Inorganic phosphate additives in meals and adaptations to 5-days of dietary inorganic phosphate loading alter acute calcium homeostasis in two randomized cross-over studies in healthy adults.

Diets containing inorganic phosphate additives are unbalanced with respect to calcium and these diets have been linked to the development of altered bone metabolism. Using 2 randomized cross-over studies in healthy humans, we (1) characterized the hormonal and urinary response to 2 meals with the same reported phosphorus amount (562-572 mg), where one was manufactured with inorganic phosphate additives and a comparatively lower Ca:P molar ratio (0.26 vs 0.48), and (2) assessed how acute homeostatic mechanisms adapt following 5-d exposure to recommended dietary phosphorus amount (~700 mg P/d) compared to a diet enriched with inorganic phosphate additives (~1100 mg P/d). Participants were then challenged with 500 mg of oral phosphorus in the form of inorganic phosphate after an overnight fast following each diet condition. Measurements included serum calcium, phosphate, PTH, and fibroblast growth factor 23 , vitamin D metabolites, and urine calcium and phosphate excretion. Following the meal containing inorganic phosphate additives with a low Ca:P ratio, serum phosphate was higher and more phosphate was excreted in the urine compared to the low additive meal. Although the Ca:P and calcium content was lower in the high additive meal, the same amount of calcium was excreted into the urine. Subsequently, increasing only dietary phosphate through additives resulted in lower 24-h excretion of calcium. The oral phosphate challenge promoted urinary calcium excretion, despite no consumption of calcium, which was attenuated when pre-acclimated to a high phosphate diet. These data suggest that ingestion of inorganic phosphate promotes calcium excretion, but homeostatic mechanisms may exist to reduce calcium excretion that are responsive to dietary intake of phosphate. Future studies are required to evaluate potential implication of diets enriched with inorganic phosphate additives on bone health.

Vitamin D status and treatment in ESKD; links to improved CKD-MBD laboratory parameters in a real-world setting.

INTRODUCTION: Vitamin D insufficiency is common in patients who receive hemodialysis yet there is no clear guidance regarding surveillance or treatment. We hypothesized that increasing 25(OH)D3 levels is associated with lower phosphate, parathyroid hormone (PTH) and alkaline phosphatase (ALP). METHODS: Baseline 25(OH)D3 level was measured in all patients receiving in-centre hemodialysis in June, 2017. Laboratory parameters were measured every 6 (phosphate, calcium) or 12 weeks (25(OH)D3, PTH, ALP) until February, 2021. In September, 2018 a treatment algorithm of 50,000 IU weekly until sufficient, followed by 50,000 IU monthly was suggested. Generalized linear mixed regression models including linear spline effects, a log link function, and random effects were used to examine the impact of increasing 25(OH)D3 levels on calcium, phosphate, ALP and PTH. RESULTS: Of 697 participants, 15% and 57% had vitamin D deficiency (25(OH)D3 < 25 nmol/L) and insufficiency (between 25 and 74 nmol/L). Incorporating up to 7272 observations, increasing 25(OH)D3 was associated with significantly decreasing PTH for 25(OH)D3 levels between 25 and 75 nmol/L regardless of vitamin D treatment. In an interaction model, the negative slope between 25(OH)D3 and PTH remained significant beyond 75 nmol/L in the absence of calcitriol. Increasing 25(OH)D3 was associated with significantly decreasing phosphate for 25(OH)D3 levels between 25 and 75nmol/L regardless of vitamin D treatment, and below 25 nmol/L in values of untreated patients. Calcium increased across the spectrum of 25(OH)D3 regardless of vitamin D treatment. 0.2% of 25(OH)D3 levels exceeded 250 nmol/L and 2.1% of calcium levels exceeded the normal range. CONCLUSIONS: Vitamin D treatment in a real-world setting was safe and associated with lower PTH levels. Whether improved biochemical markers translate to a reduction in.

Lifestyle Empowerment for Alzheimer's Prevention Prescribed by Physicians: Methods and Adaptations to COVID-19.

The health care system is insufficiently capitalizing on the benefits of physical exercise in America's aging population. Few tools exist to help clinicians incorporate physical activity into their clinical care, while barriers limit older adults from initiating and maintaining exercise programs. The Lifestyle Empowerment for Alzheimer's Prevention (LEAP! Rx) Program has been designed to support providers and participants in lifestyle change. LEAP! Rx uses two forms of participant enrollment: physician referrals through electronic health records and self-referrals to test the efficacy of delivering a community-based exercise and healthy lifestyle program to older adults. After referral into the program, participants are randomized to receive the LEAP! Rx Program or are placed in a standard-of-care group to receive the program later. The LEAP! Rx program consists of a personalized and structured exercise program, lifestyle education, and mobile health monitoring. This includes a 12-week Empowerment phase with coaching and supervised exercise training, followed by a 40-week Lifestyle phase with intermittent supervised exercise and coaching. Lifestyle education includes monthly, evidence-based classes on optimal aging. The evaluation of LEAP! Rx focuses on 1) the assessment of implementation and scalability of the LEAP!Rx Program for clinicians and patients 2) the effect of the LEAP! Rx Program on cardiorespiratory fitness, 3) the impact of the LEAP! Rx Program on secondary intervention outcome measures of chronic disease risk factors, including insulin resistance, body composition, and lipids. If successful, this study's findings could advance future healthcare practices, providing a new and practical approach to aging and chronic disease prevention.

Serum total testosterone is associated with phosphate and calcium excretion in response to oral phosphate loading in healthy middle-aged males.

Androgen receptors are expressed in the kidney and serum testosterone is negatively associated with serum phosphate in males, suggesting a role of testosterone in renal phosphate handling. In this cross-sectional study, we examined the association of serum total and free testosterone with acute phosphate and calcium excretion in males in response to an oral phosphate challenge. Thirty-five healthy adult males with normal baseline testosterone levels consumed a 500 mg phosphorus drink and the urinary excretion of minerals, as well as levels of relevant circulating parameters, were assessed at baseline and hourly for 4 h. Serum total testosterone was positively associated with overall phosphate excretion (r = 0.35, p = 0.04) and calcium excretion (r = 0.44, p = 0.00) in response to the challenge. Serum free testosterone was positively associated with post-challenge calcium excretion (r = 0.34, p = 0.048), but significance was not reached for phosphate excretion (r = 0.31, p = 0.07). Serum total and free testosterone were not associated with parathyroid hormone, fibroblast growth factor-23, or vitamin D-key factors implicated in phosphate and calcium regulation. Overall, higher serum total testosterone levels in healthy middle-aged males are associated with a greater capacity to acutely excrete phosphate and calcium after a single oral phosphate challenge, suggesting potential ramifications of testosterone deficiency related to mineral homeostasis.

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.

Neurological Impairment in Critically Ill Patients on Dialysis: Research Letter for the INCOGNITO-AKI Feasibility Study.

Background: Acute kidney injury (AKI) resulting in kidney replacement therapy is rising among critically ill adults. Long-term kidney replacement therapy and critical illness are independently linked to acute and prolonged cognitive impairment, and structural brain pathology. Poor regional cerebral oxygenation (rSO2) may be a contributing factor. Objective: To assess the feasibility of testing the association between intradialytic rSO2 and acute and long-term neurological outcomes. Design: Longitudinal observational study. Setting and Participants: We enrolled patients initiating continuous kidney replacement therapy or intermittent hemodialysis in the Kingston Health Sciences Centre (KHSC) Intensive Care Unit (ICU). Measurements and Methods: rSO2 was monitored during the first 72 hours of continuous kidney replacement therapy or throughout each intermittent hemodialysis session. We measured acute neurological impairment by daily delirium screening and long-term neurocognitive outcomes using the Kinarm robot, Repeatable Battery for the Assessment of Neuropsychological Status, and brain magnetic resonance imaging. Results: Of 484 ICU patients, 26 met the screening criteria. Two declined, and 13 met at least one exclusion criteria. Eleven patients were enrolled. Eight died in ICU, one died 2 months after discharge, and one declined follow-up. Data capture rates were high: rSO2/vitals (91.3%), and delirium screening and demographics (100%). Longitudinal testing was completed in 50% (1 of 2) of survivors. Limitations: Enrollment was low due to a variety of factors, limiting our ability to evaluate long-term outcomes. Conclusion: rSO2 and delirium data collection is feasible in critically ill patients undergoing kidney replacement therapy; high mortality limits follow-up.

Contexte: L'insuffisance rénale aiguë (IRA) menant à une thérapie de remplacement rénal est en augmentation chez les adultes aux soins intensifs. Un séjour aux soins intensifs et la thérapie de remplacement rénal à long terme sont indépendamment liés à des déficits cognitifs aigus et prolongés ainsi qu'à des pathologies structurelles du cerveau. La faible saturation régionale du cerveau en oxygène (rSO2) pourrait être un facteur contributif. Objectif: Évaluer la possibilité de tester l'association entre la rSO2 intradialytique et les résultats neurologiques aigus et chroniques. Type d'étude: Étude observationnelle longitudinale. Cadre et sujets de l'étude: Nous avons recruté des patients qui entamaient une thérapie de remplacement rénal en continu ou une hémodialyse intermittente à l'unité des soins intensifs (USI) du Kingston Health Sciences Centre (KHSC). Mesures et méthodologie: La rSO2 a été surveillée pendant les 72 premières heures de thérapie de remplacement rénal en continu, ou tout au long de chaque séance d'hémodialyse intermittente. Nous avons mesuré les déficits neurologiques aigus par un dépistage quotidien du délirium et les atteintes neurocognitives à long terme à l'aide du robot Kinarm, de la Repeatable Battery for the Assessment of Neuropsychological Status et de l'imagerie par résonance magnétique cérébrale. Résultats: Sur les 484 patients hospitalisés à l'USI, 26 répondaient aux critères de sélection. Deux ont refusé de participer à l'étude et treize satisfaisaient à au moins un critère d'exclusion. Onze patients ont été inclus à l'étude. Huit patients sont décédés à l'USI, un est décédé deux mois après sa sortie de l'hôpital et un a refusé le suivi. Les taux de saisie des données étaient élevés: rSO2 et paramètres vitaux (91,3 %), dépistage du délirium et démographie (100 %). Des tests longitudinaux ont été effectués chez 50 % (1 de 2) des survivants. Limites: Le taux d'inscription était faible en raison de divers facteurs, ce qui a limité notre capacité à évaluer les résultats à long terme. Conclusion: Il est possible de collecter des données sur la rSO2 et le délirium chez les patients de soins intensifs qui suivent une thérapie de remplacement rénal; un taux de mortalité élevé a limité le suivi. Trial Registration: clinicaltrials.gov, registration number NCT04722939.

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.

Vascular calcification maladaptively participates in acute phosphate homeostasis.

AIMS: Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. This process is especially relevant in the setting of chronic kidney disease (CKD), where exposure to increased phosphate is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated mineral dysregulation induces pathological accumulation of phosphate causing vascular calcification (VC). Our objective was to determine whether the systemic response to acute phosphate challenges is altered by VC. METHODS AND RESULTS: After bolus phosphate administration, circulating and tissue deposition of this challenge was assessed in two rat models of VC using a radiolabelled phosphate tracer. In an adenine-induced model of CKD (N = 70), animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration (P < 0.01), and the discordant deposition could be traced to the calcified arteries (11.4 [7.5-13.1] vs.43.0 [35.5-53.7] pmol/ng tissue, P < 0.001). In a non-CKD model of VC, calcification was induced with 0.5 ug/kg calcitriol and then withdrawn (N = 24). New phosphate uptake by the calcified vasculature correlated to the pre-existing burden of calcification (r = 38, P < 0.001) and was substantially attenuated in the absence of calcification stimulus (P < 0.01). Phosphate accrual was stimulated by the phosphate challenge and not present to the same degree during passive disposition of circulating phosphate. Further, the form of phosphate that deposited to the vasculature was predominately amorphous inorganic phosphate and not that which was bound in matured calciprotein particles. CONCLUSIONS: In the process of calcification, arteries acutely deposit substantial amorphous phosphate while blunting the elevation in the circulation, thereby altering the systemic disposition of phosphate and identifying VC as a participatory mineral homeostatic organ. This study demonstrates the negative vascular consequence of acute fluctuations in circulating phosphate, and supports the importance of phosphate bioavailability and diet management in CKD patients as a mediator of cardiovascular risk.

Sex Differences in Phosphate Homeostasis: Females Excrete More Phosphate and Calcium After an Oral Phosphate Challenge.

CONTEXT: Dietary consumption of phosphate is increasing, and elevated serum phosphate is associated with increased cardiovascular disease (CVD) risk. Sex differences in phosphate homeostasis and response to changes in dietary phosphate intake, which are not captured by clinically measured analytes, may contribute to differences in CVD presentation and bone disease. OBJECTIVE: To assess sex differences in acute phosphate homeostasis in response to a single oral phosphate challenge. DESIGN: Cross-sectional. SETTING: General community. PARTICIPANTS: 78 participants (40-76 years) with measured glomerular filtration rate >60 mL/min/1.73 m2 and no clinically diagnosed CVD and 14 young healthy adults. MAIN OUTCOME MEASURES: To elucidate subtle alterations in phosphate homeostasis, we employ an acute challenge whereby the hormonal response, circulating mineral levels, and urinary excretion are assessed following an oral challenge of phosphate. RESULTS: Although both males and females had similar changes in circulating phosphate, calcium, and parathyroid hormone in response to the challenge, females excreted ∼1.9x more phosphate and ∼2.7x more calcium than males, despite not consuming calcium. These sex differences were recapitulated in healthy young adults. This excretion response did not correlate to age, serum phosphate, or estradiol levels. The females with greater excretion of phosphate had higher levels of bone resorption markers compared to formation markers. CONCLUSIONS: Taken together, these data identify sex differences in acute phosphate homeostasis, specifically that females may mobilize and excrete endogenous sources of calcium and phosphate in response to oral phosphate compared to males. While high levels of dietary phosphate negatively impact bone, our results suggest that females may incur more risk from these diets.

Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (the iPACK-HD study): a randomized, placebo-controlled multi-center, pilot trial.

BACKGROUND: Vitamin K activates matrix Gla protein (MGP), a key inhibitor of vascular calcification. There is a high prevalence of sub-clinical vitamin K deficiency in patients with end-stage kidney disease. METHODS: A parallel randomized placebo-controlled pilot trial was designed to determine whether 10 mg of phylloquinone thrice weekly versus placebo modifies coronary artery calcification progression over 12 months in patients requiring hemodialysis with a coronary artery calcium score (CAC) ≥30 Agatston Units (ClinicalTrials.gov identifier NCT01528800). The primary outcome was feasibility (recruitment rate, compliance with study medication, study completion and adherence overall to study protocol). CAC score was used to assess calcification at baseline and 12 months. Secondary objectives were to explore the impact of phylloquinone on vitamin K-related biomarkers (phylloquinone, dephospho-uncarboxylated MGP and the Gla-osteocalcin to Glu-osteocalcin ratio) and events of clinical interest. RESULTS: A total of 86 patients with a CAC score ≥30 Agatston Units were randomized to either 10 mg of phylloquinone or a matching placebo three times per week. In all, 69 participants (80%) completed the trial. Recruitment rate (4.4 participants/month) and medication compliance (96%) met pre-defined feasibility criteria of ≥4.17 and ≥90%, respectively. Patients randomized to phylloquinone for 12 months had significantly reduced levels of dephospho-uncarboxylated MGP (86% reduction) and increased levels of phylloquinone and Gla-osteocalcin to Glu-osteocalcin ratio compared with placebo. There was no difference in the absolute or relative progression of coronary artery calcification between groups. CONCLUSION: We demonstrated that phylloquinone treatment improves vitamin K status and that a fully powered randomized trial may be feasible.

The 1,24,25(OH)3D3 metabolite in clinical and experimental CKD: Impact of calcitriol treatment.

Calcitriol, and other vitamin D receptor activators, remain a primary treatment for elevated parathyroid hormone levels in patients with end stage kidney disease. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D3 and 1,25(OH)2D3 in rats with experimental kidney disease treated with calcitriol and in a cross-sectional analysis of patients requiring hemodialysis. Methods: Animals were stratified by creatinine into a time control group or calcitriol (20 ng/kg/day) for 3 weeks following CKD induction using a dietary adenine model (0.25% adenine). Hemodialysis patients were recruited and demographic data including calcitriol prescription was obtained by chart review and participant interview. Vitamin D metabolites were assessed using LC-MS/MS. In the rat model, 1,25(OH)2D3 levels increased substantially in calcitriol-treated rats yet there was no increase in its primary metabolite: 1,24,25(OH)2D3. A lower ratio of 1,24,25(OH)2D3:1,25(OH)2D3 (1,25-VMR) was associated with increased calcium levels in calcitriol treated rats. In hemodialysis patients (N = 86), the level of 1,25(OH)2D3 was substantially higher in calcitriol-treated patients yet there was no difference between groups in 1,24,25(OH)3D3, resulting in a marked decrease in the 1,25-VMR in calcitriol treated patients. In hemodialysis patients treated with calcitriol, 1,25(OH)2D3 and a lower ratio between 1,24,25(OH)3D3 and 1,25(OH)2D3 were associated with higher serum calcium levels. Impaired metabolism of exogenous calcitriol may contribute to the adverse effects associated with this treatment. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies.

Megalin and Vitamin D Metabolism-Implications in Non-Renal Tissues and Kidney Disease.

Megalin is an endocytic receptor abundantly expressed in proximal tubular epithelial cells and other calciotropic extrarenal cells expressing vitamin D metabolizing enzymes, such as bone and parathyroid cells. The receptor functions in the uptake of the vitamin D-binding protein (DBP) complexed to 25 hydroxyvitamin D3 (25(OH)D3), facilitating the intracellular conversion of precursor 25(OH)D3 to the active 1,25 dihydroxyvitamin D3 (1,25(OH)2D3). The significance of renal megalin-mediated reabsorption of 25(OH)D3 and 1,25(OH)2D3 has been well established experimentally, and other studies have demonstrated relevant roles of extrarenal megalin in regulating vitamin D homeostasis in mammary cells, fat, muscle, bone, and mesenchymal stem cells. Parathyroid gland megalin may regulate calcium signaling, suggesting intriguing possibilities for megalin-mediated cross-talk between calcium and vitamin D regulation in the parathyroid; however, parathyroid megalin functionality has not been assessed in the context of vitamin D. Within various models of chronic kidney disease (CKD), megalin expression appears to be downregulated; however, contradictory results have been observed between human and rodent models. This review aims to provide an overview of the current knowledge of megalin function in the context of vitamin D metabolism, with an emphasis on extrarenal megalin, an area that clearly requires further investigation.

Twice versus thrice weekly hemodialysis: A systematic review.

INTRODUCTION: Thrice weekly hemodialysis (HD) is currently the norm in high income countries but there is mounting interest in twice weekly HD in certain settings. We performed this systematic review to summarize the available evidence comparing twice to thrice weekly HD. METHODS: A systematic literature search was performed in Ovid MEDLINE, Ovid Embase, and the Cochrane Central Register of Controlled Trials to identify cohort and randomized controlled trials evaluating outcomes of twice versus thrice weekly HD. The bibliographies of identified studies were hand searched to find any additional studies. Risk of bias was assessed using the Newcastle-Ottawa scale for observational studies. FINDINGS: No randomized controlled trials and 21 cohort studies were identified. Overall study quality was modest with high risk of selection bias and inadequate controlling for confounders. The most commonly evaluated outcome measures were survival and residual kidney function. No studies assessed quality of life. Study results were variable and there was no clear signal for overwhelming risk or benefit of twice versus thrice weekly HD with the exception of residual kidney function which consistently showed slower decline in the twice weekly group. DISCUSSION: There is a paucity of high quality data comparing the risks and benefits of twice vs thrice weekly HD. Randomized controlled trial evidence is required to inform clinicians and HD prescription guidelines.

Visuospatial and Executive Dysfunction in Patients With Acute Kidney Injury, Chronic Kidney Disease, and Kidney Failure: A Multilevel Modeling Analysis.

Background: Neurocognitive impairment is a common finding across the spectrum of kidney disease and carries important consequences for quality of life. We previously demonstrated that robotic technology can identify neurocognitive impairments not readily detectable by traditional testing in patients with acute kidney injury (AKI) and chronic kidney disease (CKD). Objective: The present study aimed to assess whether these quantifiable deficits in neurocognition differ based on a diagnosis of AKI, CKD, or kidney failure. Design: This was a cross-sectional analysis of participants previously enrolled in an observational study. Setting: Patients were enrolled at a tertiary academic hospital, Kingston Health Sciences Centre, Kingston, ON, Canada. Patients: Adults with AKI, CKD, or kidney failure. Measurements: Each participant underwent robotic neurocognitive assessment using the Kinarm: an interactive robotic device that uses a series of behavioral tasks involving movement of the upper limbs to precisely quantify neurocognitive impairment across a variety of neurocognitive domains. Methods: Multilevel modeling was used to determine the effect of Kinarm task type, kidney diagnostic group (AKI vs CKD vs kidney failure), and the interaction between the two, on neurocognitive performance. Results: A total of 104 participants within 1 year of an AKI event or with CKD category G3-5 were enrolled. We found that across all of the kidney diagnostic groups, participants performed worst on the Kinarm tasks of Reverse Visually Guided Reaching (b = 0.64 [95% confidence interval = 0.42, 0.85]), Visually Guided Reaching (b = 0.28 [0.07, 0.49]), and Trail Making (b = 0.50 [0.28, 0.72]), relative to all other tasks. There were no significant differences in average performance across tasks based on kidney diagnostic group. However, diagnostic group and neurocognitive task type interacted to determine performance, such that patients with AKI performed worse than those with either CKD or kidney failure on the Reverse Visually Guided Reaching task. Limitations: Kinarm assessment was performed at a single time point, and the sample size itself was small, which may lead to the risk of a false-positive association despite the use of multilevel modeling. Our sample size also did not permit inclusion of the underlying etiology of kidney impairment as a covariate in our analyses, which may have also influenced neurocognitive function. Conclusions: In this study that utilized the Kinarm to assess neurocognitive function, patients with AKI demonstrated significantly worse neurocognitive functioning than patients with CKD or kidney failure on a task measuring executive function and visuomotor control.

Contexte: La déficience neurocognitive est fréquemment observée dans le spectre des maladies rénales et elle entraîne des conséquences importantes sur la qualité de vie. Nous avons précédemment démontré que la technologie robotique peut identifier les troubles neurocognitifs qui ne sont pas facilement détectables par les tests traditionnels chez les patients atteints d'insuffisance rénale aiguë (IRA) et d'insuffisance rénale chronique (IRC). Objectif: La présente étude visait à déterminer si ces déficits quantifiables dans les fonctions neurocognitives diffèrent selon un diagnostic d'IRA, d'IRC ou d'insuffisance rénale terminale (IRT). Type d'étude: Analyse transversale des participants précédemment inscrits à une étude observationnelle. Cadre: Les patients avaient été recrutés dans un hôpital universitaire tertiaire, le Kingston Health Sciences Centre, de Kingston (Ontario) au Canada. Sujets: Des adultes atteints d'IRA, d'IRC ou d'IRT. Mesures: Chaque participant a subi une évaluation neurocognitive robotique à l'aide du Kinarm: un dispositif robotique interactif qui utilise une série de tâches comportementales impliquant des mouvements des membres supérieurs pour quantifier avec précision les troubles neurocognitifs dans divers domaines neurocognitifs. Méthodologie: On a utilisé une modélisation à plusieurs niveaux pour déterminer l'effet du type de tâche Kinarm, du groupe de diagnostic rénal (IRA c. IRC c. IRT), et l'interaction entre les deux, sur la performance neurocognitive. Résultats: L'étude porte sur les 104 patients atteints d'IRC de stade G3-5 ou ayant vécu un épisode d'IRA dans l'année. Nous avons constaté que, dans tous les groupes de diagnostic, les participants ont obtenu les pires résultats pour les tâches Kinarm de l'atteinte guidée visuellement inversée (b = 0,64 [intervalle de confiance à 95 %: 0,42-0,85)), de l'atteinte guidée visuellement (b = 0,28 [0,07-0,49]) de création de parcours (b = 0,50 [0,28-0,72]), par rapport à toutes les autres tâches. Aucune différence significative n'a été observée dans le rendement moyen entre les tâches selon le diagnostic rénal. Cependant, le groupe de diagnostic et le type de tâche neurocognitive ont interagi pour déterminer les performances, de sorte que les patients atteints d'IRA ont obtenu de moins bons résultats que les patients atteints d'IRC ou d'IRT pour la tâche d'atteinte visuelle inversée guidée. Limites: L'évaluation Kinarm n'a été effectuée qu'une seule fois, sur un échantillon plutôt faible, ce qui pourrait entraîner un risque d'association faussement positive malgré l'utilisation d'une modélisation à plusieurs niveaux. La taille de notre échantillon n'a pas permis d'inclure l'étiologie sous-jacente de l'atteinte rénale comme covariable dans nos analyses, ce qui aurait pu également influencer la fonction neurocognitive. Conclusion: Dans cette étude où le Kinarm a été utilisé pour évaluer la fonction neurocognitive, les patients atteints d'IRA ont montré des fonctions neurocognitives significativement inférieures à celles des patients atteints d'IRC ou d'IRT lors de tâches mesurant la fonction exécutive et le contrôle visuomoteur.

The metabolism of 1,25(OH)2D3 in clinical and experimental kidney disease.

Chronic kidney disease (CKD) results in calcitriol deficiency and altered vitamin D metabolism. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D3 and 1,25(OH)2D3 in a cross-sectional analysis of participants with a range of kidney function assessed by precise measured GFR (mGFR) (N = 143) and in rats with the induction and progression of experimental kidney disease. Vitamin D metabolites were assessed with LC-MS/MS. Circulating measures of 24-hydroxylation of 25(OH)D3 (24,25(OH)2D3:25(OH)D3) precisely decreased according to mGFR in humans and progressively in rats with developing CKD. In contrast, the 1,24,25(OH)3D3: 1,25(OH)2D3 vitamin D metabolite ratio increased in humans as the mGFR decreased and in rats with the induction and progression of CKD. Human participants taking cholecalciferol had higher circulating 1,24,25(OH)3D3, despite no increase of 1,25(OH)2D3. This first report of circulating 1,24,25(OH)3D3 in the setting of CKD provides novel insight into the uniquely altered vitamin D metabolism in this setting. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies. The potential that 24-hydroxylated products have biological activity of is an important area of future research.

Can Peer Review Be Kinder? Supportive Peer Review: A Re-Commitment to Kindness and a Call to Action.

Peer review aims to select articles for publication and to improve articles before publication. We believe that this process can be infused by kindness without losing rigor. In 2014, the founding editorial team of the Canadian Journal of Kidney Health and Disease (CJKHD) made an explicit commitment to treat authors as we would wish to be treated ourselves. This broader group of authors reaffirms this principle, for which we suggest the terminology "supportive review."

L'évaluation par les pairs vise à sélectionner les articles à publier et à en améliorer le contenu avant publication. Nous sommes d'avis que ce processus peut être fait avec bienveillance sans perdre en rigueur. En 2014, l'équipe de rédaction fondatrice du Canadian Journal of Kidney Health and Disease (CJKHD) a pris l'engagement ferme de traiter les auteurs comme ses membres souhaiteraient eux-mêmes être traités. Aujourd'hui, notre groupe élargi d'auteur(e)s réaffirme ce principe pour lequel nous proposons la terminologie « évaluation constructive ¼.

Association of Clonal Hematopoiesis of Indeterminate Potential with Worse Kidney Function and Anemia in Two Cohorts of Patients with Advanced Chronic Kidney Disease.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in CKD is unknown. METHODS: We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.73m2. We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. RESULTS: At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE), compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or ESKD over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. CONCLUSIONS: In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.

Adverse childhood experiences and adult self-harm in a female forensic population.

AIMS AND METHOD: This study aimed to investigate the prevalence of adverse childhood experiences (ACEs) among patients in a female forensic psychiatric in-patient medium-secure unit, and to analyse the link between ACEs, adulthood self-harm and associated comorbidities and risk factors. The study used a cross-sectional design, with data gathered from the anonymised electronic health records of patients. RESULTS: It was found that there was a high prevalence of both ACEs and self-harm among this patient group, and that there was a relationship between the two; those with more ACEs were more likely to have self-harmed during adulthood. Of the individual ACE categories, it was also demonstrated that emotional abuse had a significant association with adulthood self-harm. CLINICAL IMPLICATIONS: In medium-secure settings for women, implementation of trauma-informed care will be beneficial because of the high number of those with mental disorders who have experienced adversity during their childhood.