Determination of a Serum 25-Hydroxyvitamin D Reference Ranges in Japanese Adults Using Fully Automated Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Despite an increasing interest in vitamin D status, a reference range of the nutrient has not been fully established. This is partly due to a paucity of standardized measuring systems with high throughput. In addition, the range may vary by populations and may change with modernization of lifestyles. OBJECTIVES: This study aims to calculate the current reference concentration of 25-hydroxyvitamin D (25(OH)D) among healthy people living in an urban area in Japan. METHODS: A newly developed fully automated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system was used to measure serum 25(OH)D concentrations. Reproducibility was assessed by measuring standardized samples. Accuracy was validated by comparing with commercially available immunoassays. Then, mass screening was conducted targeting participants who received medical checkups in Tokyo from April 2019 to March 2020, and the reference ranges were calculated. RESULTS: The coefficients of variations of interoperator and interday reproducibility were 4.1%-8.5% and 3.7%-8.0% for 25-hydroxyvitamin D2 (25(OH)D2) and 4.7%-7.0% and 4.0%-6.9% for 25-hydroxyvitamine D3, respectively. The measured total 25(OH)D concentrations correlated well with those measured by immunoassays. In total, 5518 participants were measured for 25(OH)D concentrations, among whom 98% showed inadequate concentrations (<30 ng/mL). The reference ranges of total 25(OH)D for female, male, and total participants were 7-30 ng/mL, 5-27 ng/mL, and 6-29 ng/mL, respectively. After excluding those with abnormal renal and liver function, the range was 6-30 ng/mL. CONCLUSIONS: The high prevalence of vitamin D insufficiency among seemingly healthy population may be attributed to lifestyle characteristics of people living in urban areas of Japan, including spending less time outdoors and lower intake of traditional foods. Longitudinal follow-up and mass screenings targeting different population will help elucidate reasons for discrepancies between official guidelines and the observed concentrations, to which the well-validated measurement system is essential.

Safety and effectiveness of ferric citrate hydrate in serum phosphorus management of patients with chronic kidney disease: a long-term, real-world, observational, post-marketing surveillance study.

BACKGROUND: Ferric citrate hydrate (FC) is an oral iron-based phosphate binder that is used to treat hyperphosphatemia in patients with chronic kidney disease (CKD). This post-marketing surveillance study was performed to investigate the long-term safety and effectiveness of FC. METHODS: This prospective, multicenter, observational post-marketing surveillance study was performed in a real-world setting in Japan. The study involved CKD patients with hyperphosphatemia receiving FC who were undergoing either hemodialysis or peritoneal dialysis or were non-dialysis-dependent. Adverse drug reactions, iron- and erythrocyte-related parameters (i.e., levels of serum ferritin, transferrin saturation, and hemoglobin), and serum levels of phosphorus, corrected calcium, and intact parathyroid hormone were monitored for up to 104 weeks. RESULTS: Safety was evaluated in 2723 patients. Of these patients, 20.5% discontinued FC because of adverse events, and 3.9% discontinued FC because of unsatisfactory effectiveness. Iron-related parameters gradually increased after the initiation of FC treatment but stabilized after week 36. Effectiveness was analyzed in 2367 patients. Serum phosphorus immediately decreased, and the effect persisted for 104 weeks. CONCLUSION: In this 104 week surveillance study, no new safety concerns were noted. The safety profile was not obviously different from those in pre-approval clinical trials and the 52 week interim report of this surveillance study. The serum ferritin level of most patients was below the upper limit of the target range, and iron overload risk was not evident. Long-term FC treatment effectively controlled serum phosphorus.

Safety and efficacy of etelcalcetide, an intravenous calcimimetic, for up to 52 weeks in hemodialysis patients with secondary hyperparathyroidism: results of a post-marketing surveillance in Japan.

BACKGROUND: Etelcalcetide is a second-generation calcimimetic for the management of secondary hyperparathyroidism (SHPT) in patients on dialysis. We performed a post-marketing surveillance (PMS) to obtain information on the safety and efficacy of etelcalcetide in clinical practice in Japan. METHODS: This PMS enrolled SHPT patients who started initial treatment with etelcalcetide between April 1, 2017 and February 28, 2018 in Japan. Safety [adverse drug reactions (ADRs)] and efficacy [serum intact parathyroid hormone (iPTH), corrected calcium (cCa), phosphorous (P), and alkaline phosphatase (ALP)] were recorded for up to 52 weeks or until treatment discontinuation. Treatment decisions were at the physician's discretion. RESULTS: Of 1226 patients enrolled across 282 centers, safety and efficacy data were available for 1195 and 1192, respectively, while 933 continued treatment to Week 52. The starting dose was 5 mg in 82.0% of patients. There were 218 ADRs in 169 patients (14.1%). Metabolism and nutrition disorders (8.8%), adverse laboratory test results (1.8%), and gastrointestinal disorders (1.6%) were the most frequent classes of ADRs. Hypocalcemia-related ADRs occurred in 104 patients (8.7%). The percentage of patients with iPTH levels within the target range (60-240 pg/mL) steadily increased from 19.5% at Week 0 to 64.1% at Week 52 or last dose. cCa, P, and ALP levels remained well controlled. CONCLUSION: This was the first real-world, large-scale, long-term observational PMS of etelcalcetide in Japan. We did not observe any new safety concerns. Etelcalcetide was associated with clinically relevant improvements in serum iPTH and maintenance of serum cCa, P, and ALP levels.

Association of fibroblast growth factor 23 and α-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study.

BACKGROUND: Fibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients. METHODS: The ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted. RESULTS: Patients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p <  0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean ± standard deviation (SD): - 0.2 ± 0.8 loge pg/mL vs. 0.2 ± 0.8 loge pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and α-klotho were not significantly different between the FC and control groups (mean ± SD: - 0.1 ± 0.8 loge pg/mL vs. 0.1 ± 0.9 loge pg/mL; p = 0.33, and 2.0 ± 91.5 pg/mL vs. - 8.9 ± 145.3; p = 0.58, respectively). However, both forms of FGF23 and α-klotho were not significantly associated with each other in both groups. CONCLUSIONS: Iron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and α-klotho under the condition of serum P and Hb were maintained. TRIAL REGISTRATION: ASTRIO study ( UMIN000019176 , registered at UMIN Clinical Trials Registry on October 1, 2015).

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.

Influence of dialysate Ca concentrations on the therapeutic effects of etelcalcetide with concomitant drugs in patients with secondary hyperparathyroidism.

AIM: Secondary hyperparathyroidism (SHPT), a complication of haemodialysis, is commonly treated with calcimimetics. The impact of dialysates containing different calcium (Ca) concentrations on clinical efficacy of calcimimetics are unclear. We examined whether dialysate Ca concentrations influence the efficacy and dosing of etelcalcetide with concomitant drugs. METHODS: We performed post hoc analyses of a 52-week, open-label, multicentre study of etelcalcetide in Japanese SHPT patients to determine whether dialysate Ca influences the therapeutic effects of etelcalcetide with concomitant drugs. We evaluated the differences in serum intact parathyroid hormone (iPTH), corrected Ca (cCa) and phosphate levels among three dialysate Ca concentration groups (2.5, 2.75 or 3.0 mEq/L Ca). Tartrate-resistant acid phosphatase 5b (TRACP-5b) and bone alkaline phosphatase (BAP) levels were also compared. Since the dialysate Ca concentration may influence dose adjustment, we assessed the etelcalcetide and concomitant drug doses. RESULTS: There were no clinically meaningful differences in iPTH, cCa and phosphate levels among the 2.5, 2.75 and 3.0 mEq/L groups (n = 34, 64 and 35, respectively) over 52 weeks. At Week 52, more than 82%, 71% and 67% of patients had iPTH, cCa and phosphate levels within target ranges (60-240 pg/mL, 8.4-10.0 mg/dL and 3.5-6.0 mg/dL, respectively) across the three groups. TRACP-5b and BAP levels decreased by Week 52 regardless of dialysate Ca. Changes in etelcalcetide and concomitant drug doses were generally similar in each group. CONCLUSION: The efficacy and dosing of etelcalcetide with concomitant drugs were essentially unaffected by the dialysate Ca concentration. Patients showed improvements in bone hypermetabolism during treatment.

Clinical outcome of incident peritoneal dialysis patients with diabetic kidney disease.

BACKGROUND: Although peritoneal dialysis (PD) is becoming more widespread, PD among diabetic patients carries some concerns, such as worsened glycemic control due to constant exposure to glucose and operational errors due to diabetic complications. However, several technical advances could overcome these disadvantages. We, therefore, aimed to compare technical and patient survival between diabetic and non-diabetic PD patients. METHODS: We conducted a historical cohort study of 103 patients (mean age, 57 ± 16 years; 75 males, 32 diabetic patients) who started PD between January 2011 and January 2016. Kaplan-Meier survival analysis was used to compare technical and patient survivals between diabetic and non-diabetic patients. Multivariate Cox regression analysis was used to estimate the effects of the presence of diabetes on these outcomes. RESULTS: Technical and patient survivals did not differ significantly between groups (P = 0.62, P = 0.34, respectively). In addition, presence of diabetes affected neither technical nor patient survival in multivariate analysis (hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.58-2.82 and HR 0.80; 95% CI 0.22-2.68, respectively). CONCLUSIONS: Technical and patient survivals of diabetic PD patients were not inferior to those of non-diabetic PD patients. These results suggest that no hesitation is warranted in initiating PD for diabetic patients with end-stage renal disease.

Long-term effects of etelcalcetide as intravenous calcimimetic therapy in hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a serious major complication in hemodialysis patients with chronic kidney disease. Long-term maintenance of serum phosphate, calcium, and parathyroid hormone (PTH) levels in appropriate ranges in these patients is a major challenge. We investigated the efficacy and safety of long-term treatment with etelcalcetide, a novel intravenous calcimimetic, in Japanese SHPT patients on long-term hemodialysis. METHODS: This study was a multicenter open-label study. A total of 191 hemodialysis patients with serum intact PTH (iPTH) > 240 pg/mL were enrolled. Etelcalcetide was administered thrice weekly for 52 weeks, with an initial dose of 5 mg and flexibility to adjust the dose between 2.5 and 15 mg and to adjust the dosing of concomitant medications for SHPT. The efficacy endpoint was the proportion of patients with serum iPTH decreased to the target range (60-240 pg/mL). RESULTS: Serum iPTH levels decreased immediately after etelcalcetide was started. At the end of the study, 87.5% (95% confidence interval 81.4-92.2; 140/160 patients) of patients achieved target serum iPTH levels, with control of serum calcium and phosphate levels. Adverse events, mostly mild to moderate, were reported by 96.8% of patients and led to study discontinuation in 7.4% of patients. Nausea, vomiting, and symptomatic hypocalcemia were found in 4.7, 9.5, and 1.1%, with 0.5, 1.1, and 1.1% considered treatment-related. CONCLUSIONS: Etelcalcetide effectively maintained serum iPTH, calcium, and phosphate levels in appropriate ranges with concomitant medications for SHPT for 52 weeks in Japanese hemodialysis patients, and was safe and well tolerated. REGISTRATION NUMBER: JapicCTI-142665.

A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a major complication associated with chronic kidney disease. We evaluated the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, in Japanese haemodialysis patients with SHPT. METHODS: In this phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, etelcalcetide was administered three times per week at an initial dose of 5 mg, and subsequently adjusted to doses between 2.5 and 15 mg at 4-week intervals for 12 weeks. A total of 155 SHPT patients with serum intact parathyroid hormone (iPTH) levels ≥300 pg/mL were assigned to receive etelcalcetide (n = 78) or placebo (n = 77). The primary endpoint was the proportion of patients with decreased serum iPTH to the target range proposed by the Japanese Society for Dialysis Therapy (60-240 pg/mL). The major secondary endpoint was the proportion of patients with ≥30% reductions in serum iPTH from baseline. RESULTS: The proportion of patients meeting the primary endpoint was significantly higher for etelcalcetide (59.0%) versus placebo (1.3%). Similarly, the proportion of patients meeting the major secondary endpoint was significantly higher for etelcalcetide (76.9%) versus placebo (5.2%). Serum albumin-corrected calcium, phosphorus and intact fibroblast growth factor-23 levels were decreased in the etelcalcetide group. Nausea, vomiting and symptomatic hypocalcaemia were mild with etelcalcetide. Serious adverse events related to etelcalcetide were not observed. CONCLUSIONS: This study demonstrated the efficacy and safety of etelcalcetide. As the only available intravenous calcium-sensing receptor agonist, etelcalcetide is likely to provide a new treatment option for SHPT in haemodialysis patients.

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.

A 12-week dose-escalating study of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese hemodialysis patients
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AIMS: To evaluate dose-escalation of etelcalcetide (ONO-5163/AMG 416), a novel, intravenous (IV), long-acting calcium-sensing receptor agonist, for treatment of secondary hyperparathyroidism (SHPT) in Japanese hemodialysis patients. MATERIALS AND METHODS: In this multicenter study, IV injections of etelcalcetide (3 times a week for 12 weeks) were administered, with dose escalation every 4 weeks depending on changes in serum intact parathyroid hormone (iPTH) and corrected calcium (cCa). A total of 24 patients participated in this study. RESULTS: Serum iPTH was reduced in a time- and dose-dependent manner, with reductions (in pg/mL) at 12 weeks of -226.1 ± 125.3, -362.5 ± 161.5, and -412.4 ± 130.2, respectively, for maximum doses of 5, 10, and 15 mg. At the end of the treatment, 50% of patients had serum iPTH levels within the target range (60 - 240 pg/mL). Serum cCa and phosphorus were reduced in parallel with iPTH. Adverse events (AEs) occurred in 20 patients (83.3%). The most frequently observed AEs (> 10%) were either mild or moderate nasopharyngitis (29.2%), decreased serum calcium (16.7%), and vomiting (12.5%). CONCLUSIONS: Dose-escalated triweekly etelcalcetide was effective for SHPT in Japanese hemodialysis patients and was satisfactorily tolerated.
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Management of phosphorus load in CKD patients.

Disturbances in mineral and bone metabolism play a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). The term "renal osteodystrophy" has recently been replaced with "CKD-mineral and bone disorder (CKD-MBD)", which includes vascular calcification as well as bone abnormalities. In Japan, proportions of the aged and long-term dialysis patients are increasing which makes management of vascular calcification and parathyroid function increasingly more important. There are three main strategies to manage phosphate load: phosphorus dietary restriction, administration of phosphate binder and to ensure in the CKD 5D setting, an adequate dialysis.

Recurrence and graft loss after renal transplantation in adults with IgA vasculitis.

BACKGROUND: IgA vasculitis, a rare condition resulting in end-stage renal disease, is a small-vessel vasculitis that affects the kidney in 49-83 % of adults. The reported recurrence rate of IgA vasculitis in renal transplant recipients is 11.5-60 %, leading to graft loss in 0-50 % of these patients. However, limited data are available on recurrence and graft loss after renal transplantation. METHODS: We evaluated renal transplant recipients seen from 1987 to 2015 at the Jikei University School of Medicine and the Department of Urology, Tokyo Women's Medical University. Using a 1:2 match, 21 patients with IgA vasculitis and 42 controls were selected. The mean post-transplant follow-up was 121 ± 69 months for IgA vasculitis and 147 ± 66 months for the controls. RESULTS: The 15-year patient survival was 100 % in IgA vasculitis and 97.6 % in the controls (p = 0.22). The 5-, 10-, and 15-year graft survival rates were 95.2, 90.5, and 81 % in IgA vasculitis and 100, 90.5, and 88.1 % in the controls, respectively (p = 0.63). The recurrence rate was 28.6 % (6 of 21 cases) and half of them (3 of 6 cases) showed histological activity (ISKDC III). We treated them with methylprednisolone pulse therapy and/or tonsillectomy. None of the recurrence cases lost the allograft. CONCLUSION: The long-term patient and graft survival of IgA vasculitis in renal transplantation were comparable with the previous reports. The recurrence rate was 28.6 %, but none of the recurrent cases showed allograft loss in this study. We speculate that methylprednisolone pulse therapy and/or tonsillectomy prevent the progression of recurrent IgA vasculitis.

Possible prevention of uremic nausea by vitamin D receptor activators in non-dialysis patients with stage 5 chronic kidney disease.

BACKGROUND: Nausea is a major uremic symptom and a frequent indication for starting dialysis. However, preventive medication for uremic nausea has not yet been identified. Vitamin D receptor activators (VDRAs) may prevent uremic nausea via their pleiotropic actions. The objective of this study was to explore whether VDRA administration during the predialysis period is associated with a reduced prevalence of uremic nausea just prior to beginning dialysis. METHODS: A multicenter, retrospective, cross-sectional study was performed to identify a medication to prevent uremic nausea. Patients with stage 5 CKD who were followed-up over 3 months were included. The primary outcomes examined were the prevalence of uremic nausea, congestive heart failure (CHF), and intractable edema at dialysis commencement. The predictor variable was VDRA use during the predialysis period. RESULTS: One thousand five hundred and thirty six patients who had just begun dialysis in nine Japanese facilities between January 2006 and October 2013 were included. Two hundred and thirty (15.0%) patients had commenced dialysis because of uremic nausea, and three hundred and ninety two (25.5%) patients had been using VDRAs before initiating dialysis. Logistic regression analysis showed that, among the medications examined in this study, only VDRA use was independently associated with a lower frequency of uremic nausea (OR 0.512, 95% CI 0.347-0.738, P = 0.0003). On the other hand, CHF and intractable edema were not associated with VDRA administration. CONCLUSION: Use of VDRAs during the predialysis period was the only factor associated with a lower prevalence of uremic nausea, suggesting that VDRAs may prevent uremic nausea in patients with advanced CKD.

Efficacy and safety of sucroferric oxyhydroxide compared with sevelamer hydrochloride in Japanese haemodialysis patients with hyperphosphataemia: A randomized, open-label, multicentre, 12-week phase III study.

AIM: We aimed to investigate the non-inferiority of PA21 (sucroferric oxyhydroxide) to sevelamer hydrochloride (sevelamer) in terms of efficacy and safety in Japanese haemodialysis patients with hyperphosphataemia. METHODS: In this Phase III, open-label, multicentre study, 213 haemodialysis patients with hyperphosphataemia were randomized to PA21 or sevelamer treatment for 12 weeks. The primary outcome was adjusted serum phosphorus concentration at the end of treatment; the non-inferiority of PA21 was confirmed if the upper limit of the two-sided 95% confidence interval (CI) is ≤0.32 mmol/L. Secondary outcomes were corrected serum calcium and intact-parathyroid hormone concentrations. Adverse events (AEs) and adverse drug reactions (ADRs) were evaluated. RESULTS: The adjusted mean serum phosphorus concentration at the end of treatment confirmed the non-inferiority of PA21 for lowering serum phosphorus compared with sevelamer (1.62 vs 1.72 mmol/L; difference, -0.11 mmol/L; 95% CI, -0.20 to -0.02 mmol/L). The mean daily tablet intake was 5.6 ± 2.6 and 18.7 ± 7.1 tablets in the PA21 and sevelamer groups, respectively. The incidences of AEs and ADRs were not significantly different between the two groups. CONCLUSION: The non-inferiority of PA21 to sevelamer was confirmed for the treatment of Japanese haemodialysis patients with hyperphosphataemia. PA21 was effective, safe, and well tolerated, while having a considerably lower pill burden than sevelamer.

Risk factors for encapsulating peritoneal sclerosis: Analysis of a 36-year experience in a University Hospital.

AIM: Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication that occurs in peritoneal dialysis (PD) therapy. The present study aimed to identify the risk factors, especially peritonitis and biocompatible PD fluid. METHODS: The study included 703 patients who received PD between January 1980 and March 2015 at two centres. The patients were divided into two groups: those who had developed EPS (EPS group: n = 44) and those who had no documentary evidence of EPS (non-EPS group: n = 659). The independent risks of EPS were determined by univariate and multivariate logistic models. RESULTS: Encapsulating peritoneal sclerosis occurred in 44/703 (6.3%) patients between January 1980 and March 2015. In multivariate logistic models of risk factors correlated with EPS, dialysate to plasma creatinine ratio (D/P Cr) by peritoneal equilibration test (PET) and history of peritonitis were risk factors for EPS development (P < 0.01, respectively) in addition to PD duration. Especially, total duration of peritonitis, defined by period between onset and resolution of peritonitis, was an important risk factor for EPS development in patients with a history of peritonitis. Receiver operating characteristic (ROC) curve analysis revealed that cut-off point for EPS development was 36 days. Moreover, biocompatible PD fluid contributed to decreased EPS development. CONCLUSION: Both the longer duration of peritonitis and higher D/P Cr, as well as the longer PD duration, were risk factors for EPS development. Furthermore, use of biocompatible PD fluid contributed to the decrease in EPS development.

Long-Term Assessment of the Safety and Efficacy of PA21 (Sucroferric Oxyhydroxide) in Japanese Hemodialysis Patients With Hyperphosphatemia: An Open-Label, Multicenter, Phase III Study.

OBJECTIVE: The objective of this article was to assess the safety and efficacy of long-term administration of PA21. DESIGN AND METHODS: Phase III, open-label, long-term study in 15 sites in Japan. SUBJECTS: Japanese hemodialysis patients (N = 161) with hyperphosphatemia aged ≥20 years undergoing stable maintenance hemodialysis 3 times weekly, for ≥12 weeks. INTERVENTION: After a 2-week observation period with their previous hyperphosphatemia therapy, patients began the 52-week treatment with PA21, which was administered orally at an initial dose of 250 mg, 3 times daily, immediately before every meal (dosing range between 750 and 3,000 mg/day). MAIN OUTCOME MEASURE: Safety was evaluated based on the development of adverse events and adverse drug reactions (ADRs). Efficacy was evaluated according to serum phosphorus concentration, corrected serum calcium concentration, and serum intact-parathyroid hormone concentration. RESULTS: The mean serum phosphorus concentration decreased from 5.46 ± 1.06 mg/dL at baseline to 5.00 ± 1.17 mg/dL at end of treatment. The serum phosphorus concentration was maintained within the target range (3.5-6.0 mg/dL) throughout the 52 weeks of the study period with a mean of 3.3 tablets per day of PA21. Most ADRs were mild, transient, and developed early during treatment, and the incidence was not shown to increase with long-term treatment. The most frequently reported ADR was diarrhea (22.4%). CONCLUSION: Treatment with PA21 was effective in lowering and maintaining target serum phosphorus concentrations in Japanese hemodialysis patients with hyperphosphatemia over 52 weeks. PA21 was generally well tolerated in the long term.

The differences in acid-base status and the calcium parathyroid axis between peritoneal dialysis and hemodialysis.

BACKGROUND: Several guidelines have set the target levels of serum Ca, phosphorus, and parathyroid hormone (PTH) for better management of chronic kidney disease-mineral and bone disorders (CKDMBD) in dialysis patients. Although serum ionized Ca (iCa) is a biologically active component, corrected Ca (cCa) is used in clinical settings. However, the association between iCa and cCa is affected by acid-base status. We investigated the difference in acid-base and the calcium-parathyroid status between hemodialysis (HD) and peritoneal dialysis (PD). METHODS: The markers associated with CKD-MBD were measured in 142 patients receiving chronic dialysis (69 on PD and 73 on HD). RESULTS: Serum bicarbonate levels were significantly higher in the PD group than in the HD group (26.6 ± 2.8 vs. 22.9 ± 2.0 mEq/L, p < 0.01). The serum iCa levels and the iCa/cCa ratio were significantly lower in the PD group than in the HD group (iCa 1.07 ± 0.08 vs. 1.14 ± 0.08 mmol/L, p < 0.01; iCa/cCa ratio 45.5 ± 3.1% vs. 49.7 ± 3.2%, p < 0.01). The cCa levels were significantly higher in the PD group than in the HD group (9.4 ± 0.4 vs. 9.1 ± 0.4 mg/dL, p < 0.01). Intact PTH levels were significantly higher in the PD group than in the HD group (220 (40 - 581) vs. 133 (30 - 666) pg/mL, p < 0.01). CONCLUSIONS: We found that PD patients had lower iCa and higher PTH levels despite higher cCa levels as compared to HD patients. These results suggested that the assessment of both Ca and PTH should be different between PD and HD.

Associations among serum trimethylamine-N-oxide (TMAO) levels, kidney function and infarcted coronary artery number in patients undergoing cardiovascular surgery: a cross-sectional study.

BACKGROUND: Trimethylamine-N-oxide (TMAO) is a metabolite of phosphatidylcholine generated by gut microbiota and liver enzymes, and has recently been recognized as contributing to atherosclerosis. Elevated serum TMAO levels have been shown to increase the risk of cardiovascular disease (sudden death, myocardial infarction, or stroke) in patients undergoing elective coronary angiography. We aimed to clarify whether TMAO levels are associated with the number of infarcted coronary arteries as a measure of the severity of atherosclerosis, with adjustment using a priori-defined covariates such as kidney function. METHODS: By conducting a cross-sectional study of 227 patients who underwent cardiovascular surgery for coronary artery disease, valvular heart disease, or aortic disease, the association between serum TMAO levels as measured by HPLC-APCI-MS/MS and the number of infarcted coronary arteries was evaluated using ordered logistic regression models with adjustment of 10 covariates, including chronic kidney disease (CKD) stage. Unadjusted and adjusted odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were determined. RESULTS: Significantly higher TMAO levels were observed in advanced-stage CKD (p ≤ 0.001). In fully adjusted models with the 10 covariates, a significantly increased number of infarcted coronary arteries was identified in the highest quartile and quintile of TMAO compared to the lowest quartile (OR 11.9; 95 % CI 3.88-36.7, p ≤ 0.001) and quintile (OR 14.1; 95 % CI 3.88-51.2; p ≤ 0.001), respectively, independent of dyslipidemia. CONCLUSIONS: Higher serum TMAO levels may be associated with advanced CKD stages and with an increased number of infarcted coronary arteries in patients who undergo cardiovascular surgery.

[Phosphate metabolism and iron deficiency].

Autosomal dominant hypophosphatemic rickets(ADHR)is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage. Fibroblast growth factor 23(FGF23)is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. Low iron status plays a role in the pathophysiology of ADHR. Iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. It was reported that FGF23 elevation in patients with CKD, who are often iron deficient. In patients with nondialysis-dependent CKD, treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and FGF23.