health-related quality of life (HRQOL) in patients with chronic obstructive pulmonary disease (COPD), which has been seen to be more prevalent among elderly subjects. The aim of this study was to examine the association between HRQOL, physical parameters and structural alterations in lung of COPD patients. Methods: Stable COPD patients (n = 125; mean age 71.0) were studied. Both the severity of emphysema, which was expressed as the extent of the low-attenuation area (LAA%), and percentage of the large airway wall area (WA%) on high-resolution computed tomography (HRCT) were compared with various parameters of the generic and HRQOL, respectively, together with pulmonary function tests and exercise capacity. Results: The predicted value of forced expiratory volume in 1 s was significantly associated with both LAA% and WA%, but the diffusion capacity was strongly correlated with LAA% alone. Parameters of the generic and HRQOL, and almost all other parameters appeared to be significantly associated with LAA% alone, whereas no association was observed between WA% and QOL. Conclusion: We concluded that the severity of emphysema, but not that of large airway narrowing on HRCT, is associated with both generic and health-related QOL and reduced diffusion capacity. This notion might provide useful information in practice among elderly subjects who are unable to perform a spirometry.

We previously reported that a combined therapy with heparin/warfarin and reninangiotensin system (RAS) inhibitors dramatically reduces proteinuria for prolonged periods in advanced IgA nephropathy (

Objective Repeated nocturnal hypoxia is implicated in the pathogenesis of cardiovascular complications in obstructive sleep apnea syndrome (OSAS). We hypothesized that circulating vascular endothelial growth factor (VEGF) levels are affected by nocturnal hypoxemia in patients with OSAS. Methods We examined the serum VEGF levels in patients with OSAS and in control subjects. We also tested the effects of oxygen or air administration on the subjects' VEGF levels. Patients and Materials Twenty-four OSAS patients (mean age 54.2±3.6 years) and 24 age-matched control subjects (53.2±3.6 years). Their serum samples were tested. Results Serum VEGF levels at 8 : 00 AM were significantly higher in OSAS patients than in controls (p

We evaluated differences in individual peritoneal membrane transport function and nutritional status in patients with diabetes mellitus (DM) and nondiabetic (non-DM) patients on continuous ambulatory peritoneal dialysis (CAPD).We used a newly developed peritoneal function test, personal dialysis capacity, in 88 patients (44 DM and 44 non-DM) on CAPD for 1 to 210 months. Sex, age, past history of peritonitis, and duration of CAPD were matched in DM and non-DM patients.Serum albumin (mean +/- SEM) was lower in DM compared with non-DM patients: 3.0 +/- 0.1 g/dL (30 +/- 1 g/L) versus 3.5 +/- 0.1 g/dL (35 +/- 1 g/L), P0.001. Peritoneal area and dialysis protein loss were greater in DM versus non-DM patients. In multiple linear regression analysis, the only independent predictor of serum albumin in patients with DM was dialysis protein loss. In contrast, age, past history of peritonitis, duration of CAPD, caloric intake, protein nitrogen appearance and protein catabolic rate, and residual renal function did not correlate with serum albumin in DM patients. In non-DM patients, age, duration of CAPD, and past history of peritonitis, but not dialysis protein loss, were independent predictors of serum albumin. There was a significant correlation in DM patients, but not in non-DM CAPD patients, between dialysis protein loss and urinary excretion of protein (r = 0.866, P = 0.0005).In this multicenter study, peritoneal membrane transport and peritoneal protein permeability were significantly higher in DM than in non-DM patients. Hypoproteinemia in DM patients is attributable to the high permeability of the peritoneal membrane undergoing CAPD.

To the Editor: In a recent issue of the European Respiratory Journal , Barcelo et al. 1 reported results on the plasma angiotensin converting enzyme (ACE) activity and the distribution of an insertion (I)/deletion (D) polymorphism of the ACE gene both in obstructive sleep apnoea syndrome (OSAS) patients and in healthy controls. They found that ACE activity was higher in OSAS patients (53.9±2.5 international units (IU)·L−1) than in healthy controls (42.4±3.1 IU·L−1, p

Factors influencing adeno-associated virus (AAV) - mediated gene transfer to endothelial cells are not fully determined. We tested the variables pertinent to the efficiency of AAV-mediated gene transfer to human vascular endothelial cells (HUVEC) including: (i) kinetics of transduction efficiency of LacZ gene to HUVEC, (ii) the concentration and volume of vector-containing medium, (iii) the period of incubation time of AAV vectors with HUVEC, (iv) the target cell density/proliferation, (v) the duration of transgene expression. There is a dose-response relationship between moi of vectors and transduction efficiency in HUVEC. The higher moi of AAV vectors achieved more than 80% of transduction efficiency in cultured HUVEC. AAV vectors showed incubation time dependent increase in transduction efficiency of LacZ gene to the HUVEC up to 24 h of vector exposure. The foreign gene of AAV vectors preferably transduces the lower density of cells being proliferated. These results indicate that AAV-vector is efficient for gene transfer to HUVEC, and higher moi of vectors or a longer period exposure of vectors to proliferating HUVEC can facilitate efficient tranduction of foreign gene into human vascular endothelial cells in vitro.

BACKGROUND—Enzymes that contribute to the local detoxification in alveoli and bronchioles have an important role in the defence mechanism against tobacco smoke. It has been suggested that genetic susceptibility to smoking injury may confer a risk for the development of chronic obstructive pulmonary disease (COPD). The polymorphisms in glutathione S-transferase P1 (GSTP1), a xenobiotic metabolising enzyme, were investigated in patients with COPD. METHODS—Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed to genotype GSTP1 polymorphisms in exon 5 (Ile105Val) and exon 6 (Ala114Val). Blood samples were taken from 53 patients with COPD and 50 control subjects at the Tokyo University Hospital, the Juntendo University Hospital, and the Tokyo Kenbikyoin Clinic for use in the study. RESULTS—The proportion of GSTP1/Ile105 homozygotes was significantly higher in the patients with COPD than in the control subjects (79% vs 52%). The odds ratio for GSTP1/Ile105 homozygotes versus all other genotypes was 3.5 (95% CI 2.7 to 4.6) for COPD. Polymorphism at residue 114 of GSTP1 was not found in either group. CONCLUSIONS—Genetic polymorphism of exon 5 of GSTP1 may be associated with COPD because the GSTP1/Ile105 genotype is predominantly found in COPD. It is suggested that the GSTP1/Ile105 genotype may be less protective against xenobiotics in tobacco smoke.

To the Editors: In a recent issue of the European Respiratory Journal , El Solh et al. 1 demonstrated that allopurinol improves endothelial dysfunction in patients with moderate-to-severe obstructive sleep apnoea (OSA). Because xanthine oxidase inhibition with allopurinol prevents the formation of superoxide free radicals, which leads to better endothelial function, El Solh et al. 1 speculated that excess activity of xanthine oxidase contributes significantly to vasodilatory impairment in patients with OSA. The study was a sophisticated prospective, randomised, crossover design, minimising the presence of confounding variables and eliminating inherent individual variations in terms of the generation of free radicals, hyperaemic vascular reactivity or response to treatment. However, a number of arguable assumptions were made in the article of El Solh et al. 1. First, endothelial function assessment using hyperaemia-induced flow-mediated vasodilation (FMD) is not always …

To the Editors: In a recent issue of the European Respiratory Journal , Vazir et al. 1 demonstrated that spectral analysis of heart rate variations (HRV) may be useful as a “rule-out test” for sleep-disordered breathing (SDB) in patients with mild-to-moderate congestive heart failure (CHF). This is an interesting approach to the diagnosis of SDB in CHF patients without sleepiness. As CHF patients with Cheyne–Stokes respiration (CSR)/central sleep apnoea (CSA) are often asymptomatic, this noninvasive approach may be effective to rule out SDB in patients. However, we feel that there are a number of problems with the article by Vazir et al. 1. First, HRV analysis cannot be applied in patients with arrhythmia, including atrial fibrillation (AF). In a group of patients with CHF, it has been demonstrated that there is a considerable association between AF and CSA …

Takashi Motegi,1,2 Rupert C Jones,3 Takeo Ishii,1,2 Kumiko Hattori,1,2 Yuji Kusunoki,1,2 Ryuko Furutate,2 Kouich Yamada,1,2 Akihiko Gemma,1 Kozui Kida1,2 1Divisions of Pulmonary Medicine, Infectious Disease, and Oncology, Department of Internal Medicine, 2Respiratory Care Clinic, Nippon Medical School, Tokyo, Japan; 3Respiratory Research Unit, Peninsula Medical School, Plymouth, UK Background: Prediction of future exacerbations of chronic obstructive pulmonary disease (COPD) is a major concern for long-term management of this disease. Aim: To determine which of three multidimensional assessment systems (the body mass index, obstruction, dyspnea, and exercise capacity [BODE] index; dyspnea, obstruction, smoking, exacerbations [DOSE] index; or age, dyspnea, obstruction [ADO] index) is superior for predicting exacerbations. Methods: This was a 2-year prospective cohort study of COPD patients. Pulmonary function tests, the 6-minute walk distance (6MWD), Modified Medical Respiratory Council (MMRC) dyspnea scores, chest computed-tomography measurements, and body composition were analyzed, and predictions of exacerbation by the three assessment systems were compared. Results: Among 183 patients who completed the study, the mean annual exacerbation rate was 0.57 events per patient year, which correlated significantly with lower predicted forced expiratory volume in 1 second (FEV1) (P < 0.001), lower transfer coefficient of the lung for carbon monoxide (%DLco/VA) (P = 0.021), lesser 6MWD (P = 0.016), higher MMRC dyspnea score (P = 0.001), higher DOSE index (P < 0.001), higher BODE index (P = 0.001), higher ADO index (P = 0.001), and greater extent of emphysema (P = 0.002). For prediction of exacerbation, the areas under the curves were larger for the DOSE index than for the BODE and ADO indices (P < 0.001). Adjusted multiple logistic regression identified the DOSE index as a significant predictor of risk of COPD exacerbation. Conclusion: In this study, the DOSE index was a better predictor of exacerbations of COPD when compared with the BODE and ADO indices. Keywords: frequency of exacerbation, multidimensional assessment systems, DOSE index, BODE index A Letter to the Editor has been received and published for this article.