The Role of Vitamin D in Modulating Mesenchymal Stem Cells and Endothelial Progenitor Cells for Vascular Calcification.

Vascular calcification, which involves the deposition of calcifying particles within the arterial wall, is mediated by atherosclerosis, vascular smooth muscle cell osteoblastic changes, adventitial mesenchymal stem cell osteoblastic differentiation, and insufficiency of the calcification inhibitors. Recent observations implied a role for mesenchymal stem cells and endothelial progenitor cells in vascular calcification. Mesenchymal stem cells reside in the bone marrow and the adventitial layer of arteries. Endothelial progenitor cells that originate from the bone marrow are an important mechanism for repairing injured endothelial cells. Mesenchymal stem cells may differentiate osteogenically by inflammation or by specific stimuli, which can activate calcification. However, the bioactive substances secreted from mesenchymal stem cells have been shown to mitigate vascular calcification by suppressing inflammation, bone morphogenetic protein 2, and the Wingless-INT signal. Vitamin D deficiency may contribute to vascular calcification. Vitamin D supplement has been used to modulate the osteoblastic differentiation of mesenchymal stem cells and to lessen vascular injury by stimulating adhesion and migration of endothelial progenitor cells. This narrative review clarifies the role of mesenchymal stem cells and the possible role of vitamin D in the mechanisms of vascular calcification.

Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification.

Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).

Dietary Leucine Supplement Ameliorates Hepatic Steatosis and Diabetic Nephropathy in db/db Mice.

Dietary leucine supplementation has been explored for the therapeutic intervention of obesity and obesity-induced metabolic dysfunctions. In this study, we aim to examine the effects of dietary leucine supplementation in db/db mice. Mice were treated with or without leucine (1.5% w/v) in drinking water for 12 weeks. The leucine supplement was found to reduce insulin resistance and hepatic steatosis in db/db mice. Using Nuclear Magnetic Resonance (NMR)-based lipidomics, we found that the reduction of hepatic triglyceride synthesis was correlated with attenuated development of fatty liver. In addition, diabetic nephropathy (DN) was also ameliorated by leucine. Using liquid chromatography⁻time-of-flight mass spectrometry (LC-TOF MS)-based urine metabolomics analysis, we found that the disturbance of the tricarboxylic acid (TCA) cycle was reversed by leucine. The beneficial effects of leucine were probably due to AMP-activated protein kinase (AMPK) activation in the liver and kidneys of db/db mice. Thus, dietary leucine supplementation may potentially be a nutritional intervention to attenuate hepatic steatosis and early DN in type II diabetes.

Role of nutritional vitamin D in osteoporosis treatment.

Osteoporosis is a systemic skeletal disorder characterized by a decrease in bone mass and microarchitectural deterioration of bone tissue. The World Health Organization has defined osteoporosis as a decrease in bone mass (50%) and bony quality (50%). Vitamin D, a steroid hormone, is crucial for skeletal health and in mineral metabolism. Its direct action on osteoblasts and osteoclasts and interaction with nonskeletal tissues help in maintaining a balance between bone turnover and bone growth. Vitamin D affects the activity of osteoblasts, osteoclasts, and osteocytes, suggesting that it affects bone formation, bone resorption, and bone quality. At physiological concentrations, active vitamin D maintains a normal rate of bone resorption and formation through the RANKL/OPG signal. However, active vitamin D at pharmacological concentration inhibits bone resorption at a higher rate than that of bone formation, which influences the bone quality and quantity. Nutritional vitamin D rather than active vitamin D activates osteoblasts and maintains serum 25(OH)D3 concentration. Despite many unanswered questions, much data support nutritional vitamin D use in osteoporosis patients. This article emphasizes the role of nutritional vitamin D replacement in different turnover status (high or low bone turnover disorders) of osteoporosis together with either anti-resorptive (Bisphosphonate, Denosumab et.) or anabolic (Teriparatide) agents when osteoporosis persists.

Role of Vitamin D in Uremic Vascular Calcification.

The risk of cardiovascular death is 10 times higher in patients with CKD (chronic kidney disease) than in those without CKD. Vascular calcification, common in patients with CKD, is a predictor of cardiovascular mortality. Vitamin D deficiency, another complication of CKD, is associated with vascular calcification in patients with CKD. GFR decline, proteinuria, tubulointerstitial injury, and the therapeutic dose of active form vitamin D aggravate vitamin D deficiency and reduce its pleiotropic effect on the cardiovascular system. Vitamin D supplement for CKD patients provides a protective role in vascular calcification on the endothelium by (1) renin-angiotensin-aldosterone system inactivation, (2) alleviating insulin resistance, (3) reduction of cholesterol and inhibition of foam cell and cholesterol efflux in macrophages, and (4) modulating vascular regeneration. For the arterial calcification, vitamin D supplement provides adjunctive role in regressing proteinuria, reverse renal osteodystrophy, and restoring calcification inhibitors. Recently, adventitial progenitor cell has been linked to be involved in the vascular calcification. Vitamin D may provide a role in modulating adventitial progenitor cells. In summary, vitamin D supplement may provide an ancillary role for ameliorating uremic vascular calcification.

RISK OF AGE-RELATED MACULAR DEGENERATION IN END-STAGE RENAL DISEASE PATIENTS RECEIVING LONG-TERM DIALYSIS.

PURPOSE: This study investigated the risk of age-related macular degeneration (AMD) in patients with end-stage renal disease (ESRD) receiving long-term dialysis and compared the risk between various dialysis modalities using propensity score-matching methods. METHODS: From the National Health Insurance Research Database of Taiwan, the authors identified 27,232 patients with ESRD newly diagnosed from 2000 to 2010, including 9,287 patients on peritoneal dialysis (PD) and 17,945 patients on hemodialysis (HD). A total of 108,928 controls without kidney disease were randomly selected and frequency matched by age, sex, and index year of ESRD patients. The authors established an additional HD cohort matched by propensity scores of PD patients (N = 9,256 each). All cohorts were followed up until the end of 2011 to measure the incidence of AMD. RESULTS: The incidences of AMD were 1.84, 4.03, 5.37, and 3.50 per 1,000 person-years in the control, ESRD (PD and HD), PD, and HD cohorts, respectively. The hazard ratios for AMD were 1.72, 2.47, and 1.43 for the ESRD, PD, and HD cohorts, with 95% confidence intervals of 1.50 to 1.97, 2.05 to 2.98, and 1.22 to 1.68, respectively, compared with the control cohort. The patients on PD exhibited a hazard ratio of 1.74 (95% confidence interval = 1.27-2.38) for developing AMD compared with propensity score-matched patients on HD. CONCLUSION: Patients with ESRD may exhibit a higher risk of AMD than people without kidney disease. Patients on PD may be more likely to develop AMD than patients on HD.

Programming a nonvolatile memory-like sensor for KRAS gene sensing and signal enhancement.

A programmable field effect-based electrolyte-insulator-semiconductor (EIS) sensor constructed with a nonvolatile memory-like structure is proposed for KRAS gene DNA hybridization detection. This programmable EIS structure was fabricated with silicon oxide (SiO2)/silicon nitride (Si3N4)/silicon oxide on a p-type silicon wafer, namely electrolyte-oxide-nitride-oxide-Si (EONOS). In this research, voltage stress programming from 4 to 20V was applied to trigger holes confinement in the nitride-trapping layer that, consequently, enhances the DNA attachment onto the sensing surface due to additional electrostatic interaction. Not solely resulting from the higher DNA load, the programming may affect the orientation of the DNA that finally contributes to the change in capacitance. Findings have shown that a higher voltage program is able to increase the total capacitance and results in ~3.5- and ~5.5-times higher sensitivities for a series of concentrations for complementary DNA and wild type versus mutant DNA hybridization detection, respectively. Overall, it has been proven that the voltage program on the nonvolatile memory-like structure of EONOS is a notable candidate for genosensor development, scoping the diagnosis of a single nucleotide polymorphism (SNP)-related disease.

Association of vitamin D3 with alveolar bone regeneration in dogs.

Designed sockets prepared on the mandibles of nine Beagle dogs were divided into three groups: Calcitriol +Alloplast, Alloplast and Empty. Five of the nine dogs received Vit.D3 and calcium supplement (Vit.D/Ca group), while the other four dogs without supplements were assigned to Non-Vit.D/Ca group. After 4 weeks, the extent of vertical ridge resorption (VRR), bone density (density), new bone formation (NBF) and implant stability quotient (ISQ) were measured. Following systemic Vit.D/Ca administration, the Empty subgroup showed significant differences from the Calcitriol + Alloplast subgroup on variants NBF/Density/VRR and the Alloplast subgroup on items NBF/Density/ISQ/VRR. Alternatively, the Calcitriol + Alloplast subgroup revealed higher values of NBF/Density/ISQ (P < 0.001) and a lower VRR value (P = 0.001) than the Alloplast subgroup. Although there were no significant differences in NBF (P = 0.349), density (P = 0.796), ISQ (P = 0.577) and VRR (0.979) comparisons on alloplast treatment between the Vit.D/Ca and Non-Vit.D/Ca groups, local application with Calcitriol + Alloplast demonstrated better NBF/Density/ISQ (P = 0.02 to <0.001) effects than which of Alloplast subgroups. Consequently, the results showed that both systemic and local vitamin D3 treatment might accelerate bone regeneration in dogs. Within the using dose, systemic vitamin D3 treatment displayed a superior stimulating effect than local vitamin D3 application did.

Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens.

BACKGROUND: A previous study in type 2 diabetic patients with high-normal body lead burdens showed that EDTA chelation therapy for 3 months slows progressive diabetic nephropathy during a 12-month follow-up. The effect of a longer course of therapy on kidney function decrease over a longer follow-up is not known. STUDY DESIGN: A 12-month run-in phase, then a randomized single-blind study with a 27-month intervention. SETTING & PARTICIPANTS: University medical center; 50 patients (serum creatinine, 1.5-3.9 mg/dL) with high-normal body lead burden (≥80-<600 µg) were randomly assigned to the treatment and control groups. INTERVENTION: The treatment group received weekly chelation therapy for 3 months to reduce their body lead burden to <60 µg and then as needed for 24 months to maintain this level. The control group received placebo for 3 months and then weekly for 5 weeks at 6-month intervals for 24 months. OUTCOMES: The primary end point was change in estimated glomerular filtration rate (eGFR) over time. A secondary end point was a 2-fold increase in baseline serum creatinine level or the requirement for renal replacement therapy. MEASUREMENTS: Body lead burdens were assessed by EDTA mobilization tests and eGFR was calculated using the equation for Chinese patients with type 2 diabetes. RESULTS: Mean baseline eGFRs in the treatment and control groups were similar. After 3 months of chelation therapy, the change in eGFR in the treatment group (+1.0 ± 4.8 mL/min/1.73 m(2)) differed significantly from that in the control group (-1.5 ± 4.8 mL/min/1.73 m(2); P = 0.04). In the subsequent 24-month intervention, the yearly rate of decrease in eGFR (5.6 ± 5.0 mL/min/1.73 m(2) per year) in the treatment group was slower than that (9.2 ± 3.6 mL/min/1.73 m(2) per year; P = 0.04) in the control group. 17 (68%) control-group patients and 9 (36%) treatment-group patients achieved the secondary end point. LIMITATIONS: Small sample size, not double blind. CONCLUSIONS: A 27-month course of EDTA chelation therapy retards the progression of diabetic nephropathy in type 2 diabetic patients with high-normal body lead burdens.

Long-term outcome of repeated lead chelation therapy in progressive non-diabetic chronic kidney diseases.

BACKGROUND: Previous research suggest that repeated lead-chelation therapy decelerates progression of renal insufficiency in non-diabetic (non-DM) patients with high-normal body lead burden (BLB). Study findings are limited by relatively short-term follow-up and small sample size. METHODS: A total of 116 non-DM patients with chronic kidney diseases (serum creatinine level of 1.5-3.9 mg/dl), high-normal BLB (>60 microg and <600 microg) and no lead exposure history were randomly assigned to a chelation or control group in this 4-year clinical trial. For 3 months, the 58 chelation group patients received initial lead-chelation therapy with calcium disodium EDTA, and the 58 control group patients received placebos. During the ensuing 48 months, repeated chelation therapy was administered weekly to chelation group patients unless, on repeated testing, BLB was <60 microg; the control group patients received weekly placebo infusions for 5 weeks at 6-month intervals. RESULTS: Mean change in the glomerular filtration rate (GFR) in the chelation group was -1.8 +/- 8.8 ml/min/1.73 m(2), as compared with -12.7 +/- 8.4 ml/min/1.73 m(2) in the control group (P <0.0001) at study end. Chelation group rates of decline in the GFR was lower than that in the control group, although they had similar decline rates before chelation. At study end, 18 patients, including 15 control group patients, had elevated serum creatinine levels to two times the baseline values. Both Cox and Kaplan-Meier analysis demonstrated repeated chelation therapy was the important determining factor of progression of renal insufficiency. CONCLUSIONS: Repeated chelation therapies can, over a four-year period, slow progression of renal insufficiency in non-DM patients with high-normal BLB.