Systematic review of the nuclear factor erythroid 2-related factor 2 (NRF2) system in human chronic kidney disease: alterations, interventions and relation to morbidity.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (NRF2) and its effectors NAD(P)H:quinoneoxidoreductase 1 (NQO1) and haem oxygenase 1 (HO-1) are of interest in kidney disease. We therefore reviewed studies about their status in patients with chronic kidney disease (CKD). METHODS: We undertook systematic searches of PubMed and Excerpta Medica dataBASE (EMBASE) databases. Alterations of NRF2, NQO1 and HO-1 in CKD, their responses to interventions and their relation to clinically relevant parameters were reported. RESULTS: We identified 1373 articles, of which 32 studies met the inclusion criteria. NRF2 levels were decreased in the majority of analyses of CKD patients. Half of the analyses showed a similar or increased NQO1 level versus control, whereas in half of the analyses NQO1 was decreased. Most of the studies reported either an increased or similar HO-1 level in CKD patients compared with controls. For patients with CKD Stages 1-4, studies reported positive correlations to markers of kidney disease severity. Also, positive associations of NQO1/HO-1 levels to inflammation and comorbidities were reported. One-third of the studies showed discordant changes between gene expression and protein level of NRF2 system components. Two-thirds of intervention studies (50% dietary, such as using resistant starch) reported an increase of NRF2, NQO1 or HO-1. CONCLUSIONS: In patients with CKD, NRF2 expression was downregulated, while NQO1 and HO-1 showed varying alterations related to inflammation, comorbidities and severity of kidney damage. Interventions that increased NRF2 system components were described, but their effectiveness and clinical relevance require further clinical studies of high quality. Research on gene expression together with protein analyses is indispensable to understand NRF2 system alterations in CKD.

Dietary cinnamaldehyde activation of TRPA1 antagonizes high-salt induced hypertension through restoring renal tubular mitochondrial dysfunction.

BACKGROUND: Renal proximal tubule plays a pivotal role in regulating sodium reabsorption and thus blood pressure. Transient receptor potential ankyrin 1 (TRPA1) has been reported to protect against renal injury by modulating mitochondrial function. We hypothesize that the activation of TRPA1 by its agonist cinnamaldehyde may mitigates high salt intake induced hypertension by inhibiting urinary sodium reabsorption through restoration of renal tubular epithelial mitochondrial function. METHODS: Trpa1-deficient (Trpa1-/-) mice and wild-type (WT) mice were fed standard laboratory chow [normal diet (ND) group, 0.4% salt], standard laboratory chow with 8% salt [high-salt diet (HS) group] or standard laboratory chow with 8% salt plus 0.015% cinnamaldehyde [high-salt plus cinnamaldehyde diet (HSC) group] for six months. Urinary sodium excretion, ROS production, mitochondrial function and the expression of NHE3 and Na+/K+-ATPase of renal proximal tubules were determined. RESULTS: Chronic dietary cinnamaldehyde supplementation reduced tail systolic blood pressure and 24-hour ambulatory arterial pressure in HS-fed WT mice. Compared with the mice fed HS, cinnamaldehyde supplementation significantly increased urinary sodium excretion, inhibited excess ROS production and alleviated mitochondrial dysfunction of renal proximal tubules in WT mice. However, these effects of cinnamaldehyde were absent in Trpa1-/- mice. Furthermore, chronic dietary cinnamaldehyde supplementation blunted HS-induced upregulation of NHE3 and Na+/K+-ATPase in WT mice but not Trpa1-/- mice. CONCLUSION: The present study demonstrated that chronic activation of Trpa1 attenuates HS-induced hypertension by inhibiting urinary sodium reabsorption through restoring renal tubular epithelial mitochondrial function. Renal TRPA1 may be a potential target for the management of excessive dietary salt intake-associated hypertension.

Plasma concentrations of extracellular matrix protein fibulin-1 are related to cardiovascular risk markers in chronic kidney disease and diabetes.

BACKGROUND: Fibulin-1 is one of a few extracellular matrix proteins present in blood in high concentrations. We aimed to define the relationship between plasma fibulin-1 levels and risk markers of cardiovascular disease. METHODS: Plasma fibulin-1 was determined in subjects with chronic kidney disease (n = 32; median age 62.5, inter-quartile range 51 - 73 years) and 60 age-matched control subjects. Among kidney disease patients serological biomarkers related to cardiovascular disease (fibrinogen, interleukin 6, C-reactive protein) were measured. Arterial applanation tonometry was used to determine central hemodynamic and arterial stiffness indices. RESULTS: We observed a positive correlation of fibulin-1 levels with age (r = 0.38; p = 0.033), glycated hemoglobin (r = 0.80; p = 0.003), creatinine (r = 0.35; p = 0.045), and fibrinogen (r = 0.39; p = 0.027). Glomerular filtration rate and fibulin-1 were inversely correlated (r = -0.57; p = 0.022). There was a positive correlation between fibulin-1 and central pulse pressure (r = 0.44; p = 0.011) and central augmentation pressure (r = 0.55; p = 0.001). In a multivariable regression model, diabetes, creatinine, fibrinogen and central augmentation pressure were independent predictors of plasma fibulin-1. CONCLUSION: Increased plasma fibulin-1 levels were associated with diabetes and impaired kidney function. Furthermore, fibulin-1 levels were associated with hemodynamic cardiovascular risk markers. Fibulin-1 is a candidate in the pathogenesis of cardiovascular disease observed in chronic kidney disease and diabetes.

Nrf2 Protein Serum Concentration in Human CKD Shows a Biphasic Behavior.

Oxidative stress contributes to the progression of chronic kidney disease (CKD) and CKD-related mortality. The nuclear factor erythroid 2-related factor 2 (Nrf2) is essential in the regulation of cellular redox status, and Nrf2-activating therapies are under evaluation in several chronic diseases, including CKD. It is therefore inevitable to understand how Nrf2 behaves in advancing CKD. We analyzed Nrf2 protein concentrations in patients with varying extents of CKD but without renal replacement therapy, and in healthy subjects. Compared to healthy controls, Nrf2 protein was upregulated in mild to moderate kidney function impairment (G1-3). Within the CKD population, we found a significant positive correlation between Nrf2 protein concentration and kidney function (estimated glomerular filtration rate). In severe kidney function impairment (G4,5), Nrf2 protein was reduced compared to mild to moderate kidney function impairment. We conclude that Nrf2 protein concentration in severe kidney function impairment is reduced relative to the mild to moderate kidney function impairment where increased Nrf2 protein concentrations prevail. With respect to the implementation of Nrf2 targeted therapies, it will be necessary to explore in which population of patients with CKD such therapies are able to effectively add to the endogenous Nrf2 activity.

Nasal continuous positive airway pressure: influence on digital volume pulse in obstructive sleep apnoea patients.

Obstructive sleep apnoea (OSA) is linked to increased cardiovascular risk. This risk can be reduced by nasal continuous positive airway pressure (nCPAP) treatment. As OSA is associated with an increase of several vasoconstrictive factors, we investigated whether nCPAP influences the digital volume pulse wave. We performed digital photoplethysmography during sleep at night in 94 consecutive patients who underwent polysomnography and 29 patients treated with nCPAP. Digital volume pulse waves were obtained independently of an investigator and were quantified using an algorithm for continuous automated analysis. In patients with OSA and an apnoea/hypopnoea index (AHI) of >10 events · h(-1), a significant vasoconstriction was observed during the night (p<0.0001 by Friedman's test). A significant positive correlation existed between vasoconstriction and AHI (Spearman correlation, r = 0.27; p<0.01; n = 94) and the arousal index (Spearman correlation, r = 0.21; p < 0.05; n = 94). After 6 months of nCPAP treatment, the AHI was significantly reduced from 27 ± 3 events · h(-1) to 4 ± 2 events · h(-1) (each n = 29; p<0.001) and vasoconstriction during the night was significantly reduced from 10 ± 3% to 3 ± 1% (p<0.01). We show changes in the reflective index during the night consistent with vasoconstriction in patients with OSA, which are significantly reduced after 6 months of nCPAP treatment.

Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D.

BACKGROUND: Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. METHODS: An 8-week randomized, placebo-controlled, double-blind parallel intervention study was conducted in haemodialysis (HD) and non-HD CKD patients. Treatment consisted of 40,000 IU of cholecalciferol orally per week. Plasma 25-hydroxyvitamin D (25-OHD), plasma 1,25-dihydroxyvitamin D (1,25-diOHD), plasma parathyroid hormone (PTH), serum phosphate, ionized serum calcium and serum fibroblast growth factor 23 (FGF-23) were analysed. We also investigated biomarkers related to cardiovascular disease (plasma D-dimer, plasma fibrinogen, plasma von Willebrand factor antigen and activity, plasma interleukin 6, plasma C-reactive protein, blood pressure, aortic augmentation index, aortic pulse wave velocity and 24-h urinary protein loss). Objective and subjective health variables were assessed (muscle function tests, visual analogue scores and Health Assessment Questionnaire). RESULTS: Fifty-two CKD patients with 25-OHD <50 nmol/L at screening were included. Cholecalciferol supplementation led to a significant increase to a median of 155 nmol/L 25-OHD (interquartile range 137-173 nmol/L) in treated patients (n = 25, P < 0.001). In non-HD patients, we saw a significant increase in 1,25-diOHD (n = 13, P < 0.01) and a lowering of PTH (n = 13, P < 0.001). This was not observed in HD patients. Cholecalciferol supplementation caused a significant increase in serum calcium and FGF-23. CONCLUSIONS: 25-OHD replenishment was effectively obtained with the employed cholecalciferol dosing. In non-HD patients, it had favourable effects on 1,25-diOHD and PTH. Vitamin D-supplemented patients must be monitored for hypercalcaemia. The present study could not identify significant pleiotropic effects of 25-OHD replenishment.

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls.

The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a physiologic activity range. Oxidative stress and alterations in Nrf2-system activity are central for chronic-kidney-disease (CKD) progression and CKD-related morbidity. Activation of the Nrf2 system in CKD is in multiple ways related to inflammation, kidney fibrosis, and mitochondrial and metabolic effects. In human CKD, both endogenous Nrf2 activation and repression exist. The state of the Nrf2 system varies with the cause of kidney disease, comorbidities, stage of CKD, and severity of uremic toxin accumulation and inflammation. An earlier CKD stage, rapid progression of kidney disease, and inflammatory processes are associated with more robust Nrf2-system activation. Advanced CKD is associated with stronger Nrf2-system repression. Nrf2 activation is related to oxidative stress and moderate uremic toxin and nuclear factor kappa B (NF-κB) elevations. Nrf2 repression relates to high uremic toxin and NF-κB concentrations, and may be related to Kelch-like ECH-associated protein 1 (Keap1)-independent Nrf2 degradation. Furthermore, we review the effects of pharmacological Nrf2 activation by bardoxolone methyl, curcumin, and resveratrol in human CKD and outline strategies for how to adapt future Nrf2-targeted therapies to the requirements of patients with CKD.

Involvement of Inflammasome Components in Kidney Disease.

Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1ß and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.

Superoxide dismutase type 1 in monocytes of chronic kidney disease patients.

We analyzed proteomic profiles in monocytes of chronic kidney disease (CKD) patients and healthy control subjects. Two-dimensional electrophoresis (2-DE) and silver staining indicated differences in protein pattern. Among the analyzed proteins, superoxide dismutase type 1 (SOD1), which was identified both by MS/MS mass-spectrometry and immunoblotting, was reduced in kidney disease. We characterized SOD1 protein amount, using quantitative in-cell Western assay and immunostaining of 2-DE gel blots, and SOD1 gene expression, using quantitative real-time polymerase chain reaction (PCR), in 98 chronic hemodialysis (HD) and 211 CKD patients, and 34 control subjects. Furthermore, we showed that different SOD1 protein species exist in human monocytes. SOD1 protein amount was significantly lower in HD (normalized SOD1 protein, 27.2 ± 2.8) compared to CKD patients (34.3 ± 2.8), or control subjects (48.0 ± 8.6; mean ± SEM; P < 0.05). Analysis of SOD1 immunostaining showed significantly more SOD1 protein in control subjects compared to patients with CKD or HD (P < 0.0001, analysis of main immunoreactive protein spot). SOD1 gene expression was significantly higher in HD (normalized SOD1 gene expression, 17.8 ± 2.3) compared to CKD patients (9.0 ± 0.7), or control subjects (5.5 ± 1.0; P < 0.0001). An increased SOD1 gene expression may indicate increased protein degradation in patients with CKD and compensatory increase of SOD1 gene expression. Taken together, we show reduced SOD1 protein amount in monocytes of CKD, most pronounced in HD patients, accompanied by increased SOD1 gene expression.

Higher serum levels of free ĸ plus λ immunoglobulin light chains ameliorate survival of hemodialysis patients.

BACKGROUND/AIMS: Impaired immune function is common in patients with chronic renal failure. Now, we determined whether serum levels of free immunoglobulin light chains predict mortality in patients with chronic kidney disease stage 5 on hemodialysis. METHODS: We performed a prospective cohort study of 160 hemodialysis patients with a median follow-up of 15 months (interquartile range, 3-44 months). Serum levels of free κ and λ immunoglobulin light chains were measured at the start of the study. The primary end point was mortality from any cause. RESULTS: In survivors, median serum levels of free κ plus λ immunoglobulin light chains were significantly higher compared with nonsurvivors (p < 0.05). Survival was significantly longer in those patients who had serum levels of free κ plus λ immunoglobulin light chains above the median compared with patients with serum levels below the median of 210 mg/l (χ(2) = 5.91; p = 0.015 by log-rank, Mantel-Cox, test). We performed univariate and multivariate regression analysis showing that older age and lower serum levels of free κ plus λ immunoglobulin light chains predicted mortality in hemodialysis patients. CONCLUSION: Higher serum levels of free κ plus λ immunoglobulin light chains ameliorate survival in hemodialysis patients.

Alterations of retinol-binding protein 4 species in patients with different stages of chronic kidney disease and their relation to lipid parameters.

Retinol-binding protein 4 (RBP4) is elevated in patients with chronic kidney disease (CKD) and has been discussed as marker of kidney function. In addition to an elevated concentration, the existence of truncated RBP4 species, RBP4-L (truncated at last C-terminal leucine) and RBP4-LL (truncated at both C-terminal leucines), has been reported in serum of hemodialysis patients. Since little is known about the occurrence of RBP4 species during the progression of CKD it was the aim of this study to analyse this possible association. The presence of RBP4, RBP4-L, RBP4-LL and transthyretin (TTR) was assessed in serum of 45 healthy controls and 52 patients with stage 2-5 of CKD using ELISA and RBP4 immunoprecipitation with subsequent MALDI-TOF-MS analysis. A reduction of glomerular filtration rate was accompanied by a gradual elevation of RBP4 serum levels and relative amounts of RBP4-LL. Correlation analysis revealed a strong association of the RBP4-TTR ratio with parameters of lipid metabolism and with diabetes-related factors. In conclusion, RBP4 serum concentration and the appearance of RBP4-LL seem to be influenced by kidney function. Furthermore, the RBP4-TTR ratio may provide diagnostic potential with regard to metabolic complications in CKD patients.

Noninvasive pulse wave analysis for the determination of central artery stiffness.

Central artery stiffness predicts cardiovascular structural damage and clinical outcome. It is controversial whether central artery stiffness can be determined by noninvasive measurements. We compared noninvasive determination of central artery stiffness obtained from applanation tonometry of the peripheral radial artery waveform with invasive measurements of the ratio of pulse-pressure-to-stroke-volume. A total of 112 invasive measurements of the ratio of pulse-pressure-to-stroke-volume and noninvasive determinations of central artery stiffness were performed in 49 patients on the intensive care unit. In 13 out of 112 attempts of noninvasive measurements (12%) radial pulse could not be obtained using applanation tonometry because of cardiac arrhythmia or radial pulse could not be detected. These 13 failing noninvasive measurements were attempted in 7 patients. In the remaining cases we found a significant correlation between noninvasively obtained central artery stiffness and invasive measurements of the ratio of pulse-pressure-to-stroke-volume (Spearman r=0.40; p<0.0001). The association between invasive and noninvasive measurements was confirmed using Bland-Altman plots. Furthermore, a norepinephrine-induced increase of arterial stiffness was detected both invasively and noninvasively. Noninvasive determination of central artery stiffness obtained from peripheral radial artery waveform should be useful in clinical practice although it cannot be performed in every patient.

Mortality risk in hemodialysis patients with increased arterial stiffness is reduced by attainment of classical clinical performance measures.

BACKGROUND: We determined whether attainment of classical clinical performance measures for hemodialysis care improves survival in hemodialysis patients with increased arterial stiffness. METHODS: We performed a prospective cohort study of 538 hemodialysis patients with a median follow-up of 19 months (interquartile range 8-30). Arterial stiffness was measured using applanation tonometry. Clinical performance measure targets were hemoglobin value >or=110 g/l, serum albumin value >or=37 g/l and measured single-pool Kt/V urea value >or=1.2. RESULTS: During follow-up, 217 patients (40%) died. In non-survivors, arterial stiffness of large arteries (S1) was significantly higher compared with survivors (p = 0.0002). An analysis of hemodialysis patients who were alive 18 months after inclusion into the study showed that survival was significantly longer in those patients that met >or=2 clinical performance measure targets compared with patients that met

High glucose enhances transient receptor potential channel canonical type 6-dependent calcium influx in human platelets via phosphatidylinositol 3-kinase-dependent pathway.

BACKGROUND: Transient receptor potential canonical type 6 (TRPC6) channels mediating 1-oleoyl-2-acetyl-sn-glycerol (OAG)-induced calcium entry have been identified on human platelets. In the present study we tested the hypothesis that hyperglycemia increases the expression of TRPC6 channels. METHODS AND RESULTS: Platelets from healthy control subjects and patients with type 2 diabetes mellitus were incubated with glucose and calcium influx was measured using the fluorescent dye technique. TRPC channel protein expression was investigated using immunofluorescence and fluorescence microscopy of single platelets. Administration of 25 mmol/L glucose significantly enhanced the OAG-induced calcium influx, which was attenuated by inhibitors of the phosphatidylinositol 3-kinase, wortmannin or LY294002. The glucose-enhanced and OAG-induced calcium influx was concentration- and time-dependent. Glucose significantly increased the TRPC6 protein expression in platelets to 131+/-12% (n=33; P<0.05), whereas the expression of TRPC1, TRPC3, TRPC4, or TRPC5 were unchanged. The glucose-induced TRPC6 expression was significantly attenuated in the presence of wortmannin or LY294002. Platelets from patients with type 2 diabetes mellitus showed increased TRPC6 expression compared to nondiabetic individuals (P<0.05). CONCLUSIONS: The study indicates that high glucose increases TRPC6 channel protein expression on the platelet surface which is mediated by a phosphatidylinositol 3-kinase-dependent pathway.

N-acetylcysteine improves arterial vascular reactivity in patients with chronic kidney disease.

BACKGROUND: Patients with stage 5 chronic kidney disease show increased cardiovascular morbidity and mortality that are partly related to impaired arterial vascular reactivity. We investigated whether intravenous administration of the antioxidant acetylcysteine improves arterial vascular reactivity in these patients. METHODS: Arterial vascular reactivity was determined during reactive hyperemia by photoplethysmography of digital pulse waves in a randomized, prospective, placebo-controlled cross-over study of 24 patients with stage 5 chronic kidney disease with and without infusion of acetylcysteine during hemodialysis. Acetylcysteine (5 g in 5% glucose in a final volume of 50 ml) was continuously administered intravenously during one hemodialysis session. RESULTS: In the absence of acetylcysteine, the reflective index was 38.5 +/- 9.4 (mean +/- SD; n = 24) at baseline and 33.8 +/- 9.9 during reactive hyperemia, immediately after the hemodialysis session; thus there was no significant vasodilatation (p > 0.05), indicating impaired arterial vascular reactivity in these patients. However, when the hemodialysis session in the same patients was performed in the presence of acetylcysteine, the reflective index significantly decreased from 37.9 +/- 8.6 at baseline to 30.2 +/- 10.3 during reactive hyperemia (n = 24; p < 0.01). CONCLUSION: The present study shows that intravenous administration of acetylcysteine during hemodialysis significantly improves arterial vascular reactivity during reactive hyperemia.

Association of transient receptor potential canonical type 3 (TRPC3) channel transcripts with proinflammatory cytokines.

We investigated whether expression of non-selective cation channels of the transient receptor potential canonical (TRPC) channel family are associated with proinflammatory cytokines in monocytes. Using quantitative RT-PCR we studied the expression of TRPC3, interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) in monocytes from 15 patients with essential hypertension and 16 age- and sex-matched normotensive control subjects. We observed an approximately 8-fold increase of TRPC3 transcripts in monocytes from patients with essential hypertension compared to normotensive control subjects (p<0.05). We found an approximately 3-fold increase of IL-1beta, and an approximately 9-fold increase of TNF-alpha in patients with essential hypertension compared to normotensive control subjects (each p<0.05). We observed a significant correlation between TRPC3 transcripts with systolic blood pressure, expression of IL-1beta, and TNF-alpha. Using quantitative RT-PCR we observed an association of TRPC3 transcripts and proinflammatory cytokines in monocytes.

Impaired vascular reactivity in patients with chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) show increased cardiovascular morbidity. We hypothesized that vascular properties which can be routinely evaluated noninvasively are related to different stages of CKD and their clinical and biochemical characteristics. METHODS: Arterial vascular properties were quantified by the reflective index using digital photoplethysmography in 260 patients with CKD. Patients were grouped according to estimated glomerular filtration rate (eGFR). Additional measurements were performed in 50 healthy control subjects. RESULTS: In patients with CKD stage 1 and 2 (n = 115; age 65 +/- 1 years) the reflective index was 30 +/- 1%, whereas in patients with CKD stage 3 and 4 (n = 60; age 72 +/- 1 years) the reflective index was 36 +/- 1%, and in patients with CKD stage 5 (n = 85; age 64 +/- 1 years) the reflective index was 36 +/- 1% (p < 0.01 by Kruskal-Wallis test) indicating increased arterial stiffness in advanced CKD. Arterial vascular reactivity was significantly impaired in patients with advanced stages of CKD (stage 1 and 2, 78 +/- 12%; stage 3 and 4, 32 +/- 12%; stage 5, 33 +/- 12%; p < 0.01). Univariate analysis showed a significant correlation of the reflective index and eGFR (Pearson r = -0.24; p < 0.0001). Multivariate regression analysis showed an independent association of the reflective index and eGFR (adjusted correlation coefficient, -0.24; p < 0.001). CONCLUSION: The advanced stages of CKD are associated with increased vascular stiffness and impaired vascular reactivity and these changes are already present in CKD stage 3 and 4.

Effect of amlodipine on cardiovascular events in hypertensive haemodialysis patients.

BACKGROUND: Hypertensive haemodialysis patients may be at a high risk for cardiovascular events. This study was undertaken to ascertain whether the calcium channel blocker amlodipine reduces mortality and cardiovascular events in these high-risk patients. METHODS: We evaluated the effects of amlodipine on cardiovascular events in 251 hypertensive haemodialysis patients in an investigator-designed, prospective, randomized, double-blind, placebo-controlled, multicenter trial. One hundred and twenty-three patients were randomly assigned to amlodipine (10 mg once daily) and 128 to placebo. The primary endpoint was mortality from any cause. The secondary endpoint was a composite variable consisting of mortality from any cause or cardiovascular event. Analysis was by intention-to-treat. The trial was registered with ClinicalTrials.gov (number NCT00124969). RESULTS: The median age of patients was 61 years (25% percentile - 75% percentile, 47-69), and the median follow-up was 19 months (8-30). Fifteen (12%) of the 123 patients assigned to amlodipine and 22 (17%) of the 128 patients assigned to placebo had a primary endpoint [hazard ratio 0.65 (95% CI 0.34-1.23); P = 0.19]. Nineteen (15%) of the 123 haemodialysis patients assigned to amlodipine and 32 (25%) of the 128 haemodialysis patients assigned to placebo reached the secondary composite endpoint [hazard ratio 0.53 (95% CI 0.31-0.93); P = 0.03]. CONCLUSION: Amlodipine safely reduces systolic blood pressure and it may have a beneficial effect on cardiovascular outcomes in hypertensive haemodialysis patients.

Noninvasive cardiac output determination using applanation tonometry-derived radial artery pulse contour analysis in critically ill patients.

Conventional thermodilution cardiac output (CO) monitoring is limited mainly to intensive care units and operating rooms because it requires the use of invasive techniques. To reduce the potential for complications and to broaden the applicability of hemodynamic monitoring, noninvasive methods for CO determination are being sought. Applanation tonometry allows noninvasive CO estimation through pulse contour analysis, but the method has not been evaluated in critically ill patients. We therefore performed noninvasive radial artery applanation tonometry in 49 critically ill medical intensive care unit patients and compared CO estimates to invasive CO measurements obtained using a pulmonary artery catheter or the PiCCO transpulmonary thermodilution system. One-hundred-sixteen measurements were performed, and patients were receiving vasopressor support during 78 measurements. When the data were analyzed with bias and precision statistics, a large bias of 2.03 L x min(-1) x m(-2) and a high percentage error of 85% were found between the invasive measurements and applanation tonometry-derived CO estimates, with the noninvasive CO results being significantly lower than the invasive ones (P < 0.001). There was no significant difference in bias between the patients who were receiving vasopressor support and those who were not (P = 0.874) or between patients with good and poor applanation tonometry pressure waveform signal quality (P = 0.071). Whereas a significant increase in the invasively determined CO was observed when a fluid bolus was administered (n = 7, P = 0.016), these changes were not reflected by the noninvasive method. We conclude that radial artery applanation tonometry is not suitable to determine CO in critically ill hemodynamically unstable patients.

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis.

BACKGROUND: Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. METHODS AND RESULTS: We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level meta-analysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial-level meta-analysis, and 24 trials (2051 participants) contributed to individual-participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascular measures (flow-mediated dilatation, 0.37% [95% confidence interval, -0.23 to 0.97]; carotid-femoral pulse wave velocity, 0.00 m/s [95% confidence interval, -0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. CONCLUSIONS: Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.