Association between phosphate binder pill burden and mortality risk in patients on maintenance hemodialysis: a single-center cohort study with 7-year follow-up of 513 patients.

BACKGROUND: Dialysis patients often take multiple oral medications, leading to a high pill burden. Phosphate binders (PBs) account for a large proportion of this daily pill burden (DPB). The relationship between DPB and mortality risk remains unclear, and we hypothesized that this relationship might be influenced by the proportion of PBs to all medications. METHODS: We divided DPB into those derived from PBs and non-PB drugs and analyzed the association with mortality risk over a 7-year period in 513 chronic hemodialysis patients using a baseline model. RESULTS: The median (interquartile range) DPB from all drugs was 15.8 (11.2-21.0) pills/day/patient, and the median ratio of PB pills to all drug pills was 29.3 (13.7-45.9)% at baseline. During a median observation period of 5.2 years, 161 patients (31.4%) died. Kaplan-Meier analysis showed no significant difference in all-cause mortality between PB users and non-users. However, a significant survival advantage was observed in the highest tertile of DPB from PBs compared to the lowest tertile. Conversely, the highest tertile of DPB from non-PB drugs was associated with worse survival. Consequently, the highest tertile of the ratio of PBs to all pills was associated with better survival. This association remained significant even after adjusting for patient characteristics in the Cox proportional hazards model. However, when serum nutritional parameters were included as covariates, the significant association disappeared. CONCLUSIONS: Dialysis patients prescribed a higher rate of PB pills to all medications exhibited a lower mortality risk, possibly due to their better nutritional status.

Discovery of Self-Assembling Small Molecules as Vaccine Adjuvants.

Immune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long-lasting adaptive immune responses of vaccines. Presented here is a study that takes advantage of a self-assembling small-molecule library for the development of a novel vaccine adjuvant. Cell-based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6, also named cholicamide) whose well-defined nanoassembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus-like assembly enters the cells and stimulates the innate immune response through Toll-like receptor 7 (TLR7), an endosomal TLR that detects single-stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here pave the way for a new approach to discovering and designing self-assembling small-molecule adjuvants against pathogens, including emerging viruses.

Recent Advances in the Management of Vascular Calcification in Patients with End-Stage Renal Disease.

BACKGROUND: Vascular calcification (VC) is common in patients with chronic kidney disease (CKD) including end-stage renal disease (ESRD). The pathogenesis of VC is complex, resulting in increased arterial stiffening, which is associated with cardiovascular mortality. In addition to traditional cardiovascular risk factors, CKD patients also have a number of non-traditional cardiovascular risk factors that may play an important role in the pathogenesis of VC. SUMMARY: Management of CKD-mineral bone disorder using conventional therapeutic approaches, which include restricting dietary phosphate, administering phosphate binders, and using active vitamin D and calcimimetics, may inhibit the progression of VC, but these approaches remain controversial because recommended biochemical targets are difficult to achieve. Current treatment strategies focus on correcting abnormal calcium, phosphate, parathyroid hormone, and vitamin D levels in ESRD patients. Novel therapies for addressing VC include magnesium and vitamin K supplementation, which are currently being investigated in randomized controlled trials. This review summarizes current treatment strategies and therapeutic targets for the management of VC in patients with ESRD. Key Messages: A better understanding of the potential therapeutic approaches to VC may lead to improved mortality rates among patients with CKD including those on dialysis. Fetuin-A inhibits VC by binding to the nanoparticles of calcium and phosphate, preventing mineral accretion. These particles are known as calciprotein particles and may provide an important pathway for mineral transport and clearance. This review article summarizes the current management of VC in patients with ESRD.

Short-term effect of electrical nerve stimulation on spinal reciprocal inhibition during robot-assisted passive stepping in humans.

The purpose of this study was to investigate the effect of electrical stimulation to the common peroneal nerve (CPN) on the spinal reflex and reciprocal inhibition (RI) during robot-assisted passive ground stepping (PGS) in healthy subjects. Five interventions were applied for 30 min in healthy subjects: PGS alone; strong CPN stimulation [50% of the maximal tibialis anterior (TA) M-wave, functional electrical stimulation (FES)] alone; weak CPN stimulation [just above the MT for the TA muscle, therapeutic electrical stimulation (TES)] alone; PGS with FES; and PGS with TES. FES and TES were applied intermittently to the CPN at 25 Hz. The soleus (Sol) H-reflex and RI, which was assessed by conditioning the Sol H-reflex with CPN stimulation, were investigated before (baseline), and 5, 15 and 30 min after each intervention. The amplitudes of the Sol H-reflex were not significantly different after each intervention as compared with the baseline values. The amounts of RI were significantly decreased 5 min after PGS with FES as compared with the baseline values, whereas they were significantly increased 5 and 15 min after PGS with TES. The other interventions did not affect the amount of RI. These results suggest that interventions that combined PGS with CPN stimulation changed the spinal RI in an intensity-dependent manner.

Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients.

Approximately 5-10% of patients with end-stage renal disease (ESRD) exhibit hyporesponsiveness to erythropoiesis-stimulating agents (ESAs), defined as a continued need for higher than 300 IU/kg/week doses of epoetin or a 1.5 mg/kg/week dose of darbepoetin. ESA hyporesponsiveness contributes to the morbidity, mortality and health-care economic burden of ESRD patients. The most common causes of ESA resistance are absolute or functional iron deficiency and inflammation. Maintaining adequate iron stores is clearly accepted as the most important strategy for reducing the ESA requirement and for enhancing ESA efficacy. Recent clinical studies have shown that iron administration to ESRD patients is associated with an increased risk of infection and atherosclerosis. ESA hyporesponsiveness due to chronic inflammation in ESRD patients has been reported to be improved by a number of interventions, including the use of biocompatible hemodialysis membranes, ultrapure dialysate, ascorbic acid therapy, vitamin E supplementation, and statin therapy. Other causes of ESA hyporesponsiveness include inadequate dialysis, hyperparathyroidism, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, primary bone marrow disorders, myelosuppressive agents, hemoglobinopathies, hemolysis, and hypersplenism. This article summarizes the common causes of ESA hyporesponsiveness and the proposed therapeutic interventions.

Additional reduction in serum phosphorus levels by pulverized lanthanum carbonate chewable in hemodialysis patients.

Lanthanum carbonate (LC) is one of the relatively new phosphate binders. The general LC dosage form is a chewable pharmaceutical preparation. This investigation was targeted to subjects who do not chew LC chewable preparations adequately, for the purpose of studying the clinical efficacy of changing to pulverized prescriptions, such as changes in serum phosphorus levels (P levels). The study took place at Minamisenju Hospital in October 2011, with 41 subjects on maintenance hemodialysis. We pulverized all of the LC chewable medicines of the LC insufficient mastication group (non-chewing: NC group, n = 18) using a crusher, and changed them to pulverized prescriptions. The testing period was set at 10 weeks. In the NC group, there was a significant lowering of P levels from 5.86 ± 1.31 mg/dL before pulverization of the LC chewable preparation (week 0) to 5.38 ± 1.26 mg/dL after 2 weeks of administration of the pulverized medication (P = 0.0310), 5.20 ± 1.25 mg/dL after 4 weeks (P = 0.0077), and 5.12 ± 1.34 mg/dL after 6 weeks (P = 0.0167). P levels in other patients than NC group showed no significant change. In this study, the P levels in the NC group was lowered significantly by changing the LC chewable to the pulverized prescription, and the residual LC images on the abdominal X-rays disappeared to the point where they could barely be confirmed.

Vitamin D receptor agonist supplementation and suppression of inflammation may have advantage for all-cause mortality in hemodialysis patients.

BACKGROUND: Vitamin D deficiency is common in hemodialysis (HD) patients. The aim of this study was to determine whether HD patients with low 25-hydroxyvitamin D [25(OH)D] levels are at increased risk of mortality. METHODS: This was a prospective cohort study of Japanese HD patients. We selected all patients with measured serum 25(OH)D levels at the time of entry. We assessed the impact of low serum 25(OH)D levels on the long-term mortality of HD patients by performing Cox regression analyses. Associations between serum 25(OH)D levels and all-cause mortality were also investigated. RESULTS: Data from 100 patients (mean age 61.0 ± 11.8 years, 64 % males) were available. There was a high prevalence (55 %) of 25(OH)D insufficiency < 20 ng/ml, and 51 % of study subjects were treated with alfacalcidol. Twenty-four patients died during a follow-up period of 4.6 years. There were no significant associations between serum 25(OH)D levels and all-cause mortality (p = 0.777). After adjustments for possible confounders, the hazard ratio (with 95 % CI) for all-cause mortality was 1.091 (1.024-1.167) for age, 0.734 (0.566-1.167) for dialysis vintage, 1.012 (0.995-1.031) for serum total cholesterol values, 2.028 (1.093-3.701) for serum phosphate levels, and 0.291 (0.088-0.855) for treatment with alfacalcidol. A survival advantage of alfacalcidol treatment was observed (log-rank, p = 0.0150). The group of subjects whose serum (25(OH)D level was <20 ng/ml and who were not treated with alfacalcidol had the highest mortality rate. CONCLUSION: Vitamin D deficiency in HD patients who had not taken vitamin D receptor agonist (VDRA) is associated with an increased risk of all-cause mortality. VDRA supplementation may suppress chronic inflammation and have some advantage for mortality of HD patients with vitamin D deficiency.

The use of H1-receptor antagonists and left ventricular remodeling in patients on chronic hemodialysis.

Suppression of left ventricular (LV) remodeling secondary to heart failure seems critical to improve the prognosis of hemodialysis (HD) patients. This is a retrospective study on the relationship of an antiallergic drug and antihistamines with LV hypertrophy. A total of 149 patients (88 males and 61 females) were entered in the study. Mean age was 66.7 years and mean duration of dialysis 14.4 years. Twenty-three patients received oral treatment with an antiallergic drug or second-generation antihistamines, 3 with the antiallergic drug and 20 with antihistamines. The multivariate analysis using LV mass index (LVMI) as the objective variable extracted the following independent factors: male sex, erythropoietin (EPO)/w, uric acid (UA), total cholesterol, antihistamines, antiallergic drug, and calcium channel blocker (CCB), with a standard regression coefficient of 0.187, 0.196, 0.212, -0.262, -0.215, -0.149 and -0.173, respectively. This study suggests a suppressive role of second-generation antihistamines on LV remodeling. Male sex, high-dose EPO/w, and elevated UA were considered as aggravating factors, and CCB as a suppressive factor.

Different effects of L/N-type and L-type calcium channel blockers on the renin-angiotensin-aldosterone system in SHR/Izm.

BACKGROUND: The L/N-type calcium channel blocker (CCB) cilnidipine has been demonstrated to suppress sympathetic nerve activity. In the present study, we investigated the effects of cilnidipine on the renin-angiotensin-aldosterone system (RAAS) in SHR/Izm rats to confirm differences from the effects of L-type CCB. METHODS: Male SHR/Izm rats received vehicle, cilnidipine (0.3, 3 mg/kg) or amlodipine (0.3, 3 mg/kg) by gavage for systolic blood pressure (SBP) measurement. For biochemical analyses, the experiments were performed under anesthesia. RESULTS: Low doses of cilnidipine or amlodipine had no effect on SBP or RAAS parameters. A high dose of either drug produced similar effects on SBP levels. Although cilnidipine had no effect on plasma renin activity or the plasma angiotensin II level, amlodipine significantly increased these parameters as compared to levels in the vehicle group. The cilnidipine group had a significantly lower plasma aldosterone level and renal cortical tissue norepinephrine level than the vehicle group. CONCLUSIONS: Cilnidipine had effects different from those of L-type CCB on the RAAS in SHR/Izm rats. Our results indicate that suppression of RAAS hyperactivity by cilnidipine can be partly explained by its sympatholytic action.

Arterial stiffness in patients with non-diabetic chronic kidney disease (CKD).

BACKGROUND: Patients with chronic kidney disease (CKD) have a high prevalence of cardiovascular disease (CVD). Arterial stiffness plays an important role in the pathogenesis of CVD; however, to date, there have been no reports of the assessment of arterial stiffness in patients at different stages of non-diabetic CKD. METHODS: We studied 50 patients with non-diabetic CKD (stages 1-5, 5D) receiving medical treatment at Tokyo Women's Medical University. Pulse wave velocity (PWV) was assessed using an applanation tonometer to determine arterial compliance. All current medications were recorded and biochemical parameters were analyzed. RESULTS: Non-diabetic CKD stage 5D patients had a higher PWV, and higher serum levels of C-reactive protein (CRP), Ca, P and intact parathyroid hormone (iPTH) than non-diabetic CKD stage 1-5 patients (p=0.03, p=0.009, p=0.006, p=0.00005, and p=0.002, respectably). As compared to non-diabetic CKD stage 1-2 patients, patients with non-diabetic CKD stage 3-5 were older, and had higher serum levels of P and iPTH and a higher PWV (p=0.0002, p=0.009, p=0.03, and p=0.004). Nephrosclerosis was associated with a higher PWV, higher serum levels of CRP, and a higher prevalence of CVD than patients with CKD of other origins. CONCLUSION: We showed a stepwise increase of arterial stiffness with increasing disease severity stage in patients with CKD not associated with diabetes mellitus. CKD caused by nephrosclerosis was found to be associated with increased arterial stiffness and to be a risk factor for CVD.