Mugurel Apetrii

Relationship between Serum Magnesium Levels and Cardiovascular Events in Chronic Kidney Disease Patients

Background: Magnesium is an essential ion for all living cells because over 300 enzymes require the presence of magnesium for their catalytic action. To date, no group has evaluated magnesium as a cardiovascular risk factor in chronic kidney disease (CKD) subjects, in which closely interrelated factors and potential confounders such as endothelial dysfunction, insulin resistance (the homeostasis model assessment (HOMA) index) and inflammation (expressed as serum C-reactive protein (CRP) levels) were also considered. Methods: Between March 2006 and December 2010, 283 CKD patients were followed up for time-to-event analysis until the occurrence of fatal or nonfatal cardiovascular events. Endothelium-dependent vasodilatation (flow-mediated dilatation; FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation) of the brachial artery were assessed noninvasively using high-resolution ultrasound. Results: From the univariate analysis of FMD, it appears that a higher magnesium level is associated with less endothelial dysfunction. When a multivariate analysis was performed, magnesium and estimated glomerular filtration rates (eGFR) maintained a strong positive correlation with FMD, supporting the hypothesis that higher levels of magnesium may protect against endothelial damage. In univariate Cox proportional hazards models, FMD, magnesium, high sensitivity CRP, the HOMA index, eGFR, comorbid diabetes, hypertension, smoking status, systolic blood pressure, serum phosphate and intact parathormone emerged as significant predictors for cardiovascular outcomes. Kaplan-Meier curves showed significantly higher cardiovascular mortality rates in CKD patients whose serum magnesium levels were below 2.05 mg/dl. Conclusions: This observational cohort study showed that magnesium may be an independent predictor of future cardiovascular outcomes and is the first study demonstrating such a role in etiologically diagnosed CKD patients, across different stages.

Predicting mortality in haemodialysis patients: a comparison between lung ultrasonography, bioimpedance data and echocardiography parameters

BACKGROUND The use of lung ultrasonography to evaluate extravascular lung water and its consequences has received growing attention in different clinical areas, including, in recent years, end-stage renal disease patients treated by haemodialysis (HD). Lung congestion is a direct consequence of either overall overhydration and/or cardiac dysfunction, but the exact contribution of each of these tests to mortality is unknown. METHODS In this prospective observational study, we enrolled 96 patients from a single HD unit undergoing thrice weekly HD. We used three different methods of evaluation: lung ultrasonography (pre- and post-dialysis), bioimpedance spectroscopy (pre- and post-dialysis) and echocardiography (pre-dialysis). The objective of the study was to test for the first time the prognostic value of ultrasound lung comets (ULC) combined with bioimpedance-derived data [total body water (TBW), extravascular water, hydration status-ΔHS] and several echocardiographic parameters. Mortality was analysed after a median of 405.5-day follow-up. RESULTS Pre-dialysis lung congestion was classified as moderate (ULC = 16-30) in 19.8% of the patients and severe in 12.5% of patients (ULC > 30), while only 19.8% appear to be hyperhydrated (ΔHS > 15%). The pre-dialysis ultrasound lung congestion score correlated significantly with all of the bioimpedance-derived parameters. In a multivariate Cox model that included ULC score, demographic, ecocardiographic and bioimpedance parameters, the factors that remained significantly associated with survival time were the pre-dialysis ULC score and left ventricular mass index. The pre-HD ULC score has a significant discriminating power for survival, while the bioimpedance-derived hydration status has no discriminatory abilities in terms of survival. CONCLUSIONS To our knowledge, this study is the first one that compares three different strategies to predict mortality in haemodialysed patients. The lung comet score emerged as the best predictor for the relationship hydration status-mortality, independently of bioimpedance-derived parameters in this population.

Lipid, blood pressure and kidney update 2013

The year 2013 proved to be very exciting as far as landmark trials and new guidelines in the field of lipid disorders, blood pressure and kidney diseases. Among these are the International Atherosclerosis Society Global Recommendations for the Management of Dyslipidemia, European Society of Cardiology (ESC)/European Society of Hypertension Guidelines for the Management of Arterial Hypertension, American Diabetes Association Clinical Practice Recommendations, the Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease (CKD) Patients, the American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, the Joint National Committee Expert Panel (JNC 8) Evidence-Based Guideline for the Management of High Blood Pressure in Adults, the American Society of Hypertension/International Society of Hypertension Clinical Practice Guidelines for the Management of Hypertension in the Community, the American College of Physicians Clinical Practice Guideline on Screening, Monitoring, and Treatment of Stage 1–3 CKD and many important trials presented among others during the ESC Annual Congress in Amsterdam and the American Society of Nephrology Annual Meeting—Kidney Week in Atlanta, GA. The paper is an attempt to summarize the most important events and reports in the mentioned areas in the passing year.

Overhydration, Cardiac Function and Survival in Hemodialysis Patients

Background and objectives Chronic subclinical volume overload occurs very frequently and may be ubiquitous in hemodialysis (HD) patients receiving the standard thrice-weekly treatment. It is directly associated with hypertension, increased arterial stiffness, left ventricular hipertrophy, heart failure, and eventually, higher mortality and morbidity. We aimed to assess for the first time if the relationship between bioimpedance assessed overhydration and survival is maintained when adjustments for echocardiographic parameters are considered. Design, setting, participants and measurements A prospective cohort trial was conducted to investigate the impact of overhydration on all cause mortality and cardiovascular events (CVE), by using a previously reported cut-off value for overhydration and also investigating a new cut-off value derived from our analysis of this specific cohort. The body composition of 221 HD patients from a single center was assessed at baseline using bioimpedance. In 157 patients supplemental echocardiography was performed (echocardiography subgroup). Comparative survival analysis was performed using two cut-off points for relative fluid overload (RFO): 15% and 17.4% (a value determined by statistical analysis to have the best predictive value for mortality in our cohort). Results In the entire study population, patients considered overhydrated (using both cut-offs) had a significant increased risk for all-cause mortality in both univariate (HR = 2.12, 95%CI = 1.30–3.47 for RFO>15% and HR = 2.86, 95%CI = 1.72–4.78 for RFO>17.4%, respectively) and multivariate (HR = 1.87, 95%CI = 1.12–3.13 for RFO>15% and HR = 2.72, 95%CI = 1.60–4.63 for RFO>17.4%, respectively) Cox survival analysis. In the echocardiography subgroup, only the 17.4% cut-off remained associated with the outcome after adjustment for different echocardiographic parameters in the multivariate survival analysis. The number of CVE was significantly higher in overhydrated patients in both univariate (HR = 2.46, 95%CI = 1.56–3.87 for RFO >15% and HR = 3.67, 95%CI = 2.29–5.89 for RFO >17.4%) and multivariate (HR = 2.31, 95%CI = 1.42–3.77 for RFO >15% and HR = 4.17, 95%CI = 2.48–7.02 for RFO >17.4%) Cox regression analysis. Conclusions The study shows that the hydration status is associated with the mortality risk in a HD population, independently of cardiac morphology and function. We also describe and propose a new cut-off for RFO, in order to better define the relationship between overhydration and mortality risk. Further studies are needed to properly validate this new cut-off in other HD populations.

Silymarin in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Type 2 diabetes mellitus (T2DM) is associated with increased risk of cardiovascular disease and nephropathy—now the leading cause of end-stage renal disease and dialysis in Europe and the United States. Inflammation and oxidative stress play a pivotal role in the development of diabetic complications. Silymarin, an herbal drug with antioxidant and anti-inflammatory properties, may improve glycemic control and prevent the progression of the complications. In a systematic review and meta-analysis including five randomized controlled trials and 270 patients, routine silymarin administration determines a significant reduction in fasting blood glucose levels (−26.86 mg/dL; 95% CI −35.42–18.30) and HbA1c levels (−1.07; 95% CI −1.73–0.40) and has no effect on lipid profile. Benefits for silymarin on proteinuria and CKD progressions are reported in only one small study and are uncertain. However, being aware of the low quality of the available evidence and elevated heterogeneity of these studies, no recommendation can be made and further studies are needed.

Changes in arterial stiffness following dialysis in relation to overhydration and to endothelial function.

IntroductionCardiovascular (CV) morbidity and mortality are greatly enhanced in patients with chronic kidney disease, partly due to increased arterial stiffness.Material and methodThe study included 63 stable HD patients. Stiffness parameters were evaluated by applanation tonometry before the mid-week HD sessions. Pre-HD bioimpedance parameters were measured. A phase angle <six degrees was previously reported as abnormal, reflecting extracellular overhydration. Fluid status was evaluated echocardiographic by measuring the inferior vena cava (IVC) diameter. Endothelium-dependent and endothelium-independent vascular reactivity were assessed by changes in Alx following sublingual nitroglycerin and inhaled salbutamol.ResultsPWV directly correlated with patients’ age and dialysis vintage. Patients with a phase angle <6°, were significantly overhydrated (larger IVC, increased ECW, and lower ICW), had stiffer arteries and greater left ventricle mass (LVM), compared with those with a phase angle >6°. Overhydration increases arterial stiffness, but has no influence on either EID or ED vascular reactivity.ConclusionIn hemodialysis, volume overload is an important contributor to increased arterial stiffness and modifies cardiovascular status especially by LV hypertrophy. Achieving normohydration may significantly ameliorate cardiac abnormalities and arterial stiffness and may impact major clinical events and CV mortality.

What would we like to know, and what do we not know about fibroblast growth factor 23?

Recently, a new view of the molecular mechanisms of phosphate homeostasis and secondary hyperparathyroidism pathogenesis has been proposed, with fibroblast growth factor 23 (FGF23) as a novel player in the field. FGF23 is a 32-kDa peptide secreted by the osteocytes involved in the control of phosphate homeostasis and calcitriol metabolism. FG23 is constantly elevated in advanced chronic kidney disease (CKD) patients, and recent studies have indicated that high levels are associated with the progression of CKD and with higher mortality rates in hemodialysis patients. In the CKD population, high serum FGF23 concentration seems to predict the occurrence of refractory secondary hyperparathyroidism, by inducing a resistance of the parathyroid glands to FGF23, and to be associated with higher mortality risk in incident hemodialysis patients. FGF23 appears to be involved in bone metabolism, but a direct effect of FGF23 on bone disease in humans has not yet been elucidated, even if the inhibitory effect of FGF23 on osteoblast activity that has been described in animal models and hereditary rickets is clearly connected with FGF23 deficiency. The association between altered levels of FGF23 and bone disease could be mainly due to the dysregulation of phosphate-handling and vitamin D metabolism, more than to a direct antiosteoblastic activity of FGF23. FGF23 appears to be a new biomarker, which is independently associated with several cardiovascular risk factors such as endothelial dysfunction, arterial stiffness and left ventricular hypertrophy, in the general population as well as in early CKD. All of the above have been related to cardiovascular and general mortality. Until now, we know that elevated FGF23 levels in dialysis patient are associated with several cardiovascular adverse outcomes mentioned above; the clinical relevance of high FGF23 values in dialysis patients remains unclear, because therapy with active vitamin D sterols further increases FGF23 levels but, on the other hand, is associated with a survival benefit in dialysis patients. This paradox highlights the need for future prospective randomized trials to evaluate the correlation between vitamin D therapy and FGF23 levels in dialysis patients. In the clinical setting, there are still different FGF23 actions that need investigation. In this sense, increased knowledge of mineral metabolism disorder alterations in CKD may be used to improve diagnostics and select future treatments.

Superior predictive value for NTproBNP compared with high sensitivity cTnT in dialysis patients: a pilot prospective observational study.

Background/Aims: The clinical utility of the new biomarker, high sensitivity cardiac T troponin (hs-cTnT) is still unclear in dialysis patients. Furthermore, the prognostic value of combining N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and hs-cTnT has not been explored so far. The objective of this pilot study was to determine the utility of hs-cTnT alone versus hs-cTnT in combination with NT-proBNP for predicting death in a stable hemodialysis cohort. Methods: A prospective observational pilot study including 98 chronic asymptomatic hemodialysis patients with a follow up period of 24 months was designed. The cut-off values for NT-proBNP and hs-cTnT were calculated using receiver operating characteristic (ROC) analysis, using mortality as an end-point. Based on the cut-off values, the cohort was divided into four groups. Group 1 - NT-proBNP < 14275 pg/ml and hs-cTnT < 69.48 ng/l; group 2 - NT-proBNP < 14275 pg/ml and hs-cTnT > 69.48 ng/l; group 3 - NT-proBNP > 14275 pg/ml and hs-cTnT < 69.48 ng/l; group 4 - NT-proBNP > 14275 pg/ml and hs-cTnT > 69.48 ng/l. Survival for each group was determined using the Kaplan-Meier method and Cox regression analysis. Results: During the follow-up period 16 patients died. According to the ROC curves analysis, the cut-off point for hs-cTnT and for NT-proBNP were 69.43 ng/l (AUC = 0.618; p = 0.04) and 14275 pg/ml (AUC = 0.722; p = 0.003), respectively. In univariate Cox analysis, both hs-cTnT (HR = 3.34; p = 0.016) and NT-proBNP (HR = 5.94; p = 0.01) were predictors of death. In the multivariable Cox proportional hazards model, only NT-pro-BNP levels above the cut-off value remained an independent predictor of all-cause mortality. The combined elevation of both biomarkers did not improve significantly the prognostic value compared with NT-proBNP alone (HR = 6.15 versus HR =4 .78; p = 0.338). Conclusion: NT-pro-BNP is a strong predictor of overall mortality in asymptomatic hemodialysis patients. The addition of hs-cTnT did not improve the prognostic accuracy compared with NT proBNP alone.

Impact of surgical parathyroidectomy on chronic kidney disease-mineral and bone disorder (CKD-MBD) – A systematic review and meta-analysis

For more than 6 decades, many patients with advanced chronic kidney disease (CKD) have undergone surgical parathyroidectomy (sPTX) for severe secondary hyperparathyroidism (SHPT) mainly based historical clinical practice patterns, but not on evidence of outcome.We aimed in this meta-analysis to evaluate the benefits and harms of sPTX in patients with SHPT. We searched MEDLINE (inception to October 2016), EMBASE and Cochrane Library (through Issue 10 of 12, October 2016) and website clinicaltrials.gov (October 2016) without language restriction. Eligible studies evaluated patients reduced glomerular filtration rate (GFR), below 60 mL/min/1.73 m2 (CKD 3–5 stages) with hyperparathyroidism who underwent sPTX. Reviewers working independently and in duplicate extracted data and assessed the risk of bias. The final analysis included 15 cohort studies, comprising 24,048 participants. Compared with standard treatment, sPTX significantly decreased all-cause mortality (RR 0.74 [95% CI, 0.66 to 0.83]) in End Stage Kidney Disease (ESKD) patients with biochemical and / or clinical evidence of SHPT. sPTX was also associated with decreased cardiovascular mortality (RR 0.59 [95% CI, 0.46 to 0.76]) in 6 observational studies that included almost 10,000 patients. The available evidence, mostly observational, is at moderate risk of bias, and limited by indirect comparisons and inconsistency in reporting for some outcomes (eg. short term adverse events, including documented voice change or episodes of severe hypocalcaemia needing admission or long-term adverse events, including undetectable PTH levels, risk of fractures etc.). Taken together, the results of this meta-analysis would suggest a clinically significant beneficial effect of sPTX on all-cause and cardiovascular mortality in CKD patients with SHPT. However, given the observational nature of the included studies, the case for a properly conducted, independent randomised controlled trial comparing surgery with medical therapy and featuring many different outcomes from mortality to quality of life (QoL) is now very strong.

Bone and mineral disorders in chronic kidney disease: implications for cardiovascular health and ageing in the general population

The patient with chronic kidney disease (CKD) represents an extreme model for arteriosclerosis, vascular calcification, and bone disorders, all of which are also associated with ageing in the general population. These pathological features are also relevant to other common chronic health disorders such as diabetes, and chronic inflammatory and cardiovascular diseases. Although management and interventions for these major risk factors are now incorporated into most public health guidelines (eg, smoking cessation and control of bodyweight and blood pressure, as well as glucose and cholesterol concentrations), some residual cardiovascular risk is not reduced by implementation of these interventions. CKD should be regarded as an atypical disease in which both traditional and novel cardiovascular risk factors have effects on outcomes. But CKD can also be viewed conceptually as an accelerator of traditional cardiovascular risk factors. Findings from research into mineral bone disorder associated with CKD (CKD-MBD) could help the medical community to better understand the vascular actions of certain molecules, such as phosphates, fibroblast growth factor 23, parathyroid hormone, sclerostin, or vitamin D and their relevance to the management of different pathologies in the general population. Importantly, these components, which are recognised in nephrology, could help to explain residual risk of cardiovascular events in the general population. Thus, achieving a better understanding of CKD-MBDs could provide substantial insight into future treatments for arteriosclerosis and osteoporosis, which are strongly associated with ageing and morbidity in the general population.