Long-term Efficacy and Safety of Upacicalcet in Japanese Hemodialysis Patients with Secondary Hyperparathyroidism: Open-label 52-week Study.

Introduction Upacicalcet is a novel injectable calcimimetic. This phase 3 multicenter open-label study aimed to assess the long-term efficacy and safety of upacicalcet in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). Methods Japanese HD patients with serum intact parathyroid hormone (iPTH) levels >240 pg/mL and corrected calcium (cCa) levels ≥8.4 mg/dL were enrolled. Upacicalcet with a dose range of 25-300 µg was administered after each dialysis for 52 weeks. The main efficacy endpoint was the percentage of patients achieving the target iPTH level (60-240 pg/mL). Results A total of 157 patients were enrolled, of whom 138 completed the study. Overall, 94.2% of patients achieved the target serum iPTH level at week 52. Neither symptomatic hypocalcemia nor cCa level <7.5 mg/dL occurred despite the negligible increase of concomitant vitamin D receptor activators and calcium carbonate. Upacicalcet improved the control of serum phosphate (P) and calcium levels regardless of baseline PTH levels and decreased intact fibroblast growth factor-23 levels. The largest parathyroid glands shrank, irrespective of their baseline volume or prior calcimimetic usage. Upacicalcet was well-tolerated, with no adverse events requiring dose reduction. Conclusion This is the first study to show that a calcimimetic improves serum P and cCa control without inducing severe hypocalcemia in patients with iPTH levels ≤300 pg/mL. Upacicalcet is efficacious in HD patients with mild-to-severe SHPT, with few safety concerns.

Effects of evocalcet on parathyroid calcium-sensing receptor and vitamin D receptor expression in uremic rats.

Little is known about the effect of the recently developed calcimimetic evocalcet (Evo) on parathyroid calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression. We examined the effects of Evo and cinacalcet (Cina) on CaSR and VDR expression in 5/6 nephrectomized Sprague-Dawley rats fed a high-phosphorus diet for 4 weeks to develop secondary hyperparathyroidism (SHPT). These uremic rats were divided into 4 groups-baseline control (Nx4W) and groups with additional treatment with either the Vehicle, Evo, or Cina for 2 weeks; normal rats were used as normal controls (NC). Blood parameters and parathyroid tissue were analyzed. CaSR and VDR expression levels were determined using immunohistochemistry. The degree of kidney injury and hyperphosphatemia was similar in the uremic groups (Nx4W, Vehicle, Cina, and Evo). Serum parathyroid hormone levels were significantly higher in the Nx4W and Vehicle groups than in the NC group. This increase was significantly suppressed in the Cina and Evo groups compared with that in the Vehicle group. Serum calcium levels were significantly and equally lower in the Cina and Evo groups relative to those in the Vehicle group. CaSR expression was significantly lower in the Nx4W and Vehicle groups than in the NC group. This downregulation was of an equally lesser magnitude in the Cina and Evo groups. A similar trend was observed for VDR expression. These results indicate that Evo and Cina treatment can increase parathyroid CaSR and VDR expression in uremic rats with SHPT, which could provide better control of mineral and bone disorder markers.

Fibroblast Growth Factor 23 Exacerbates Cardiac Fibrosis in Deoxycorticosterone Acetate-Salt Mice With Hypertension.

Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease; however, the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model with mild chronic kidney disease and hypertension as well as heart failure with a preserved ejection fraction. Wild-type male mice were randomly allocated to 4 groups: normal control, vehicle-treated DOCA-salt mice, FGF23-treated DOCA-salt mice, and FGF23- and calcitriol-treated DOCA-salt mice. The DOCA-salt mice received the agents via the CIV route for 10 days using an infusion minipump. DOCA-salt mice that received FGF23 showed a marked increase in the serum FGF23 level, and echocardiography in these mice revealed heart failure with a preserved ejection fraction. These mice also showed exacerbation of myocardial fibrosis, concomitant with an inverse and significant correlation with Cyp27b1 expression. Calcitriol treatment attenuated FGF23-induced cardiac fibrosis and improved diastolic function via inhibition of transforming growth factor-ß signaling. This effect was independent of the systemic and local levels of FGF23. These results suggest that CIV FGF23 loading exacerbates cardiac fibrosis and that locally abnormal vitamin D metabolism is involved in this mechanism. Calcitriol attenuates this exacerbation by mediating transforming growth factor-ß signaling independently of the FGF23 levels.

Optimal Phosphate Control Related to Coronary Artery Calcification in Dialysis Patients.

BACKGROUND: In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC). Hyperphosphatemia has been reported to be associated with the severity of CAC. However, the optimal phosphate range in patients on dialysis remains unknown. This study was planned to compare the effects on CAC progression of two types of noncalcium-based phosphate binders and of two different phosphate target ranges. METHODS: We conducted a randomized, open-label, multicenter, interventional trial with a two by two factorial design. A total of 160 adults on dialysis were enrolled and randomized to the sucroferric oxyhydroxide or lanthanum carbonate group, with the aim of reducing serum phosphate to two target levels (3.5-4.5 mg/dl in the strict group and 5.0-6.0 mg/dl in the standard group). The primary end point was percentage change in CAC scores during the 12-month treatment. RESULTS: The full analysis set included 115 patients. We observed no significant difference in percentage change in CAC scores between the lanthanum carbonate group and the sucroferric oxyhydroxide group. On the other hand, percentage change in CAC scores in the strict group (median of 8.52; interquartile range, -1.0-23.9) was significantly lower than that in the standard group (median of 21.8; interquartile range, 10.0-36.1; P=0.006). This effect was pronounced in older (aged 65-74 years) versus younger (aged 20-64 years) participants (P value for interaction =0.003). We observed a similar finding for the absolute change in CAC scores. CONCLUSIONS: Further study with a larger sample size is needed, but strict phosphate control shows promise for delaying progression of CAC in patients undergoing maintenance hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluate the New Phosphate Iron-Based Binder Sucroferric Oxyhydroxide in Dialysis Patients with the Goal of Advancing the Practice of EBM (EPISODE), jRCTs051180048.

Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although most IgAN cases are sporadic, few show a familial aggregation. However, the prevalence and prognosis of IgAN individuals with positive familial history (FH) of renal disorders remains uncertain. To address these issues, we conducted a longitudinal observational study on a single-institution cohort of patients with biopsy-proven IgAN. METHODS: A total of 467 IgAN patients who underwent renal biopsy during 1994 to 2019 were ascertained to have positive- or negative-FH by history taking and were followed for an average of 8.9 years. We compared the clinical and pathological features of the two subgroups. The primary outcome, a composite of a hard endpoint (end-stage renal disease [ESRD]) and surrogate endpoint (a 50% or more reduction in the estimated glomerular filtration rate [eGFR] from baseline), was evaluated. To estimate the risk for progression to ESRD, a Cox proportional hazards analysis was performed for a subset of patients who underwent follow-up for > 2 years and had an eGFR > 30 mL/min/1.73 m2 at baseline (n = 389; observation, 8.7 years). RESULTS: Positive-FH subtype accounted for 11.6% (n = 54) of all IgAN patients. At baseline, there were no significant differences between the positive- and negative-FH subgroups regarding age, sex, comorbid disease, MEST-C score, observation period, and therapeutic interventions. However, the eGFR value at baselines was significantly lower in the positive-FH subgroup than in the negative-FH subgroup (P < 0.01). On multivariate analysis, positive-FH emerged an independent determinant of poorer renal outcomes (odds ratio, 2.31; 95% confidence interval, 1.10-4.85; P = 0.03), after adjusting for confounding factors. eGFR at follow-up was significantly lower in the positive-FH subgroup than in the negative-FH subgroup after adjustment for age and observation period. CONCLUSIONS: Positive-FH was found in 11.6% of all IgAN patients, consistent with the incidence seen in previous literature. A significantly lower eGFR at baseline and last follow-up and unfavorable renal outcomes in the positive-FH subgroup suggest that certain genetic risk factors predisposing to renal failure may exist in a fraction of our IgAN cohort. (331 words).

Early response of the parathyroid gland to withdrawal of a calcimimetic compound in uremic rats.

Little is known about changes in parathyroid cells when calcimimetics are withdrawn. We examined the response of parathyroid glands to cinacalcet (Cina) withdrawal in uremic Sprague-Dawley rats fed a high-phosphate diet to develop secondary hyperparathyroidism and divided into groups treated with vehicle (UC), Cina, and Cina and maxacalcitol (Maxa), a vitamin D receptor activator (CiNa + Maxa). After 2 wk of treatment, vehicle and Cina were withdrawn and Maxa was continued. Rats were analyzed immediately (day 0) and 7 days (day 7) after withdrawal. The Cina and CiNa + Maxa groups had significantly lower parathyroid hormone (PTH) than the UC group on day 0, although PTH in the Cina group reached UC levels on day 7. On day 0, there were significantly more proliferating cell nuclear antigen-positive cells in the UC group compared with normal controls, and this increase was significantly suppressed in the Cina and CiNa + Maxa groups. On day 7, the Cina group, but not the CiNa + Maxa group, showed a significant increase in proliferating cell nuclear antigen-positive cells compared with the UC group. This increase was related to parathyroid cell diameter regression to UC levels, whereas combination treatment maintained diameter suppression. These results indicate that parathyroid growth activity is stimulated by Cina withdrawal, although the PTH level was not further increased. Continuous administration of Cina may be required for optimal control of secondary hyperparathyroidism, and simultaneous use of a vitamin D receptor activator may be advisable during Cina withdrawal.

Clinical prediction models for progression of chronic kidney disease to end-stage kidney failure under pre-dialysis nephrology care: results from the Chronic Kidney Disease Japan Cohort Study.

BACKGROUND: Reliable prediction tools are needed to identify patients with chronic kidney disease (CKD) at greater risk of developing end-stage kidney failure (ESKF). We developed and validated clinical prediction models (CPMs) for CKD progression to ESKF under pre-dialysis nephrology care using CKD-Japan Cohort (CKD-JAC) data. METHODS: We prospectively followed up 2034 participants with CKD, defined as an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2, aged 20-75 years for a mean of 3.15 years. We randomly divided the overall analysis set into development and validation cohorts. In the development cohort, CPMs were developed using Cox proportional hazard regression, and the goodness of fit was evaluated. In the validation cohort, discrimination and calibration of the developed CPMs were evaluated. We also validated developed CPMs in the dataset with the bootstrap method. RESULTS: ESKF onset was observed in 206 and 216 patients in the development (20.3%) and validation (21.2%) cohorts, respectively. Goodness of fit, discrimination, and calibration were worse for a simple model including age, sex, and eGFR than for a complicated model (plus albuminuria, systolic blood pressure, diabetes, serum albumin, and hemoglobin). The mean absolute difference between the observed and predictive probabilities of ESKF onset at 3 years was lower for the complicated model than for the simple model (1.57 vs. 1.87%). CONCLUSIONS: CPMs employing readily available data could precisely predict progression to ESKF in patients with CKD stage G3a to G5. These developed CPMs may facilitate more appropriate clinical care and shared decision-making between clinicians and patients.

Association between serum Na-Cl level and renal function decline in chronic kidney disease: results from the chronic kidney disease Japan cohort (CKD-JAC) study.

BACKGROUND: Metabolic acidosis, which reduces serum bicarbonate levels, contributes to the progression of chronic kidney disease (CKD). The difference between sodium and chloride (Na-Cl) may theoretically predict serum bicarbonate levels. This study aimed to evaluate serum Na-Cl level as a risk factor for renal function decline among patients who participated in the chronic kidney disease Japan cohort (CKD-JAC) study. METHODS: The association between low Na-Cl concentration (< 34 mmol/L) and composite renal function decline events (any initiation of renal replacement therapy or 50% decline in estimated glomerular filtration rate) was evaluated among 2143 patients with CKD stage G3a-4. Using Cox regression analysis, hazard ratios (HRs) were estimated after adjusting for the following covariates: age, sex, diabetes mellitus, diabetic nephropathy, cardiovascular disease, anemia, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, loop diuretics, cigarette smoking, body mass index, serum albumin, systolic blood pressure, urine albumin-to-creatinine ratio, and CKD stage. RESULTS: Composite renal function decline events were observed in 405 patients (18.9%) over the 4-year follow-up period. Low serum Na-Cl level (< 34 mmol/L) was independently associated with a greater risk for composite renal function decline events (HR 1.384; 95% confidence interval [CI], 1.116-1.717). Subgroup analyses identified that the association between low Na-Cl level and composite renal function decline events was stronger among patients with CKD stage G4 and those with anemia. CONCLUSIONS: Our investigation suggests that Na-Cl is an independent predictor of CKD progression, especially among patients with CKD stage G4 and those with anemia.

Truncal Adiposity Influences High-Density Lipoprotein Cholesterol Levels and Cardiovascular Events in Hemodialysis Patients.

OBJECTIVE: Adiposity influences lipid metabolism and atherosclerotic cardiovascular disease (CVD) in the general population. The aim of the present study was to assess the association between fat mass (FM) and lipid metabolism and CVD events among patients on hemodialysis (HD). METHODS: This prospective observational study examined 240 patients on prevalent HD. Blood samples were obtained before dialysis at baseline to measure lipids, high-sensitivity C-reactive protein (hs-CRP), interleukin-6, and adiponectin. Lipids and hs-CRP were measured every 3 months for 12 months. FM was estimated by dual energy x-ray absorptiometric scan at baseline and 12 months later. Patients were then prospectively followed up for 36 months after the 1-year measurement period, and composite CVD events were estimated. RESULTS: Truncal FM was positively correlated with body mass index, hs-CRP, interleukin-6, total cholesterol, low-density lipoprotein-C, triglyceride, and negatively correlated with high-density lipoprotein (HDL)-C and adiponectin at baseline. HDL-C levels were repeatedly decreased, and triglyceride and non-HDL-C were serially increased in the patient group with truncal FM > 7,000 g at both baseline and 12 months (large truncal FM group) compared with the other groups. Cox proportional hazards models adjusted for confounders showed composite CVD events occurred significantly in patients with large truncal FM and continuous low HDL-C levels. CONCLUSIONS: Truncal adiposity influences lipid metabolism in patients on HD, and the prevalence of CVD events may be increased in those patients with high fat and lipid abnormalities, especially continuously low HDL-C levels.

Association of Circulatory Iron Deficiency With an Enlarged Heart in Patients With End-Stage Kidney Disease.

OBJECTIVES: High prevalence of iron deficiency (ID) and cardiomyopathy have been observed in patients with end-stage kidney disease (ESKD). Our objective was to clarify associations between ID and cardiac remodeling in patients with ESKD. DESIGN AND METHODS: A cross-sectional study was conducted using 1974 Japanese patients with ESKD at the initiation of maintenance dialysis. Levels of hemoglobin (Hb), iron status, and cardiac enlargement as assessed by the cardiothoracic ratio (CTR) were determined immediately before the first hemodialysis session. Circulatory ID was defined as transferrin saturation (TSAT) < 20%, and stored ID was defined as ferritin level <100 ng/dL. RESULTS: The mean age was 67 years. Median CTR was 54.0%. The prevalence of circulatory and stored ID was found to be 38% and 34%, respectively. CTR was higher in patients with circulatory ID than in those without. Even in ESKD patients without overhydration, significant negative association was observed between TSAT and CTR. Higher odds ratios in parallel with higher CTR categories compared with the reference category of CTR <45% were found in patients with TSAT <20% on multinomial analysis, but ferritin did not show any significant associations. The odds ratio for CTR >54% showed an upward trend in patients with TSAT <20% (odds ratio: 1.3) and <10% (odds ratio: 1.6) compared with the reference, even after adjusting for confounding variables such as Hb and ferritin. However, that phenomenon was eliminated by adding usage of an iron agent. CONCLUSIONS: Circulatory ID is closely associated with an enlarged heart independent of ferritin and Hb. Iron supplementation in the predialysis phase of chronic kidney disease may prevent cardiac remodeling independent of Hb level in patients chronic kidney disease.

A mutation in transcription factor MAFB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome.

Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MAFB, a leucine zipper transcription factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MAFB recognition element. Additionally, immunohistochemistry indicated reduced MAFB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MAFB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MAFB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.

Effect of Continuous Intravenous Calcium Loading on Fibroblast Growth Factor 23 in Normal and Uremic Rats.

Fibroblast growth factor 23 (FGF23) is associated with mortality in patients with CKD. However, the mechanisms underlying stimulation of FGF23 remain to be investigated. We examined whether hypercalcemia induced by continuous intravenous (CIV) calcium (Ca) infusion regulates FGF23 levels in normal rats (Normal) and 5/6 nephrectomized uremic rats (Nx). Microinfusion pumps were implanted in the Normal and Nx rats for CIV Ca infusion, and blood, urine, kidney, and tibia were collected. The results showed an increase in serum Ca-stimulated FGF23 independently of serum phosphate (P) and creatinine levels in Normal and Nx rats. FGF23 mRNA from the tibia was also increased by the Ca infusion. Despite high FGF23 levels after Ca infusion, urinary P excretion was decreased. Renal α-Klotho expression was significantly reduced by Ca infusion. These results suggest that intravenous Ca loading might stimulate FGF23 production from bone in normal and uremic rats. Reduction of renal P excretion suggests that the bioactivity of FGF23 is inhibited, and the decrease in renal α-Klotho expression might have a role in this pathological process. In conclusion, CIV Ca loading increased FGF23 in normal and uremic rats, and renal α-Klotho is necessary to maintain the bioactivity of FGF23 as a phosphaturic factor.

Anemia in conventional hemodialysis: Finding the optimal treatment balance.

Renal anemia is a serious and common complication in hemodialysis (HD) patients. The introduction of erythropoiesis-stimulating agents (ESAs) has dramatically improved hemoglobin levels and outcomes. Several interventional studies reported that excessive correction of anemia and the massive use of ESA can trigger cardiovascular disease (CVD), and consequently may worsen the prognosis of patients undergoing HD. Therefore, it has been widely recognized that large doses of ESA should be used with caution. An effective use of iron preparations is required to yield the optimal effect of ESA. It is well-known that iron utilization is inhibited under pathological conditions, such as chronic inflammation, resulting in ESA resistance. It is postulated that a new class of therapeutic agents for renal anemia, hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitors, will have beneficial treatment effects in patients on HD. HIF is induced by hypoxia and promotes erythropoietin production. In the absence of a hypoxic state, HIF is decomposed by the HIF catabolic enzyme. HIF-PH inhibitors inhibit this degrading enzyme and stimulate endogenous erythropoietin production via HIF induction. Additionally, HIF-PH inhibitors promote effective utilization of iron and raise erythropoietin to physiological concentrations. Accordingly, HIF-PH inhibitors improve anemia and iron metabolism. It appears that this effect persists irrespective of chronic inflammatory conditions. HIF-PH inhibitors do not overshoot erythropoietin above physiological concentrations like ESAs. Therefore, it is hypothesized that HIF-PH inhibitors would not increase the risk of CVD in patients undergoing HD.

Practice pattern of physician's directions of exercise restriction in patients with chronic kidney disease: results from the Chronic Kidney Disease Japan Cohort study.

BACKGROUND: The practice patterns of exercise restrictions for patients with chronic kidney disease have not been adequately evaluated yet; thus, we examined them using a cross-sectional design and explored the factors related with those restrictions. METHODS: The Chronic Kidney Disease Japan Cohort study was a multicentre cohort study of Japanese patients (age 20-75 years) living in Japan. We used the information in the questionnaire on the restriction of physical activities offered by physicians to the patients during enrolment. We initially considered and used the following data as the clinical factors that the physician used for decision making on the directions of restriction of physical activities: age, sex, cause of chronic kidney disease (CKD), comorbid diseases, body mass index (BMI), systolic blood pressure, estimated glomerular filtration rate (eGFR) and urine albumin. The logistic regression model was used to explore the factors and estimate their adjusted odds ratio with regard to physician's direction of restriction of physical activities. RESULTS: Physician's direction of exercise restrictions was implemented in 9.9% of the participants. In 17 facilities, the proportion of physician's direction of exercise restriction ranged from 2.9 to 17.8%. The logistic regression analysis showed that the proportion of the factors such as younger age, cardiovascular disease, congestive heart failure and lower eGFR was higher in patients with physician's direction of exercise restrictions. CONCLUSIONS: The findings from this study suggested the factors related with prescribing exercise restrictions. Further studies examining which patients with CKD need direction of exercise restrictions are needed.

Dose-response efficacy and safety of PA21 in Japanese hemodialysis patients with hyperphosphatemia: a randomized, placebo-controlled, double-blind, Phase II study.

BACKGROUND: Hyperphosphatemia is common in chronic kidney disease (CKD) and associated with mortality and morbidity. We aimed to evaluate the dose-dependent efficacy and safety of PA21 (sucroferric oxyhydroxide), an iron-based phosphate binder, in Japanese hemodialysis patients with hyperphosphatemia. METHODS: In this double-blind, multicenter, Phase II study, 183 patients were randomized to placebo or PA21 at doses of 250, 500, 750, or 1000 mg (based on iron content) three times/day for 6 weeks. The primary efficacy endpoint was the mean change in serum phosphorus levels from baseline to end of treatment in each group. Adverse reactions were evaluated. RESULTS: The change in serum phosphorus level was significantly greater in each PA21 group than in the placebo group (analysis of covariance: P < 0.001 for all groups). A dose-dependent change in serum phosphorus levels was observed in the PA21 groups. A notable decrease in mean serum phosphorus levels to the target level of ≤6 mg/dL was shown starting at Week 1 in all PA21 groups. The cumulative achievement rates for target serum phosphorus level at the end of treatment were generally >80 % in all PA21 groups. The major adverse reaction reported was diarrhea; however, most cases were mild. CONCLUSIONS: PA21 was an effective and safe treatment that decreased serum phosphorus levels starting at 1 week of treatment when administered as one 250-mg tablet three times/day. PA21 demonstrated a dose-dependent phosphorus lowering effect up to 3000 mg/day. PA21 may be a new treatment alternative with relatively low pill burden for Japanese hemodialysis patients with hyperphosphatemia.

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.

Research on kidney and mineral metabolism in Japan: past, present, and future.

Since the identification of the kidney was the main site for the synthesis of calcitriol (1α, 25-dihydroxycholecalciferol), research on chronic kidney disease (CKD)-associated mineral metabolism disorders and their management has made rapid progress. Various active analogues of calcitriol have clinically become available for treating secondary hyperparathyroidism (SHPT), which is a representative mineral metabolism abnormality in CKD patients. A calcimimetic compound cinacalcet hydrochloride has also been developed for the medical management of SHPT through a different mechanism involving the calcium-sensing receptor. The concept of CKD-mineral and bone disorder (CKD-MBD) was proposed in 2006 to provide a comprehensive understanding of a disorder related to mineral metabolism abnormalities of CKD, based on the fact that these abnormalities are closely associated with cardiovascular disease as well as bone disorders (renal osteodystrophy). There has been a recent surge in the development of phosphate binders for CKD-MBD, focused on an effort to improve mortality. In Japan, high-quality basic and clinical research on CKD-MBD has led to the development of novel therapeutic drugs, such as maxacalcitol, falecalcitriol, and bixalomer. New practice guidelines have been published and are widely adapted in clinical practice.

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.

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.