Prevalence of Asymptomatic SARS-CoV-2 Infection in Japan.

Importance: Real-world evidence of SARS-CoV-2 transmission is needed to understand the prevalence of infection in the Japanese population. Objective: To conduct sentinel screening of the Japanese population to determine the prevalence of SARS-CoV-2 infection in asymptomatic individuals, with complementary analysis for symptomatic patients as reported by active epidemiologic surveillance used by the government. Design, Setting, and Participants: This cross-sectional study of a sentinel screening program investigated approximately 1 million asymptomatic individuals with polymerase chain reaction (PCR) testing for SARS-CoV-2 infection between February 22 and December 8, 2021. Participants included children, students, employed adults, and older individuals, as well as volunteers to broadly reflect the general Japanese population in the 14 prefectures of Japan that declared a state of emergency. Saliva samples and a cycle threshold (Ct) value of approximately 40 as standard in Japan were used. Polymerase chain reaction testing for symptomatic patients was separately done by public health authorities, and the results were obtained from the Ministry of Health, Labour, and Welfare of Japan to complement data on asymptomatic infections from the present study. Main Outcomes and Measures: Temporal trends in positivity and prevalence (including surges of different variants) and demographic associations (eg, age, geographic location, and vaccination status) were assessed. Results: The positive rate of SARS-CoV-2 infection in 1 082 976 asymptomatic individuals (52.08% males; mean [SD] age 39.4 [15.7] years) was 0.03% (95% CI, 0.02%-0.05%) during periods without surges and a maximum of 0.33% (95% CI, 0.25%-0.43%) during peak surges at the Japanese standard Ct value of approximately 40; however, the positive rate would have been 10-fold less at a Ct value of 25 as used elsewhere in the world (eg, UK). There was an increase in patients with a positive PCR test result with a Ct value of 25 or 30 preceding surges in infection and hotspots of asymptomatic infections. Conclusions and Relevance: In this cross-sectional study of asymptomatic SARS-CoV-2 infection in the general population of Japan in 2021, as investigated by sentinel surveillance, a low rate of infection was seen in the Japanese population compared with reported levels elsewhere in the world. This finding provides real-world data on the state of infection in Japan.

Evaluation of major national dementia policies and health-care system preparedness for early medical action and implementation.

With population growth and aging, the number of people with dementia and related disorders will grow substantially in the years ahead, bringing with it significant societal, health-care, and economic challenges. Here, we analyze dementia policies of seven major countries in Asia/Pacific, Europe, and North America to identify opportunities for early actions to mitigate disease burden. We find that most countries are addressing this need by including a specific focus on early action in their national dementia strategies (five of seven countries), implementing public health initiatives for risk reduction, prevention, and early detection and diagnosis (six of seven countries); supporting enabling research for early detection and risk reduction (six of seven countries); and enacting a system for early, regular brain health screening (one of seven). We discuss risks and opportunities for integrating early action policies and conducting additional systematic research to understand the potential benefits and impacts of these policies.

Fukushima Nuclear Power Plant accident: Various issues with iodine distribution and medication orders.

Immediately after the Great East Japan Earthquake on March 11, 2011, the public could not receive accurate information concerning about the reality of the accident at the Fukushima Nuclear Power Plant because of communication problems with mobile phone base stations caused by power outages and the inadequate use of communication satellites between local governments. These telecommunications troubles caused not only a delay between the Japanese central government to local governments, but also a failure in conveying the seriousness of the accident to residents. The central government issued evacuation orders, but in some areas, a delay was seen in the time residents took to notice the orders. Some residents were forced to change their evacuation site several times and move to areas with higher radiation exposure. Although iodine preparations needed to be distributed to saturate the thyroid gland and reduce the uptake of iodine-131, a radioactive isotope, many municipalities were unable to secure them. Preparations were distributed on March 15, 2011 when the detectable amount of radioactive isotopes peaked, but only the Naraha and Miharu towns received them. At the time of the Fukushima Nuclear Power Plant accident, communication lines had already been interrupted by the major earthquake that struck on March 11, and information systems between local governments were not communicating well. With such a social infrastructure, residential evacuation orders were inadequate, and the delivery of medication was extremely difficult. The experience of the Fukushima Nuclear Power Plant accident suggests that the government should have distributed iodine preparations to residents living within a 30-km radius of the plant in advance, so that they could learn about the background and side effects of the drug beforehand. This distribution strategy is similar to that of targeted antivirus prophylaxis (TAP), which is an extralegal policy carried out in situations where face-to-face medical treatment is impossible because of an outbreak during a pandemic.

Authors' reply: Independent investigation may be more reliable in the event with political nature.

We welcome their additional suggestion that the government should publish potential causes for and implications of the additional outbreak beyond the quarantine to the international scientific community so that similar outbreaks may be swiftly prevented. However, given the absence of government-driven publications, we published this report based on our independent investigation, which may be more reliable considering the inherently sensitive and political nature of the events.

Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene­like 1 (Plagl1), which encodes a C2H2 zinc­finger transcription factor, occurs in hypocretin neuron­ablated transgenic mice, suggesting that PLAGL1 is co­expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro­hypocretin transcription is functionally modulated by PLAGL1. Double immunostaining indicated that the majority of hypocretin neurons were positive for PLAGL1 immunoreactivity in the nucleus. Notably, PLAGL1 immunoreactivity in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detected in the nuclei of hypocretin neurons following sleep deprivation. Chromatin immunoprecipitation revealed that endogenous PLAGL1 may bind to a putative PLAGL1­binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription. These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.

Morphological characteristics of p75 neurotrophin receptor-positive cells define a new type of glial cell in the rat dorsal root ganglia.

In the dorsal root ganglia (DRG), two types of glial cells (Schwann cells and satellite glial cells) have been identified based on cell morphology and expression of specific markers. In the present study, we observed unknown glial cells that were positive for p75 neurotrophin receptor (p75NTR), and therefore were immunohistochemically and ultrastructurally characterized for the first time. These cells exhibited stronger immunoreactivity against an anti-p75NTR antibody than the DRG neurons (hereafter referred to as p75NTR++ cells). Moreover, these cells covered the glial cells surrounding proximal process of the large-diameter DRG neurons. The proximal process is called "dendro-axon." The p75NTR++ cells were predominantly distributed where the first myelinating Schwann cells appear. The p75NTR++ cells were also positive for the pan-glial cell markers S100, nestin, and Sox10, but negative for fibroblast and macrophage markers. Moreover, they were negative for a satellite glial cell marker, inwardly rectifying potassium channel Kir4.1, as well as a nonmyelinating Schwann cell marker, glial fibrillary acidic protein. In addition, their morphological features were distinct from those of the myelinating Schwann cells. To investigate the three-dimensional ultrastructure of the p75NTR++ cells, we used array tomography combined with correlative light and electron microscopic observation. Three-dimensional ultrastructural observation revealed that the p75NTR++ cells loosely covered glial cells around the dendro-axons with highly ramified processes. Glial cells with these morphological features have not been reported before, indicating that the p75NTR++ glial cells are a new glial cell type in the DRG. Our results will give new insights into cell-cell relationships.

Differential expression of nuclear lamin subtypes in the neural cells of the adult rat cerebral cortex.

Lamins are type V intermediate filament proteins that are located beneath the inner nuclear membrane. In mammalian somatic cells, LMNB1 and LMNB2 encode somatic lamins B1 and B2, respectively, and the LMNA gene is alternatively spliced to generate somatic lamins A and C. Mutations in lamin genes have been linked to many human hereditary diseases, including neurodegenerative disorders. Knowledge about lamins in the nervous system has been accumulated recently, but a precise analysis of lamin subtypes in glial cells has not yet been reported. In this study we investigated the composition of lamin subtypes in neurons, astrocytes, oligodendrocyte-lineage cells, and microglia in the adult rat cerebral cortex using an immunohistochemical staining method. Lamin A was not observed in neurons and glial cells. Lamin C was observed in astrocytes, mature oligodendrocytes and neurons, but not observed in oligodendrocyte progenitor cells. Microglia also did not stain positive for lamin C which differed from macrophages, with lamin C positive. Lamin B1 and B2 were observed in all glial cells and neurons. Lamin B1 was intensely positive in oligodendrocyte progenitor cells compared with other glial cells and neurons. Lamin B2 was weakly positive in all glial cells compared to neurons. Our current study might provide useful information to reveal how the onset mechanisms of human neurodegenerative diseases are associated with mutations in genes for nuclear lamin proteins.

Associations of employment status and educational levels with mortality and hospitalization in the dialysis outcomes and practice patterns study in Japan.

BACKGROUND: Socioeconomic status (SES) factors such as employment, educational attainment, income, and marital status can affect the health and well-being of the general population and have been associated with the prevalence of chronic kidney disease (CKD). However, no studies to date in Japan have reported on the prognosis of patients with CKD with respect to SES. This study aimed to investigate the influences of employment and education level on mortality and hospitalization among maintenance hemodialysis (HD) patients in Japan. METHODS: Data on 7974 HD patients enrolled in Dialysis Outcomes and Practice Patterns Study phases 1-4 (1999-2011) in Japan were analysed. Employment status, education level, demographic data, and comorbidities were abstracted at entry into DOPPS from patient records. Mortality and hospitalization events were collected during follow-up. Patients on dialysis < 120 days at study entry were excluded from the analyses. Cox regression modelled the association between employment and both mortality and hospitalization among patients < 60 years old. The association between education and outcomes was also assessed. The association between patient characteristics and employment among patients < 60 years old was assessed using logistic regression. RESULTS: During a median follow-up of 24.9 months (interquartile range, 18.4-32.0), 10% of patients died and 43% of patients had an inpatient hospitalization. Unemployment was associated with mortality (hazard ratio [HR] = 1.57; 95% confidence interval [CI]: 1.05-2.36) and hospitalization (HR = 1.25; 95% CI: 1.08-1.44). Compared to patients who graduated from university, patients with less than a high school (HS) education and patients who graduated HS with some college tended to have elevated mortality (HR = 1.41; 95% CI, 1.04-1.92 and HR = 1.36; 95% CI: 1.02-1.82, respectively) but were not at risk for increased hospitalizations. Factors associated with unemployment included lower level of education, older age, female gender, longer vintage, and several comorbidities. CONCLUSIONS: Employment and education status were inversely associated with mortality in patients on maintenance HD in Japan. Employment but not education was also inversely associated with hospitalizations. After adjustment for comorbidities, the associations with clinical outcomes tended to be stronger for employment than education status.

Frequent monitoring of mineral metabolism in hemodialysis patients with secondary hyperparathyroidism: associations with achievement of treatment goals and with adjustments in therapy.

Background: Dialysis guidelines in Japan recommend more frequent measurement of mineral metabolism markers than the Kidney Disease: Improving Global Outcomes guidelines. However, the extent to which frequent marker measurement contributes to achievement of target ranges and to therapy adjustment is unknown. Methods: This multicenter cohort study involved 3276 hemodialysis patients with secondary hyperparathyroidism. Data on laboratory measurements and drug prescriptions were collected every 3 months. Main exposures were frequencies of measuring serum calcium and phosphorus [weekly/biweekly/monthly (reference)] and serum parathyroid hormone (PTH) [monthly/bimonthly/trimonthly (reference)] levels. Outcomes were achievement of guideline-specified ranges of mineral metabolism markers when serum levels were over, and maintenance of ranges when levels were already within, respective specified ranges, use of intravenous vitamin D receptor activator (VDRA) and initiation of cinacalcet use. Associations were examined via generalized estimating equations. Results: When serum marker levels exceeded the target range, weekly measurement of calcium and phosphorus was positively associated with achievement of the guideline-specified calcium range [adjusted odds ratio (AOR): 1.57, 95% confidence interval (CI) 1.09-2.26] but not phosphorus range (AOR: 0.99, 95% CI 0.74-1.33). Monthly measurement of PTH was positively associated with achievement of the guideline-specified PTH range (AOR: 1.14, 95% CI 1.01-1.27). When serum marker levels were within the guideline-specified range, increased frequency of measurements was not associated with in-range maintenance of marker levels for any of the three mineral markers assessed. Regarding treatment regimen, relatively frequent measurement of serum calcium and phosphorus was positively associated with cinacalcet initiation and relatively frequent measurement of serum PTH with cinacalcet initiation and intravenous VDRA use. Conclusions: Our results suggest that increasing frequency of measurements is helpful when serum marker levels exceed the target range, partially via adjustment in the therapeutic regimen. We found no evidence that frequent measurements are helpful when mineral levels are already within target ranges.

Influence of Staff Encouragement on Perceived Burden of Dietary Restriction Among Patients Living Alone.

To help relieve the burden of dietary restrictions experienced by many hemodialysis (HD) patients, dialysis staff may encourage patients, with no consideration to the degree of family support. Here, we clarified the effect of staff encouragement and living conditions on the burden of dietary restrictions in HD patients. This retrospective cohort study was conducted using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) I and III. We enrolled patients aged 18-75 years on HD therapy for at least 3 months. We categorized patients into four groups based on combinations of level of staff encouragement (high or low) and living condition (alone or with family) at baseline survey. Patients who felt they received high staff encouragement and lived with their family were set as the control. The main outcome was increase in patients' perceived burden of dietary restriction after 1 year. 1377 (69.1%) felt they received high staff encouragement, and 176 (9.1%) were living alone. After 1 year, 537 (26.9%) patients reported feeling an increased burden of dietary restriction. A low level of staff encouragement did not increase the burden in any patients, regardless of living situation. However, a high level of staff encouragement did increase the burden in patients living alone (adjusted odds ratio: 1.57, 95% confidence interval: 1.05-2.36). We observed an unexpected association between high staff encouragement and increased burden of dietary restriction among patients living alone. Staff encouragement may not relieve patients' burden with respect to dietary restriction and may in fact exacerbate it.

PTH-dependence of the effectiveness of cinacalcet in hemodialysis patients with secondary hyperparathyroidism.

Cinacalcet lowers parathyroid hormone levels. Whether it can prolong survival of people with chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) remains controversial, in part because a recent randomized trial excluded patients with iPTH <300 pg/ml. We examined cinacalcet's effects at different iPTH levels. This was a prospective case-cohort and cohort study involving 8229 patients with CKD stage 5D requiring maintenance hemodialysis who had SHPT. We studied relationships between cinacalcet initiation and important clinical outcomes. To avoid confounding by treatment selection, we used marginal structural models, adjusting for time-dependent confounders. Over a mean of 33 months, cinacalcet was more effective in patients with more severe SHPT. In patients with iPTH ≥ 500 pg/ml, the reduction in the risk of death from any cause was about 50% (Incidence Rate Ratio [IRR] = 0.49; 95% Confidence Interval [95% CI]: 0.29-0.82). For a composite of cardiovascular hospitalization and mortality, the association was not statistically significant, but the IRR was 0.67 (95% CI: 0.43-1.06). These findings indicate that decisions about using cinacalcet should take into account the severity of SHPT.

Contribution of dysregulated serum magnesium to mortality in hemodialysis patients with secondary hyperparathyroidism: a 3-year cohort study.

BACKGROUND: The extent of contribution of disturbed magnesium balance to mortality remains unclear among hemodialysis patients. METHODS: This was a cohort study involving 3276 patients on maintenance hemodialysis at 86 facilities in Japan from 2008 to 2010 who had secondary hyperparathyroidism (SHPT). Baseline serum magnesium (sMg) values were categorized into quintiles (≤2.3, >2.3-2.5, >2.5-2.7, >2.7-3.0 and >3.0 mg/dL), and the middle quintile was set as the reference. Outcome was all-cause death. Independent contribution to all-cause death was assessed via Cox regression to generate population-attributable fractions (PAFs). RESULTS: A total of 2165 patients from 68 facilities were analyzed. The lowest quintile of sMg was positively associated with lower serum potassium and albumin levels, higher C-reactive protein (CRP) levels and prevalence of atrial fibrillation and cerebrovascular disease than the other quintiles. The highest sMg quintile was positively associated with higher potassium levels, and negatively associated with lower serum albumin levels and higher intact parathyroid hormone and CRP levels and prevalence of cerebrovascular disease than the other quintiles. During a median follow-up of 3 years, the lowest and the second lowest quintiles of sMg were associated with all-cause death [adjusted hazard ratio (HR) 1.737, 95% confidence interval (95% CI) 1.200-2.512 and HR 1.675, 95% CI 1.254-2.238, respectively). Point estimates of adjusted HRs of the highest and the second highest sMg quintiles were higher than those of the middle quintile for all-cause death. Adjusted PAFs of lower sMg and of higher and lower sMg for all-cause death were 24.0% (95% CI 13.0-35.0%) and 30.7% (95% CI 14.5-46.8%), respectively. CONCLUSION: In hemodialysis patients with SHPT, dysregulated sMg is an important contributor to all-cause death. Further studies are warranted to examine whether or not correction of sMg improves survival.

Prescription of potentially inappropriate medications to elderly hemodialysis patients: prevalence and predictors.

BACKGROUND: In elderly hemodialysis (HD) patients, the risk of medication-related problems is particularly high. Thus, certain medications should generally not be prescribed to those patients. The Beers criteria for potentially inappropriate medications (PIMs) have been publicized. Still, with regard to elderly HD patients, the prevalence and risk factors for prescription of PIMs are unknown. METHODS: This was a cross-sectional study of data from the Japan Dialysis Outcomes and Practice Patterns Study (2002-08). Patients were included if they were 65 years old or older and were currently receiving HD treatment at a hospital or clinic. We counted the number of patients who were prescribed at least one PIM, as defined by the modified Beers criteria. We used multiple logistic regression analysis to determine which patient characteristics and facility characteristics were associated with prescription of PIMs. RESULTS: Data from 1367 elderly patients were analyzed. More than half of the patients (57%) had been prescribed a PIM. The three most frequently prescribed PIMs were H2 blockers (33%), antiplatelet agents (19%) and α-blockers (13%). PIM prescriptions were less likely at facilities that conducted multidisciplinary rounds {adjusted odds ratio (AOR): 0.67 [95% confidence interval (CI): 0.48-0.93]} and at teaching hospitals [AOR: 0.59 (95% CI, 0.39-0.90)]. PIM prescriptions are more likely if more than one physician has clearance to alter the HD regimen [AOR: 1.65 (95% CI, 1.12-2.44)]. CONCLUSIONS: PIMs were prescribed to many elderly HD patients in Japan. Nephrologists should become more aware of PIMs. Multidisciplinary rounds could benefit patients by reducing the prescription of PIMs.

Vascular access care and treatment practices associated with outcomes of arteriovenous fistula: international comparisons from the Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Vascular access (VA) guidelines recommend the native arteriovenous fistula (AVF) as VA of first choice for chronic hemodialysis patients. AVF management is important in hemodialysis patient care. AVF survival is associated with various physical factors, but the effects of dialysis treatment factors upon AVF survival are still not clear. METHODS: Study patients were treated at 498 dialysis facilities participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) 2 or 3 (2002-2007). Analyses included 1,183 incident hemodialysis patients (on dialysis ≤7 days and using an AVF at study entry) and 949 prevalent patients (on dialysis >7 days at DOPPS entry and using a new AVF created during study observation). AVF survival was modeled from the study entry date for incident patients and date of first AVF use for prevalent patients. Predictors of primary and final AVF survival were compared across Japan, North America and Europe/Australia/New Zealand (EUR/ANZ) with adjustments for patient characteristics. RESULTS: No meaningful relationship was seen between AVF survival and various physician and staff practices. However, patients with prior catheter use displayed higher rates of primary and final AVF failure. Final AVF failure rates were higher in facilities with higher median blood flow rates (BFR). They were also greater in North America and EUR/ANZ than in Japan, but this difference was substantially attenuated after accounting for regional differences in facility median BFR. CONCLUSION: AVF longevity differed according to the DOPPS region, and was related to prior patient catheter use and facility BFR practice. Further longitudinal studies may help demonstrate meaningful associations between VA-handling skill and patency.

Differential responses of endogenous adult mouse neural precursors to excess neuronal excitation.

Adult neurogenesis in the subgranular zone of the hippocampus (SGZ) is enhanced by excess as well as mild neuronal excitation, such as chemoconvulsant-induced brief seizures. Because most studies of neurogenesis after seizures have focused on the SGZ, the threshold of neuronal excitation required to enhance neurogenesis in the subventricular zone (SVZ) is not clear. Therefore, we examined the responses of SVZ precursors to brief generalized clonic seizures induced by a single administration of the chemoconvulsant pentylenetetrazole (PTZ). Cell cycle progression of precursors was analysed by systemic administration of thymidine analogues. We found that brief seizures immediately resulted in cell cycle retardation in the SVZ. However, the same effect was not seen in the SGZ. This initial cell cycle retardation in the SVZ was followed by enhanced cell cycle re-entry after the first round of mitosis, leading to precursor pool expansion, but the cell cycle retardation and expansion of the precursor pool were transient. Cell cycle progression in the PTZ-treated group returned to normal after one cell cycle. The numbers of precursors in the SVZ and new neurons in the olfactory bulb, which are descendants of SVZ precursors, were not significantly different from those in control mice more than 2 days after seizures. Because similar effects were observed following electroconvulsive seizures, these responses are likely to be general effects of brief seizures. These results suggest that neurogenesis in the SVZ is more tightly regulated and requires stronger stimuli to be modified than that in the SGZ.

Prescription patterns and mineral metabolism abnormalities in the cinacalcet era: results from the MBD-5D study.

BACKGROUND AND OBJECTIVES: Prescription patterns for hemodialysis patients with secondary hyperparathyroidism have varied widely since market introduction of cinacalcet. This study examined associations between prescription patterns and subsequent laboratory values. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients subcohort, 1716 prevalent hemodialysis patients (4048 sets for repeated measures between January 2008 and July 2009) with an intact parathyroid hormone (iPTH) level >180 pg/ml who used intravenous vitamin D receptor activator (VDRA) without cinacalcet were selected. Prescription patterns were defined based on cinacalcet administration (starting or not) and VDRA dosage change (decreased [<-25%], stable [-25% to 25%], or increased [>25%]). Proportion differences (PDs) were determined for decreasing iPTH levels by at least one category (<180, 180-299, 300-499, and ≥500 pg/ml) and for achieving target phosphorus (3.5-6.0 mg/dl) and calcium (8.4-10.0 mg/dl) levels, adjusting for potential confounders. RESULTS: The starting cinacalcet and increased VDRA patterns were associated with decreasing iPTH levels (PD, 0.25 and 0.13; 95% confidence intervals [95% CIs], 0.19-0.31 and 0.09-0.17, respectively); combination use had an additive association (PD, 0.34; 95% CI, 0.20-0.42). The starting cinacalcet and decreased VDRA combination was associated with simultaneously achieving target phosphorus (PD, 0.12; 95% CI: 0.04-0.20) and calcium (PD, 0.09; 95% CI, 0.01-0.17) levels. CONCLUSIONS: Certain combinations of cinacalcet and VDRA were associated with decreasing iPTH and achieving targets for phosphorus and calcium. Combinations may prove advantageous versus VDRA alone in managing secondary hyperparathyroidism.

Disappearance of association in diabetic patients on hemodialysis between anemia and mortality risk: the Japan dialysis outcomes and practice pattern study.

We previously demonstrated that anemia was not associated with mortality in hemodialysis patients with cardiovascular disease (CVD). Since diabetes mellitus (DM) accelerates CVD, the influence of DM on the relationship between anemia and mortality was examined using the data obtained from 1,385 DM patients and 2,583 non-DM hemodialysis patients recruited into the Dialysis Outcomes Practice Pattern Study in Japan (J-DOPPS). When all patients were stratified into four groups on their hematocrit levels, mortality rate was significantly and steadily lower in the subgroups with the higher levels of hematocrit by the Kaplan-Meier method (p = 0.0003 by log-rank test). When DM and non-DM patients were analyzed separately, a significant association of lower hematocrit levels with higher mortality disappeared in DM patients (p = 0.6280), in contrast with its retention in non-DM counterparts (p < 0.0001). Multivariable-adjusted Cox proportional hazards models demonstrated a significant association between hematocrit with all-cause mortality in non-DM patients after adjustment for age, gender, BMI, hemodialysis duration, SBP, DBP, albumin, total cholesterol, calcium, phosphorus, and intact PTH (p = 0.046), whereas this association disappeared in DM patients in the same model (p = 0.583). In conclusion, these results suggested that the association between anemia and higher mortality disappeared in DM hemodialysis patients, in contrast with non-DM counterparts.

Time-dependent resistance to erythropoiesis-stimulating agent and mortality in hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study.

BACKGROUND/AIMS: Resistance to erythropoiesis-stimulating agent (ESA) is associated with mortality in hemodialysis (HD) patients. Time-dependent variability of ESA resistance has been not investigated adequately, although consistently high ESA resistance is expected to be a high risk for mortality. Our aim, therefore, was to investigate consistently high ESA resistance as an independent predictor of mortality in HD patients. METHODS: This study evaluated 2,104 Japanese HD patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) III. ESA resistance index (ERI) was defined as the weekly weight-adjusted dose of ESA divided by hemoglobin concentration. The average ERI was calculated from ERI levels every 4 months throughout the observation period for each patient. To assess the size of the fluctuation in average ERI during the observation periods according to ERI quartiles at the enrollment periods, six patient groups were defined on the basis of patterns of ERI level fluctuation: low-low (Low), intermediate-intermediate (Intermediate), high-high (High), low-intermediate, intermediate-high, and low-high. RESULTS: The number of deaths among the patients was 227 (10.8%), which included 113 (5.4%) cases of cardiovascular disease (CVD). In multivariate analysis after adjustment for age, albumin, C-reactive protein, comorbidities, etc., the High group was independently and significantly related to all-cause and CVD-related mortality (OR = 2.33, 95% CI: 1.33-4.07, p = 0.002, and OR = 2.09, 95% CI: 1.05-4.14, p = 0.035, respectively). CONCLUSION: Factoring out fluctuating ERI increases the ability of consistently high ERI levels as an independent risk factor for all-cause and CVD mortality in HD patients.