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Materia Socio-medica Apr 2015Alteration in vitamin D metabolism has a central role in the pathogenesis of secondary hyperparathyroidism (SHPT) and is also associated with increased cardiovascular... (Review)
Review
Alteration in vitamin D metabolism has a central role in the pathogenesis of secondary hyperparathyroidism (SHPT) and is also associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). For more than sixty years, vitamin D, nutritional vitamin D (ergocalciferol, cholecalciferol or calcifediol) and nonselective vitamin D receptor (VDR) activators (calcitriol, alfacalcidol) have been used in the prevention and treatment of SHPT. In the last twenty years, selective VDR activators (paricalcitol, maxacalcitol) have been used to target SHPT. However, there are many open questions regarding use of nutritional vitamin D or VDR activators. The K/DOQI and KDIGO guidelines recommended testing for vitamin D insufficiency and deficiency in patients with CKD, but there is no consensus on the definition of vitamin D insufficiency in CKD. There are a many open questions, for example, regarding the optimal nutritional vitamin D type and the dose and co-administration of nutritional vitamin and VDR activators. Therapy with VDRAs is required in the majority of patients with CKD, particularly in dialysis patients. However, when to start with VDRAs is not so apparent. Is PTH level the only indication of when to start therapy? Although VDRAs are very effective in lowering PTH levels and bone metabolism the effect of patients mortality is not so straightforward. Despite many unanswered questions, there is a large body of experimental and clinical data to support vitamin D use in patients with CKD. To obtain answers to the open questions, we need more randomized controlled trials.
PubMed: 26005391
DOI: 10.5455/msm.2015.27.122-124 -
Biochimica Et Biophysica Acta.... Mar 2021Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium...
Chemopreventive effects of vitamin D and its analogue, paricalcitol, in combination with 5-fluorouracil against colorectal cancer: The role of calcium signalling molecules.
BACKGROUND
Although vitamin D (VD) is chemoprotective and enhances 5-fluorouracil (5-FU) cytotoxicity against colorectal cancer (CRC), little is known about its potential calcium (Ca)-mediated anti-tumorigenic actions. Therefore, this study compared between VD and its non-calcaemic analogue, Paricalcitol (Pcal), ± 5-FU in relation to chemoprevention and Ca-mediated apoptosis in vivo and in vitro.
METHODS
Seventy male mice were distributed to: negative controls, positive controls (PC), VD, Pcal, 5-FU, VD + 5-FU and Pcal+5-FU groups. All groups, except negative, received two consecutive azoxymethane (AOM)-injections (10 mg/Kg/week) for CRC induction. VD (1000 IU/kg; three times/week) and Pcal (1.25 μg/kg; three times/week) injections started week-16 post-AOM and for 10 weeks. Three successive 5-FU cycles began at week-21 (50 mg/Kg/week). Similar protocols with VD, Pcal and/or 5-FU were applied in the HT29 colon cancer cells.
RESULTS
The PC group had abundant malignant tumours, markedly elevated proliferation markers (survivin/CCND1) and declines in cyclin-dependent kinase-inhibitor-1A, pro-apoptotic molecules (p53/BAX/cytochrome_C/caspase-3), tissue Ca concentrations and Ca-dependent proteins (CaSR/CAM/CAMKIIA). All monotherapies equally reduced tumour numbers and proliferation markers whilst promoting the anti-tumorigenic molecules. VD and/or 5-FU, but not Pcal monotherapy, enhanced Ca levels and Ca-related molecules (CaSR/CAM/CAMKIIA/BAX/cytochrome_C) in vivo and in vitro. However, VD + 5-FU co-therapy showed the lowest tumour numbers, the highest cell numbers in sub-G1 phase of cell cycle, alongside the most effective modulations of oncogenes, tumour suppressors and Ca-related molecules at the gene and protein levels in vivo and in vitro.
CONCLUSIONS
VD was superior than Paricalcitol in potentiating 5-FU cytotoxicity, possibly by upregulating several Ca-related molecules involved in tumour suppression.
Topics: Animals; Anticarcinogenic Agents; Calcium; Calcium Signaling; Cell Cycle Checkpoints; Cholecalciferol; Colorectal Neoplasms; Disease Progression; Ergocalciferols; Fluorouracil; HT29 Cells; Humans; Male; Mice; Mice, Inbred BALB C
PubMed: 33338596
DOI: 10.1016/j.bbadis.2020.166040 -
Optimizing the cost-effectiveness of treatment for chronic kidney disease-mineral and bone disorder.Kidney International Supplements Dec 2013Chronic kidney disease-mineral and bone disorder (CKD-MBD) is an important risk factor in patients with CKD, and some medications for treating CKD-MBD have been recently... (Review)
Review
Chronic kidney disease-mineral and bone disorder (CKD-MBD) is an important risk factor in patients with CKD, and some medications for treating CKD-MBD have been recently marketed. Because assessment of health-care cost-effectiveness is growing in importance with increases in health expenditures, several cost-effectiveness analyses for new medications such as sevelamer, lanthanum carbonate, cinacalcet hydrochloride, and paricalcitol have been conducted. The results of these analyses have stimulated discussion on the efficient use of these medications and, in some cases, have affected treatment recommendation. However, most of these studies had methodological problems, one of them being that the effectiveness of medications was estimated based on changes of surrogate parameters, such as vascular calcification or serum biochemistry values. Furthermore, even if cost-effectiveness analyses were based on a given clinical trial, the results might differ from country to country. To provide greater health benefits under limited health expenditures based on the results of cost-effectiveness analyses, it is necessary to confirm the effectiveness of medications through well-designed clinical trials having mortality as the primary end point. In addition, cost-effectiveness analyses need to be performed separately for each country.
PubMed: 25019030
DOI: 10.1038/kisup.2013.95 -
Journal of the American Society of... Jan 2011Recent studies implicate Wnt/β-catenin signaling in podocyte dysfunction. Because vitamin D analogs can inhibit β-catenin in other tissues, we tested whether the...
Recent studies implicate Wnt/β-catenin signaling in podocyte dysfunction. Because vitamin D analogs can inhibit β-catenin in other tissues, we tested whether the vitamin D analog paricalcitol could ameliorate podocyte injury, proteinuria, and renal fibrosis in adriamycin (ADR) nephropathy. Compared with vehicle-treated controls, paricalcitol preserved expression of nephrin, podocin, and WT1; prevented proteinuria; and reduced glomerulosclerotic lesions induced by ADR. Paricalcitol also inhibited expression of proinflammatory cytokines, reduced renal infiltration of monocytes/macrophages, hampered activation of renal myofibroblasts, and suppressed expression of the fibrogenic TGF-β1, CTGF, fibronectin, and types I and III collagen. Selective suppression of renal Wnt4, Wnt7a, Wnt7b, and Wnt10a expression after ADR accompanied these renoprotective effects of paricalcitol. Significant upregulation of β-catenin, predominantly in podocytes and tubular epithelial cells, accompanied renal injury; paricalcitol largely abolished this induction of renal β-catenin and inhibited renal expression of Snail, a downstream effector of Wnt/β-catenin signaling. Administration of paricalcitol also ameliorated established proteinuria. In vitro, paricalcitol induced a physical interaction between the vitamin D receptor and β-catenin in podocytes, which led to suppression of β-catenin-mediated gene transcription. In summary, these findings suggest that paricalcitol prevents podocyte dysfunction, proteinuria, and kidney injury in adriamycin nephropathy by inhibiting Wnt/β-catenin signaling.
Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Doxorubicin; Ergocalciferols; Glomerular Mesangium; Male; Mice; Mice, Inbred BALB C; Podocytes; Proteinuria; Signal Transduction; Vitamin D; Wnt Proteins; beta Catenin
PubMed: 21030600
DOI: 10.1681/ASN.2009121236 -
International Immunopharmacology Nov 2021Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.
BACKGROUND
Vitamin D receptor (VDR) and NLRP3 inflammasome play critical roles in lupus nephritis (LN) pathogenesis.
AIM OF THE STUDY
This study explored the therapeutic effect of VDR agonist on LN and its molecular mechanism to inhibit NLRP3 signalling.
METHODS
C57BL/6 mice, lupus-prone MRL/lpr mice, and VDR agonist paricacitol-treated MRL/lpr mice (300 ng/kg/mouse per dose, 5 times/week for 8 weeks from 8 weeks old) were used to assess kidney histopathology and measure proteinuria, serum anti-ds-DNA antibody and expression of NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis. We used mouse renal tubular epithelial cells (mRTECs) to identify protein-protein interactions and examine the effects of paricalcitol.
RESULTS AND CONCLUSION
LN pathogenesis decreased after paricalcitol treatment. We observed a marked improvement in renal pathology and a time-dependent decrease urine protein and serum anti-dsDNA antibody levels. In 16-week-old MRL/lpr LN mice, the upregulated expression of NLRP3/caspase-1/IL-1β/IL-18 axis was significantly downregulated after paricalcitol treatment. Paricalcitol can reverse the apoptosis induced by anti-dsDNA antibody via the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis in mRTECs. Furthermore, paricalcitol suppressed NF-κB nuclear translocation by competitively binding to importin-4. In summary, the VDR agonist can alleviate LN by modulating the NF-κB/NLRP3/caspase-1/IL-1β/IL-18 axis and suppressing the NF-κB nuclear translocation.
Topics: Animals; Apoptosis; Caspase 1; Caspases; Cell Culture Techniques; Ergocalciferols; Female; Interleukin-18; Interleukin-1beta; Karyopherins; Kidney; Lupus Nephritis; Mice; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, Calcitriol; Signal Transduction
PubMed: 34536747
DOI: 10.1016/j.intimp.2021.108131 -
Jornal Brasileiro de Nefrologia 2019Mineral bone disorder is a common feature of chronic kidney disease. Lion face syndrome is rare complication of severe hyperparathyroidism in end-stage renal disease...
Mineral bone disorder is a common feature of chronic kidney disease. Lion face syndrome is rare complication of severe hyperparathyroidism in end-stage renal disease patients, which has been less commonly reported due to dialysis and medical treatment advances in the last decade. The early recognition of the characteristic facial deformity is crucial to prompt management and prevent severe disfigurement. The authors present a rare case of severe hyperparathyroidism presenting with lion face syndrome and bone fractures.
Topics: Adult; Bone Density; Bone Density Conservation Agents; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Female; Fractures, Bone; Humans; Hyperostosis Frontalis Interna; Hypocalcemia; Kidney Failure, Chronic; Parathyroidectomy; Postoperative Complications; Renal Dialysis; Teriparatide; Treatment Outcome
PubMed: 30720853
DOI: 10.1590/2175-8239-JBN-2018-0198 -
Iranian Journal of Kidney Diseases Nov 2017The Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines on the management of bone disease in patients with chronic kidney disease recommend periodic...
INTRODUCTION
The Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines on the management of bone disease in patients with chronic kidney disease recommend periodic measurement of serum calcium, phosphorus, vitamin D, and parathyroid hormone levels after kidney transplantation, with the frequencies that will vary according to the severity of bone disease and graft function. Paricalcitol, a selective vitamin D receptor activator, is indicated in the prevention and treatment of secondary hyperparathyroidism.
MATERIALS AND METHODS
We retrospectively evaluated the effect of treatment with paricalcitol among our kidney transplant recipients. We monitored the effect of paricalcitol on bone density; the plasma levels of parathyroid hormone, calcium, and phosphorus; and proteinuria and calciuria. Comparisons were made between these parameters before treatment and 12 months after treatment.
RESULTS
Eighty-eight kidney transplant recipients with a mean age at the time of transplantation of 47.1 ± 10.5 years were receiving paricalcitol. On average, paricalcitol was included into the treatment for 48 months from transplantation (median, 27 months). The patients had significantly improved bone density (P < .001), significantly lower parathyroid hormone levels (P < .001), and significantly decreased proteinuria (P = .02) after 12 months of treatment. During the treatment with paricalcitol, the immunosuppressive therapy, dose of prednisone, body mass index, and vitamin D levels had not significantly changed. Nor had any significant change occurred to graft function.
CONCLUSIONS
Paricalcitol is an effective therapy for secondary hyperparathyroidism in kidney transplant recipients.
Topics: Adult; Biomarkers; Bone Density; Bone Density Conservation Agents; Ergocalciferols; Female; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Slovakia; Time Factors; Treatment Outcome
PubMed: 29190607
DOI: No ID Found -
Biomedicines Nov 2018Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval... (Review)
Review
Oncolytic viruses have emerged as a novel class of anti-cancer therapeutics with one virus already receiving United States Food and Drug Administration (FDA) approval (talimogene laherparepvec) and many others undergoing testing in clinical trials. These viruses have direct lytic effects on tumor cells as well as immunomodulatory functions to increase inflammatory cell infiltrates in the tumor microenvironment. Despite all of the advances in cancer care, pancreatic cancer remains a highly lethal malignancy. One of the main barriers to successful systemic treatment of the disease is the fibrotic tumor stroma, as the unique extracellular matrix creates an environment that promotes tumor growth and is resistant to chemotherapy and other anti-cancer agents. The pleiotropic effects of Vitamin D have been widely studied, but recent research has now demonstrated it to be an effective agent in modulating pancreatic cancer stroma to facilitate the enhanced delivery of cytotoxic chemotherapy and immunogenicity in response to treatment. This review will explore the combination of Vitamin D with oncolytic viruses and how this novel application of Vitamin D's ability to modulate pancreatic tumor stroma may result in a potential mechanism for increasing the efficacy of oncolytic virotherapy in pancreatic cancer.
PubMed: 30400571
DOI: 10.3390/biomedicines6040104 -
BMC Nephrology Sep 2013Vitamin D insufficiency correlates with mortality risk among patients with chronic kidney disease (CKD). The survival benefits of active vitamin D treatment have been... (Meta-Analysis)
Meta-Analysis Observational Study Review
BACKGROUND
Vitamin D insufficiency correlates with mortality risk among patients with chronic kidney disease (CKD). The survival benefits of active vitamin D treatment have been assessed in patients with CKD not requiring dialysis and in patients with end stage renal disease (ESRD) requiring dialysis.
METHODS
MEDLINE, Embase, the Cochrance Library, and article reference lists were searched for relevant observational trials. The quality of the studies was evaluated using the Newcastle-Ottawa Scale (NOS) checklist. Pooled effects were calculated as hazard ratios (HR) using random-effects models.
RESULTS
Twenty studies (11 prospective cohorts, 6 historical cohorts and 3 retrospective cohorts) were included in the meta-analysis., Participants receiving vitamin D had lower mortality compared to those with no treatment (adjusted case mixed baseline model: HR, 0.74; 95% confidence interval [95% CI], 0.67-0.82; P <0.001; time-dependent Cox model: HR, 0.71; 95% CI, 0.57-0.89; P <0.001). Participants that received calcitriol (HR, 0.63; 95% CI, 0.50-0.79; P <0.001) and paricalcitol (HR, 0.43 95% CI, 0.29-0.63; P <0.001) had a lower cardiovascular mortality. Patients receiving paricalcitol had a survival advantage over those that received calcitriol (HR, 0.95; 95% CI, 0.91-0.99; P <0.001).
CONCLUSIONS
Vitamin D treatment was associated with decreased risk of all-cause and cardiovascular mortality in patients with CKD not requiring dialysis and patients with end stage renal disease (ESRD) requiring dialysis. There was a slight difference in survival depending on the type of vitamin D analogue. Well-designed randomized controlled trials are necessary to assess the survival benefits of vitamin D.
Topics: Comorbidity; Dietary Supplements; Humans; Incidence; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Survival Rate; Treatment Outcome; Vitamin D; Vitamin D Deficiency
PubMed: 24066946
DOI: 10.1186/1471-2369-14-199 -
Kidney International Supplements Sep 2011Progressive loss of kidney function leads to reduced production of calcitriol (1,25-dihydroxyvitamin D; active vitamin D) and an imbalance in serum calcium (Ca) and... (Review)
Review
Progressive loss of kidney function leads to reduced production of calcitriol (1,25-dihydroxyvitamin D; active vitamin D) and an imbalance in serum calcium (Ca) and phosphorus (P) levels, which are associated with progression of renal failure as well as increased rates of cardiovascular (CV) events and mortality. In addition, multifactorial hypocalcemia and resistance to parathyroid hormone (PTH) can lead to prolonged and excessive synthesis and secretion of PTH, eventually leading to development of secondary hyperparathyroidism and renal osteodystrophy. These changes associated with chronic kidney disease (CKD), extending beyond bone and related biochemical abnormalities, have prompted the development of the term CKD-mineral and bone disorder to describe its systemic nature. Excessive P loading, among other factors, will promote vascular calcification (VC), and PTH production will affect bone remodeling. Although administration of calcitriol increases serum Ca levels and decreases PTH, it is also associated with elevated Ca × P product. Therefore, compounds that selectively activate vitamin D receptors (VDR activators), potentially reducing Ca-P toxicity and distinctly affecting pathogenic mechanisms of VC, might enhance CV and renal protection, increase the vitamin D therapeutic window, and thus provide a significant clinical benefit. Moreover, selective VDR activators have been associated with improvement in survival, at least among dialysis patients. Thus, selective VDR activators should be considered a novel and interesting approach to enhance the standard of care in CKD patients.
PubMed: 25018911
DOI: 10.1038/kisup.2011.28