Bisphosphonate FYB-931 Prevents High Phosphate-Induced Vascular Calcification in Rat Aortic Rings by Altering the Dynamics of the Transformation of Calciprotein Particles.

Patients with chronic kidney disease develop vascular calcification, owing to impaired calcium and phosphate metabolism. The prevention of vascular calcification is important to improve the prognosis of such patients. In this study, we investigated whether treatment with FYB-931, a novel bisphosphonate compound, prevents vascular calcification in rat aortic rings cultured in high-phosphate medium for 9 days, assessed by measurement of the calcium content and the degree of calcium deposition, visualized using von Kossa staining. The effect on the transformation of calciprotein particles (CPPs) from primary to secondary CPPs was assessed using a fluorescent probe-based flow cytometric assay. FYB-931 dose-dependently prevented high phosphate-induced aortic calcification, but failed to rapidly cause the regression of high phosphate-induced vascular calcification once it had developed. Furthermore, the treatment dose-dependently inhibited the high phosphate-induced transformation from primary to secondary CPPs. In addition, the treatment with FYB-931 prevented the transformation from primary to secondary CPPs in vitamin D3-treated rats as a model of ectopic calcification, consistent with the results from rat aortic rings. In conclusion, treatment with FYB-931 prevents high phosphate-induced rat aortic vascular calcification by altering the dynamics of CPP transformation. This finding suggests that inhibition of the transformation from primary to secondary CPPs is an important target for the prevention of vascular calcification in patients with chronic kidney disease.

[The prevention and treatment of vascular calcification.]

We had called the various bone disorder in chronic kidney disease(CKD)as a "ROD:renal osteodystrophy" until last decade. However the concept of ROD have changed into the chronic kidney disease-mineral and bone disease(CKD-MBD)within this decade. This concept is containing systemic disorder affected mortality. Vascular calcification is an independent risk factor for the development of cardiovascular disease and mortality. The best strategy to prevent and treat vascular calcification would consist of the CKD-MBD management. It is expected that the treatment of preventing directly vascular calcification to appear by finding the detailed mechanism in the future.

Dietary Changes Involving Bifidobacterium longum and Other Nutrients Delays Chronic Kidney Disease Progression.

BACKGROUND: Recent studies suggest that prebiotic and/or probiotic treatments ameliorate kidney function in humans and animals by improving the gut environment. However, the gut microbiota and kidney disease interactions remain to be determined. This study investigated whether synbiotics modulate the gut microbiota and ameliorate kidney function using a rat model of chronic kidney disease (CKD). As uremic toxins are associated with CKD-related mineral and bone disorder, the secondary aim was to evaluate the relationship between synbiotics and secondary hyperparathyroidism (SHPT). METHODS: 5/6 nephrectomy (Nx) rats were developed as the CKD model. Sham-operated (sham) rats were used as the control. To investigate the effectiveness of prebiotics (glutamine, dietary fiber, and oligosaccharide) and probiotics (Bifidobacterium longum strain; GFOB diet), rats were randomly assigned to 4 groups: Nx group fed the GFOB diet (n = 10); Nx group fed the control (CON) diet (n = 10); sham group fed the GFOB diet (n = 5); and sham group fed the control diet (n = 5). Blood, feces, and kidney samples were collected and analyzed. RESULTS: Serum creatinine (Cre) and blood urea nitrogen in the Nx GFOB group were significantly lower than those in the Nx CON group. Serum indoxyl sulfate in the Nx GFOB group was lower than that in the Nx CON group, and significantly correlated with serum Cre. Inorganic phosphorus and intact parathyroid hormone in the Nx GFOB group were significantly lower than those in the Nx CON group. CONCLUSION: Improving the gut environment using synbiotics ameliorated kidney function and might be a pharmacological treatment for SHPT without any serious adverse events.

Acute kidney injury: Epidemiology, outcomes, complications, and therapeutic strategies.

Acute kidney injury (AKI) is one of the most common serious complications for all hospital admissions, with its incidence increasing among hospitalized patients, particularly those in the intensive care unit. Despite significant improvements in critical care and dialysis technology, AKI is associated with an increased risk of short- and long-term mortality, prolonged hospital stays, and dialysis dependence. These risks are particularly relevant for critically ill patients with AKI severe enough to require renal replacement therapy (RRT). No specific pharmacologic treatment has been established to treat AKI. Hence, the mainstay treatment for patients with AKI is RRT even though there are still several problematic issues regarding its use including RRT modality, dose, and timing. Recently, the impact of AKI on an increased risk of progression to chronic kidney disease (CKD) and end-stage renal disease requiring dialysis or transplantation is attracting increased attention.

Expression and localization of fibroblast growth factor (FGF)23 and Klotho in the spleen: its physiological and functional implications.

The FGF23-Klotho signaling axis is known to exert anti-aging effects via calcium-phosphorus metabolism. In mice deficient in FGF23-Klotho signaling, however, the number of splenocytes is reduced. FGF23 is expressed in both bone and spleen, with regulation of its production differing in these organs. As FGF23-Klotho signaling may play an immunological role in the spleen, splenocytes in male C57BL/6J mice were assayed for expression of Klotho or FGF23 by flow cytometry and immunohistochemistry. Cells that expressed Klotho included CD45R/B220+ CD21/CD35+ CD1d+ CD43- marginal zone B cells. These cells also expressed FGF receptor 1, indicating that Klotho-positive B cells could respond to FGF23. Plasmacytoid dendritic cells (pDCs) with CD11c+ CD45R/B220+ CD11b- CD8α- were found to produce FGF23. Klotho-positive cells and FGF23-producing cells were present in close proximity to each other, suggesting that FGF23 produced by pDCs may act within a limited area. These findings indicate that FGF23-Klotho signaling could play a biological or immunological role in the spleen.

Tonsillectomy with steroid pulse therapy has more effect on the relapse rate than steroid pulse monotherapy in IgA nephropathy patients.

AIMS: Both steroid pulse (SP) monotherapy and the combination of tonsillectomy and SP therapy (TSP) are effective for achieving clinical remission (CR), defined as negative hematuria and proteinuria, in patients with IgA nephropathy (IgAN). The role of tonsillectomy in the treatment of IgAN has been analyzed only from the aspect of CR or renal survival after TSP treatment, so there is no evidence of its effect on the relapse after CR. METHODS: We retrospectively investigated relapse (re-appearance of urinary abnormalities) from CR after TSP or SP monotherapy in 62 IgAN patients (mean follow-up, 70.1 ± 35.3 months). The SP therapy comprised 0.5 g methylprednisolone administered intravenously on 3 consecutive days followed by oral prednisolone (30 mg/day) on 4 consecutive days, with the course repeated 3 times. Oral prednisolone (30 mg/day) was then given on alternative days and gradually tapered and finished over 1 year. Tonsillectomy was performed either before or within 6 months of starting SP therapy. RESULTS: At baseline, the mean age was 34.6 years, the mean serum creatinine (Cr) level was 0.9 mg/dl, and the mean level of proteinuria was 876 mg/day. There were no differences between the TSP group (41 patients) and SP monotherapy group (21 patients). In total, 24 of the TSP and 10 of the SP patients achieved CR. Of the 34 patients who achieved CR, 13 relapsed after TSP or SP monotherapy. Using Kaplan-Meier analysis, tonsillectomy was associated with a lower incidence of relapse from CR after treatment (p = 0.045). Multivariate Cox regression analysis revealed that tonsillectomy reduced the rate of from CR after SP therapy. CONCLUSION: Tonsillectomy was associated with a reduction in the relapse rate from CR after SP therapy in IgAN patients.

Overlapping Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy with Mutation in CFI in a Japanese Patient: A Case Report.

A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.

Vascular calcification estimated by aortic calcification area index is a significant predictive parameter of cardiovascular mortality in hemodialysis patients.

BACKGROUND: Vascular calcification is a feature of arteriosclerosis. In hemodialysis (HD) patients, vascular calcification progresses rapidly. This study used the aortic calcification area index (ACAI), an index of vascular calcification, to evaluate vascular calcification factors in HD patients, to investigate correlations between ACAI and long-term prognosis and to assess correlations between various factors and long-term prognosis. METHODS: Subjects comprised 137 patients on maintenance HD. ACAI was measured as an index of vascular calcification as measured by abdominal plain computed tomography. The patients were divided into a high ACAI (H) group and a low ACAI (L) group according to whether the ACAI was below or above the mean value (21.4%) of ACAI, and long-term all-cause death and cardiovascular death rates were compared between groups. Risk factors for all-cause death and cardiovascular death were examined by Cox hazard analysis. RESULTS: During follow-up (mean follow-up period 95.3 ± 50.3 months), 76 patients died, including 46 cardiovascular deaths. Deaths included 51 of 70 patients (67.1%) in Group H and 25 of 67 patients (37.3%) in Group L. Cardiovascular death rates were 51.4 and 14.9%, respectively. On Kaplan-Meier analysis, the number of all-cause deaths was significantly higher in Group H (P < 0.001, log-rank test). Similarly, the number of cardiovascular deaths was significantly higher in Group H. Multivariate Cox proportional hazards analysis showed that ACAI (%) was a significant prognostic indicator for cardiovascular death (hazard ratio 1.03; 95% confidence interval 1.00-1.06, P = 0.03). CONCLUSION: High ACAI was clearly correlated with mortality rate in HD patients, particularly cardiovascular mortality rate. ACAI was a useful long-term prognostic indicator in HD patients.

Crystal Growth and Characterization of n-GaN in a Multiple Quantum Shell Nanowire-Based Light Emitter with a Tunnel Junction.

Here, we systematically investigated the growth conditions of an n-GaN cap layer for nanowire-based light emitters with a tunnel junction. Selective-area growth of multiple quantum shell (MQS)/nanowire core-shell structures on a patterned n-GaN/sapphire substrate was performed by metal-organic vapor phase epitaxy, followed by the growth of a p-GaN, an n++/ p++-GaN tunnel junction, and an n-GaN cap layer. Specifically, two-step growth of the n-GaN cap layer was carried out under various growth conditions to determine the optimal conditions for a flat n-GaN cap layer. Scanning transmission electron microscopy characterization revealed that n++-GaN can be uniformly grown on the m-plane sidewall of MQS nanowires. A clear tunnel junction, involving 10-nm-thick p++-GaN and 3-nm-thick n++-GaN, was confirmed on the nonpolar m-planes of the nanowires. The Mg doping concentration and distribution profile of the p++-GaN shell were inspected using three-dimensional atom probe tomography. Afterward, the reconstructed isoconcentration mapping was applied to identify Mg-rich clusters. The density and average size of the Mg clusters were estimated to be approximately 4.3 × 1017 cm-3 and 5 nm, respectively. Excluding the Mg atoms contained in the clusters, the remaining Mg doping concentration in the p++-GaN region was calculated to be 1.1 × 1020 cm-3. Despite the lack of effective activation, a reasonably low operating voltage and distinct light emissions were preliminarily observed in MQS nanowire-based LEDs under the optimal n-GaN cap growth conditions. In the fabricated MQS-nanowire devices, carriers were injected into both the r-plane and m-plane of the nanowires without a clear quantum confinement Stark effect.

Fibroblast growth factor 23 production in bone is directly regulated by 1{alpha},25-dihydroxyvitamin D, but not PTH.

Fibroblast growth factor 23 (FGF23), which is primarily produced by osteocytes in bone, regulates renal phosphate excretion and 1α,25-dihydroxyvitamin D [1,25(OH)(2)D(3)] metabolism. Patients with chronic kidney disease (CKD) have increased levels of circulating serum FGF23, but the direct effect on circulating FGF23 levels in renal insufficiency is still unclear. To identify the major regulator of FGF23 synthesis in renal insufficiency, we compared the effect of parathyroid hormone (PTH) and 1,25(OH)(2)D(3) on FGF23 synthesis in the calvariae of normal rats with that of uremic rats in vitro. 1,25(OH)(2)D(3) treatment significantly increased the FGF23 concentration in the medium from both groups, but the degree of increase in the uremic group was markedly higher than in the control group. A significant increase in FGF23 mRNA expression occurred as early as 4 h after treatment and reached the maximum within 8 h in the uremic group, whereas in the normal group a significant increase in FGF23 mRNA expression was observed only at 8 h. In addition, the expression of vitamin D receptor (VDR) mRNA in the calvariae of uremic rats was markedly higher than in normal rats. However, in neither group did PTH treatment affect the medium FGF23 concentration or the FGF23 mRNA levels. These results suggest that FGF23 synthesis in bone is regulated by 1,25(OH)(2)D(3) directly, not by PTH, and that increased VDR mRNA expression induced the relatively swift and strong response in the uremic group.

Excessive ADAM17 activation occurs in uremic patients and may contribute to their immunocompromised status.

INTRODUCTION: We previously reported that fibroblast growth factor 23 (FGF23)-klotho signaling plays a role in B cell immunity. Despite high serum levels of FGF23, a decline in immunity is frequently observed in patients on hemodialysis (HD); thus, abnormalities in the FGF23-klotho signaling pathway in immune cells may occur in these patients. METHODS: We analyzed the number of klotho-positive cells in peripheral blood mononuclear cells from 10 male and 6 female patients on HD and 5 healthy male subjects using flow cytometry. We analyzed the abundance of cleaved klotho protein in the murine B cell line, A20, and in the serum of HD patients and healthy subjects (HS) using flow cytometry and Western blotting. The serum level of A disintegrin and metalloprotease 17 (ADAM17) was measured in HD patients and HS using enzyme-linked immunosorbent assay. RESULTS: The number of klotho-positive B cells was reduced in HD patients. Serum ADAM17 was responsible for the reduction in klotho, as a specific ADAM17 inhibitor reversed this change. The total serum levels of ADAM17 were similar in HD patients and HS; however, activated ADAM17 was increased in the serum of HD patients. CONCLUSIONS: We concluded that abnormal ADAM17 activation could contribute to the immunocompromised status in patients on HD, in line with the reported role of ADAM17 as an anti-inflammatory and immunosuppressive factor.

Correlation between haemoglobin level and type of erythropoiesis-stimulating agent at initiation of haemodialysis.

Background Renal anaemia worsens because of the uraemic status immediately before the initiation of haemodialysis. The haemoglobin level in patients with chronic kidney disease is correlated with cardiovascular disease and mortality. Objective This study was performed to determine whether short- and long-acting erythropoiesis-stimulating agents are correlated with the pre-haemodialysis haemoglobin level in patients with chronic kidney disease. Setting This study was conducted at the Blood Purification Center in Wakayama Medical University. Method We enrolled 364 patients undergoing initiation of haemodialysis from January 2009 to June 2015 and analysed them for > 3 months prior to the initiation of haemodialysis. In total, 168 patients were included in the final analysis based on the inclusion and exclusion criteria. Main outcome measures The correlation of the haemoglobin level at the initiation of haemodialysis with various factors according to the type of erythropoiesis-stimulating agent used. Results The median haemoglobin level was 8.8 g/dL, and long-acting erythropoiesis-stimulating agents were used by 69.6% of the patients. Long-acting erythropoiesis-stimulating agents were used significantly more often in patients with high than low haemoglobin levels. The haemoglobin levels at the initiation of haemodialysis and 1 month prior tended to be significantly higher in patients taking long-than short-acting erythropoiesis-stimulating agents. The serum levels of iron and albumin and the use of long-acting erythropoiesis-stimulating agents were independently correlated with the haemoglobin level at the initiation of haemodialysis in the multivariate regression analysis. In addition, the left ventricular mass index was significantly correlated with the haemoglobin level at the initiation of haemodialysis. Conclusion Long-acting erythropoiesis-stimulating agents were correlated with higher haemoglobin levels and may be more useful for patients with a low left ventricular mass index at the initiation of haemodialysis.

Association between serum lipids, polyunsaturated fatty acids, and prognosis in maintenance hemodialysis patients.

INTRODUCTION: Risks of mortality and cardiovascular disease (CVD) are significantly higher in hemodialysis (HD) patients than in the general population, where dyslipidemia is an established risk factor for CVD and mortality. There is no clear conclusion, however, whether dyslipidemia is a significant risk factor for CVD and mortality in HD patients. Similarly, the association between the polyunsaturated fatty acids (PUFAs) and the mortality is not clear in HD patients. METHODS: We retrospectively investigated mortality and CVD events in 420 HD patients. We classified patients into high- and low-lipid groups depending on their lipid levels. Survival rates were calculated using the Kaplan-Meier analysis and evaluated by the log-rank test. The risk estimates were computed using a multivariate Cox proportional hazard analysis. FINDINGS: During their follow-up (June 2011 to June 2016), 151 patients died (37 of CVD), and 112 patients experienced new CVD events. On Kaplan-Meier analysis, the number of all-cause deaths and CVD events were significantly higher in the low HDL-cholesterol group (P < 0.01, log-rank test). Similarly, the number of all-cause deaths was significantly higher in the high eicosapentaenoic acid/arachidonic acid ratio group (P < 0.01, log-rank test). Multivariate Cox proportional analysis showed that HDL-cholesterol was a significant prognostic indicator for new onset of CVD events (low: 0, high: 1, hazard ratio 0.66, 95% confidence interval 0.44-0.97; P = 0.04). DISCUSSION: In HD patients, LDL-cholesterol and non-HDL-cholesterol levels are not associated with mortality or CVD events. The HDL-cholesterol level, however, is an independent predictor of new CVD events even in HD patients.

Active vitamin D and vitamin D analogs stimulate fibroblast growth factor 23 production in osteocyte-like cells via the vitamin D receptor.

Osteocytes play an important role in the regulation of serum phosphorus by producing fibroblast growth factor 23 (FGF23). FGF23 production is stimulated by 1α,25-dihydroxyvitamin D in osteocytes. However, it is unclear whether vitamin D induces FGF23 production in osteocytes directly. Therefore, we investigated vitamin D-induced FGF23 production in osteocyte-like cells derived from MC3T3-E1 osteocyte progenitor cells. We also investigated differences in the induction of FGF23 by 1α,25-dihydroxyvitamin D and various vitamin D analogs. MC3T3-E1 cells were differentiated into osteocyte-like cells (MCT3-E1-OLCs) by treatment with various agents including ß-glycerophosphate and ascorbic acid. MCT3-E1-OLCs were stimulated with 1α,25-dihydroxyvitamin D3 and subsequent FGF23 gene expression was 2631 ± 605 times higher compared with untreated cells. The expression of FGF23 in MCT3-E1-OLCs transfected with a knockdown sequence against vitamin D receptor (VDR) was significantly decreased compared with that in cells transfected with the control vector. Therefore, the induction of FGF23 in osteocytes by vitamin D may be primarily mediated via VDR. The potential of 25(OH)vitamin D3, paricalcitol, and maxacalcitol to induce FGF23 production was almost the same as that of 1α,25-dihydroxyvitamin D3. However, falecalcitriol and eldecalcitol demonstrated a reduced potential to induce FGF23 compared with 1α,25-dihydroxyvitamin D3. Our results demonstrate that FGF23 induction is different among the analogs of 1α,25-dihydroxyvitamin D3. Therefore, an appropriate vitamin D analog should be chosen for each patient with mineral and bone disorder, considering its effect on FGF23 production.

An Analysis of Medication Adherence and Patient Preference in Long-term Stable Maintenance Hemodialysis Patients in Japan.

Objective This follow-up survey report describes medication adherence and patient preferences, beliefs, and expectations of maintenance hemodialysis treatment in Japan. Methods This patient-reported questionnaire-based survey was conducted in six regions in Japan from September 2016 to November 2016. Patients The questionnaire was provided to 700 patients (50-79 years old) on maintenance hemodialysis for >3 years who were members of the Japan Association of Kidney Disease Patients. Patients were randomly selected by a stratified sampling method based on patient distribution observed from the Japanese Society for Dialysis Therapy Renal Data Registry. Results A total of 524 (74.9%) complete patient questionnaires were evaluated; the mean (SD) age was 66.6 (7.2) years (men, 63.4%) with a dialysis vintage of 16.9 (9.1) years. Adherence was high for all types of medications: between 76.7% for phosphate binders and 95.7% for antidiabetic medications. The most common reason for a missed dose was forgetting to take medication [52.5% (117/223)]. Patient preference for oral medication was as low as 0.9% (1/110), 9% (31/345), and 2.9% (2/69) for patients who felt mental burden, felt no mental burden, and neither, respectively, with their current treatment regimen. In addition, 37.8% (198/524) of patients responded that the elimination of 1 medication (1 tablet) would reduce their mental burden. Conclusion The results of this survey show that overall medication adherence is high in Japanese patients on maintenance hemodialysis. While many patients perceive an absence of mental burden, they still prefer to avoid oral medication when possible.

A Survey of Drug Burden in Patients Undergoing Maintenance Hemodialysis in Japan.

Objective This report presents a part of a survey pertaining to drug burden in maintenance hemodialysis patients in Japan. Methods A patient-reported questionnaire-based survey was conducted from September to November 2016 in six regions in Japan. Patients A total of 700 patients (50-79 years old) on maintenance hemodialysis for >3 years and members of the Japan Association of Kidney Disease Patients (JAKDP) were provided with the questionnaire. They were randomly selected using stratified sampling according to patient distribution observed from the Japanese Society for Dialysis Therapy Renal Data Registry (JSDT JRDR). Results A total of 524 (74.9%) patient questionnaires were evaluated [mean (standard deviation; SD) age, 66.6 (7.2) years; males, 63.4%; dialysis vintage, 16.9 (9.1) years]. Patients' age, gender, and regional distribution were similar to the JSDT JRDR. They were taking an average (SD) of 16.4 (8.34) and 16.3 (8.55) oral medications/day on dialysis and nondialysis days, respectively. A majority of the patients were taking ≥10 oral medications/day on dialysis (75.1%) and nondialysis (74.4%) days, with phosphate binders being the most taken (7.0 tablets/day). A similar proportion (74.4%, 72.9%, respectively) was taking ≥6 different types of oral medications/day. Most patients were taking oral medications 3 (31%, 33%), 4 (24%, 22%), and ≥5 times (31%, 30%) a day, respectively. The drug burden was similar on dialysis and nondialysis days and did not vary with dialysis vintage. Conclusion The number, type, and frequency of oral medications in maintenance hemodialysis patients are high in Japan. The proportion of phosphate binders was highest among the prescription medications.

Severe refractory infection due to renocolic fistula in a patient with a giant kidney and ADPKD undergoing long-term hemodialysis.

Renocolic fistula is rare. Renal cyst infection is a serious complication in patients with autosomal dominant polycystic kidney disease (ADPKD). We present a case of refractory renal cyst infection due to renocolic fistula in a patient with ADPKD. A 65-year-old man with ADPKD on hemodialysis visited our hospital with complaints of fever and left abdominal pain. We diagnosed renal cyst infection with abdominal computed tomography scans. After hospitalization, gas shadow was observed in the left renal cyst. Percutaneous puncture of the cyst was performed. Because contrast medium into the left renal cyst through nephrostomy was flowing into the descending colon, renocolic fistula was diagnosed. The patient underwent nephrectomy combined with partial descending colonic resection and splenectomy, but he died. Renocolic fistula is probably hidden in some refractory renal cyst infection cases. This case report aims to create awareness of renocolic fistula, so that early diagnosis and intervention can salvage such patients.