Nicole M. Isbel

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.

A Randomized Trial of Dietary Sodium Restriction in CKD

There is a paucity of quality evidence regarding the effects of sodium restriction in patients with CKD, particularly in patients with pre-end stage CKD, where controlling modifiable risk factors may be especially important for delaying CKD progression and cardiovascular events. We conducted a double-blind placebo-controlled randomized crossover trial assessing the effects of high versus low sodium intake on ambulatory BP, 24-hour protein and albumin excretion, fluid status (body composition monitor), renin and aldosterone levels, and arterial stiffness (pulse wave velocity and augmentation index) in 20 adult patients with hypertensive stage 3-4 CKD as phase 1 of the LowSALT CKD study. Overall, salt restriction resulted in statistically significant and clinically important reductions in BP (mean reduction of systolic/diastolic BP, 10/4 mm Hg; 95% confidence interval, 5 to 15 /1 to 6 mm Hg), extracellular fluid volume, albuminuria, and proteinuria in patients with moderate-to-severe CKD. The magnitude of change was more pronounced than the magnitude reported in patients without CKD, suggesting that patients with CKD are particularly salt sensitive. Although studies with longer intervention times and larger sample sizes are needed to confirm these benefits, this study indicates that sodium restriction should be emphasized in the management of patients with CKD as a means to reduce cardiovascular risk and risk for CKD progression.

Randomized, Controlled Trial of Topical Exit-Site Application of Honey (Medihoney) versus Mupirocin for the Prevention of Catheter-Associated Infections in Hemodialysis Patients

The clinical usefulness of hemodialysis catheters is limited by increased infectious morbidity and mortality. Topical antiseptic agents, such as mupirocin, are effective at reducing this risk but have been reported to select for antibiotic-resistant strains. The aim of the present study was to determine the efficacy and the safety of exit-site application of a standardized antibacterial honey versus mupirocin in preventing catheter-associated infections. A randomized, controlled trial was performed comparing the effect of thrice-weekly exit-site application of Medihoney versus mupirocin on infection rates in patients who were receiving hemodialysis via tunneled, cuffed central venous catheters. A total of 101 patients were enrolled. The incidences of catheter-associated bacteremias in honey-treated (n = 51) and mupirocin-treated (n = 50) patients were comparable (0.97 versus 0.85 episodes per 1000 catheter-days, respectively; NS). On Cox proportional hazards model analysis, the use of honey was not significantly associated with bacteremia-free survival (unadjusted hazard ratio, 0.94; 95% confidence interval, 0.27 to 3.24; P = 0.92). No exit-site infections occurred. During the study period, 2% of staphylococcal isolates within the hospital were mupirocin resistant. Thrice-weekly application of standardized antibacterial honey to hemodialysis catheter exit sites was safe, cheap, and effective and resulted in a comparable rate of catheter-associated infection to that obtained with mupirocin (although the study was not adequately powered to assess therapeutic equivalence). The effectiveness of honey against antibiotic-resistant microorganisms and its low likelihood of selecting for further resistant strains suggest that this agent may represent a satisfactory alternative means of chemoprophylaxis in patients with central venous catheters.

OBESITY IS ASSOCIATED WITH WORSENING CARDIOVASCULAR RISK FACTOR PROFILES AND PROTEINURIA PROGRESSION IN RENAL TRANSPLANT RECIPIENTS

Obesity is associated with adverse cardiovascular (CV) parameters and may be involved in the pathogenesis of allograft dysfunction in renal transplant recipients (RTR). We sought the spectrum of body mass index (BMI) and the relationships between BMI, CV parameters and allograft function in prevalent RTR. Data were collected at baseline and 2 years on 90 RTR (mean age 51 years, 53% male, median transplant duration 7 years), categorized by BMI (normal, BMI ≤ 24.9 kg/m2; pre‐obese, BMI 25–29.9 kg/m2; obese, BMI ≥ 30 kg/m2). Proteinuria and glomerular filtration rate (eGFRMDRD) were determined.

Does renal failure cause an atherosclerotic milieu in patients with end-stage renal disease?☆

PURPOSE Atherosclerotic vascular disease is the main cause of morbidity and mortality in patients with end-stage renal disease, but the independent contribution of renal failure rather than associated risk factors is unclear. We sought to examine the relative contribution of these factors to the severity of atherosclerosis by measuring intima-medial thickness and brachial artery reactivity in uremic patients and controls. SUBJECTS AND METHODS Cardiovascular risk factors, including lipid and homocysteine levels, were evaluated in 213 patients (69 on hemodialysis, 60 on peritoneal dialysis, and 82 nonuremic controls). High-resolution B-mode ultrasonography with automated off-line analysis was used to measure the intima-medial thickness in the common carotid artery and to measure the lumen diameter of the brachial artery at rest, during reactive hyperemia, and after sublingual nitroglycerine. The correlations of risk factors with intima-medial thickness and brachial reactivity were examined using a general linear regression model. RESULTS Patients with renal failure had a greater mean (+/- SEM) maximum intima-medial thickness than controls (0.83 +/- 0.02 mm versus 0.70 +/- 0.02 mm, P < 0.05), but the brachial artery response to reactive hyperemia was not significantly different between the renal failure patients and the control group (4.7% +/- 6.1% versus 6.1% +/- 8.6% dilatation, P > 0.05). The uremic state was an independent predictor of intima-medial thickness (r2 = 0.16, P < 0.001) but not of brachial artery reactivity (P = 0.99). CONCLUSION The atherosclerotic burden in patients with renal failure, as indicated by an increased intima-medial thickness, may reflect effects of uremia that are independent of cardiovascular risk factors.

Macrophage migration inhibitory factor expression in human renal allograft rejection.

BACKGROUND Macrophage migration inhibitory factor (MIF) plays a pivotal role in immune-mediated diseases. Despite the long-standing association of MIF with the delayed-type hypersensitivity response, the potential role of MIF in allograft rejection is unknown. METHODS MIF expression was assessed by in situ hybridization and immunohistochemistry staining in 62 biopsies of human renal allograft rejection and in normal human kidney. RESULTS MIF mRNA and protein is constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells, some glomerular epithelial cells, and vascular smooth muscle cells. In both acute and chronic renal allograft rejection, there was marked up-regulation of MIF mRNA and protein expression by intrinsic kidney cells such as tubular epithelial cells and vascular endothelial and smooth muscle cells. There was also MIF expression by infiltrating macrophages and T cells. Of note, macrophage and T cell infiltrates were largely restricted to areas with marked up-regulation of MIF expression, potentially contributing to the development of severe tubulitis and intimal or transmural arteritis. Quantitative analysis found that increased MIF expression in allograft rejection gave a highly significant correlation with macrophage and T cell accumulation in both the glomerulus and interstitium (P<0.001). In addition, the number of MIF+ tubules and interstitial MIF+ cells correlated significantly with the severity of allograft rejection (P<0.01), and the loss of renal function (P<0.01). In contrast, no up-regulation of renal MIF expression and no leukocyte accumulation was seen in allograft biopsies without evidence of rejection. CONCLUSIONS This is the first study to demonstrate that local MIF expression is up-regulated during allograft rejection. The association between up-regulation of MIF expression, macrophage and T cell infiltration and the severity of renal allograft rejection suggests that MIF may be an important mediator in the process of allograft rejection.

Metabolic syndrome in severe chronic kidney disease: Prevalence, predictors, prognostic significance and effects of risk factor modification

Background:  Metabolic syndrome (MS) is a significant risk factor for cardiovascular disease, mortality and chronic kidney disease (CKD) in the general population. However, the prevalence, predictors, prognostic value and treatment of MS in the CKD population have not been rigorously studied.

Impact of obesity on renal transplant outcomes

SUMMARY:  Obesity is a frequent and important consideration to be taken into account when assessing patient suitability for renal transplantation. In addition, posttransplant obesity continues to represent a significant challenge to health care professionals caring for renal transplant recipients. Despite the vast amount of evidence that exists on the effect of pretransplant obesity on renal transplant outcomes, there are still conflicting views regarding whether obese renal transplant recipients have a worse outcome, in terms of short‐ and long‐term graft survival and patient survival, compared with their non‐obese counterparts. It is well established that any association of obesity with reduced patient survival in renal transplant recipients is mediated in part by its clustering with traditional cardiovascular risk factors such as hypertension, dyslipidaemia, insulin resistance and posttransplant diabetes mellitus, but what is not understood is what mediates the association of obesity with graft failure. Whether it is the higher incidence of cardiovascular comorbidities jeopardising the graft or factors specific to obesity, such as hyperfiltration and glomerulopathy, that might be implicated, currently remains unknown. It can be concluded, however, that pre‐ and posttransplant obesity should be targeted as aggressively as the more well‐established cardiovascular risk factors in order to optimize long‐term renal transplant outcomes.

The impact of automated eGFR reporting and education on nephrology service referrals

Background. Serum creatinine concentration is an unreliable and insensitive marker of chronic kidney disease (CKD). To improve CKD detection, the Australasian Creatinine Consensus Working Committee recommended reporting of estimated glomerular filtration rate (eGFR) using the four-variable Modification of Diet in Renal Disease (MDRD) formula with every request for serum creatinine concentration. The aim of this study was to evaluate the impact of automated laboratory reporting of eGFR on the quantity and quality of referrals to nephrology services in Southeast Queensland, Australia. Methods. Outpatient referrals to a tertiary and regional renal service, and a single private practice were prospectively audited over 3–12 months prior to and 12 months following the introduction of automated eGFR reporting and concomitant clinician education. The appropriateness of referrals to a nephrologist was assessed according to the Kidney Check Australia Taskforce (KCAT) criteria. Significant changes in the quantity and/or quality of referrals over time were analysed by exponentially weighed moving average (EWMA) charts with control limits based on ±3 standard deviations. Results. A total of 1019 patients were referred to the centres during the study period. Monthly referrals overall increased by 40% following the introduction of eGFR reporting, and this was most marked for the tertiary renal service (52% above baseline). The appropriateness of nephrologist referrals, as adjudicated by the KCAT criteria, fell significantly from 74.3% in the 3 months pre-eGFR reporting to 65.2% in the 12 months thereafter (P < 0.05). Nevertheless, a greater absolute number of CKD patients were appropriately being referred for nephrologist review in the post-eGFR period (24 versus 15 per month). Patients referred following the introduction of eGFR were significantly more likely to be older (median 63.2 versus 59.3 years, P < 0.05), diabetic (25 versus 18%, P = 0.05) and have stage 3 CKD (48% versus 36%, P < 0.01). Conclusion. The introduction of automated eGFR calculation has led to an overall increase in referrals with a small but significant decrease in referral quality. The increase in referrals was seen predominantly in older and diabetic patients with stage 3 CKD and appeared to result in net benefit.

Once- versus twice-daily tacrolimus: Are the formulations truly equivalent?

Tacrolimus is a cornerstone immunosuppressant agent in the prevention of organ rejection following transplantation. While typically administered twice daily (Prograf®), a modified-release once-daily formulation (Advagraf®) has recently been developed and licensed for use. To date, the majority of published data relating to the use of Advagraf® have arisen from industry-sponsored clinical trials. These have shown that conversion from Prograf® to Advagraf® on a 1 mg: 1 mg basis in both stable and de novo kidney and liver transplant recipients yields lower peak concentrations (Cmax) but equivalent overall drug exposure (area under the concentration-time curve from 0 to 24 hours post-dose; AUC24) and trough concentrations (Cmin). This has led to the proposal that the same total daily dose, target Cmin and therapeutic drug monitoring (TDM) strategies can be applied irrespective of preparation. However, while Advagraf® fulfils criteria for bioequivalence according to the European Medicines Agency and US FDA, lower tacrolimus exposure has been observed in the majority of clinical studies, particularly in the early post-transplant period. This has resulted in a need for higher doses of Advagraf® compared with Prograf® to achieve similar Cmin values. Significant between-subject variability in the Cmin/AUC24 relationship with Advagraf® has also been demonstrated, suggesting possible problems with TDM based on Cmin values. In non-comparative conversion studies, Advagraf® demonstrated similar efficacy and safety to Prograf®. However, phase III studies in de novo kidney and liver transplant recipients have shown higher rates of acute rejection with Advagraf®, possibly explained by the differing Cmax values achieved with the two preparations. While it has been suggested that once-daily administration may improve compliance, no studies have proven this to be the case. This article reviews the pharmacokinetics, efficacy, adverse effects and utility of Advagraf® in relation to its equivalence to Prograf®, and areas that require additional research are identified.