Are There Any Pleiotropic Benefits of Vitamin D in Patients With Diabetic Kidney Disease? A Systematic Review of Randomized Controlled Trials.

Background: Type 2 diabetes (T2D) and kidney disease are risk factors for vitamin D deficiency. Native forms of vitamin D have a lower risk of hypercalcemia than calcitriol, the active hormone. The enzyme responsible for activating native vitamin D is now known to be expressed throughout the body; therefore, native vitamin D may have clinically relevant effects in many body systems. Objective: The objective of this systematic review was to examine the effect of native vitamin D supplementation on clinical outcomes and surrogate laboratory measures in patients with T2D and diabetic kidney disease (DKD). Design: Systematic review. Setting: Randomized controlled trials (RCTs) conducted in any country. Patients: Adults with T2D and DKD receiving supplementation with any form of native vitamin D (eg, ergocalciferol, cholecalciferol, calcifediol). Measurements: Clinical outcomes and surrogate clinical and laboratory measures reported in each of the trials were included in this review. Methods: The following databases were searched from inception to January 31, 2023: Embase, MEDLINE, Cochrane CENTRAL, Web of Science, ProQuest Dissertations and Theses, and medRxiv. Only RCTs examining supplementation with a native vitamin D form with a control or placebo comparison group were included. We excluded studies reporting only vitamin D status or mineral metabolism parameters, without any other outcomes of clinical relevance or surrogate laboratory measures. Study quality was evaluated using the Cochrane risk-of-bias tool (RoB2). Results were synthesized in summary tables for each type of outcome with the P values from the original studies displayed. Results: Nine publications were included, corresponding to 5 separate RCTs (377 participants total). Mean age ranged from 40 to 63. All trials administered vitamin D3. Intervention groups experienced improvements in vitamin D status and a reduction in proteinuria in 4 of the 5 included RCTs. There was a decrease in low-density lipoprotein and total cholesterol in the 2 trials in which they were measured. Improvements in bone mass, flow-mediated dilation, and inflammation were also reported, but each was only measured in 1 RCT. Effects on glucose metabolism, high-density lipoprotein, triglycerides, blood pressure, oxidative stress, and kidney function were mixed. No serious adverse effects were reported. Limitations: Limitations include the small number of RCTs and lack of information on the use of drugs that affect measured outcomes (eg, proteinuria-lowering renin-angiotensin-aldosterone system inhibitors and lipid-lowering medication) in most studies. Our study is also limited by the absence of a prestudy protocol and registration. Conclusions: Native vitamin D is a safe treatment that improves vitamin D status in patients with DKD. Vitamin D may modify proteinuria and lipid metabolism in DKD, but further well-designed trials that include well-established treatments are necessary. Overall, there is limited evidence for beneficial pleiotropic effects of vitamin D in patients with DKD.

Contexte: Le diabète de type 2 (DT2) et l'insuffisance rénale sont des facteurs de risque pour une carence en vitamine D. Les formes natives de la vitamine D représentent un risque plus faible d'hypercalcémie que le calcitriol, la forme active sur le plan hormonal de la vitamine D. On sait maintenant que l'enzyme responsable de l'activation de la vitamine D peut être exprimée dans tout le corps et donc, que la vitamine D native peut avoir des effets cliniquement significatifs dans de nombreux systèmes de l'organisme. Objectif: Examiner l'effet d'une supplémentation en vitamine D native sur les résultats cliniques et les mesures de laboratoire de substitution de patients atteints de DT2 et de maladie rénale diabétique (MRD). Conception: Revue systématique. Sources: Les essais contrôlés randomisés (ECR) pertinents, sans égard au pays où ils ont été menés. Sujets: Des adultes atteints de DT2 et de MRD recevant une supplémentation de toute forme de vitamine D native (ergocalciférol, cholécalciférol, calcifédiol). Mesures: Les mesures biologiques et cliniques de substitution ainsi que les résultats cliniques rapportés dans chacun des essais inclus. Méthodologie: Une recherche des articles pertinents a été effectuée dans les bases de données Embase, MEDLINE, Cochrane CENTRAL, Web of Science, ProQuest Dissertations and Theses et medRxiv depuis leur création jusqu'au 31 janvier 2023. Seuls les ECR examinant la supplémentation avec une forme native de vitamine D contre un groupe témoin ou un placebo ont été inclus. Nous avons exclu les études ne rapportant que le statut en vitamine D ou les paramètres du métabolisme minéral, sans aucun autre résultat significatif sur le plan clinique ou mesure de laboratoire de substitution. La qualité des études a été évaluée à l'aide de l'outil Cochrane sur le risque de biais (RoB2). Les résultats ont été résumés dans des tableaux récapitulatifs pour chaque type de résultat avec les valeurs de p tirées des essais originaux. Résultats: Neuf publications ont été incluses, lesquelles portaient sur cinq ECR distincts (377 participants au total). L'âge moyen des sujets variait de 40 à 63 ans. De la vitamine D3 avait été administrée dans tous les essais. Dans quatre des cinq ECR inclus, le groupe d'intervention avait connu une amélioration du statut en vitamine D et une réduction de la protéinurie. Une diminution des LDL et du cholestérol total avait été observée dans les deux essais où ces paramètres avaient été mesurés. Des améliorations de la masse osseuse, de la dilatation médiée par le débit et de l'inflammation avaient également été rapportées, mais chacun de ces paramètres n'avait été mesuré que dans un seul ECR. Lorsque rapportés, les effets sur le métabolisme du glucose, les HDL, les triglycérides, la pression artérielle, le stress oxydatif et la fonction rénale étaient mitigés. Aucun effet indésirable grave à la supplémentation n'a été signalé. Limites: Les résultats sont limités par le faible nombre d'ECR inclus et par le manque d'information dans la plupart des études sur l'utilisation de médicaments qui affectent les résultats mesurés (par exemple, les inhibiteurs du SRAA abaissant la protéinurie et les médicaments abaissant le taux de lipides). Aussi, notre étude n'est pas enregistrée et ne comportait pas de protocole pré-étude. Conclusion: La supplémentation en vitamine D native est sûre et elle améliore le statut en vitamine D des patients atteints de MRD. La vitamine D semble modifier la protéinurie et le métabolisme lipidique en contexte de MRD, mais d'autres essais bien conçus et intégrant des traitements bien établis sont nécessaires. Globalement, il existe peu de données probantes sur les effets pléiotropiques bénéfiques de la vitamine D chez les patients atteints de MRD.

Does Native Vitamin D Supplementation Have Pleiotropic Effects in Patients with End-Stage Kidney Disease? A Systematic Review of Randomized Trials.

Vitamin D has been shown to have multiple pleiotropic effects beyond bone and mineral metabolism, with purported roles in cardiovascular disease, cancer, and host immunity. Vitamin D deficiency is common in patients with end-stage kidney disease (ESKD); however, current clinical practice has favored the use of the active hormone. Whether vitamin D deficiency should be corrected in patients with ESKD remains unclear, as few randomized trials have been conducted. In this systematic review, we summarize the current evidence examining whether vitamin D supplementation improves outcomes, beyond mineral metabolism, in patients with ESKD. Data from randomized controlled trials of adults with ESKD were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection from inception to February 2023. Twenty-three trials composed of 2489 participants were identified for inclusion. Data were synthesized by two independent reviewers and summarized in tables organized by outcome. Outcomes included measures of mortality, cardiovascular disease, inflammation, muscle strength/function, nutrition, patient well-being, and outcomes specific to ESKD including erythropoietin usage, pruritus, and dialysis access maturation. The Cochrane risk of Bias Tool (RoB 2, 2019) was used to assess study quality. Overall, our findings indicate a minimal and varied benefit of native vitamin D supplementation. From the largest studies included, we determine that vitamin D has no demonstrated effect on patient-reported measures of well-being or utilization of erythropoietin, nor does it change levels of the inflammation biomarker C-reactive protein. Included trials were heterogeneous with regards to outcomes, and the majority studied small participant populations with a relatively short follow-up. We conclude that vitamin D supplementation corrects vitamin D deficiency and is safe and well-tolerated in humans with ESKD. However, it is not clear from clinical trials conducted to date that a causal pathway exists between 25(OH)D and pleiotropic effects that is responsive to vitamin D treatment.

Vitamin K Supplementation for the Prevention of Cardiovascular Disease: Where Is the Evidence? A Systematic Review of Controlled Trials.

Matrix gla protein (MGP) is an important vitamin K-dependent inhibitor of vascular calcification. High levels of uncarboxylated, dephosphorylated MGP have been associated with vascular calcification and are responsive to vitamin K treatment. In this systematic review, we summarize the available evidence examining whether vitamin K supplementation improves surrogate measures of cardiovascular disease including artery and valve calcification, atherosclerosis and artery stiffening. Data from controlled trials of adults were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science Core Collection. We identified nine randomized controlled trials for review, including trials of vitamin K1 or vitamin K2 supplementation, that assessed a surrogate measure of cardiovascular disease including arterial calcification, atherosclerosis or arterial stiffening. For each trial, the risk of bias was assessed applying Cochrane Collaboration methodology. The findings indicate that vitamin K does not consistently prevent progression of calcification, atherosclerosis or arterial stiffness. There may be some benefit in people with calcification at study entry. Studies were heterogenous, with relatively short follow-up and outcome measures were varied. While vitamin K supplementation clearly improves the carboxylation of dephosphoylated MGP, its role in mitigating vascular calcification is uncertain, based on current evidence.

PTH suppression by calcitriol does not predict off-target actions in experimental CKD.

Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25-(OH)2 D3 ) is a former first-line VDRA in CKD treatment. However, a consequence of its use in CKD is accelerated vascular calcification (VC). An experimental CKD model was used to determine whether altering the calcitriol delivery profile to obtain different PTH suppression levels could improve vascular health outcomes. High adenine diet (0.25%) was used to generate experimental CKD in rats. CKD rats were treated using different calcitriol dosing strategies: (a) 20 ng/kg SD (n = 8), (b) 80 ng/kg SD (n = 8), (c) 5 ng/kg QID (n = 9), or (d) 20 ng/kg QID (n = 9). Multiple targets of calcitriol were assessed which include arterial calcium and phosphate as well as circulating calcium, phosphate, PTH, FGF-23, VWF, and vitamin D metabolome. PTH suppression occurred dose-dependently after 1-week calcitriol treatment (P < .01), but the suppressive effect was lost over time. Both VC and circulating FGF-23 increased > 10× in all calcitriol-treated rats (P < .05 and P < .001, respectively); similarly, circulating VWF increased at all time points (P < .05). Ad-hoc analysis of CKD morbidities in treated rats indicated no differences in negative outcomes based on PTH suppression level (minimal-, target-, and over-). Comparing different calcitriol dosing strategies revealed the following: (a) despite initial calcitriol-influenced PTH suppression across all treatments, the ability to continually suppress PTH was markedly reduced by study conclusion and (b) PTH suppression level is not an adequate proxy for improvements in overall CKD morbidity. These findings show (a) a more holistic approach to evaluate CKD treatment efficacy aside from PTH suppression is needed and (b) that other VDRA therapies should be examined in CKD treatment.

Changes in vascular calcification and bone mineral density in calcium supplement users from the Canadian Multi-center Osteoporosis Study (CaMOS).

BACKGROUND AND AIMS: Calcium supplements have been associated with increased cardiovascular events. This study investigates the relationship between calcium supplement use and the 5 year progression of abdominal aorta calcification (AAC) in participants from one center of the Canadian Multi-Centre Osteoporosis Study (CaMOS). METHODS: Participants (n = 296; 217 women and 79 men) had lateral spine X-rays and DEXA bone mineral density (BMD) scans (femoral neck, lumbar spine and total hip) taken at two time points within a 5 year interval. AAC was assessed using the Framingham Method. Calcium supplement use was assessed by a facilitated health history questionnaire and medication inventory. RESULTS: AAC significantly increased over 5 years, AAC progression was significantly greater in calcium supplement users, as compared to non-users, overall and in females. The amount of calcium was positively correlated to AAC progression. A multi-variable linear regression model was generated for women only, as there were not enough men for multivariable modelling. Calcium supplement use and amount remained significantly associated with AAC progression after adjustment for age, hypertension, diabetes and smoking history. Change in AAC score was not associated with change in BMD T-Score. In univariate analyses of males, calcium supplement use was associated with a significantly greater BMD loss at the lumbar spine, hip, and femoral neck. CONCLUSIONS: Older female calcium supplement users had significantly higher AAC progression over 5 years, but did not have any significant BMD preservation. These results suggest that vascular calcification may contribute to the cardiovascular events observed in calcium supplement users.

Inhibiting the progression of arterial calcification with vitamin K in HemoDialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease.

BACKGROUND: Cardiovascular disease, which is due in part to progressive vascular calcification, is the leading cause of death among patients with end stage kidney disease (ESKD) on dialysis. A role for vitamin K in the prevention of vascular calcification is plausible based on the presence of vitamin K dependent proteins in vascular tissue, including matrix gla protein (MGP). Evidence from animal models and observational studies support a role for vitamin K in the prevention of vascular calcification. A large-scale study is needed to investigate the effect of vitamin K supplementation on the progression of vascular calcification in patients with ESKD, a group at risk for sub-clinical vitamin K deficiency. METHODS/DESIGN: We plan a prospective, randomized, double-blind, multicenter controlled trial of incident ESKD patients on hemodialysis in centers within North America. Eligible subjects with a baseline coronary artery calcium score of greater than or equal to 30 Agatston Units, will be randomly assigned to either the treatment group (10 mg of phylloquinone three times per week) or to the control group (placebo administration three times per week). The primary endpoint is the progression of coronary artery calcification defined as a greater than 15% increase in CAC score over baseline after 12 months. DISCUSSION: Vitamin K supplementation is a simple, safe and cost-effective nutritional strategy that can easily be integrated into patient care. If vitamin K reduces the progression of coronary artery calcification it may lead to decreased morbidity and mortality in men and women with ESKD. TRIAL REGISTRATION: NCT 01528800.

CONTEXTE: La maladie cardiovasculaire, qui est partiellement attribuable à la calcification vasculaire progressive, est la cause principale de décès chez les patients atteints d'insuffisance rénale terminale (IRT) en hémodialyse. La vitamine K pourrait jouer un rôle dans la prévention de la calcification vasculaire, en raison de la présence de protéines dépendantes à la vitamine K dans les tissus vasculaires, dont l'ostéocalcine. Le modèle animal, de même que des études d'observation, témoignent du rôle de la vitamine K dans la prévention de la calcification vasculaire. Une étude réalisée à grande échelle serait nécessaire afin d'étudier l'effet de la supplémentation de vitamine K sur la progression de la calcification vasculaire chez les patients atteints d'IRT, un groupe à risque pour les carences infracliniques en vitamine K. MÉTHODE/TYPE D'ÉTUDE: Nous prévoyons effectuer un essai clinique aléatoire, à double insu et multicentrique auprès de patients atteints d'IRT, traités en hémodialyse hospitalière en Amérique du Nord. On affectera au hasard les sujets admissibles qui présentent dans l'artère coronaire un taux de calcium supérieur ou égal à 30 unités d'Agatston, soit au groupe auquel on administre un traitement (10 mg de phylloquinone trois fois par semaine), soit au groupe témoin (administration du placebo trois fois par semaine). Le critère d'évaluation principal est la progression de la calcification de l'artère coronaire, définie comme une augmentation supérieure à 15% (résultat CAC) par rapport au point de référence, au bout de douze mois. DISCUSSION: La supplémentation de vitamine K est une stratégie nutritionnelle à la fois simple, sécuritaire et rentable, qui peut être aisément intégrée aux soins aux patients. S'il s'avère que la vitamine K réduit la progression de la calcification de l'artère coronaire, il pourrait y avoir une diminution de la morbidité et de la mortalité chez les hommes et les femmes atteints d'IRT.

Calcification of the internal pudendal artery and development of erectile dysfunction in adenine-induced chronic kidney disease: a sentinel of systemic vascular changes.

INTRODUCTION: Chronic kidney disease (CKD), erectile dysfunction (ED), and cardiovascular disease share common vascular etiologies and risk factors. AIM: Using a rat model, this is the first study to characterize the consequences of CKD in the onset and development of ED associated with differential regional vascular calcification and circulatory changes. METHODS: Stable CKD was generated at 3 weeks in male Sprague-Dawley rats given dietary adenine and progressed until 7 weeks. Mineral content and morphometry were assessed in the internal pudendal arteries (IPAs), thoracic aorta, and carotid artery. Endothelial function was determined via changes in serum von Willebrand factor (VWF) and endothelium-dependent relaxation of the thoracic aorta. RESULTS: In severe CKD rats, calcium and phosphate content in all arteries increased, and pulse wave velocity was elevated. Distal IPA segments, in particular, were the first to calcify, but penile tissue per se did not. CKD rats had endothelial dysfunction, as indicated by a decrease in acetylcholine-mediated relaxation (∼40%) and an increase in serum VWF (∼40%), as well as increased lumen diameter (20%) of the distal IPA. Erectile function, assessed using a centrally acting dopaminergic agent, was significantly impaired by 7 weeks (∼40%). CONCLUSIONS: In CKD, the distal IPA appears to be more susceptible to vascular dysfunction and calcification. Additionally, the onset of ED may be an important sentinel of impending systemic vascular disease. To confirm this concept, future experimental and clinical studies will need to examine a range of vessel types and the use of supplementary methods to assess erectile function.

Water-soluble vitamins in people with low glomerular filtration rate or on dialysis: a review.

People with low glomerular filtration rate and people on dialysis are spontaneously at risk for vitamin deficiency because of the potential for problems with decreased appetite and decreased sense of smell and taste, leading to decreased intake, and because decreased energy or decreased cognitive ability results in difficulties in shopping and cooking. Imposed dietary restrictions because of their renal dysfunction and because of comorbidities such as hypertension and diabetes exacerbate this problem. Finally, particularly for water-soluble vitamins, loss may occur into the dialysate. We did not identify any randomized trials of administering daily doses close to the recommended daily allowances of these vitamins. In people who are eating at all, deficiencies of B5 and B7 seem unlikely. It is unclear whether supplements of B2 and B3 are necessary. Because of dialyzability and documented evidence of insufficiency in dialysis patients, B1 supplementation is likely to be helpful. B6, B9, and B12 are implicated in the hyperhomocysteinemia observed in patients on dialysis. These vitamins have been studied in combinations, in high doses, with the hope of reducing cardiovascular outcomes. No reductions in patient-important outcomes were seen in adequately powered randomized trials. Because of their involvement in the homocysteine pathway, however, supplementation with lower doses, close to the recommended daily allowances, may be helpful. Vitamin C deficiency is common in patients on dialysis who are not taking supplements: low-dose supplements are warranted. Vitamins for dialysis patients contain most or all of the B vitamins and low-dose vitamin C. We are not aware of any medical reasons to choose one over another.

Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease.

The leading cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease, with vascular calcification being a key modifier of disease progression. A local regulator of vascular calcification is vitamin K. This γ-glutamyl carboxylase substrate is an essential cofactor in the activation of several extracellular matrix proteins that inhibit calcification. Warfarin, a common therapy in dialysis patients, inhibits the recycling of vitamin K and thereby decreases the inhibitory activity of these proteins. In this study, we sought to determine whether modifying vitamin K status, either by increasing dietary vitamin K intake or by antagonism with therapeutic doses of warfarin, could alter the development of vascular calcification in male Sprague-Dawley rats with adenine-induced CKD. Treatment of CKD rats with warfarin markedly increased pulse pressure and pulse wave velocity, as well as significantly increased calcium concentrations in the thoracic aorta (3-fold), abdominal aorta (8-fold), renal artery (4-fold), and carotid artery (20-fold). In contrast, treatment with high dietary vitamin K1 increased vitamin K tissue concentrations (10-300-fold) and blunted the development of vascular calcification. Thus, vitamin K has an important role in modifying mechanisms linked to the susceptibility of arteries to calcify in an experimental model of CKD.