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Very high-dose cholecalciferol and arteriovenous fistula maturation in ESRD: a randomized, double-blind, placebo-controlled pilot study.

ABSTRACT: While vitamin D is critical for optimal skeletal health, it also appears to play a significant role in vascular homeostasis. This pilot study compared arteriovenous (AV) access outcomes following cholecalciferol supplementation compared to placebo in end-stage renal disease patients preparing to undergo AV access creation.A total of 52 adult hemodialysis patients preparing for arteriovenous fistula (AVF) creation were randomized to receive perioperative high-dose cholecalciferol versus placebo in this double-blind, randomized, placebo-controlled pilot study. The primary outcome was mean response to high-dose oral cholecalciferol versus placebo, and secondary outcome AV access maturation at 6 months. Logistic regression was used to assess the association between AV access maturation and baseline, posttreatment and overall change in vitamin D concentration.A total of 45% of cholecalciferol-treated and 54% of placebo-treated patients were successfully using their AVF or arteriovenous graft (AVG) at 6 months (p=0.8). Baseline serum concentrations of 25(OH)D and 1,25(OH)2D did not differ between those who experienced AVF or AVG maturation and those who did not (p=0.22 and 0.59, respectively). Similarly, there was no relationship between AVF or AVG maturation and posttreatment serum 25(OH)D and 1,25(OH)2D concentration (p=0.24 and 0.51, respectively).Perioperative high-dose vitamin D3 therapy does correct 25(OH)D level but does not appear to have an association with AV access maturation rates. Future research may include extended preoperative vitamin D3 therapy in a larger population or in certain subpopulations at high risk for AVF failure.

SUBMITTER: Wasse H

PROVIDER: S-EPMC3979512 | biostudies-literature | 2014 Mar-Apr

REPOSITORIES: biostudies-literature

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Very high-dose cholecalciferol and arteriovenous fistula maturation in ESRD: a randomized, double-blind, placebo-controlled pilot study.

Wasse Haimanot H Huang Rong R Long Qi Q Zhao Yize Y Singapuri Salman S McKinnon William W Skardasis George G Tangpricha Vin V

The journal of vascular access 20131007 2

<h4>Purpose</h4>While vitamin D is critical for optimal skeletal health, it also appears to play a significant role in vascular homeostasis. This pilot study compared arteriovenous (AV) access outcomes following cholecalciferol supplementation compared to placebo in end-stage renal disease patients preparing to undergo AV access creation.<h4>Methods</h4>A total of 52 adult hemodialysis patients preparing for arteriovenous fistula (AVF) creation were randomized to receive perioperative high-dose ...[more]

PMID: 24101420

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Project description:BACKGROUND:The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. METHODS:Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. RESULTS:Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. CONCLUSIONS:Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

Project description:BackgroundArteriovenous fistula (AVF) maturation is a process involving remodeling of venous arm of the AVFs. It is a challenge to balance adaptive AVF remodeling and neointima formation. In this study we temporally controlled Notch activation to promote AVF maturation while avoiding neointima formation.MethodsTemporal Notch activation was controlled by regulating the expression of Notch transcription factor, RBP-Jκ, or dnMAML1 (dominant negative MAML2) in vascular smooth muscle cells (VSMCs). AVF mouse model was created and VSMC phenotype dynamic changes during AVF remodeling were determined.ResultsActivated Notch was found in the nuclei of neointimal VSMCs in AVFs from uremic mice. We found that the VSMCs near the anastomosis became dedifferentiated and activated after AVF creation. These dedifferentiated VSMCs regained smooth muscle contractile markers later during AVF remodeling. However, global or VSMC-specific KO of RBP-Jκ at early stage (before or 1 week after AVF surgery) blocked VSMC differentiation and neointima formation in AVFs. These un-matured AVFs showed less intact endothelium and increased infiltration of inflammatory cells. Consequently, the VSMC fate in the neointima was completely shut down, leading to an un-arterialized AVF. In contrast, KO of RBP-Jκ at late stage (3 weeks after AVF surgery), it could not block neointima formation and vascular stenosis. Inhibition of Notch activation at week 1 or 2, could maintain VSMC contractile markers expression and facilitate AVF maturation.ConclusionsThis work uncovers the molecular and cellular events in each segment of AVF remodeling and found that neither sustained increasing nor blocking of Notch signaling improves AVF maturation. It highlights a novel strategy to improve AVF patency: temporally controlled Notch activation can achieve a balance between adaptive AVF remodeling and neointima formation to improve AVF maturation.Translational perspectiveAdaptive vascular remodeling is required for AVF maturation. The balance of wall thickening of the vein and neointima formation in AVF determines the fate of AVF function. Sustained activation of Notch signaling in VSMCs promotes neointima formation, while deficiency of Notch signaling at early stage during AVF remodeling prevents VSMC accumulation and differentiation from forming a functional AVFs. These responses also delay EC regeneration and impair EC barrier function with increased inflammation leading to failed vascular remodeling of AVFs. Thus, a strategy to temporal regulate Notch activation will improve AVF maturation.

Dataset Information

Very high-dose cholecalciferol and arteriovenous fistula maturation in ESRD: a randomized, double-blind, placebo-controlled pilot study.

Publications

Very high-dose cholecalciferol and arteriovenous fistula maturation in ESRD: a randomized, double-blind, placebo-controlled pilot study.

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