Shingo Fukuma

Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan.

BACKGROUND Patient responsiveness to erythropoiesis-stimulating agents (ESAs), notoriously difficult to measure, has attracted attention for its association with mortality. We defined categories of ESA responsiveness and attempted to clarify their association with mortality. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Data from Japans dialysis registry (2005-2006), including 95,460 adult hemodialysis patients who received ESAs. PREDICTOR We defined 6 categories of ESA responsiveness based on a combination of ESA dosage (low [<6,000 U/wk] or high [≥6,000 U/wk]) and hemoglobin level (low [<10 g/dL], medium [10-11.9 g/dL], or high [≥12 g/dL]), with medium hemoglobin level and low-dose ESA therapy as the reference category. OUTCOMES All-cause and cardiovascular mortality during 1-year follow-up. MEASUREMENTS HRs were estimated using a Cox model for the association between responsiveness categories and mortality, adjusting for potential confounders such as age, sex, postdialysis weight, dialysis duration, comorbid conditions, serum albumin level, and transferrin saturation. RESULTS Median ESA dosage (4,500-5,999 U/wk) was used as a cutoff point, and mean hemoglobin level was 10.1 g/dL in our cohort. Of 95,460 patients during follow-up, 7,205 (7.5%) died of all causes, including 5,586 (5.9%) cardiovascular deaths. Low hemoglobin levels and high-dose ESA therapy were both associated with all-cause mortality (adjusted HRs, 1.18 [95% CI, 1.09-1.27] for low hemoglobin level with low-dose ESA and 1.44 [95% CI, 1.34-1.55] for medium hemoglobin level with high-dose ESA). Adjusted HRs for high-dose ESA with low hemoglobin level (hyporesponsiveness) were 1.94 (95% CI, 1.82-2.07) for all-cause and 2.02 (95% CI, 1.88-2.17) for cardiovascular mortality. We also noted the interaction between ESA dosage and hemoglobin level on all-cause mortality (likelihood ratio test, P = 0.002). LIMITATIONS Potential residual confounding from unmeasured factors and single measurement of predictors. CONCLUSIONS Mortality can be affected by ESA responsiveness, which may include independent and interactive effects of ESA dose and hemoglobin level. Responsiveness category has prognostic importance and clinical relevance in anemia management.

Abnormal Mineral Metabolism and Mortality in Hemodialysis Patients With Secondary Hyperparathyroidism: Evidence From Marginal Structural Models Used to Adjust for Time-Dependent Confounding

BACKGROUND Hemodialysis patients with mineral and bone disorders (MBDs) have an abnormally high relative risk of death, but their absolute risk of death is unknown. Further, previous studies have not accounted for possible time-dependent confounding of the association between MBD markers and death due to the effect of markers of MBD on treatments, which subsequently may affect MBD markers. STUDY DESIGN Multicenter, 3-year, prospective, case-cohort study. SETTING & PARTICIPANTS 8,229 hemodialysis patients with secondary hyperparathyroidism (parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators) at 86 facilities in Japan. PREDICTORS Serum phosphorus, calcium, and parathyroid hormone levels. OUTCOME All-cause mortality. MEASUREMENTS Marginal structural models were used to compute absolute differences in all-cause mortality associated with different levels of predictors while accounting for time-dependent confounding. RESULTS The association between phosphorus level and mortality appeared U-shaped, although only higher phosphorus level categories reached statistical significance: compared to those with phosphorus levels of 5.0-5.9 mg/dL (1.61-1.93 mmol/L), patients with the highest (≥9.0 mg/dL [≥2.90 mmol/L]) phosphorus levels had 9.4 excess deaths/100 person-years (rate ratio, 2.79 [95% CI, 1.26-6.15]), whereas no association was found for the lowest phosphorus category (<3.0 mg/dL [<0.97 mmol/L]; rate ratio, 1.54 [95% CI, 0.87-2.71]). Similarly, hypercalcemia (≥10.0 mg/dL [≥2.50 mmol/L]) was associated with excess deaths, and the highest level of hypercalcemia (≥11.0 mg/dL [≥2.75 mmol/L]) was associated with 5.8 excess deaths/100 person-years (rate ratio, 2.38 [95% CI, 1.77-3.21]) compared to those with levels of 9.0-9.4 mg/dL (2.25-2.37 mmol/L). Abnormally high parathyroid hormone levels were not associated with excess deaths. LIMITATIONS Possible residual confounding. CONCLUSIONS These results reinforce the idea that serum calcium (in addition to phosphorus) level is an important predictor of the absolute risk of death in hemodialysis patients with secondary hyperparathyroidism.

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.

Use of Renin-Angiotensin System Inhibitors Is Associated with Reduction of Fracture Risk in Hemodialysis Patients

Background Patients with chronic kidney disease, especially those undergoing dialysis treatment and having secondary hyperparathyroidism, have a high risk of bone fracture. The renin-angiotensin system (RAS) is associated with osteoclastic bone resorption. We aimed to examine whether the use of RAS inhibitors reduces the incidence of fracture in hemodialysis patients. Methods and Findings This was a multicenter, 3-year, prospective, observational study. From 2008 to 2011, maintenance hemodialysis patients with secondary hyperparathyroidism (N = 3,276) treated with angiotensin converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB) at baseline were followed for a mean of 2.7 years. The association between the use of ACEI/ARB and hospitalization rate owing to fracture was examined by using Cox regression models. Effect modifications by the severity of secondary hyperparathyroidism (intact parathyroid hormone [iPTH] level), sex, and systolic blood pressure were also examined. The incidence proportion of fracture-related hospitalization was 5.42% throughout the observation period. ACEI/ARB use was associated with a lower rate of fracture-related hospitalization (adjusted hazard ratio, 0.65; 95% confidence interval [CI], 0.45–0.92). This association was not significantly affected by sex (P = 0.56) or systolic blood pressure levels (P = 0.87). The hazard ratios adjusted by iPTH levels were qualitatively different, but not statistically significant (P = 0.11): 0.77 (95% CI, 0.42–1.39), 0.38 (95% CI, 0.20–0.73), 0.59 (95% CI, 0.29–1.21), and 1.29 (95% CI, 0.58–2.42) for the first, second, third and fourth quartiles of iPTH, respectively. Conclusions Use of RAS inhibitors is associated with a lower rate of fracture-related hospitalization in hemodialysis patients with secondary hyperparathyroidism. Trial Registration ClinicalTrials.gov NCT00995163

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.

Majority of systematic reviews published in high-impact journals neglected to register the protocols: a meta-epidemiological study

OBJECTIVES To describe the registration of systematic review (SR) protocols and examine whether or not registration reduced the outcome reporting bias in high-impact journals. STUDY DESIGN AND SETTING We searched MEDLINE via PubMed to identify SRs of randomized controlled trials of interventions. We included SRs published between August 2009 and June 2015 in the 10 general and internal medicinal journals with the highest impact factors in 2013. We examined the proportion of SR protocol registration and investigated the relationship between registration and outcome reporting bias using multivariable logistic regression. RESULTS Among the 284 included reviews, 60 (21%) protocols were registered. The proportion of registration increased from 5.6% in 2009 to 27% in 2015 (P for trend <0.001). Protocol registration was not associated with outcome reporting bias (adjusted odds ratio [OR] 0.85, 95% confidence interval [CI] 0.39-1.86). The association between Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) adherence and protocol registration was not statistically significant (OR 1.09, 95% CI 0.59-2.01). CONCLUSIONS Six years after the launch of the PRISMA statement, the proportion of protocol registration in high-impact journals has increased some but remains low. The present study found no evidence suggesting that protocol registration reduced outcome reporting bias.

A new prognostic index for overall survival in malignant pleural mesothelioma: the rPHS (regimen, PS, histology or stage) index.

OBJECTIVE Existing prognostic indices for malignant pleural mesothelioma do not incorporate the recent advances in oncology care. The purpose of this study was to provide a prognostic index for overall survival in malignant pleural mesothelioma patients treated with chemotherapy with pemetrexed or best supportive care in the recent clinical setting. METHODS A retrospective cohort study was performed in two hospitals in Japan (2007-13). The primary outcome was overall survival. The Cox proportional hazards model was used for multivariable analyses to identify prognostic factors. A final model was chosen based on both clinical and statistical significance. RESULTS A total of 283 patients (chemotherapy: n = 228, best supportive care: n = 55) were enrolled in the study. On multivariate analysis, regimen including platinum plus pemetrexed, a performance status >0, non-epithelial histological type and Stage IV disease predicted poor overall survival in chemotherapy patients. As hazard ratios of individual risk factors were approximately similar, a prognostic index for overall survival was constructed by counting the risk factors. Median overall survival in chemotherapy patients decreased by each one-point increase in this count: 1030 days for zero; 658 days for one; 373 days for two; 327 days for three; 125 days for four. Internal validation using the bootstrapping technique showed robustness of the model (c-index, 0.677; 95% confidence interval, 0.624-0.729). Further, the discrimination was consistent in best supportive care patients (c-index, 0.799; 95% confidence interval, 0.725-0.874). CONCLUSIONS This novel index can provide clinicians and malignant pleural mesothelioma patients with a better framework for discussing prognosis at the time of diagnosis.

Minor Elevation in C-Reactive Protein Levels Predicts Incidence of Erythropoiesis-Stimulating Agent Hyporesponsiveness among Hemodialysis Patients

Background: Hemodialysis (HD) patients occasionally experience minor asymptomatic elevation in C-reactive protein (CRP) levels, which may be associated with difficulty in managing renal anemia using erythropoiesis-stimulating agents (ESAs). Here, we assessed whether elevation of CRP predicts future incidences of ESA hyporesponsiveness. Methods: A total of 2,956 HD patients lacking ESA hyporesponsiveness and infectious diseases were enrolled, and the association between CRP levels and incidence of ESA hyporesponsiveness was assessed. CRP levels were divided into 4 categories (normal [<1.0 mg/l], mild [1.0≤ CRP <3.0 mg/l], moderate [3.0≤ CRP <10.0 mg/l] and high [≥10.0 mg/l]). The primary outcome was the cumulative incidence of ESA hyporesponsiveness, defined as a failure to achieve hemoglobin level ≥10 g/dl despite receiving high doses of ESAs (≥9,000 U/week recombinant human epoetin [rHuEPO]-α or rHuEPO-β and ≥60 μg/week darbepoetin-α) during 12 months of follow-up. Results: The cumulative incidence of ESA hyporesponsiveness was 134 (4.8%) occurrences over 4 months and 300 (12.4%) over 12 months. The elevated CRP groups had significantly higher incidence of ESA hyporesponsiveness over 4 months of follow-up than the normal reference group (adjusted relative risk [RR] 1.6, 95% CI 1.0-2.6 for moderate; adjusted RR 2.5, 95% CI 1.5-4.1 for high). Furthermore, the association remained consistent even over 12 months (adjusted RR 1.4, 95% CI 1.0-1.8 for moderate; adjusted RR 1.6, 95% CI 1.1-2.4 for high). Conclusions: Elevated CRP levels were associated with future incidence of ESA hyporesponsiveness from low-grade inflammation (3.0≤ CRP <10.0 mg/l).

Effect of an educational program on attitudes towards deceased organ donation.

BACKGROUND Organ shortage for transplantation remains a serious global issue. We assessed the effects of an educational program on changing attitudes of medical students towards deceased organ donation. MATERIAL AND METHODS We conducted a non-randomized trial involving medical students who had not previously signed a donor card. Third-year medical students (n=86, program group) received an information pamphlet followed by a 60-min classroom lecture by a transplant physician who was himself a kidney transplant recipient and finally another information pamphlet containing a donor card. First-year students (n=87, control group) received the same two pamphlets only. The primary outcome was signing a donor card. The secondary outcomes included willingness to sign a donor card, willingness to donate organs, family discussion about deceased organ donation, and knowledge. Outcomes were measured by questionnaires before and after the intervention. RESULTS A higher proportion of students of the program group signed a donor card than the pamphlet group (8.1% vs. 0%, respectively). After propensity score adjustment, the program was associated with higher proportion of willingness to sign a donor card (91.9% vs. 73.6%; adjusted proportion ratio 1.28 [95% CI 1.11-1.48]), family discussion (18.6% vs. 6.9%; 2.85 [1.15-7.03]), and increased knowledge. There were no significant differences between the two groups in willingness to donate organs after brain death (64.0% vs. 60.9%; 1.12 [0.90-1.40]) and cardiac death (77.9% vs. 71.3%; 1.11 [0.93-1.33]). CONCLUSIONS The educational program delivered by a transplant physician and a recipient may alter the attitudes of medical students towards deceased organ donation.

The role of digital rectal examination for diagnosis of acute appendicitis: A systematic review and meta-analysis

Background Digital rectal examination (DRE) has been traditionally recommended to evaluate acute appendicitis, although several reports indicate its lack of utility for this diagnosis. No meta-analysis has examined DRE for diagnosis of acute appendicitis. Objectives To assess the role of DRE for diagnosis of acute appendicitis. Data Sources Cochrane Library, PubMed, and SCOPUS from the earliest available date of indexing through November 23, 2014, with no language restrictions. Study Selection Clinical studies assessing DRE as an index test for diagnosis of acute appendicitis. Data Extraction and Synthesis Two independent reviewers extracted study data and assessed the quality, using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Bivariate random-effects models were used for the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) as point estimates with 95% confidence intervals (CI). Main Outcomes and Measures The main outcome measure was the diagnostic performance of DRE for diagnosis of acute appendicitis. Results We identified 19 studies with a total of 7511 patients. The pooled sensitivity and specificity were 0.49 (95% CI 0.42–0.56) and 0.61 (95% CI 0.53–0.67), respectively. The positive and negative likelihood ratios were 1.24 (95% CI 0.97–1.58) and 0.85 (95% CI 0.70–1.02), respectively. The DOR was 1.46 (0.95–2.26). Conclusion and Relevance Acute appendicitis cannot be ruled in or out through the result of DRE. Reconsideration is needed for the traditional teaching that rectal examination should be performed routinely in all patients with suspected appendicitis.