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Children (Basel, Switzerland) May 2023Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000...
Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.
PubMed: 37238410
DOI: 10.3390/children10050862 -
BMC Nephrology Aug 2019Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells. Endothelial markers, ICAM-1 and VCAM-1, are implicated in atherosclerosis and associated with cardiovascular risk. Chronic kidney disease (CKD) patients have endothelial dysfunction and high levels of endothelial derived MPs. Vitamin D treatment has been reported to ameliorate endothelial function in CKD patients. We aimed to examine cell specific MP profiles and concentrations of MPs expressing the atherosclerotic markers ICAM-1 and VCAM-1 after treatment with paricalcitol in patients with CKD stage 3-4.
METHODS
Sub-study of the previously reported SOLID trial where 36 patients were randomly assigned to placebo, 1 or 2 μg paricalcitol, for 12 weeks. MPs were measured by flow cytometry after labelling with antibodies against endothelial (CD62E), platelet (CD62P, CD41, CD154) leukocyte (CD45) and vascular (CD54, CD106) markers.
RESULTS
Patients had a mean age of 65 years with a mean eGFR of 40 mL/min/1.73m. Concentrations of ICAM-1 positive MPs were significantly reduced by treatment (repeated measures ANOVA p = 0.04). Repeated measures MANOVA of concentrations of endothelial, platelet and leukocyte MPs showed sustained levels in the 2 μg treatment group (p = 0.85) but a decline in the 1 μg (p = 0.04) and placebo groups (p = 0.005).
CONCLUSIONS
Treatment with paricalcitol reduces concentrations of ICAM-1 positive MPs. This is accompanied by sustained concentrations of all cell specific MPs in the 2 μg group, and decreasing concentrations in the other groups, possibly due to a more healthy and reactive endothelium with paricalcitol treatment.
Topics: Aged; Aged, 80 and over; Cell-Derived Microparticles; Double-Blind Method; Ergocalciferols; Female; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Receptors, Calcitriol; Renal Insufficiency, Chronic; Vascular Cell Adhesion Molecule-1
PubMed: 31370809
DOI: 10.1186/s12882-019-1445-4 -
Journal of Medical Economics Mar 2020Patients with chronic kidney disease (CKD) not on dialysis frequently have vitamin D insufficiency (VDI) and secondary hyperparathyroidism (SHPT), which are associated... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients with chronic kidney disease (CKD) not on dialysis frequently have vitamin D insufficiency (VDI) and secondary hyperparathyroidism (SHPT), which are associated with an increased risk of cardiovascular (CV) disease, fracture, CKD progression, and death. This study estimated the cost-effectiveness of extended-release calcifediol (ERC) vs paricalcitol for the treatment of patients with CKD stages 3-4 that have SHPT and VDI. An economic analysis of SHPT treatments among a hypothetical cohort of 1,000 patients with CKD Stage 3 and 4 with SHPT and VDI was developed to estimate differences in the rates and costs of CV events, fractures, CKD stage progression, and mortality in patients treated with ERC and paricalcitol. A Markov model was developed with 1-year cycles and a 5-year time horizon from a US Medicare payer perspective with costs valued in 2017 US dollars. The outcomes of the model were rates of clinical events, total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Across a 1,000-person cohort, ERC was the dominant (less costly, more effective) treatment strategy when compared with paricalcitol. Treatment with ERC resulted in cost savings of $14.8 M (95% CI = -$10.0 M-$45.2 M) and an incremental gain of 340 QALYs (95% CI = 200-496) compared to treatment with paricalcitol. Bridging biochemical levels to clinical outcomes may not represent real-world risk of the clinical events modeled. Future real-world outcomes of patients treated with ERC and paricalcitol may be used to evaluate the model results. This model demonstrated favorable short- and long-term clinical benefits associated with the use of ERC in patients with CKD Stage 3 and 4 with SHPT and VDI, suggesting ERC may be cost-effective from the Medicare perspective compared to paricalcitol.
Topics: Aged; Aged, 80 and over; Calcifediol; Cardiovascular Diseases; Cost-Benefit Analysis; Delayed-Action Preparations; Ergocalciferols; Female; Fractures, Bone; Health Expenditures; Humans; Hyperparathyroidism, Secondary; Male; Markov Chains; Medicare; Quality-Adjusted Life Years; Renal Insufficiency, Chronic; Risk Factors; United States
PubMed: 31726882
DOI: 10.1080/13696998.2019.1693385 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Glomerulosclerosis and tubulointerstitial fibrosis (TIF) are closely involved in the development of diabetic nephropathy (DN). Moreover, the development of TIF is...
Glomerulosclerosis and tubulointerstitial fibrosis (TIF) are closely involved in the development of diabetic nephropathy (DN). Moreover, the development of TIF is closely related to epithelial-to-mesenchymal transition (EMT). Tanshinone IIA (Tan) has various pharmacological effects, especially the anti-fibrotic effect. And it is mainly used in the clinical treatment of cardiovascular diseases. Currently, the protective effect of Tan on DN and its possible mechanism have not been clearly elucidated. Our previous studies illustrated that Tan could improve the EMT of HK-2 cells induced by high glucose by regulating the vitamin D receptor (VDR)/Wnt/β-catenin pathway. Here, we collected demographic information and laboratory results from the National Health and Nutrition Examination Survey (NHANES) database in order to investigate the relationship between VD and DN. Then, we established a DN model and treated DN rats with Tan and paricalcitol (Par) for 6 weeks. We subsequently compared the changes in general condition, renal function, pathological changes, and TIF-related protein expression levels of control rats, DN rats induced by STZ, DN rats with Tan at 5.4 mg/kg, DN rats with Tan at 10.8 mg/kg, and DN rats with Par at 0.054 µg/kg, to explore the effect and mechanism of Tan and Par on DN rats. The results showed that VD had a protective effect against DN in diabetic patients. And we found that Tan had a protective effect on renal fibrosis in DN rats, which was superior to Par in improving the symptoms of "three more and one less," reducing fasting blood glucose level, improving renal index, BUN/SCr, and UACR, reducing histopathological damage of kidney, and improving the expression of fibrosis-related proteins in kidney tissue by regulating VDR/Wnt/β-catenin pathway. Tan was superior to Par in ameliorating tubulointerstitial fibrosis by regulating VDR/Wnt/β-catenin pathway in rats with diabetic nephropathy.
Topics: Animals; Diabetic Nephropathies; Receptors, Calcitriol; Abietanes; Wnt Signaling Pathway; Male; Fibrosis; Ergocalciferols; Rats, Sprague-Dawley; Diabetes Mellitus, Experimental; Rats; Kidney; beta Catenin
PubMed: 37991543
DOI: 10.1007/s00210-023-02853-3 -
Cell Metabolism Nov 2020SARS-CoV-2 pneumonitis can quickly strike to incapacitate the lung, leading to severe disease and sometimes death. In this perspective, we suggest that vitamin D...
SARS-CoV-2 pneumonitis can quickly strike to incapacitate the lung, leading to severe disease and sometimes death. In this perspective, we suggest that vitamin D deficiency and the failure to activate the vitamin D receptor (VDR) can aggravate this respiratory syndrome by igniting a wounding response in stellate cells of the lung. The FDA-approved injectable vitamin D analog, paricalcitol, suppresses stellate cell-derived murine hepatic and pancreatic pro-inflammatory and pro-fibrotic changes. Therefore, we suggest a possible parallel program in the pulmonary stellate cells of COVID-19 patients and propose repurposing paricalcitol infusion therapy to restrain the COVID-19 cytokine storm. This proposed therapy could prove important to people of color who have higher COVID-19 mortality rates and lower vitamin D levels.
Topics: Animals; Betacoronavirus; COVID-19; Coronavirus Infections; Cytokines; Drug Repositioning; Ergocalciferols; Humans; Mice; Pandemics; Pneumonia, Viral; Receptors, Calcitriol; SARS-CoV-2; Vitamin D Deficiency; Wound Healing
PubMed: 32941797
DOI: 10.1016/j.cmet.2020.09.007 -
Life Sciences Oct 2019Vitamin D and its receptor, vitamin D receptor (VDR), have renoprotection effect against diabetic nephropathy (DN). But the exact mechanism has not been fully...
AIMS
Vitamin D and its receptor, vitamin D receptor (VDR), have renoprotection effect against diabetic nephropathy (DN). But the exact mechanism has not been fully elucidated. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase-derived metabolites of arachidonic acid, protecting against diabetes and DN. Herein, we hypothesized that activation of VDR attenuated high glucose-induced cellular injury in renal tubular epithelial cells partially through up-regulating CYP2J5 expression.
MAIN METHODS
Streptozotocin (STZ) was injected to induce diabetic in wild type and Vdr mice. The effects of VDR knockout and an activator of VDR, paricalcitol, on the renal injury were detected. In vitro, a murine kidney proximal tubule epithelial cell line BU.MPT induced by high glucose were treated with or without paricalcitol (30 mM) for 12 h or 24 h.
KEY FINDINGS
The expression of CYP2J5 was significantly decreased both in wild type and Vdr diabetic mice induced by STZ. The STZ-induced kidney architecture damage and apoptosis rate in Vdr mice were more severe. In vitro, high glucose treatment strongly reduced the CYP2J5 expression and the synthesis of 14,15-EET in BU.MPT cells. Supplement of 14,15-EET significantly reduced the lactate dehydrogenase (LDH) release induced by high glucose in BU.MPT cells. Furthermore, treatment with paricalcitol attenuated cellular injury and restored the expression of CYP2J5 reduced by high glucose in BU.MPT cells.
SIGNIFICANCE
We conclude that activation of VDR attenuates high glucose-induced cellular injury partially dependent on CYP2J5 in murine renal tubule epithelial cells and paricalcitol may represent a potential therapy for DN.
Topics: Animals; Cell Line; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Ergocalciferols; Gene Deletion; Gene Expression Regulation; Glucose; Kidney Tubules, Proximal; Male; Mice; Mice, Knockout; Receptors, Calcitriol
PubMed: 31415769
DOI: 10.1016/j.lfs.2019.116755 -
Biomedicine & Pharmacotherapy =... May 2020Multiple sclerosis (MS) is known as an autoimmune disease in the central nervous system (CNS) characterized by motor deficits, pain, fatigue, cognitive impairment, and...
Multiple sclerosis (MS) is known as an autoimmune disease in the central nervous system (CNS) characterized by motor deficits, pain, fatigue, cognitive impairment, and sensory and visual dysfunction. MS is considered to be resulted from significant inflammatory response. Paricalcitol (Pari) is a vitamin D2 analogue, which has been indicated to show anti-inflammatory activities in kidney and heart diseases. In the present study, if Pari could ameliorate the experimental autoimmune encephalomyelitis (EAE) was investigated. Here, the C57BL/6 mice were immunized using myelin oligodendrocyte glycoprotein 35-55 (MOG). Subsequently, Pari was intraperitoneally injected into the mice. As for in vitro analysis, RAW264.7 and Jurkat cells were incubated with Pari together with corresponding stimulus. The results indicated that Pari administration reduced the paralytic severity, neuropathology and apoptosis in MOG-treated mice compared to the MOG single group. Pari also exhibited a significantly inhibitory effect on immune cell infiltration, glial cell activation, expression of pro-inflammatory factors and the activation of nuclear factor κB (NF-κB). The expression of pro-inflammatory regulators and the translocation of NF-κB from cytoplasm into nuclear in RAW264.7 and Jurkat cells under specific stimulation was clearly down-regulated by Pari incubation. Furthermore, we found that suppressing NF-κB with its inhibitor combined with Pari could further reduce the expression of pro-inflammatory factors and associated proteins. These data illustrated that Pari could diminish MOG-triggered EAE, as well as macrophages and T cells activation through blocking NF-κB activation. Collectively, Pari might have therapeutic effects in mouse models with MS.
Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Calcium-Binding Proteins; Caspase 3; Cell Line; Cell Proliferation; Cyclooxygenase 2; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Ergocalciferols; Glial Fibrillary Acidic Protein; Humans; I-kappa B Proteins; Inflammation; Jurkat Cells; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microglia; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; NF-kappa B; Nitric Oxide Synthase Type II; Peptide Fragments; Poly (ADP-Ribose) Polymerase-1; Primary Cell Culture; RAW 264.7 Cells; Signal Transduction; Spinal Cord
PubMed: 32106388
DOI: 10.1016/j.biopha.2019.109528 -
PloS One 2020Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome...
Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome in renal transplant recipients (RTRs). Vitamin D-receptor (VDR) activation is postulated to modulate inflammation and endothelial function. We aimed to explore if a synthetic vitamin D, paricalcitol, could influence systemic inflammation and immune activation in RTRs. Newly transplanted RTRs were included in an open-label randomized controlled trial on the effect of paricalcitol on top of standard care over the first post-transplant year. Fourteen pre-defined circulating biomarkers reflecting leukocyte activation, endothelial activation, fibrosis and general inflammatory burden were analyzed in 74 RTRs at 8 weeks (baseline) and 1 year post-engraftment. Mean changes in plasma biomarker concentrations were compared by t-test. The expression of genes coding for the same biomarkers were investigated in 1-year surveillance graft biopsies (n = 60). In patients treated with paricalcitol circulating osteoprotegerin levels increased by 0.19 ng/ml, compared with a 0.05 ng/ml increase in controls (p = 0.030). In graft tissue, a 21% higher median gene expression level of TNFRSF11B coding for osteoprotegerin was found in paricalcitol-treated patients compared with controls (p = 0.026). Paricalcitol treatment did not significantly affect the blood- or tissue levels of any other investigated inflammatory marker. In RTRs, paricalcitol treatment might increase both circulating and tissue levels of osteoprotegerin, a modulator of calcification, but potential anti-inflammatory treatment effects in RTRs are likely very modest. [NCT01694160 (2012/107D)]; [www.clinicaltrials.gov].
Topics: Biomarkers; Ergocalciferols; Female; Gene Expression Regulation; Humans; Inflammation; Kidney Transplantation; Leukocytes; Male; Middle Aged
PubMed: 33326471
DOI: 10.1371/journal.pone.0243759 -
Clinical Journal of the American... Mar 2020In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the...
BACKGROUND AND OBJECTIVES
In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D) is routinely used. We examined standard laboratory parameters of patients on in-center hemodialysis receiving intravenous vitamin D who switched to oral calcitriol.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
We conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation.
RESULTS
A total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0-5.5 mg/dl, and iPTH 150-600 pg/ml) were comparable between groups (45% versus 45%; =0.96). Hospital admissions, length of hospital stay, and survival were comparable between groups. An as-treated analysis and excluding those receiving cinacalcet did not reveal significant between-group differences.
CONCLUSIONS
Among patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.
Topics: Administration, Intravenous; Administration, Oral; Aged; Biomarkers; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Drug Substitution; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Renal Dialysis; Retrospective Studies; Time Factors; Treatment Outcome; United States; Vitamins
PubMed: 32111702
DOI: 10.2215/CJN.07960719 -
Journal of Hematology Dec 2021The monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-β (EB); however, how...
Monthly Continuous Erythropoietin Receptor Activator Versus Weekly Epoetin-Beta, Similar Hemoglobinization but Different Anisocytosis Degree in Hemodialysis Patients: A Randomized Controlled Trial.
BACKGROUND
The monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-β (EB); however, how the different pharmacologic properties affect the red blood cell (RBC) size determined by RBC distribution width (RDW) has not been evaluated yet. We assess the potential differences in iron metabolism, plasma erythropoietin (EPO), hepcidin, and soluble α-Klotho (α-Klotho) levels as an emergent hematopoiesis factor.
METHODS
Thirty-seven chronic hemodialysis patients were included from January 2010 to November 2011 and randomized (1:1) to continue with EB or to convert to monthly CERA. Primary outcome was the mean change in Hb between groups at months 0, 3 and 6, and the percentage of patients who maintained stable Hb (Hb ± 1 g/dL from baseline level to month 6). Secondary outcomes were the influence on the erythropoietic process and iron metabolism markers. Thirty-one patients completed the study (CERA: n = 15, EB: n = 16).
RESULTS
The mean (95% confidence interval (CI)) Hb difference between groups was 0.28 g/dL (-0.36 to 0.93). There was no difference between the percentages of patients with stable Hb levels. In the CERA group RDW values increased progressively (interaction erythropoietin-stimulating agent (ESA) type and time on RDW values, F (1.57, 45.60) = 17.17, P < 0.01, partial η = 0.37) and the mean corpuscular volume changed at the different time points, (F (2, 28) = 29.12, P = 0.03, partial η = 0.23). During the evaluation period, in the CERA group, EPO was higher, and hepcidin and ferritin decreased significantly. α-Klotho decreased in both groups and correlated negatively with the changes on the RDW and positively with transferrin and serum iron. The number of serious adverse events was higher at the CERA group.
CONCLUSIONS
Monthly CERA maintained Hb concentrations; however, it showed a significant effect on RDW, probably due to its impact on the EPO and hepcidin levels. α-Klotho decreased significantly in both groups, and its changes correlated with the changes in iron metabolism. Whether the RDW evolution was associated with the serious adverse events (SAEs) is a feasible hypothesis that needs to be confirmed in large studies.
PubMed: 35059087
DOI: 10.14740/jh862