Feasibility, long-term safety, and immune monitoring of regulatory T cell therapy in living donor kidney transplant recipients.

Short-term outcomes in kidney transplantation are marred by progressive transplant failure and mortality secondary to immunosuppression toxicity. Immune modulation with autologous polyclonal regulatory T cell (Treg) therapy may facilitate immunosuppression reduction promoting better long-term clinical outcomes. In a Phase I clinical trial, 12 kidney transplant recipients received 1-10 × 106 Treg per kg at Day +5 posttransplantation in lieu of induction immunosuppression (Treg Therapy cohort). Nineteen patients received standard immunosuppression (Reference cohort). Primary outcomes were rejection-free and patient survival. Patient and transplant survival was 100%; acute rejection-free survival was 100% in the Treg Therapy versus 78.9% in the reference cohort at 48 months posttransplant. Treg therapy revealed no excess safety concerns. Four patients in the Treg Therapy cohort had mycophenolate mofetil withdrawn successfully and remain on tacrolimus monotherapy. Treg infusion resulted in a long-lasting dose-dependent increase in peripheral blood Tregs together with an increase in marginal zone B cell numbers. We identified a pretransplantation immune phenotype suggesting a high risk of unsuccessful ex-vivo Treg expansion. Autologous Treg therapy is feasible, safe, and is potentially associated with a lower rejection rate than standard immunosuppression. Treg therapy may provide an exciting opportunity to minimize immunosuppression therapy and improve long-term outcomes.

Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials.

BACKGROUND: Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. METHODS: The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. FINDINGS: The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. INTERPRETATION: Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. FUNDING: The 7th EU Framework Programme.

Left ventricular global longitudinal strain is associated with cardiovascular risk factors and arterial stiffness in chronic kidney disease.

BACKGROUND: Global longitudinal strain (GLS) has emerged as a superior method for detecting left ventricular (LV) systolic dysfunction compared to ejection fraction (EF) on the basis that it is less operator dependent and more reproducible. The 2-dimensional strain (2DS) method is easily measured and integrated into a standard echocardiogram. This study aimed to determine the relationship between GLS and traditional and chronic kidney disease (CKD)-related risk factors of cardiovascular disease (CVD) in patients with CKD. METHODS: A cross sectional study of patients with moderate CKD stages 3 and 4 (n = 136). Clinical characteristics, anthropometric, biochemical data including markers of inflammation [C-reactive protein (CRP)], uremic toxins [indoxyl sulphate (IS), p-cresyl sulphate (PCS)], and arterial stiffness [pulse wave velocity (PWV)] were measured. Inducible ischemia was detected using exercise stress echocardiogram. GLS was determined from 3 standard apical views using 2-dimensional speckle tracking and EF was measured using Simpson's rule. Associations between GLS and traditional and CKD-related risk factors were explored using multivariate models. RESULTS: The study population parameters included: age 59.4 ± 9.8 years, 58 % male, estimated glomerular filtration rate (eGFR) 44.4 ± 10.1 ml/min/1.73 m(2), GLS -18.3 ± 3.6 % and EF 65.8 % ± 7.8 %. This study demonstrated that GLS correlated with diabetes (r = 0.21, p = 0.01), history of heart failure (r = 0.20, p = 0.01), free IS (r = 0.24, p = 0.005) free PCS (r = 0.23, p = 0.007), body mass index (BMI) (r = 0.28, p < 0.001), and PWV (r = 0.24, p = 0.009). Following adjustment for demographic, baseline co-morbidities and laboratory parameters, GLS was independently associated with free IS, BMI and arterial stiffness (R(2) for model = .30, p < 0.0001). CONCLUSIONS: In the CKD cohort, LV systolic function assessed using GLS was associated with uremic toxins, obesity and arterial stiffness.

The effect of 25-hydroxyvitamin D on insulin sensitivity in obesity: is it mediated via adiponectin?

There has been substantial recent interest in using vitamin D to improve insulin sensitivity and preventing/delaying diabetes in those at risk. There is little consensus on the physiological mechanisms and whether the association is direct or indirect through enhanced production of insulin-sensitising chemicals, including adiponectin. We examined cross-sectional associations between serum 25-hydroxyvitamin D (25(OH)D) and insulin sensitivity (Matsuda index), parathyroid hormone (PTH), waist circumference, body mass index (BMI), triglycerides (TG), total and high molecular weight (HMW) adiponectin, HMW : total adiponectin ratio (HMW : total adiponectin), and total cholesterol : HDL cholesterol ratio (TC:HDL cholesterol) in 137 Caucasian adults of mean age 43.3 ± 8.3 years and BMI 38.8 ± 6.9 kg/m(2). Total adiponectin (standardised ß = 0.446; p < 0.001), waist circumference (standardised ß = -0.216; p < 0.05), BMI (standardised ß = -0.212; p < 0.05), and age (standardised ß = -0.298; p < 0.001) were independently associated with insulin sensitivity. Serum 25(OH)D (standardised ß = 0.114; p = 0.164) was not associated with insulin sensitivity, total or HMW adiponectin, HMW : total adiponectin, or lipids. Our results provide the novel finding that 25(OH)D is not associated with HMW adiponectin or HMW : total adiponectin in nondiabetic, obese adults and support the lack of association between 25(OH)D and lipids noted by others in similar groups of patients.

Vitamin D does not improve the metabolic health of patients with chronic kidney disease stage 3-4: a randomized controlled trial.

AIM: To assess the impact of vitamin D supplementation (cholecalciferol) on the insulin sensitivity and metabolic health of patients with chronic kidney disease (CKD). METHODS: Twenty-eight adult patients with CKD stages 3-4 were recruited from the outpatient department of the Princess Alexandra Hospital (Brisbane, Australia) to a double-blind randomized trial of cholecalciferol (vitamin D3) 2000 IU/day or placebo for 6 months. Metabolic parameters at baseline were compared with 20 non-CKD adults. The primary outcome was an improvement in insulin resistance (glucose disposal rate, GDR) at 6 months (quantified by hyperinsulinaemic euglycaemic clamp). Carbohydrate and lipid oxidation rates were assessed by indirect calorimetry. RESULTS: At baseline, patients were significantly insulin-resistant compared with lean younger non-CKD individuals (n = 9; GDR 3.42 vs. 5.76 mg/kg per minute, P = 0.001), but comparable with their age-, gender- and weight-matched non-CKD counterparts (n = 11; 3.42 vs. 3.98 mg/kg per minute, P = 0.4). 25-Hydroxyvitamin D did not change in the placebo group, but rose from 95 ± 37 to 146 ± 25 nmol/L with treatment (P = 0.0001). Post treatment, there was no difference in GDR between groups (GDR 3.38 vs. 3.52 mg/kg per minute, ancova P = 0.4). There was a relative increase in hyperinsulinaemic oxidative disposal of glucose with treatment (within-group P = 0.03). CONCLUSION: Supplementation with cholecalciferol in CKD 3-4 results in appreciable increases in 25-hydroxyvitamin D concentrations, but does not increase insulin sensitivity. The insulin resistance observed was similar among age-, sex- and body mass index-matched individuals with and without CKD. Whether renal dysfunction per se has any influence on the insulin sensitivity of an individual should be the subject of future work.

Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial.

BACKGROUND: From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19. METHODS: TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464). FINDINGS: Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62-1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88-2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group. INTERPRETATION: Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation. FUNDING: UK Medical Research Council, UK National Institute for Health Research Cambridge Biomedical Research Centre, Eli Lilly and Company, Alexion Pharmaceuticals, and Addenbrooke's Charitable Trust.

Multimodality vascular imaging in CKD: divergence of risk between measured parameters.

BACKGROUND: High cardiovascular risk in chronic kidney disease (CKD) patients appears only partly attributable to atherosclerosis, with much of the remaining risk being ascribed to other vasculature abnormalities, including endothelial dysfunction, arterial stiffness and vascular calcification (VC). To date, these factors have been primarily studied in isolation or in dialysis patients. This study performed a global vascular assessment in moderate CKD and assessed the relationships with both traditional and novel risk factors. METHODS: This was a prospective cross-sectional analysis of 120 patients (age 60 ± 10 years; estimated glomerular filtration rate 25-60 mL/min/1.73m(2)). Demographic, clinical and biochemical characterization was performed. VC was characterized by lateral lumbar radiograph; arterial stiffness by aortic pulse-wave velocity (PWV); atheroma burden by carotid intima-media thickness (cIMT) and endothelial function by flow-mediated dilation (FMD) of the brachial artery. RESULTS: VC was highly prevalent (74%), and FMD generally poor (FMDΔ 3.3 ± 3.3%). There were significant correlations between all vascular parameters; although these were predominantly explained by age. cIMT was independently associated with classical risks and also PWV (adjusted standardized ß = 0.31, P = 0.001). However, traditional risks showed almost no independent associations with other vascular measurements. In contrast, serum phosphate and 1,25-dihydroxyvitamin D (1,25-OHD) correlated with PWV and the presence of VC, respectively. After adjustment, every 1 pg/mL increase in 1,25-OHD was related to a 3% reduction in the chance of VC (odds ratio 0.97; 95% confidence interval 0.94-1.00, P = 0.03). Medication use, HOMA-IR and C-reactive protein did not correlate with any of the vascular measures. CONCLUSIONS: This study demonstrates extensive vascular disease across multimodality imaging in moderate CKD. Atherosclerotic burden correlated with traditional risks and PWV, while higher 1,25-OHD was associated with less VC. The lack of association between renal function and imaging indices raises the possibility of a threshold, rather than graded uraemic effect on vascular health that warrants further exploration.

Predictors of vitamin D status in predialysis chronic kidney disease patients: a cross-sectional analysis in a high ultraviolet climate.

OBJECTIVE: To determine vitamin D status in a subtropical climate among an unselected, referred predialysis chronic kidney disease (CKD) population; assess risks and correlates; and review whether higher 25-hydroxyvitamin D (25-OHD) concentration can mitigate the decrement in circulating 1,25-dihydroxyvitamin D (1,25-OHD) normally encountered with advancing CKD. DESIGN: Prospective cross-sectional cohort study. SETTING: Renal unit in Brisbane, Australia (27°28' S). SUBJECTS: Five hundred ninety-three consecutive CKD patients (stage 1 to 5). MAIN OUTCOME MEASURE: 25-OHD insufficiency (concentrations: 15 to 30 ng/mL) and deficiency (<15 ng/mL), bone-mineral parameters, including 1,25-OHD, calcium, and phosphate. RESULTS: Despite potentially higher environmental ultraviolet (UV) exposure, only 48% of patients with CKD were 25-OHD sufficient. Traditional risks for hypovitaminosis D were maintained, and sufficiency was independently predicted by testing in the summer/autumn period (odds ratio [OR]: 2.77, 95% confidence interval [CI]: 1.88 to 4.08, P < .001), male gender (OR: 2.18, 95%CI: 1.46 to 3.24, P < .001), Caucasian race (OR: 2.28, 95%CI: 1.37 to 3.78, P = .001), hypoalbuminemia (OR: 0.47, 95%CI: 0.25 to 0.85, P = .01), macroalbuminuria (OR: 0.60, 95%CI: 0.39 to 0.92, P = .02), and normal body mass index (OR: 1.94, 95%CI: 1.22 to 3.07, P = .005). Vitamin D sufficiency was also associated with higher corrected calcium (0.4 mg/dL increments; OR: 1.29, 95%CI: 1.08 to 1.55, P = .005). Although circulating 25-OHD concentrations were relatively maintained across the range of renal function observed, 1,25-OHD concentrations decreased with advancing CKD. CONCLUSION: 25-OHD insufficiency is mitigated but still highly prevalent in patients with CKD in a high ambient UV environment. Despite the maintenance of relatively higher 25-OHD concentrations with advancing CKD, substrate availability does not appear to be a major determinant of circulating 1,25-OHD.

Transplantation Without Overimmunosuppression (TWO) study protocol: a phase 2b randomised controlled single-centre trial of regulatory T cell therapy to facilitate immunosuppression reduction in living donor kidney transplant recipients.

INTRODUCTION: Regulatory T cell (Treg) therapy has been demonstrated to facilitate long-term allograft survival in preclinical models of transplantation and may permit reduction of immunosuppression and its associated complications in the clinical setting. Phase 1 clinical trials have shown Treg therapy to be safe and feasible in clinical practice. Here we describe a protocol for the TWO study, a phase 2b randomised control trial of Treg therapy in living donor kidney transplant recipients that will confirm safety and explore efficacy of this novel treatment strategy. METHODS AND ANALYSIS: 60 patients will be randomised on a 1:1 basis to Treg therapy (TR001) or standard clinical care (control). Patients in the TR001 arm will receive an infusion of autologous polyclonal ex vivo expanded Tregs 5 days after transplantation instead of standard monoclonal antibody induction. Maintenance immunosuppression will be reduced over the course of the post-transplant period to low-dose tacrolimus monotherapy. Control participants will receive a standard basiliximab-based immunosuppression regimen with long-term tacrolimus and mycophenolate mofetil immunosuppression. The primary endpoint is biopsy proven acute rejection over 18 months; secondary endpoints include immunosuppression burden, chronic graft dysfunction and drug-related complications. ETHICS AND DISSEMINATION: Ethical approval has been provided by the National Health Service Health Research Authority South Central-Oxford A Research Ethics Committee (reference 18/SC/0054). The study also received authorisation from the UK Medicines and Healthcare products Regulatory Agency and is being run in accordance with the principles of Good Clinical Practice, in collaboration with the registered trials unit Oxford Clinical Trials Research Unit. Results from the TWO study will be published in peer-reviewed scientific/medical journals and presented at scientific/clinical symposia and congresses. TRIAL REGISTRATION NUMBER: ISRCTN: 11038572; Pre-results.

Shining D' light on chronic kidney disease: mechanisms that may underpin the cardiovascular benefit of vitamin D.

Hypovitaminosis D is a significant health-care burden worldwide, particularly in susceptible populations such as those with chronic kidney disease (CKD). Recent epidemiological studies have identified that both higher serum vitamin D concentrations and use of vitamin D supplements may confer a survival benefit both in terms of all-cause and cardiovascular mortality. There is potential to investigate this inexpensive therapy for the CKD population, which suffers excessive cardiovascular events, although the mechanisms explaining this link have yet to be fully elucidated. This review discusses potential mechanisms identified in the basic science literature that may provide important insights into how vitamin D may orchestrate a change in cardiovascular risk profile through such diverse mechanisms as inflammation, atherogenesis, glucose homeostasis, vascular calcification, renin-angiotensin regulation and alterations in cardiac physiology. Where available, the clinical translation of these concepts to intervention trials in the CKD population will be reviewed.

ChAdOx1 nCOV-19 vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis (CVST).

A 27-year-old fit and well man presented with intermittent headaches associated with eye floaters and vomiting. His symptoms started 48 hours after having the first dose of ChADOx1 nCOV-19 vaccine (Vaxzevria, previously AstraZeneca COVID-19 vaccine; AstraZeneca) and bloods showed raised D-dimer, low platelets and fibrinogen. CT venogram demonstrated significant cerebral venous sinus thrombosis. He was immediately started on intravenous immunoglobulins and dabigatran after liasing with haematologist. The next day, he complained of worsening headache and new homonymous hemianopia. Repeat CT of the head showed an acute parenchymal bleed with subdural extension and was given idarucizumab and high-dose steroids. He had an emergency decompressive craniotomy and external ventricular drain as his intracranial pressures were difficult to control. Despite full medical and surgical management, his intracranial pressures continued to rise and his brain injury was felt to be too devastating and was deemed unsurvivable.

Reactivation of IgA vasculitis following COVID-19 vaccination.

A 23-year-old man presented to the acute assessment unit with acute-onset haematuria within 24 hours of receiving his second dose of the Pfizer-BioNTech COVID-19 vaccine. He had been diagnosed with IgA vasculitis 8 months previously. IgA vasculitis is an autoimmune condition characterised by palpable purpura affecting the lower limbs, abdominal pain, arthralgia and renal disease. He was diagnosed with an acute exacerbation of IgA vasculitis and was discharged with oral prednisolone. Reactivation or first presentation of IgA vasculitis is a rare but increasingly recognised complication of COVID-19 vaccination. This is an important new differential in the assessment of patients with haematuria following COVID-19 vaccination.

Evaluation of limited sampling strategies for mycophenolic acid after mycophenolate mofetil intake in adult kidney transplant recipients.

Multiple limited sampling strategies (LSSs) have been proposed for estimation of mycophenolic acid (MPA) area under the concentration-time curve from 0 to 12 hours postdose (AUC 0-12) after mycophenolate mofetil intake. The aim of this study was to provide summary information on all published LSSs for MPA and to evaluate their predictive performance in an independent population of kidney transplant recipients. Seventy-eight LSSs for MPA were identified. Sixty-nine full AUC profiles were collected from 45 subjects (25 cotreated with cyclosporine and 20 with tacrolimus). Predicted MPA AUC 0-12, calculated by applying the relevant concentration measurements within the LSS equations, was compared with full AUC calculated by using all concentration measurements in the linear trapezoidal rule. Four error indices (median prediction error, median percentage prediction error [MPPE], root median squared prediction error, and median absolute percentage prediction error [MAPE]) were used to evaluate bias and imprecision. Twelve of the 25 LSSs for cyclosporine-cotreated recipients and one of the 53 LSSs for tacrolimus-cotreated recipients displayed acceptable (less than 15%) bias and imprecision. In the cyclosporine group, two equations demonstrated the highest predictive power, one that used four time points in the first 6 hours postdose (r2 = 0.84, MPPE 1.6%, MAPE 7.8%) and one that used four time points in the first 4 hours postdose (r2 = 0.76, MPPE -0.8%, MAPE 10.2%). In the tacrolimus group, an equation that used two time points in the first 4 hours postdose was superior (r2 = 0.80, MPPE -3.0%, MAPE 13.6%). Application of the LSSs most appropriate for cyclosporine-cotreated patients to the tacrolimus-cotreated group resulted in clinically unacceptable bias and imprecision and vice versa. High variability in performance of LSSs highlights the importance of validating any LSS before applying it to an alternative population. Attention to comedication use is of particular relevance when choosing a LSS.

A case of mistaken identity: An unusual presentation of neoplastic meningitis and a reminder of the hallmark features.

This case offers an opportunity for education on the manifestations of neoplastic meningitis, a revision of the hallmark investigative features, and a reminder of the utilization of lumbar puncture in investigating unexplained neurological symptoms. Additionally, it emphasises the need for clinicians to avoid "diagnostic anchoring" when faced with recurrent attenders.

Educational case: a patient with proteinuria.

This is an educational case suitable for all readers, but aimed particularly at trainees preparing for MRCP. Using the example of a patient presenting to clinic with proteinuria, aspects of differential diagnosis, pathology and management are explored.

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: a randomised controlled trial.

BACKGROUND: Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN: This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION: To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data.

IMPORTANCE: Low levels of vitamin D are associated with elevated blood pressure (BP) and future cardiovascular events. Whether vitamin D supplementation reduces BP and which patient characteristics predict a response remain unclear. OBJECTIVE: To systematically review whether supplementation with vitamin D or its analogues reduce BP. DATA SOURCES: We searched MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.com augmented by a hand search of references from the included articles and previous reviews. Google was searched for gray literature (ie, material not published in recognized scientific journals). No language restrictions were applied. The search period spanned January 1, 1966, through March 31, 2014. STUDY SELECTION: We included randomized placebo-controlled clinical trials that used vitamin D supplementation for a minimum of 4 weeks for any indication and reported BP data. Studies were included if they used active or inactive forms of vitamin D or vitamin D analogues. Cointerventions were permitted if identical in all treatment arms. DATA EXTRACTION AND SYNTHESIS: We extracted data on baseline demographics, 25-hydroxyvitamin D levels, systolic and diastolic BP (SBP and DBP), and change in BP from baseline to the final follow-up. Individual patient data on age, sex, medication use, diabetes mellitus, baseline and follow-up BP, and 25-hydroxyvitamin D levels were requested from the authors of the included studies. For trial-level data, between-group differences in BP change were combined in a random-effects model. For individual patient data, between-group differences in BP at the final follow up, adjusted for baseline BP, were calculated before combining in a random-effects model. MAIN OUTCOMES AND MEASURES: Difference in SBP and DBP measured in an office setting. RESULTS: We included 46 trials (4541 participants) in the trial-level meta-analysis. Individual patient data were obtained for 27 trials (3092 participants). At the trial level, no effect of vitamin D supplementation was seen on SBP (effect size, 0.0 [95% CI, -0.8 to 0.8] mm Hg; P=.97; I2=21%) or DBP (effect size, -0.1 [95% CI, -0.6 to 0.5] mm Hg; P=.84; I2=20%). Similar results were found analyzing individual patient data for SBP (effect size, -0.5 [95% CI, -1.3 to 0.4] mm Hg; P=.27; I2=0%) and DBP (effect size, 0.2 [95% CI, -0.3 to 0.7] mm Hg; P=.38; I2=0%). Subgroup analysis did not reveal any baseline factor predictive of a better response to therapy. CONCLUSIONS AND RELEVANCE: Vitamin D supplementation is ineffective as an agent for lowering BP and thus should not be used as an antihypertensive agent.

Effects of exercise and lifestyle intervention on cardiovascular function in CKD.

BACKGROUND AND OBJECTIVES: CKD is associated with poor cardiorespiratory fitness (CRF). This predefined substudy determined the effect of exercise training and lifestyle intervention on CRF and explored the effect on cardiovascular risk factors and cardiac and vascular function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between February 2008 and March 2010, 90 patients with stage 3-4 CKD were screened with an exercise stress echocardiogram before enrollment. Patients (n=83) were randomized to standard care (control) or lifestyle intervention. The lifestyle intervention included multidisciplinary care (CKD clinic), a lifestyle program, and aerobic and resistance exercise training for 12 months. CRF (peak Vo2), left ventricular function, arterial stiffness, anthropometric, and biochemical data were collected at baseline and 12 months. RESULTS: Ten percent of randomized patients had subclinical myocardial ischemia at screening and completed the study without incident. There was no baseline difference among 72 patients who completed follow-up (36 in the lifestyle intervention group and 36 in the control group). The intervention increased peak Vo2 (2.8±0.7 ml/kg per minute versus -0.3±0.9 ml/kg per minute; P=0.004). There was small weight loss (-1.8±4.2 kg versus 0.7±3.7 kg; P=0.02) but no change in BP or lipids. Diastolic function improved (increased e' of 0.75±1.16 cm/s versus -0.47±1.0 cm/s; P=0.001) but systolic function was well preserved and did not change. The change in arterial elastance was attenuated (0.11±0.76 mmHg/ml versus 0.76±0.96 mmHg/ml; P=0.01). Δ peak Vo2 was associated with group allocation and improved body composition. CONCLUSIONS: Exercise training and lifestyle intervention in patients with CKD produces improvements in CRF, body composition, and diastolic function.

Cardiorespiratory fitness is independently associated with 25-hydroxyvitamin D in chronic kidney disease.

BACKGROUND AND OBJECTIVES: Vitamin D is an established important contributor to muscle function and aerobic metabolism. Hypovitaminosis D is highly prevalent in CKD patients and is associated with increased cardiovascular (CV) mortality via unknown mechanisms. Because aerobic-exercise capacity strongly predicts future CV events, we hypothesized that vitamin D status could be linked to CV outcomes via an effect on maximum aerobic-exercise capacity in patients with CKD and that this effect may be mediated in part via its actions on muscle strength and functional ability. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Baseline demographic, anthropometric, and biochemical data were collected in a cross-sectional study of patients with moderate CKD. Peak aerobic capacity was determined during treadmill stress testing using metabolic equivalence of tasks. Physical activity was assessed using the Active Australia questionnaire, grip strength by dynamometer, and functional capacity by "Up & Go" testing. RESULTS: The study included 85 participants (age 59.5 ± 9.7 years, 60% male, 44% diabetic, 92% Caucasian; mean serum 25-hydroxyvitamin D [25-OHD] 78.4 ± 29.4 nmol/L). We demonstrated that 25-OHD status was independently associated with aerobic-exercise capacity (ß = 0.2; P = 0.008). Aerobic-exercise capacity was also predicted by younger age, white race, smaller waist circumference, absence of a previous angina history, and increasing weekly physical activity. However, neither muscle strength nor functional ability were significantly associated with 25-OHD. CONCLUSIONS: Vitamin D is independently associated with aerobic capacity in CKD patients, and this finding is not explained by changes in muscle strength or functional ability.