Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis: The J-DAVID Randomized Clinical Trial.

Importance: Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective: To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants: Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions: Treatment with 0.5 µg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures: The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results: Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, -1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52]; P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance: Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration: UMIN-CTR Identifier: UMIN000001194.

Ethical dilemmas facing chief nurses in Japan: A Pilot study.

BACKGROUND: Chief nurses are most likely to take the lead in discussing and working to resolve ethical dilemmas, creating an ethical culture within their organization that results in effective ethics training. As the first step in this process, there is a need to define the kinds of ethical dilemmas that chief nurses grapple with on a regular basis as a target for future study. RESEARCH DESIGN: Anonymous written questionnaires and semi-structured interviews. ETHICAL CONSIDERATIONS: All research procedures were approved by the Chubu University Ethics Review Board, the research institution to which the authors belong (authorization no. 250016). FINDINGS AND DISCUSSION: Responses from four chief nurses indicated that ethical dilemmas could be categorized as either those related to patient dignity or those related to management (unique to their roles as administrators). It was also learned that chief nurses struggle with the fact that although they consult with their superiors and others, these efforts do not lead to resolution. The expectation is that going forward, chief nurses will play a central role in acting as coordinators with physicians to promote better communication as well as lead group discussions aimed at providing care that respects patient dignity.

Coronary microvascular function is independently associated with left ventricular filling pressure in patients with type 2 diabetes mellitus.

BACKGROUND: Left ventricular (LV) diastolic dysfunction is known as an early marker of myocardial alterations in patients with diabetes. Because microvascular disease has been regarded as an important cause of heart failure or diastolic dysfunction in diabetic patients, we tested the hypothesis that coronary flow reserve (CFR), which reflects coronary microvascular function, is associated with LV diastolic dysfunction in patients with type 2 diabetes. METHODS: We studied asymptomatic patients with type 2 diabetes but without overt heart failure. Transthoracic Doppler echocardiography was performed that included pulsed tissue Doppler of the mitral annulus and CFR of the left anterior descending artery (induced by adenosine 0.14 mg/kg/min). The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/e') was used as a surrogate marker of diastolic function. We also evaluated renal function, lipid profile, parameters of glycemic control and other clinical characteristics to determine their association with E/e'. Patients with LV ejection fraction <50%, atrial fibrillation, valvular disease, regional wall motion abnormality, renal failure (serum creatinine >2.0 mg/dl) or type 1 diabetes were excluded. Patients with a CFR <2.0 were also excluded based on the suspicion of significant coronary artery stenosis. RESULTS: We included 67 asymptomatic patients with type 2 diabetes and 14 non-diabetic controls in the final study population. In univariate analysis, age, presence of hypertension, LV mass index, estimated glomerular filtration rate and CFR were significantly associated with E/e'. Multivariate analysis indicated that both LV mass index and CFR were independently associated with E/e'. In contrast, there were no significant associations between parameters of glycemic control and E/e'. CONCLUSIONS: CFR was associated with LV filling pressure in patients with type 2 diabetes. This result suggests a possible link between coronary microvascular disease and LV diastolic function in these subjects.

[Comparison of benefits to non-dialysis CKD patients between darbepoetin alpha and epoetin beta pegol].

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment for renal anemia in chronic kidney disease (CKD) patients. However, the difference in hematopoietic effect between darbepoetin alfa (DA) and continuous erythropoiesis receptor activator (CERA) has remained unclear in non-dialysis CKD patients. Another purpose of this study was to analyze the red blood cells indices under treatment with these two ESAs in ESA-naïve CKD patients. METHODS: This study was designed as a multicenter retrospective observational investigation, and included 61 patients receiving DA (group DA) and 36 patients receiving CERA (group CERA) for at least six months. Relative effect of these ESAs was determined by comparing means of the individual monthly average of the area under the curve above the initial level of hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) with the trapezoidal rule, which are maintenance ratios. Serial changes in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were also evaluated. RESULTS: No differences were found in the mean ratios of Hb, Hct, and RBC, and maintenance ratios of these parameters. The ratio of MCH in group CERA was decreased compared with that in group DA. Subsequent decrease in MCV was also remarkable in group CERA. CONCLUSIONS: It is speculated that iron demand increased during the administration of CERA, which was suggested by changes in the red cell indices. Reticulocyte indices and iron-related parameters could provide a more detailed explanation and the significance of iron supplementation during administration of CERA should be clarified when compared with other types of ESA.

Prunin Laurate Derived from Natural Substances Shows Antibacterial Activity against the Periodontal Pathogen Porphyromonas gingivalis.

Periodontal disease is an inflammatory disease caused by infection with periodontopathogenic bacteria. Oral care is essential to prevent and control periodontal disease, which affects oral and systemic health. However, many oral hygiene products currently on the market were developed as disinfectants, and their intense irritation makes their use difficult for young children and older people. This study investigated the antibacterial effects of prunin laurate (Pru-C12) and its analogs on periodontopathogenic bacteria, Porphyromonas gingivalis (P. gingivalis). Pru-C12 and its analogs inhibited in vitro bacterial growth at more than 10 µM and biofilm formation at 50 µM. Among its analogs, only Pru-C12 showed no cytotoxicity at 100 µM. Three of the most potent inhibitors also inhibited the formation of biofilms. Furthermore, Pru-C12 inhibited alveolar bone resorption in a mouse experimental periodontitis model by P. gingivalis infection. These findings may be helpful in the development of oral hygiene products for the prevention and control of periodontal disease and related disorders.

Influencing factors on cardiac structure and function beyond glycemic control in patients with type 2 diabetes mellitus.

BACKGROUND: We hypothesized that clinical factors other than glycemic control may influence abnormal cardiac function in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the independent factors for abnormal cardiac function among clinical factors in T2DM. METHODS: We studied 148 asymptomatic patients with T2DM without overt heart disease. Echocardiographic findings were compared between diabetic patients and 68 age-matched healthy subjects. Early (E) and late (A) diastolic mitral flow velocity and early diastolic mitral annular velocity (e') were measured for assessing left ventricular (LV) diastolic function. We evaluated insulin resistance, non-esterified fatty acid, high-sensitive CRP, estimated glomerular filtration rate, waist/hip ratio, abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and other clinical characteristics in addition to glycemic control. VAT and SAT were quantified by computed tomography. RESULTS: In T2DM, E/A and e' were significantly lower, and E/e', left atrial volume and LV mass were significantly greater than in control subjects. In multivariate liner regression analysis, VAT was an independent determinant of left atrial volume (ß =0.203, p=0.011), E/A (ß =-0.208, p=0.002), e' (ß =-0.354, p<0.001) and E/e' (ß=0.220, p=0.003). Age was also an independent determinant, whereas fasting plasma glucose and hemoglobin A1c levels were not. In addition to systolic blood pressure, waist-hip ratio (ß=0.173, p=0.024) and VAT/SAT ratio (ß=0.162, p=0.049) were independent determinants of LV mass. CONCLUSION: Excessive visceral fat accompanied by adipocyte dysfunction may play a greater role than glycemic control in the development of diastolic dysfunction and LV hypertrophy in T2DM.

Patients with adult minimal change nephrotic syndrome treated with long-term cyclosporine did not experience a reduction in their eGFR.

BACKGROUND: The long-term efficacy and safety of cyclosporine (CyA) in the treatment of adult minimal change nephrotic syndrome (MCNS) was examined. METHODS: The medical record of 15 patients diagnosed with MCNS by renal biopsy and treated with CyA for at least 2 years were reviewed. RESULTS: The mean administration period of CyA was 78.3 months. The mean CyA dose for the induction period was 2.1 ± 0.9 mg/kg and 1.7 ± 1.0 mg/kg for the maintenance period. The mean dose of prednisolone used during the induction period was 20.3 mg and 2.7 mg during the maintenance. The frequency of MCNS relapse was decreased to 0.5 times/year in patients treated with CyA, compared to treatment without CyA (2.4 times/y). Two cases of mild liver damage and 3 cases of elevated blood pressure were observed during the administration of CyA. These adverse effects improved after reducing the CyA dose or treatment with an antihypertensive agent. A decrease in the estimated glomerular filtraion rate (eGFR) was not associated with long-term CyA use. CONCLUSION: At our institution, patients who were treated for MCNS with CyA for at least 2 years experienced no deterioration in renal function.

Cetuximab-induced nephrotic syndrome in a case of metastatic rectal cancer.

Proteinuria is common adverse effect that occurs after the use of bevacizumab, but it occurs rarely during administration of cetuximab. We report the first case of nephrotic syndrome induced by cetuximab after completing mFOLFOX6 with bevacizumab followed by sLV5FU2 with bevacizumab for metastatic rectal cancer. Prior to the administration of cetuximab, the patient had never presented proteinuria. After the completion of the loading (400 mg/m(2)) and two subsequent maintenance (250 mg/m(2)) infusions of cetuximab, edema of the lower extremities occurred concomitantly with facial acneiform rash. Based on the laboratory data, diagnosis of nephrotic syndrome was made and secondary diseases of nephrotic syndrome were excluded. Oral administration of prednisolone (0.6 mg/kg/day) was initiated, resulting in no response. The trigger of nephrotic syndrome other than cetuximab was not suggested and attention on occurrence of proteinuria must be devoted to this medicine.

Light Chain Deposition Disease Recurrence in Renal Allograft after Long-Term Remission.

Light chain deposition disease (LCDD) is a rare manifestation of monoclonal gammopathy, which can lead to renal failure. We previously reported a detailed recurrence process in a case of LCDD after renal transplantation. To the best of our knowledge, no report has described the long-term clinical course and renal pathology findings of recurrent LCDD in patients after renal transplantation. In this case report, we describe the long-term clinical presentation and changes in renal pathology of the same patient after early LCDD relapse in a renal allograft. A 54-year-old woman with recurrent immunoglobulin A λ-type LCDD in an allograft was admitted 1 year post-transplant for bortezomib and dexamethasone therapy. At 2 years post-transplantation, a graft biopsy performed after complete remission was achieved, showing some glomeruli with residual nodular lesions similar to the pre-treatment renal biopsy findings. However, the enlarged subendothelial space disappeared. She remained in complete remission serologically for 6 years. Subsequently, the ratio of serum κ/λ-free light chains decreased gradually. She underwent a transplant biopsy approximately 12 years after renal transplantation due to increased proteinuria and decreased renal function. Compared with the previous graft biopsy, almost all glomeruli showed advanced nodule formation and subendothelial expansion. Because the LCDD case relapsed after long-term remission following renal transplantation, protocol biopsy monitoring might be necessary.

Matrix metalloproteinase-2 inhibition by temocapril and its important role in peritoneal transport.

1. Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodelling during peritoneal injury caused by peritoneal dialysis (PD), but MMP-2 inhibitors have not yet been used clinically. Recently, it was reported that captopril, an angiotensin-converting enzyme inhibitor (ACEI), can inhibit MMP-2. 2. To investigate the potential usefulness of ACEI during PD, the molecular interaction between the MMP-2 active site and the active form of temocapril (temocaprilat) was investigated using molecular modelling. Furthermore, the effects of temocapril on MMP-2 activity in peritoneal effluents and the peritoneal solute transport rate of PD patients were determined. 3. Temocaprilat bound to the MMP-2 active centre and recognized two hydrophobic substrate-binding sites in the MMP-2 molecular model. Matrix metalloproteinase-2 activity in peritoneal effluents was directly inhibited by temocaprilat (IC(50) 0.47 µmol/L). In one patient given temocapril, the peritoneal solute transport rate decreased gradually during PD. 4. Temocapril may prove to be an important candidate for development as a novel therapeutic agent for MMP-2 inhibition to prevent peritoneal injury caused by PD.