Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

OBJECTIVE: Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. METHODS: Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. RESULTS: The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). CONCLUSIONS: This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

Effectiveness of Long-Term Treatment with Brodalumab on Anxiety or Depressive Symptoms in Japanese Patients with Psoriasis: The ProLOGUE Study.

INTRODUCTION: Evidence on treatment effectiveness in patients with psoriasis having anxiety or depressive symptoms helps shared decision-making. This single-arm, open-label, prospective study-ProLOGUE-was conducted to assess the effectiveness of brodalumab on self-assessed anxiety and depressive symptoms in Japanese patients with psoriasis. METHODS: Patients aged ≥ 18 years with plaque psoriasis without peripheral arthritis symptoms who had responded inadequately to current therapies were enrolled at 15 Japanese facilities and received brodalumab 210 mg subcutaneously. RESULTS: A total of 73 patients were enrolled (male, 82%; median age, 54 years). The proportion of patients without anxiety symptoms changed significantly from baseline (72.6%) to weeks 12 (88.9%, p = 0.008) and 48 (87.7%, p = 0.02); the proportion of patients without depressive symptoms did not change significantly. The Generalized Anxiety Disorder-7 score (median [quartile(Q)1-Q3], 1.0 [0.0-5.0] at baseline; 0.0 [0.0-2.0] at week 12, p = 0.008; and 0.0 [0.0-1.0] at week 48, p = 0.007) and Patient Health Questionnaire-8 score (median [Q1-Q3], 2.0 [0.0-4.0] at baseline; 1.0 [0.0-4.0] at week 12, p = 0.03; and 0.0 [0.0-2.0] at week 48, p = 0.004) significantly decreased after treatment. The median Psoriasis Area and Severity Index scores after treatment were < 1, irrespective of the presence of baseline anxiety or depressive symptoms. At week 12, the health-related quality of life was more impaired in patients with versus without baseline depressive symptoms, which largely resolved at week 48. CONCLUSIONS: Brodalumab treatment resulted in the reduction of the levels of self-assessed anxiety and depressive symptoms in Japanese patients with psoriasis. Unlike anxiety symptoms, depressive symptoms did not resolve completely with brodalumab treatment. Patients with psoriasis having depressive symptoms may require long-term treatment. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier: UMIN000027783, Japan Registry of Clinical Trials identifier: jRCTs031180037.

Treatment with brodalumab is not associated with improved sleep problems in real-life patients with plaque psoriasis: Results of the ProLOGUE study.

Psoriasis impacts various aspects of patients' health-related quality of life and is associated with sleep problems. However, research discussing the associations between interleukin-17 blockage therapies and sleep problems in patients with psoriasis is insufficient. We aimed to assess the effectiveness of brodalumab in alleviating sleep problems in real-life patients with plaque psoriasis. This analysis was part of the single-arm, open-label, multicenter, prospective, cohort study, ProLOGUE (study period October 2017-March 2020), which involved Japanese patients with plaque psoriasis. Assessments included correlation of Medical Outcomes Study Sleep Scale-Revised (MOS Sleep-R) scores (Sleep Problems Index-II [SPI-II] and MOS Sleep-R subscale scores) with multiple patient-reported outcome scores and the Psoriasis Area and Severity Index (PASI) at baseline. Additionally, change from baseline in MOS Sleep-R scores was assessed at weeks 12 and 48 of brodalumab treatment. Seventy-three patients were enrolled (male 82.2%, median age 54.0 years). At baseline, the SPI-II score correlated with the Patient Health Questionnaire-8 score (Spearman correlation coefficient [ρ] = -0.474) and weakly correlated with the Itch Numeric Rating Scale (NRS; ρ = -0.366), Skin Pain NRS (ρ = -0.275), and all Treatment Satisfaction Questionnaire for Medication-9 domain scores (ρ = 0.270, ρ = 0.303, and ρ = 0.322 for effectiveness, convenience, and global satisfaction, respectively) but did not correlate with the PASI score. The SPI-II score and MOS Sleep-R subscale scores, except the Snoring score (p = 0.0319), did not significantly change from baseline to week 12 of brodalumab treatment. In conclusion, treatment with brodalumab did not improve overall sleep problems in real-life patients with plaque psoriasis, suggesting that sleep problems require attention in daily clinical practice (Japan Registry of Clinical Trials identifier, jRCTs031180037).

Medical Director Practice of Advising Increased Dietary Protein Intake in Hemodialysis Patients With Hyperphosphatemia: Associations With Mortality in the Dialysis Outcomes and Practice Patterns Study.

OBJECTIVES: Patients undergoing hemodialysis (HD) may have poor nutritional status and hyperphosphatemia. Nephrologists sometimes manage hyperphosphatemia by prescribing phosphate binders and/or recommending restriction of dietary phosphate including protein-rich foods; the later may, however, adversely affect nutritional status. DESIGN AND METHODS: The analysis includes 8805 HD patients on dialysis ≥ 120 days in 12 countries in Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 4 (2009-2011), from 248 facilities. The primary exposure variable was response to the following question: "For patients with serum albumin 3.0 g/dL and phosphate 6.0 mg/dL, do you recommend to (A) increase or (B) decrease/no change in dietary protein intake (DPI)?". The association between medical director's practice of recommending an increase in DPI and all-cause mortality was analyzed with Cox regression adjusted for potential confounders. Linear and logistic regressions were used to model the cross-sectional associations between DPI advice practice and intermediate markers of patient nutrition. RESULTS: Median follow-up was 1.6 years. In the case scenario, 91% of medical directors in North America had a practice of recommending DPI increase compared to 58% in Europe (range = 36%-83% across 7 countries) and 56% in Japan. The practice of advising DPI increase was weakly associated with lower mortality [HR (95% CI): 0.88 (0.76-1.02)]. The association tended to be stronger in patients with age 70+ years [HR (95% CI): 0.82 (0.69-0.97), P = .12 for interaction]. The practice of advising DPI increase was associated with 0.276 mg/dL higher serum creatinine levels (95% CI: 0.033-0.520) after adjustment for case mix. CONCLUSIONS: Medical director's practice of recommending an increase in DPI for HD patients with low albumin and high phosphate levels was associated with higher serum creatinine levels and potentially lower all-cause mortality. To recommend protein intake liberalization in parallel with phosphate management by physicians may be a critical practice for better nutritional status and outcomes in HD patients.

Secondary hyperparathyroidism, weight loss, and longer term mortality in haemodialysis patients: results from the DOPPS.

BACKGROUND: Wasting is a common complication of kidney failure that leads to weight loss and poor outcomes. Recent experimental data identified parathyroid hormone (PTH) as a driver of adipose tissue browning and wasting, but little is known about the relations among secondary hyperparathyroidism, weight loss, and risk of mortality in dialysis patients. METHODS: We included 42,319 chronic in-centre haemodialysis patients from the Dialysis Outcomes and Practice Patterns Study phases 2-6 (2002-2018). Linear mixed models were used to estimate the association between baseline PTH and percent weight change over 12 months, adjusting for country, demographics, comorbidities, and labs. Accelerated failure time models were used to assess 12 month weight loss as a mediator between baseline high PTH and mortality after 12 months. RESULTS: Baseline PTH was inversely associated with 12 month weight change: 12 month weight loss >5% was observed in 21%, 18%, 18%, 17%, 15%, and 14% of patients for PTH ≥600 pg/mL, 450-600, 300-450, 150-300, 50-150, and <50 pg/mL, respectively. In adjusted analyses, 12 month weight change compared with PTH 150-299 pg/mL was -0.60%, -0.12%, -0.10%, +0.15%, and +0.35% for PTH ≥600, 450-600, 300-450, 50-150, and <50 pg/mL, respectively. This relationship was robust regardless of recent hospitalization and was more pronounced in persons with preserved appetite. During follow-up after the 12 month weight measure [median, 1.0 (interquartile range, 0.6-1.7) years; 6125 deaths], patients with baseline PTH ≥600 pg/mL had 11% [95% confidence interval (CI), 9-13%] shorter lifespan, and 18% (95% CI, 14-23%) of this effect was mediated through weight loss ≥2.5%. CONCLUSIONS: Secondary hyperparathyroidism may be a novel mechanism of wasting, corroborating experimental data, and, among chronic dialysis patients, this pathway may be a mediator between elevated PTH levels and mortality. Future research should determine whether PTH-lowering therapy can limit weight loss and improve longer term dialysis outcomes.

Serum total indoxyl sulfate and clinical outcomes in hemodialysis patients: results from the Japan Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Uremic toxins are associated with various chronic kidney disease-related comorbidities. Indoxyl sulfate (IS), a protein-bound uremic toxin, reacts with vasculature, accelerating atherosclerosis and/or vascular calcification in animal models. Few studies have examined the relationship of IS with clinical outcomes in a large cohort of hemodialysis (HD) patients. METHODS: We included 1170 HD patients from the Japan Dialysis Outcomes and Practice Patterns Study Phase 5 (2012-15). We evaluated the associations of serum total IS (tIS) levels with all-cause mortality and clinical outcomes including cardiovascular (CV)-, infectious- and malignancy-caused events using Cox regressions. RESULTS: The median (interquartile range) serum tIS level at baseline was 31.6 µg/mL (22.6-42.0). Serum tIS level was positively associated with dialysis vintage. Median follow-up was 2.8 years (range: 0.01-2.9). We observed 174 deaths (14.9%; crude rate, 0.06/year). Serum tIS level was positively associated with all-cause mortality [adjusted hazard ratio per 10 µg/mL higher, 1.16; 95% confidence interval (CI) 1.04-1.28]. Association with cause-specific death or hospitalization events, per 10 µg/mL higher serum tIS level, was 1.18 (95% CI 1.04-1.34) for infectious events, 1.08 (95% CI 0.97-1.20) for CV events and 1.02 (95% CI 0.87-1.21) for malignancy events after adjusting for covariates including several nutritional markers. CONCLUSIONS: In a large cohort study of HD patients, serum tIS level was positively associated with all-cause mortality and infectious events.

Utility of the Dermatology Life Quality Index at initiation or switching of biologics in real-life Japanese patients with plaque psoriasis: Results from the ProLOGUE study.

BACKGROUND: Plaque psoriasis significantly affects patients' health-related quality of life. To aid treatment decisions, not only objective assessment by physicians but also subjective assessment by patients is important. OBJECTIVE: To assess the significance of Dermatology Life Quality Index (DLQI) evaluation at the time of biologics introduction in clinical practice in Japanese patients with plaque psoriasis. METHODS: This was a single-arm, open-label, multicenter study. At baseline, Psoriasis Area and Severity Index (PASI) and DLQI scores were measured and stratified based on DLQI scores ≥6/≤5 and PASI scores ≤10/>10. Other patient-reported outcomes assessed included EQ-5D-5L, itch numerical rating scale (NRS), skin pain NRS, Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-8 (PHQ-8), Sleep Problem Index-II (SPI-II), and Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). RESULTS: Of the 73 enrolled patients, 23 had PASI scores ≤10. Those with PASI/DLQI scores >10/≥6 had a significantly higher median PASI score than those with PASI/DLQI scores >10/≤5 (p = 0.0125). Regardless of PASI scores (>10/≤10), median itch NRS and GAD-7 scores were significantly higher in patients with DLQI scores ≥6 than in those with DLQI scores ≤5 (itch NRS, p = 0.0361 and p = 0.0086, respectively; GAD-7, p = 0.0167 and p = 0.0273, respectively). Patients with PASI/DLQI scores ≤10/≥6 had significantly higher skin pain NRS (p = 0.0292) and PHQ-8 (p = 0.0255) scores and significantly lower median SPI-II scores (p = 0.0137) and TSQM-9 Effectiveness domain scores (p = 0.0178) than those with PASI/DLQI scores ≤10/≤5. CONCLUSION: DLQI may be useful for assessing patients' concerns that cannot be identified by PASI alone while initiating biologics or switching from other biologics in clinical practice.

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Fibroblast growth factor 23 (FGF23) plays an important role in chronic kidney disease (CKD)-related mineral and bone disorders. High FGF23 levels are associated with increased risk of anaemia in non-haemodialysis CKD patients. FGF23 also negatively regulates erythropoiesis in mice. We hypothesized that higher FGF23 levels are associated with increased erythropoietin hyporesponsiveness among haemodialysis patients. METHODS: The study included 1044 patients from the Japanese Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phase 5 (2012-2015). The outcome was erythropoiesis-stimulating agent hyporesponsiveness (ESA-hypo), defined as mean Hgb <10 g/dL and standardized mean ESA dose >6000 u/week over 4 months following FGF23 measurement. The association between ESA-hypo and FGF23 was estimated using multivariable-adjusted logistic generalized estimating equation regression models. RESULTS: Patients with higher levels of FGF23 were younger and had higher levels of serum albumin, creatinine, albumin-corrected calcium, phosphorus, PTH, 25(OH)-vitamin D, and had higher percentages of intravenous (IV) iron, IV vitamin D and cinacalcet use. ESA-hypo was present in 144 patients (13.8%). Compared with the third quintile of FGF23 levels, the odds ratio (95% CI) of ESA-hypo was 2.14 (0.99, 4.62) and 1.74 (0.74, 4.11) for the first and fifth quintiles, respectively. CONCLUSION: The lowest and highest levels of FGF23 were associated with higher odds of ESA-hypo in patients on maintenance haemodialysis, although the associations were not statistically significant. The relationship between FGF23 and anaemia, and particularly the increased risks of ESA-hypo at low FGF23 levels which might be the result of energy saving, must be confirmed in larger clinical studies.

Fibroblast Growth Factor 23 and Mortality Among Prevalent Hemodialysis Patients in the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: Elevated fibroblast growth factor 23 (FGF23) levels have been strongly associated with mortality in the predialysis and incident hemodialysis populations, but few studies have examined this relationship in a large cohort of prevalent hemodialysis patients and in particular among persons with high dialysis vintage. To address this, we analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). METHODS: We included 1122 prevalent hemodialysis patients from the J-DOPPS phase 5 (2012-2015) who had FGF23 measurements. We evaluated the association of FGF23 levels with all-cause mortality and cardiovascular composite outcome using Cox regression adjusted for potential confounders. RESULTS: At study enrollment, median dialysis vintage was 5.8 years (interquartile range, 2.7-12.4 years) and median FGF23 level was 2113 pg/ml (interquartile range, 583-6880 pg/ml). During 3-year follow-up, 154 of the 1122 participants died. In adjusted analyses, higher FGF23 was associated with a greater hazard of death (hazard ratio per doubling of FGF23, 1.12; 95% confidence interval, 1.03-1.21); however, the association became weaker as the dialysis vintage increased and finally disappeared in the highest tertile (>9.4 years). Similar patterns of effect modification by dialysis vintage were observed for cardiovascular composite outcome and in time-dependent models. CONCLUSION: Elevated FGF23 was associated with mortality and cardiovascular events in prevalent hemodialysis patients, but the association was attenuated at longer dialysis vintages. This novel finding suggests that long-term hemodialysis patients may be less susceptible to the detrimental effects of FGF23 or correlated biological processes, and additional studies are needed to gain understanding of these possibilities.

Changes in 3-month mineral and bone disorder patterns were associated with all-cause mortality in prevalent hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: There is limited evidence on the association between short-term changes in mineral and bone disorder parameters and survival in maintenance hemodialysis patients. METHODS: We investigated the association between changing patterns of phosphorus, calcium and intact parathyroid hormone levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism. Each parameter was divided into three categories (low [L], middle [M] and high [H]), and the changing patterns between two consecutive visits at 3-month intervals were categorized into nine groups (e.g., L-L and M-H). The middle category was defined as 4.0-7.0 mg/dL for phosphorous, 8.5-9.5 mg/dL for calcium and 200-500 pg/mL for intact parathyroid hormone. Adjusted incidence rates and rate ratios were analyzed by weighted Poisson regression models accounting for time-dependent exposures. RESULTS: For phosphorus, shifts from low/high to middle category (L-M/H-M) were associated with a lower mortality compared with the L-L and H-H groups, whereas shifts from middle to low/high category (M-L/M-H) were associated with a higher mortality compared with the M-M group. For calcium, shifts from low/middle to high category (L-H/M-H) were associated with a higher mortality compared with the L-L and M-M groups, whereas shifts from high to middle category (H-M) were associated with a lower mortality compared with the H-H group. For intact parathyroid hormone, shifts from low to middle category (L-M) were associated with a lower mortality compared with the L-L group. CONCLUSIONS: Changes in the 3-month patterns of phosphorus and calcium toward the middle category were associated with lower mortality. Our study also suggests the importance of avoiding hypercalcemia.

Short-term effectiveness of biologics in patients with moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis.

BACKGROUND: Complete lesion clearance is important to patients with psoriasis. OBJECTIVE: To conduct a network meta-analysis of randomized controlled trials of biologic agents available for psoriasis in Japan, using mixed-treatment comparisons. METHODS: MEDLINE and EMBASE were searched to identify randomized clinical trials (placebo-controlled or head-to-head) of infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, risankizumab or guselkumab in adult patients with moderate-to-severe plaque psoriasis published in English between 01 January 2000 and 31 August 2019. We assessed the proportion of patients who achieved a 100 %, 90 % and 75 % reduction in their Psoriasis Area and Severity Index (PASI) score (PASI100, PASI90 and PASI75) at 10, 12 or 16 weeks after starting biologic treatment, using contrast-based network meta-analysis methods and risk difference (RD). Probabilities of rank and surface under the cumulative ranking (SUCRA) were also estimated. RESULTS: Data were pooled from 41 trials in 19,248 patients. All biologics were significantly more effective than placebo for PASI100, PASI90 and PASI75. The RD for PASI100 for brodalumab vs ixekizumab was 0.05 (95 % Confidence intervals [CI] -0.02, 0.11), brodalumab vs risankizumab was 0.04 (95 %CI -0.03, 0.11), and risankizumab vs ixekizumab was -0.01 (95 %CI -0.08, 0.06). The SUCRA for PASI100 and PASI90 achievement was 96.8 % and 86.8 %, respectively, for brodalumab, 82.6 % and 90.3 %, respectively for risankizumab, and 78.3 %, 80.9 %, respectively, for ixekizumab. CONCLUSION: Of the biologics assessed, brodalumab, ixekizumab and risankizumab were the greatest rates of PASI90 and PASI100 achievement, and a higher probability of being most effective in the induction phase, compared with the other biologics.

A Pooled Analysis From Phase 2b and 3 Studies in Japan of Istradefylline in Parkinson's Disease.

BACKGROUND: Characterization of patient factors associated with istradefylline efficacy may facilitate personally optimized treatment. OBJECTIVES: We aimed to examine which patient factors are associated with favorable istradefylline treatment outcomes in PD patients with motor complications. METHODS: We performed a pooled analysis of data from two identical phase 2b and 3 Japanese studies of istradefylline. Logistic regression models were used to assess the association of 12 patient characteristics with favorable outcomes. RESULTS: Off time reduction and increased good on time with istradefylline provided a significantly favorable response in patients aged ≥65 years. Off time reduction was more favorable in patients with ≥8-hour daily off time at baseline. Improvement in UPDRS Part III was favorable in patients with UPDRS Part III baseline score ≥ 20. CONCLUSIONS: Several patient factors influenced the effect of istradefylline on motor fluctuations, motor function, activities of daily living, and clinical impression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Relationship between serum calcium or phosphate levels and mortality stratified by parathyroid hormone level: an analysis from the MBD-5D study.

INTRODUCTION: There is limited evidence about the association between calcium and phosphate levels and mortality stratified by intact parathyroid hormone (iPTH) level. METHODS: We investigated whether differences in iPTH level affect the relationship between calcium and phosphate levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism (SHPT). Calcium and phosphate levels were categorized as low (< 8.5 mg/dL, < 4.0 mg/dL), medium (≥ 8.5-< 9.5 mg/dL, ≥ 4.0-< 7.0 mg/dL), and high (≥ 9.5 mg/dL, ≥ 7.0 mg/dL), respectively. iPTH levels were grouped into < 300 or ≥ 300 pg/mL. Adjusted incidence rate ratios (aIRRs) were analyzed by weighted Poisson regression. RESULTS: For calcium, patients with higher iPTH (≥ 300 pg/mL) had significantly higher all-cause mortality rates in the high than in the medium category (aIRR 1.99, 95% confidence interval [CI] 1.16-3.42), and tended to have a higher mortality rate in the low category (aIRR 2.04, 95% CI 0.94-4.42). Patients with lower iPTH (< 300 pg/mL) had higher mortality rates in the high than in the medium category (aIRR 1.65, 95% CI 1.39-1.96). For phosphate, the mortality rate was significantly higher in the high than in the medium category in patients with higher and lower iPTH (aIRR 3.23, 95% CI 1.63-6.39 for iPTH ≥ 300 pg/mL; aIRR 1.58, 95% CI 1.06-2.36 for iPTH < 300 pg/mL). CONCLUSION: High calcium and phosphate levels were associated with increased risk of mortality irrespective of iPTH level.

Postdialysis blood pressure is a better predictor of mortality than predialysis blood pressure in Japanese hemodialysis patients: the Japan Dialysis Outcomes and Practice Patterns Study.

Blood pressure (BP) is reportedly a predictor of mortality in hemodialysis (HD) patients; however, it is unclear whether pre- or postdialysis BP has greater predictive power. To evaluate the association of pre- and postdialysis BP with patient survival in Japanese HD patients, we enrolled the entire phase 3 and 4 Japan Dialysis Outcomes and Practice Patterns Study populations. Among 3176 patients, 486 were excluded because of missing data. The remaining 2690 patients were divided into five groups according to pre- or postdialysis systolic BP (SBP): <100, 100-119, 120-139, 140-159, and ≥160 mmHg; diastolic BP (DBP): <60, 60-79, 80-89, 90-99, and ≥100 mmHg; or pulse pressure (PP): <50, 50-59, 60-69, 70-79, and ≥80 mmHg. The hazard ratios for all-cause and cardiovascular mortalities were estimated according to pre- and postdialysis SBP, DBP, and PP using a Cox proportional hazards model. During the follow-up period, 495 and 193 subjects died because of any cause and cardiovascular disease (CVD), respectively. In the multivariable-adjusted Cox proportional hazards model, U-shaped associations of postdialysis SBP and PP with mortality rates were observed, but no significant associations were observed with predialysis SBP or PP. A stratified analysis showed significant interactions between history of CVD and postdialysis SBP with all-cause and cardiovascular mortality. Compared with predialysis values, postdialysis SBP and PP are better predictors of all-cause and cardiovascular mortality, showing U-shaped associations with these outcomes in Japanese HD patients.

Incidence and risk factors for febrile neutropenia in Japanese patients with non-Hodgkin B cell lymphoma receiving R-CHOP: 2-year experience in a single center (STOP FN in NHL 2).

BACKGROUND: Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition. Patients receiving granulocyte colony-stimulating factors (G-CSF) have shorter duration of neutropenia, faster recovery from fever, and shorter duration of antibiotics use. Most strategies for FN prevention using daily G-CSF and pegfilgrastim are based on overseas studies. Data on Japanese patients were lacking; thus, we previously determined the incidence of FN in non-Hodgkin B cell lymphoma (B-NHL) patients at our center. Here, we aimed to gain additional insights into pegfilgrastim use in this population. METHODS: This single-center, retrospective, observational study (STOP FN in NHL 2) enrolled patients with B-NHL who underwent a regimen comprising rituximab and CHOP therapy over a 2-year period (January 2015-June 2017). The incidence of FN in cycle 1 of chemotherapy, risk factors for FN development, and use of daily G-CSF and pegfilgrastim were evaluated. RESULTS: We evaluated 239 patients: 61 patients did not receive G-CSF and 178 received G-CSF. The incidence of FN was 10.5% (95% confidence interval [CI] 6.9-15.1%) in cycle 1 and 13.0% (95% CI 9.0-17.9%) in all cycles. The FN incidence was significantly lower (P = 0.0008) in patients receiving daily G-CSF and pegfilgrastim than patients not receiving G-CSF. Significant risk factors for FN were age ≥ 65 years, albumin < 3.5 g/dL, hemoglobin < 12 g/dL, and no prophylaxis with daily G-CSF/pegfilgrastim during cycle 1. CONCLUSIONS: The incidence of FN in cycle 1 and in all cycles and the identified risk factors were similar with those we previously reported; thus, our results validate previous findings. TRIAL REGISTRATION: UMIN000029534.

Effectiveness of cinacalcet treatment for secondary hyperparathyroidism on hospitalization: Results from the MBD-5D study.

OBJECTIVES: To elucidate the effect of cinacalcet use on all-cause and cause-specific hospitalization outcomes using a prospective cohort of maintenance hemodialysis patients. METHODS: We used data from a prospective cohort of Japanese hemodialysis patients with secondary hyperparathyroidism and examined baseline characteristics as well as longitudinal changes. All patients were cinacalcet-naïve at study enrollment. Further, we used a marginal structural model to account for time-varying confounders on cinacalcet initiation and hospitalization outcomes, and an Andersen-Gill-type recurrent event model to account for any recurring events of hospitalization in the outcome analysis using the weighted dataset. RESULTS: Among the 3,276 patients, cinacalcet treatment was initiated in 1,384 patients during the entire follow-up. Cinacalcet users were slightly younger, included more patients with chronic glomerulonephritis and fewer patients with diabetes, were more likely to have a history of parathyroidectomy, and were more often used receiving vitamin D receptor activator, phosphate binders, and iron supplements. The overall hospitalization analysis yielded a hazard ratio (HR) of 0.97 (95% confidence interval [CI]: 0.80, 1.18). A trend toward a mild protective association was observed for cardiovascular-related hospitalizations (HR: 0.85; 95% CI: 0.64, 1.14). In the subgroup analysis, a protective association was seen due to cinacalcet use for infection-related hospitalizations in the lowest intact parathyroid hormone group (HR: 0.36; 95% CI: 0.14, 0.95). CONCLUSIONS: Cinacalcet initiation in patients on maintenance hemodialysis had no effect on all-cause and cause-specific hospitalizations. Although the overall association was statistically not significant, cinacalcet may have a protective association on cardiovascular-related hospitalization in all patients and infection-related hospitalization in patient with low intact parathyroid hormone.

Strategies for the Super-Aged Dialysis Population: Survival Benefits or Alternative Goals?

BACKGROUND/AIMS: Japan's aging population has prominent epidemiological and patient characteristics. The number of hemodialysis patients aged ≥70 years is increasing. Age-adjusted mortality is improving, but some cause-specific mortalities remain unchanged, including infectious disease and malignancy, requiring combative strategies. However, survival trends for patients aged 90 years or older are not known. METHODS: We examined annual data reported by the -Japanese Society for Dialysis Therapy Renal Data Registry for the period 1987-2014 to determine survival trends. RESULTS: Survival in the super-aged group (≥90 years) is still mostly unimproved. In terms of cause-specific survival, especially death due to heart failure differs distinctly between this group and the remaining elderly patients, indicating that improving their survival is difficult. Alternative dialysis goals could therefore be considered. The major dialysis objective in this population could be to maintain quality of life and limit functional impairment. CONCLUSION: Survival of the super-aged population has not improved in the last 2 decades. Thus, withholding or withdrawing dialysis and providing conservative management without dialysis treatment could be an important option for patients aged 90 years or older.

Mineral and bone disorder management in hemodialysis patients: comparing PTH control practices in Japan with Europe and North America: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: High-circulating level of parathyroid hormone (PTH) is associated with elevated mortality in dialysis patients. The Japanese Society for Dialysis Therapy guideline suggests a lower PTH target than other international guidelines; thus, PTH control may differ in Japan compared with other regions, and be associated with mortality. METHODS: We analyzed data from hemodialysis patients with ≥3 measurements of PTH during the first 9 months after enrollment in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4-5 (2009-2015). PTH control was assessed by the mean, slope, and mean squared error (MSE) of all PTH measurements over the 9-month run-in period. Distribution of each PTH control was assessed by regions (Europe/Australia/New Zealand [Eur/ANZ], Japan and North America) and dialysis vintage. Mortality rates were compared across PTH control categories using Cox regression models. RESULTS: Mean PTH was lower in Japan than in other regions across dialysis vintage categories. In patients with dialysis vintage < 90 days, PTH level was more likely to decline > 5% per month in Japan (48% of patients) versus Eur/ANZ (35%) and North America (35%). In patients with dialysis vintage > 1 year, Japanese patients maintained steady PTH, while patients in Eur/ANZ and North America were more likely to experience a PTH increase. Mean PTH was associated with mortality in the overall samples (highest mortality rate for PTH > 600 pg/mL, hazard ratio, 1.35; 95% confidence interval, 1.20 to 1.52 vs PTH 200-399 pg/mL), and the association was obvious in the prevalent patients (hazard ratio, 1.44; 95% confidence interval, 1.26 to 1.65). PTH slope and MSE did not show significant association with mortality in the overall sample as well as in subjects stratified both by region and dialysis vintage. CONCLUSION: PTH control in hemodialysis patients, as measured by keeping a stable PTH level over 9 months, was observed in Japan contrasted with other regions. High PTH mean, but not increased PTH slope and MSE, was associated with mortality especially in prevalent patients.

Dialysate Calcium Concentration below 3.0 mEq/L Is Not Associated with Improved Outcomes in the Japanese Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Abnormal chronic kidney disease-mineral and bone disorder (CKD-MBD) markers have been associated with adverse outcomes in hemodialysis (HD) patients. Dialysate calcium concentration (D-Ca) likely influences serum calcium and phosphorus levels. Optimal D-Ca level remains unclear. We hypothesized that higher D-Ca is associated with cardiovascular events and mortality among Japanese HD patients. METHODS: Enrollment data of chronic HD patients in the prospective observational study JDOPPS, phases 1-5 (1999-2015), provided exposures and covariates. All-cause mortality, non-arrhythmic cardiovascular events (NonAR-CVE), or their composites were analyzed by D-Ca, and divided into 2.5, 2.75, and 3.0 mEq/L. To minimize confounding by indication, analyses were restricted to facilities in which at least 90% of patients received the same D-Ca prescription. Association of D-Ca level with outcomes was evaluated in Cox models stratified by phase and accounting for facility clustering. Covariates describing patient demographics, comorbidities, laboratory values, CKD-MBD therapy, and facility attributes provided adjustment. RESULTS: Of 9,201 patients included, 25.0% had D-Ca of 2.5 mEq/L; 6.8% D-Ca 2.75; and 68.2% D-Ca 3.0. Median follow-up time was 2.03 years. D-Ca was not associated with all-cause mortality, with hazards ratios for 2.5 vs. 3.0 mEq/L of 0.90 and 95% CI (0.73-1.11), nor with other outcomes. One effect modification occurred, protective for lower D-Ca on NonAR-CVE in the absence of cardiovascular comorbidities (p = 0.032), although corresponding D-Ca effects were not significant after multiple comparisons adjustment (p = 0.261 [D-Ca 2.5] and 0.125 [D-Ca 2.75]). CONCLUSION: Lowering D-Ca level below 3.0 mEq/L seems not to have a meaningful effect on patient outcomes.