The equations were constrained to include a maximum of three samples collected within 4 h after the intake to maintain clinical applicability. To assess the predictive performance of LSS, residuals for each patient were calculated based on models fitted to a dataset where that patient was omitted.0–24 using the time points 0, 2, and 4 h after ingestion (C0h-C2h-C4h) provided the highest correlation with the AUC0–24 (r2 = 0.95): AUC0–24 = 44.9 + 8.9 × C0h + 2.1 × C2h + 7.6 × C4h. Measures for bias and precision, i.e., median percentage prediction error (MPPE) and median absolute prediction error (MAPE), were 0.4 and 4.8 %, respectively. For the same patients, the correlation between C24h and AUC0–24 was worse (r2 = 0.77) while MPPE and MAPE were 6.2 and 7.2 %, respectively.The prediction formula for the AUC0h-C2h-C4h can be used for reliable estimation of the AUC0–24 of prolonged-release tacrolimus.In the outpatient department, a LSS using CThe online version of this article (doi:10.1007/s00228-015-1863-6) contains supplementary material, which is available to authorized users. Tacrolimus is a usual component of the immunosuppressive regimen after renal transplantation. While it was developed as an oral twice-daily formulation, a prolonged-release once-daily formulation was launched a few years ago. The efficacy and safety profile of prolonged-release tacrolimus are comparable to that of the twice-daily formulation , 9. KuijAlthough the relationship between tacrolimus exposure and clinical response has not yet been fully established, therapeutic drug monitoring (TDM), i.e., individualization of the dose based on concentration measurements, is indicated for tacrolimus. TDM aims to improve the efficacy of tacrolimus, prevents overexposure and associated adverse effects, and detects drug interactions or unexpected pharmacogenetic influences on exposure to this immunosuppressive drug . In an e0–24) of prolonged-release tacrolimus in them. This would also allow us to assess the performance of the trough level, as a single sample, to predict the AUC0–24 of prolonged-release tacrolimus.A more reliable estimation of the total exposure can be obtained by a limited sampling strategy (LSS). This means sampling at limited or optimal sampling times, still allowing for an accurate and precise estimation of the AUC , 19. CleWe carried out a prospective pharmacokinetic study to assess tacrolimus concentrations during a period of 24 h after ingestion of prolonged-release tacrolimus in the morning.0–24 and trough levels [Adult renal transplant patients with a stable graft function were eligible for enrolment if they used prolonged-release tacrolimus  of which the dose was not altered during the last visit to the outpatient clinic, and the two most recently measured trough levels were within the target range of 5–10 μg/L. Patients were excluded if they were unable to perform the home-based dried blood spot measurements of tacrolimus levels (see below) or if they had diarrhea (more than three stools per day) during the preceding 14 days, as we considered that diarrhea might affect the ratio between AUCh levels .The study was approved by the local ethics committee and conducted in accordance with the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual participants included in the study.A validated dried blood spot method for sampling and analysis of tacrolimus was used, which allowed participants to take their own blood samples at home . Accurac0). Subsequently, prolonged-release tacrolimus was taken and blood samples were collected at 1, 2, 4, 8, 12, and 24 h after the ingestion. On the day of the measurements, all participants took prolonged-release tacrolimus on an empty stomach and refrained from food intake until 2 h after its ingestion since it has been reported that the tacrolimus concentration profile can be influenced by meal consumption [Each pharmacokinetic profile started with measurement of the whole blood tacrolimus concentration at 24 h after the previous morning ingestion of prolonged-release tacrolimus and after overnight fasting , and time required to reach it (Tmax) were directly read from the pharmacokinetic curves. Elimination rate constant β was obtained by least squares linear regression analysis on logarithmic concentrations versus time post-dose, with the slope of the regression line being -β/2.303. Apparent clearance (Cl/F where F is bioavailability) was calculated by dividing dose by AUC0–24 and apparent volume of distribution (Vd/F) was obtained by dividing Cl/F by β.Pharmacokinetic parameters were assessed with noncompartmental methods using WinNonLin version 5.0 . The AUCTmax and daily tacrolimus dose were presented as median and range. The other data were shown as median with interquartile range. Correlations between numerical variables were calculated using the non-parametric Spearman’s rank correlation coefficient (rho).Loose concentrations and pharmacokinetic parameters were described with a geometric mean and 95 % confidence interval. 0–24. Models were constrained to include a maximum of three samples collected within 4 h after the intake to maintain clinical applicability for patients in the outpatient department. We also developed models with a maximum of three samples within 12 h after the intake since some patients execute home-based measurements by use of the dried blood spot technique. As they do not need to stay in the outpatient department for the measurements, the time span of the LSS is less relevant. We calculated the average adjusted r square for all subsets containing one, two, or three samples, and the model with the highest average r square was chosen.We carried out best subset selection multiple linear regression to derive limited sampling equations which predicted the AUCTo assess the predictive performances of the models, we calculated residuals for each patient based on models fitted to a dataset where that patient was omitted  . PotentiP values of below 0.05 were considered significant.All statistical analyses were performed with SPSS for Windows version 20.0  and R version 2.15.2. n = 1), and giving up informed consent (n = 3). All 26 participants had an isolated kidney transplantation and were of Caucasian ancestry. Other patient characteristics are shown in Table Of the thirty patients who were recruited for the study, 26 patients completed a full pharmacokinetic profile. Four exclusions were due to insufficient quality of the blood spots n = , and giv0 and 24-h post-dose trough level (C24) were 7.7 μg/L  and 8.3 μg/L (7.5–9.1), respectively. The geometric mean AUC0–24 of tacrolimus was 288 μg h/L (262–317). The mean ratio of AUC0–24 and C24 was 34.8 (33.2–36.5). The pharmacokinetics of prolonged-release tacrolimus are summarized in Supplementary Figure The median daily dose of prolonged-release tacrolimus was 4.0 mg range 1.5–10.0). The geometric mean C.5–10.0. 0–24. Relatively high adjusted r2 values, approaching 0.90, could already be reached with inclusion of only one sampling time, but r2 increased with the inclusion of two or three sampling times. The best performing limited sampling strategies for ambulatory patients in the outpatient department, based on one, two, or three time points within 4 h post-dose, are shown in Table 0–24. The adjusted r2 was 0.95 and MPPE and MAPE, measures for bias and precision of the prediction formulas, were 0.4 and 4.8 %, respectively. For patients who performed home-based measurements , an equation with sampling times at 2, 8, and 12 h post-dose revealed the best results. The adjusted r2 was 0.98 and MPPE and MAPE were 0.4 and 2.8 %, respectively (Table Various sampling time points and combinations of sampling time points were used to construct a regression model for the prediction of the AUCly Table .Table 2B24) to predict exposure to prolonged-release tacrolimus provided an adjusted r2 of 0.77 with AUC0–24. MPPE and MAPE of C24 were 6.2 and 7.2 %, respectively. The strongest correlation between a single measurement and AUC0–24 was found for C8 (adjusted r2 = 0.89) while MPPE and MAPE in this case were 1.2 and 5.2 %  on adjusted 0–24 of prolonged-release tacrolimus which are clinically applicable for ambulatory Caucasian renal transplant patients. These strategies enclose up to three sampling time points and provide an accurate and precise estimation of the AUC0–24.In this study, we developed equations to estimate AUC24) of prolonged-release tacrolimus is commonly used to establish whether exposure is adequate. The dose of prolonged-release tacrolimus is adjusted if C24 is outside the defined target range. According to most studies, there is a moderate to high correlation between trough level and exposure to prolonged-release tacrolimus [r2 of 0.77 in the current study confirms this correlation. However, concerns have been raised that this degree of correlation is not sufficient since correlation is not a good measure for predictive performance [0–24 based on trough levels was biased (yet precise). Interestingly, Scholten et al. showed that overexposure to tacrolimus in patients using the regular formulation was less frequent when dosing was based on AUC measurements as compared to trough levels only [In daily clinical practice, the trough level C4 of prolcrolimus , 20, 23.formance . It shouformance , 19. Criformance . Accordiels only . AlthougThe two main approaches for developing LSS are multiple linear regression and Bayesian analysis. They are equally valid but have different advantages and disadvantages . We prefIn our study, we did not prospectively validate our limited sampling formulas. Alternatively, we computed residuals for every patient in a model which fitted to a dataset where that patient was omitted. This analysis is a useful and appropriate approach if the sample size is small .Differences in pharmacokinetics of tacrolimus are partly explained by genetic polymorphisms of CYP3A5 . Moreove0–24 appeared higher (r2 0.95 versus 0.85) and precision appeared better (MAPE 4.8 versus 9.8 %) with our formula. Their LSS for home-based measurements contained 3 sampling time points at 0, 3, and 12 h post-dose, compared to 2, 8, and 12 h post-dose in our study. The correlation and predictive performances appeared comparable. The limited sampling strategies using the Bayesian forecasting method all enclosed sampling at 0, 1, and 3 h post-dose [One LSS using multiple linear regression and three limited sampling strategies by use of the Bayesian forecasting method have currently been published for prolonged-release tacrolimus in adult renal transplant patients , 14, 24.For this study, we used the innovative “dried blood spot” technique which has proven to be very reliable for determining tacrolimus levels . This teFinally, the AUC of tacrolimus is considered to be a better measure for exposure than the trough level . However0–24 of prolonged-release tacrolimus in ambulatory renal transplant patients. A LSS with samples obtained before the intake and at 3 and 12 h also showed a good predictive performance but it seems only suitable for patients who can execute the dried blood spot measurement at home.In conclusion, a LSS using samples collected before the intake and at 2 and 4 h post-dose can be applied for a very accurate and precise estimation of the AUCSupplementary Figure 1Tacrolimus concentration-time curve. Data are shown as geometric mean with 95 % confidence interval. (JPEG 215 kb)Supplementary Table 1(DOCX 11 kb)Supplementary Table 2(DOCX 11 kb)


The aim of this study was to determine the levels of leptin (Lep) and adiponectin (AdipoQ) in patients with gout and its relationship with joint inflammatory data and/or with metabolic syndrome (MetS) variables, during 1 year follow-up.U test, Fisher test, x2, ANOVA, Cochran Q, Pearson and Spearman correlation tests, as well as linear regression.Forty-one patients  with gout diagnosis, attending for the first time to a rheumatology department, were included. Evaluations were performed baseline, at 6 and 12 months. Variables included the following: demographic, clinical and laboratory data related to gout and associated diseases. Lep and AdipoQ determinations by the ELISA method were performed in frozen serum from each visit. The pharmacological and no-pharmacological treatment for gout and associated diseases was individualized for each patient according to published guidelines. Statistical analysis included Mann–Whitney P = 0.033]. Although not significant, also had higher Lep and lower AdipoQ levels . During follow-up, our patients had significant improvement in serum uric acid (sUA) levels and variables evaluating pain and joint swelling (P ≤ 0.05). Metabolic abnormalities tended to persist or even worsen during the monitoring period: significant increase in total cholesterol (P = 0.004), tendency to higher triglycerides (P = 0.883) and slight improvement in glycaemia (P = 0.052). Lep values increased significantly during follow-up (P = 0.001) while AdipoQ levels diminished slightly (P = 0.317). Neither Lep nor AdipoQ values showed important correlation (r > 0.5) with metabolic variables or joint swelling.In the baseline evaluation, 29.2% had MetS ; patients with MetS had higher C reactive protein (CRP) levels [34.1 ± 28.6 vs. 12.2 ± 11.2 mg/dL, This study suggests that in patients with gout, concentrations of Lep and AdipoQ are more in line with the metabolic state than with clinical disease activity. The sample size was no-probabilistic.This was a prospective cohort study (GRESGO (GRupo de EStudio de GOta) that includes patients with gout diagnosis (according to ACR and CGD criteria),The project was approved by the local ethics and research committees and in the baseline visit all patients signed an informed consent form.They were evaluated clinically by 1 of the participating rheumatologists  and received verbal and written information about gout and associated diseases.38The prescription in the baseline and subsequent visits included the following: lifestyle modifications: diet, exercise, and weight reduction, and pharmacological treatment including allopurinol or other urate-lowering drug (ULD), nonsteroidal antiinflammatory drugs (NSAID), steroids, colchicines, and treatment for associated diseases according to published recommendations for gout treatment.The visits were performed as frequent as the clinical status of each patient required, but all them attended at least to the baseline, 6 and 12 months visits. The evaluation included tender, swollen, and limited to motion joint count; the number of acute flares in the last 6 months, clinimetric evaluation .During the patient regular visit to the laboratory for biochemical determinations, 1 mL of serum was frozen at −70°C until adipocytokine determination. It was performed through indirect ELISA using a human anti-leptin antibody , human recombinant leptin , antiadiponectin antibodies , and human recombinant adiponectin (R&D Systems). All of the determinations were done in triplicate in the 3 evaluations and were reported as means and standard deviations.39 obesity (waist circumference ≥88 cm in women or ≥102 cm in men), dyslipidemia (high density lipoprotein-cholesterol (HDL-C) ≥40 mg/dL in men or ≥50 mg/dL in women, and triglycerides ≥150 mg/dL), hyperglycemia defined as fasting glucose ≥110 mg/dL or type 2 diabetes mellitus (DM2),40 hypertension (≥130/85 mm Hg or if under treatment). Mean arterial pressure (MBP) =  + systolic arterial pressure)/3.The presence of MetS and its associated entities was determined according to the criteria proposed by the Adult Treatment Panel III (ATP III):41 Chronic renal failure (CRF) was assumed when the GFR was ≤60 mL/min/1.73 m2.Glomerular filtration rate (GFR) was determined through a 24-hour creatinine clearance test and using the “modification of diet in renal disease” formula (MDRD) (GFR = 186 × (creatinine) − 1.154 × (age) − 0.203 or (× 0.742 in women)).U test, Fisher test, ANOVA with Bonferroni correction, and the χ2 tests were used to compare continuous and categorical variables in each group; we considered statistical significance level of 0.05 (both sides). The Cochran Q, Pearson and Spearman correlation tests as well as linear regression models were carried out: dependent variables: Lep o AdipoQ serum values adjusted by independent variables (forward process): metabolic variables , and variables related to inflammatory join disease activity . All statistical tests were performed using IBM SPSS Statistics 21.Demographic, clinical, and biochemical variables were reported with descriptive statistics: tendency and dispersion measures for continuous variables and proportions for dichotomous or nominal variables. The Mann–Whitney Forty-one patients with gout, mean age of 48.0 ± 12.9 years were included. Forty of them were males; 32 (78.1%) had tophaceous gout and in 80.5% of the patients we demonstrated monosodium urate crystals upon polarized light microscopy of the synovial fluid or tophi.At baseline, the mean duration of disease was 12.6 ± 10.5 years; however, none of them received adequate treatment and therefore had evidence of disease inflammatory activity (frequent acute flares in the 6 months before baseline visit and swollen and tender joints as well as an increase in acute phase reactants) and also chronicity data . Almost one third of the patients had MetS or its comprising entities, the most common of which was hypertriglyceridemia, followed by hypertension and obesity; a third of the patients had CRF , but only serum creatinine levels had a tendency to be significantly different Table .As expected, when comparing patients with MetS to those without it, the former had a greater frequency of hypertension, obesity, hyperglycemia, and dyslipidemia; however, we did not find significant differences in the related demographic or clinical variables related to gout or in the AdipoQ levels Table .We found significant improvement in the sUA values, MDRD, and in the variables evaluating joint pain and swelling at 6 and 12 months Figure .After 1 year of follow-up, only 10 patients (24.4%) had sUA levels ≤6.0 mg/dL; treatment was individualized but in general terms consisted of starting regular treatment with allopurinol at a low dose followed by a steady increase: (300 ± 189.8 mg/day at the baseline visit to 450 ± 206 mg/day at 12 months). Forty patients received allopurinol and only 1 patient received probenecid ; all patients received prophylaxis with colchicine (1 mg/day).During the follow-up, we did not find significant improvement in the associated metabolic entities, our patients showed increase in total cholesterol and tryglicerides, maintained their waist circumference and MBP, and had slight improvement in HDL-C and glycaemia Table . AlthougThe levels of adipocytokines, especially Lep, tended to increase both in the group of patients with MetS as well as overall, in the same way that metabolic abnormalities tended to persist or even worsen during follow-up Table .r > 0.5) between other metabolic variables and those measuring the activity of gout.After performing a linear correlation of the Leptin and AdipoQ values, there was no important correlation , his baseline Lep and AdipoQ serum levels were similar to the values from other patients.This study evaluated the possible relationship between improvement in clinical gout and/or metabolic data and the serum concentration of adipocytokines in patients in whom regular treatment was initiated.33During follow-up with regular treatment, the patients improved significantly in all the variables directly related to gout as joint inflammatory activity and in the sUA levels; although only one fourth of them achieved sUA ≤6.0 mg/dL. Similar to other studies, we did not find relation among the concentration of adipocytokines and sUA levels.45Lep values had relationship with obesity, MetS, and CRP, but not with gout-related variables and course during 6 and 12 months follow-up. These Lep and AdipoQ  values related to MetS course had been previously reported in patients with MetS, without gout.Interestingly CRP, a marker of systemic inflammatory state and considered a marker for joint “activity” as well as marker for metabolic and cardiovascular risk, tended to lower levels during follow-up in patients with gout associated with MetS, but not in patients without it.46Previous reports evaluating whether adipocytokines are protective or harmful in joint inflammatory diseases had been controversial. However, at the same time, some authors have reported that the presence of high levels of these adipocytokines must always be considered abnormal and may be associated with metabolic or inflammatory abnormalities; in addition, the diversity of cells containing receptors for these adipocytokines makes them scarcely specific and finally, their expression and functions seem to be different in different body tissues.Unfortunately, we were not capable of modifying most metabolic variables during 1 year of follow-up. The data are unsatisfactory because, excepting a tendency to lower glucose levels, the rest of the variables did not improve and there was even a significant increase in the total cholesterol levels; in addition, during follow-up we observed increase in the number of patients with low HDL-C values and MetS.47There are difficulties in compliance and adherence in patients with chronic diseases and especially in gout patients, in 1 study >80% of gout patients had partial and poor adherence to ULD therapy, the adherence to lifestyle modifications in them seems to be lesser, although not known.Probably, the sample size of this study, although adequate to evaluate clinical improvement, was not enough to evaluate minor changes in AdipoQ values. Finally, all the above results suggest that in patients with gout, the concentrations of Lep and AdipoQ are mainly related to the metabolic state and not the articular clinical activity itself.


Visit-to-visit variability (VVV) in blood pressure (BP) in addition to high BP has been shown to be a strong predictor of coronary events and stroke. Therefore, we investigated the associations between VVV in BP or BP levels and cardiovascular events after successful percutaneous coronary intervention (PCI).We enrolled 176 hypertensive patients who had undergone successful PCI and who had four clinic visits to measure BP until follow-up coronary angiography (CAG) at 6 - 9 months after PCI. The patients were divided into those with acute coronary syndrome  and those with stable angina pectoris . We determined VVV in BP expressed as the standard deviation (SD) of average BP, average, and the maximum and minimum BP during the follow-up period. Major adverse cardiovascular events (MACEs) , target lesion revascularization (TLR) and all-cause death) were also analyzed.There were no significant differences in VVV in BP, average BP or maximum or minimum BP between the patients with and without MACE in all patients, the ACS and SAP groups. Interestingly, in the ACS group, VVV in SBP and maximum SBP in patients with MI were significantly higher than those in patients without MI. The cut-off levels for VVV in BP and maximum SBP that gave the greatest sensitivity and specificity for MI in the ACS group were 15.1 and 138 mm Hg, respectively.Higher VVV in SBP and maximum SBP in patients with ACS after successful PCI were associated with the onset of MI. High blood pressure (BP) is a major risk factor for the onset and progression of cardiovascular disease (CVD) and stroke. Recently, visit-to-visit variability (VVV) in BP has also been shown to be a strong predictor of CVD, stroke and mortality independent of BP , althougAccording to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014), the target in BP control should be < 140/90 mm Hg . When paTo prevent the occurrence and progression of CVD, it may be important to manage both VVV in BP in addition to optimal BP in hypertensive patients with successful percutaneous coronary intervention (PCI), and we hypothesized that VVV in BP in hypertensive patients associates with major adverse cardiovascular events (MACEs) after PCI. Therefore, we investigated the associations between VVV in BP or BP levels and MACE after successful PCI.We enrolled 176 consecutive hypertensive patients who had undergone successful PCI and who had four clinic visits to measure BP until follow-up coronary angiography (CAG) at 6 - 9 months after PCI. The patients were divided into those with acute coronary syndrome  and those with stable angina pectoris . Our protocol was approved by the Ethics Committee of Fukuoka University Hospital (IRB #14-12-06). We retrospectively collected and analyzed all data using the database of Fukuoka University Hospital.CAG and PCI were performed according to the Judkins technique by the patients’ interventional cardiologists . CoronarMACEs , target lesion revascularization (TLR) and all-cause death) were analyzed throughout the follow-up period. For a diagnosis of MI, the patient had to have shown both evidence of ischemic electrocardiogram changes and elevation of cardiac enzymes. TLR was performed if the lesion had significant luminal stenosis (> 50% diameter stenosis) in the presence of angina symptoms and/or proven myocardial ischemia in the target vessel, or in follow-up CAG. All-cause death was identified during the follow-up period.In all subjects, we measured systolic BP (SBP), diastolic BP (DBP), and serum levels of triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), estimated glomerular filtration rate (eGFR), uric acid (UA), and hemoglobin A1c (HbA1c). All blood samples were drawn in the morning after the patients had fasted overnight. Laboratory data were determined using enzymatic methods. BP was determined as the mean of two measurements obtained in an office setting by the conventional cuff method using a mercury sphygmomanometer.2 (m2). Medications included angiotensin II receptor blocker (ARB)/angiotensin converting enzyme inhibitor (ACE-I), calcium channel blocker (CCB), β-blocker, diuretics, statin, nitrate, nicorandil, oral hypoglycemic agent (OHA) and insulin. With regard to the use of antiplatelets, aspirin and ticlopidine or clopidogrel were generally administered. The patient characteristics, including the history of hypertension (HTN), dyslipidemia (DL), diabetes mellitus (DM) and smoking (current and past smokers), were obtained from medical records. Patients who had a current SBP/DBP ≥ 140/90 mm Hg or who were receiving antihypertensive therapy were considered to have HTN. Patients with LDL-C ≥ 140 mg/dL and/or TG ≥ 150 mg/dL or HDL-C < 40 mg/dL, or who were receiving lipid-lowering therapy were defined as DL. DM was defined using the Japanese Diabetes Society criteria.Data on weight, height and medication use were collected. Body mass index (BMI) was calculated as weight (kg)/heightWe used the data from four clinic visits during the follow-up period and determined VVV in BP expressed as a standard deviation (SD) of average BP, average BP, and maximum and minimum BP.t test. A receiver-operating characteristic (ROC) curve analysis was used to determine the cut-off values of VVV in SBP and maximum SBP to distinguish between patients with and without MI in the ACS group at the highest possible sensitivity and specificity. A value of P < 0.05 was considered significant.Statistical analysis was performed using SAS 9.3 (SAS Institute Inc.). Data are shown as the mean ± SD. Categorical variables were compared between the groups by a Chi-square analysis. The significance of differences between mean values was evaluated by an unpaired The patient characteristics at baseline in all patients and the ACS and SAP groups are shown in Various BP parameters in all patients and the ACS and SAP groups during the follow-up period are shown in Next, An ROC curve analysis showed a higher area under the curve for a relative difference in VVV in SBP (0.83) and maximum SBP (0.83). The cut-off levels for VVV in SBP and maximum SBP that gave the greatest sensitivity and specificity for the presence of coronary thrombosis were 15.1 mm Hg  and 138 mm Hg , respectively.In this study, we investigated the association between VVV in BP and MACE in hypertensive patients after successful PCI. The most important finding was that higher VVV in SBP and maximum SBP after successful PCI due to ACS were associated with the onset of MI. On the other hand, MACE was not associated with VVV in BP, average BP or maximum or minimum BP during the follow-up period.We found that higher VVV in SBP and maximum SBP after successful PCI due to ACS may be predictors for the onset of MI. In addition, other BP parameters, including VVV in DBP, mean BP and minimum BP, were not associated with MI. Higher VVV enhances periodic pressure overload and shear stress on the CV system and contributes to the progression of atherosclerosis . DisturbVVV in SBP has been investigated more often than VVV in DBP. However, both were associated with adverse outcomes in a meta-analysis . AlthougThe number of visits, the time interval between visits, and the BP measurement protocols have varied widely across studies . It has MACE was not associated with BP parameters including VVV in BP in this study, although previous reports have indicated that VVV in BP was a strong predictor of CVD, stroke and mortality . MACE ocThere are several study limitations. First, the study included a relatively small number of patients. Second, the analysis was performed after various anti-hypertensive treatments, although there were no significant differences in the VVV in SBP and maximum SBP between patients with and without various medications (data not shown). Although aspirin and ticlopidine or clopidogrel were essentially administered with regard to the use of antiplatelets, some patients received warfarin. Third, we did not perform a logistic regression analysis due to the low percentages of MACE and MI. Prospective studies are needed to clarify these limitations.In conclusion, higher VVV in SBP and maximum SBP in hypertensive patients with ACS were associated with the onset of MI after successful PCI.


Hypertension is a complex chronic condition characterized by elevated arterial blood pressure. Management of hypertension includes non-pharmacologic strategies, which may include techniques that effectively reduce autonomic sympathetic activity. Respiratory exercises improve autonomic control over cardiovascular system and attenuate muscle metaboreflex. Because of these effects, respiratory exercises may be useful to lower blood pressure in subjects with hypertension.This randomized, double-blind clinical trial will test the efficacy of inspiratory muscle training in reducing blood pressure in adults with essential hypertension. Subjects are randomly allocated to intervention or control groups. Intervention consists of inspiratory muscle training loaded with 40 % of maximum inspiratory pressure, readjusted weekly. Control sham intervention consists of unloaded exercises. Systolic and diastolic blood pressures are co-primary endpoint measures assessed with 24 h ambulatory blood pressure monitoring. Secondary outcome measures include cardiovascular autonomic control, inspiratory muscle metaboreflex, cardiopulmonary capacity, and inspiratory muscle strength and endurance.Previously published work suggests that inspiratory muscle training reduces blood pressure in persons with hypertension, but the effectiveness of this intervention is yet to be established. We propose an adequately sized randomized clinical trial to test this hypothesis rigorously. If an effect is found, this study will allow for the investigation of putative mechanisms to mediate this effect, including autonomic cardiovascular control and metaboreflex.NCT02275377. Registered on 30 September 2014.ClinicalTrials.gov The online version of this article (doi:10.1186/s13063-016-1514-y) contains supplementary material, which is available to authorized users. Essential hypertension is a multifactorial disease characterized by chronically elevated systolic blood pressure ≥140 mmHg) or diastolic blood pressure (≥90 mmHg) 40 mmHg o, 4. The The autonomic nervous system is a major determinant of systemic blood pressure and it might be a therapeutic target in hypertension , 7. HypeRespiratory exercises are a non-pharmacologic intervention that might modulate autonomic nervous system activity and reduce blood pressure , 13. An This study aims to test the efficacy of inspiratory muscle training in reducing blood pressure in subjects with essential hypertension. It will further investigate the effects of this intervention on inspiratory metaboreflex – a putative mechanism for blood pressure reduction. The conceptual hypothesis is that inspiratory muscle training reduces mean 24 h blood pressure through modulation of sympathetic nervous system activity and muscle metaboreflex.This is a double-blind, parallel-group, sham-controlled randomized clinical trial. Participants are randomly assigned to receive inspiratory muscle training with a load equivalent to 40 % of maximum inspiratory pressure or inspiratory muscle training sham (no load) for 8 weeks. The study flowchart is depicted in Fig. Participants will be recruited from patients receiving follow-up care at the hypertension clinic or the primary health care center at the Hospital de Clínicas de Porto Alegre, a tertiary, university-affiliated teaching hospital. Public announcements  will also call for volunteers among residents of the city of Porto Alegre.2 [The study includes both male and female subjects, aged ≥35 and <65 years, previously diagnosed with essential hypertension, with a systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg. Subjects receiving no pharmacologic therapy or taking only a thiazide diuretic are eligible to enter the study. Participants must have body mass index <30 kg/m2 , practic2 , 18, and2 .Participants are excluded from the study if they have: office blood pressure ≥160/100 mmHg; severe dyspnea; diabetes mellitus; orthopedic, musculoskeletal, or neurologic limitations; significant cognitive impairment; a current or past history of deep venous thrombosis; a history of myocardial infarction or stroke in the previous 6 months; congestive heart failure; unstable angina; or pulmonary disease of any etiology (including asthma and chronic obstructive pulmonary disease); or if they are active smokers. Women who are pregnant or breastfeeding are excluded from this study. Subjects are not eligible if they participated in another clinical trial in the previous 30 days, or if there is any other condition that might impair their ability to participate in the study or follow the protocol, at the discretion of the recruiter.Participants are also directed not to change pharmacologic or non-pharmacologic treatment for hypertension  during their participation in this study.The co-primary outcomes measures are changes from baseline to end of study in mean 24 h systolic and diastolic blood pressure, as evaluated by ambulatory blood pressure monitoring.Secondary outcome measures are changes from baseline to end of study in mean daytime systolic and diastolic blood pressure; changes from baseline to end of study in mean nighttime systolic and diastolic blood pressure; heart rate variability; systolic blood pressure variability; aerobic capacity; inspiratory metaboreflex; and autonomic control.A randomization sequence has been generated using Randomization.org in blocks of four to either group 1 – inspiratory muscle training with 40 % of maximal inspiratory pressure – or group 2 – sham inspiratory muscle training. An independent person not involved in this study possesses the computer-generated randomization sequence. A research assistant not involved in participant assessment obtains the code and sets the load in each device, according to randomization. A black tape hides the loading spring from the participant and from the investigators assessing outcomes.There are no foreseen circumstances when un-blinding is permissible. When data collection is completed, the person responsible for the randomization list will provide assignment information to the investigators. Patient’s forms and other data sources are kept in a locked cabinet. Data are anonymized when entered into the database to protect confidentiality. Only investigators formally associated with the project will have access to the final study database.2 and CO2 expiration fraction in a metabolic system. Maximum oxygen consumption in each breath is recorded in ml/(Kg/min) [Participants are assessed as described in Additional file (Kg/min) , 24.Maximum inspiratory and maximum expiratory pressure serve as indicators of inspiratory and expiratory muscle strength, respectively. Maximum inspiratory and maximum expiratory pressure are assessed using a digital pressure manometer  , 26.Inspiratory muscle endurance is determined using the incremental test proposed by Martyn et al.  using thBlood pressure variability, heart rate variability, and the cardiac vagal tone are assessed to evaluate autonomic cardiovascular control. Non-invasive continuous blood pressure curves, heart rate, and electrocardiogram tracing are obtained simultaneously at a frequency of 1000 Hz using a Biopac MP150 . Data are registered in a computer with biologic signal conversion capabilities.The muscle metaboreflex is the adaptive blood flow redistribution from the peripheral circulation into the vascular bed of metabolically active (exercised) muscles . The metParticipants are extensively instructed on how to perform home-based inspiratory muscle training assisted by a Power Breathe Plus®  device. For participants’ safety, research staff are responsible for device hygiene before and after the intervention period. To perform the exercise training, subjects should be seated, obstruct the nose with a nasal clip, and breathe in and out through the mouthpiece. The goal is to keep diaphragmatic breathing at 10–15 respirations per minute for a total of 30 min per day, 7 days a week.Participants receiving active inspiratory muscle training (intervention group) perform the exercises with a load equivalent to 40 % of maximal inspiratory pressure. Those receiving the sham intervention (the control group) follow the same instructions but have no load applied to the respiratory exercises. The sham intervention was chosen as comparator because it is the most similar intervention available. It allows for blinding of investigators and participants, and is not expected to reproduce the effects of loaded exercises.The complete study protocol consists of 56 daily training sessions completed over 8 weeks. During the scheduled weekly visit to the study center, participants are questioned about possible discomforts associated with the intervention, which may include: headaches, nausea, intense muscle fatigue, muscle cramps, and chest pain. Respiratory muscle strength is then reassessed; inspiratory threshold loading is adjusted accordingly, keeping a 40 % maximum inspiratory load for the intervention group throughout the study. The staff member who receives information about treatment allocation and adjusts the load neither participates in any assessments nor communicates with participants.Participants in both groups receive a journal to register date, time, duration of training session, and possible symptoms or discomforts associated to the intervention. This serves as a mean to stimulate and estimate adherence to intervention. Adherence to the protocol is also reinforced on weekly follow-up phone calls.Sample size was estimated based on a small randomized clinical trial on the effect of inspiratory muscle training on blood pressure of hypertensive subjects in Brazil . That stt test or the Mann–Whitney U test, depending on variable distribution. As a superiority trial, differences in autonomic cardiovascular control and metaboreflex between groups will be tested with two-sided repeated-measures ANOVA. Results will be analyzed as per intention-to-treat. Participants who drop out and do not complete outcome assessment will be compared with those who completed the protocol but their data will be excluded from analysis. Statistical significance will be considered for P < 0.05. All analyses will be performed using PASW Statistics 18® .Data recorded in printed forms are kept in locked cabinets. Information is entered on Microsoft Excel spreadsheets by one person and reviewed by another. Numeric continuous variables, including blood pressure in the primary outcome measures, will be described as mean ± standard deviation or as median (interquartile range). Comparison between groups will be performed using Student’s A summary of the main findings in non-technical language will be sent to participants after study completion. Scientific papers written according to the CONSORT recommendations will be submitted for peer-reviewed publication. Study results will also be communicated as abstracts and presentations in local, national, and international scientific meetings.The effect of inspiratory muscle training on blood pressure in hypertensive individuals is not yet established. A significant reduction in blood pressure was observed in a small randomized clinical trial with six and five subject allocated to intervention and control groups, respectively . AlthougThe evaluation of inspiratory muscle metaboreflex is one of the strengths of this study. Inspiratory muscle training attenuated the metaboreflex in healthy subjects  and in pThe effects of inspiratory muscle training deserve to be better understood given the potential to help control blood pressure in hypertensive patients. The results of this study will provide evidence on the effects of inspiratory muscle training on blood pressure, in addition to inspiratory muscle metaboreflex, autonomic cardiovascular control, and other physiologic and metabolic aspects. These data will provide mechanistic insights, as well as useful clinical information for the management of hypertension.The trial is enrolling participants.ANOVA, analysis of variance; CONSORT, Consolidated Standards of Reporting TrialsAdditional file 1:Figure S1. Schedule of enrollment, intervention, and assessments. Figure S2. Inspiratory muscle metaboreflex induction protocol flowchart. (DOCX 362 kb)Supplementary material. Methods for assessment of study outcomes and other variables.


Since the association of serum uric acid and kidney transplant graft outcome remains disputable, we sought to evaluate the predictive value of uric acid level for graft survival/function and the factors could affect uric acid as time varies. A consecutive cohort of five hundred and seventy three recipients transplanted during January 2008 to December 2011 were recruited. Data and laboratory values of our interest were collected at 1, 3, 6, 12, 24 and 36 months post-transplant for analysis. Cox proportional hazard model, and multiple regression equation were built to adjust for the possible confounding variables and meet our goals as appropriate. The current cohort study lasts for 41.86 ± 15.49 months. Uric acid level is proven to be negatively associated with eGFR at different time point after adjustment for age, body mass index and male gender .Males with low eGFR but high level of TG were on CSA, diuretics and RAS inhibitors and experienced at least one episode of acute rejection and diabetic issue were associated with a higher mean uric acid level. Hyperuricemia was significantly an independent predictor of pure graft failure  after adjustment. But it was no longer an independent risk factor for graft loss after adjustment. Interestingly, higher triglyceride level can make incidence of graft loss  and death  more likely. The results of our study suggest that post-transplant elevated serum uric acid level is an independent predictor of long-term graft survival and graft function. Together with the high TG level impact on poor outcomes, further investigations for therapeutic effect are needed. For post-transplant recipients, the outcomes and mortality of kidney were the most critical problems. Unlike short-term outcome, the long-term graft/patient survival has not significantly been improved by advanced immunosuppressant. Therefore endeavors to develop effective means that could improve long-term outcomes directly or indirectly are needed s of graft loss after transplantation, in which, the leading cause of death with functioning graft is cardiovascular event(CV)[Chronic allograft nephropathy (CAN), also known as sclerosing allograft nephropathy, is the leading cause of kidney transplant failure and happevent(CV), 4. Giveevent(CV). And an At cellular and molecular level, uric acid and hyperuricemia play a role in progression of CV event and renal disease. UA induces endothelial cell dysfunction–9 and deIn epidemiological studies, independent associations between hyperuricemia and myocardial infarction, ischemic stroke CV events and CV mortality are solid–21. PredIn experimental models, mild hyperuricemia causes glomerular hypertension and blood pressure-independent small vessel disease in the kidney and promotes progression of renal disease in remnant kidney model, 29–31. Practically, the prevalence of hyperuricemia in transplant recipients is relatively common . Enough This is a retrospective cohort study of consecutive renal allograft recipients transplanted at the Urology/Transplant center of the First Hospital of Jilin University between January 2008 and December 2011. Before surgery, Patients had undergone an extensive medical evaluation for patients’ general status, comorbidity and corresponding immunocompatibility tests. Specifically, recipients with a negative lymphocytotoxicity test result, PRA<10%, and at least one HLA match are of suitability for transplantation in our center. Donor sources were either from living-related donors or DCD (donation after cardiac death) donors involved in Urology/Transplant center of the First Hospital of Jilin University.The study period (2008–2011) was chosen to provide a reasonable sample size and an at-least 3 years follow-up data after transplantation. All recipients were eligible for this analysis, in order to maintain consistency and continuity of this cohort. Corresponding serum creatinine (SCr) levels were used to estimated glomerular filtration rate (eGFR) during the same period with a new equation , 35 fit Red Cross Society of China Human Organ Donation Volunteers Registration Form . Basiliximab  was administrated 20 mg on the operation day and post-surgery day 4, and Daclizumab , which was dosed 1mg/kg on the operation will be secondly dosed on post-operative day 14. ATG  was given at 2.5 mg/kg/day for 5–7 days starting intraoperatively. All recipients received methylprednisolone 500 mg IV per day intraoperatively, followed by the same dose on the next two subsequent days after surgery, with tapering to oral prednisone at 120 mg on post-transplant day 3 when IV methylprednisolone was done. And the oral prednisone would be reduced 20 mg/d until the current dosage was 20 mg. Prednisone was further tapered, achieving 10 mg/d by 6 months. Mycophenolate mofetil  was initiated on the next day of surgery by patients’ body weight , and dose adjustments were made for gastrointestinal intolerance and bone marrow suppression. Tacrolimus (TAC) or Cyclosporin (CSA) was added to the regimen when the SCr was at or less than 4.0 mg/dl  and adjusted by monitoring its plasma concentration and patients’ renal/hepatic function.Patients were followed up according to the recommended guidelines which indicated that all organ receivers should be returning back at the follow-up house for blood routine test; hepatic/renal function; metabolic status and immunosuppression serum concentration/AUC (area under curve). Once suspicious symptoms and signs or unexplained increase in SCr and proteinuria during follow-up period was investigated, further allograft ultrasound, Lung CT scan and graft biopsy would be made to confirm acute rejection (AR) or infection. Biopsies were evaluated using Banff ‘97 criteria for evidence of acute rejection. Patients with delayed graft function (DGF) defined as the need for dialysis in the first week post-transplant.The primary outcome of this analysis was the attempt to testify the predictive value of UA level and the possible factors that might influence UA level. The secondary outcome of our study was graft survival and its correlation with hyperuricemia and UA level. Graft loss was defined as graft failure  or death with functioning graft. Pure graft failure and death with functioning kidney were considered to be split outcomes of graft loss for further analysis.Data are presented as mean ± SD or n (%), as appropriate. The groups were compared using Student’s t test, chi-square or Fisher’s exact test, when needed. Survival analysis methods including Kaplan-Meier and Cox Proportional Hazard Model were used to evaluate the independent association of UA level measured at multiple time points with graft survival after adjustment for other time-dependent and independent potential covariates. To examine the independent association between UA level and eGFR, linear regression modeling was used with adjustment for potential confounding variables, including the corresponding mean eGFR. Also, logistic regression was used to model the odds ratios (OR) for hyperuricemia. Regression model assumptions were tested with proper statistical diagnostics. To check for collinearity, variance inflation factors were calculated for the predictor variables. SPSS 19.0  and GraphPad Prism  were used for statistical analysis and figure layout.There were 573 kidney transplant recipients followed up for 41.86 ± 15.49 months are included in this cohort study. Overall, 155 patients (27.1%) were hyperuricemic and the rest 418 patients (73.0%) had normal UA level. Demographic characteristics and laboratory findings of the recruited patients are summarized in We included 333 donors in total, 240 (72.1%) DCD donors and 93 (27.9%) living-related donors separately. The most common cause of DCD donor’s death is car accident . Subsequent causes of death are cerebrovascular accident , cardiovascular accident  and brain tumor . The donors conformed to the organ quality certification in general. See Time-varying values UA, Hyperurecimia percentage, eGFR, Cyclosporine plasma concentrations , tacrolimus plasma concentrations, MMF and prednisone doses, use of RAS (renin—angiotensin System) inhibitor and diuretics at different time points post-transplant are summarized in 2 = 0.03; 6-month uric acid with 3-year eGFR r2 = 0.01). Besides, 6-month post-transplant is getting away from the definition “early”. So we only recorded single-factor analysis between 1-month and 3-month UA level and eGFR. Considering eGFR would be affected by many factors including UA level, we further built up several regression equations to predict different time point eGFRs. The results are illustrated in To examine the predictive value of UA level, we evaluated the mean eGFR levels calculated from SCr at multiple times post-transplant and UA levels obtained at 1-month, 3-month and 6-month respectively after surgery. As demonstrated in Acknowledging the predictive value of UA level, we then started to evaluate UA and its predictors. Serum UA was significantly relevant to age, male gender, DM comorbidity, cyclosporin use, RAS inhibitor use, diuretic use, TG level, rejection episode and, of course, eGFR. After adjustment for these variables, males with low eGFR but high level of TG who were on CSA, diuretics and RAS inhibitors and experienced at least one episode of acute rejection and diabetic issue were associated with a higher mean uric acid levels. When tested for odds ratio, low eGFR,medication prescription on CSA, diuretics and RAS inhibitors remained contributors to hyperuricemia (dichotomous form). More detailed results are displayed on Early post-transplant outcome is also our concern when we initiated this proposition. Because the early post-transplant outcomes may determine the long-term outcomes. Therefore we need to distinguish different long-term prognosis groups as shown on To estimate the impact of UA level and hyperuricemia on long-term transplant outcomes, Cox proportional hazard model was used to adjust for confounding factors. In accordance with our expectation, hyperuricemia was found to be a significant predictor for graft loss  during the study period was found to be an independent factor for graft loss. For pure graft failure outcome, covariates in Cox model with significance were rejection episode , introduction use  and hyperuricemia as mentioned previously. So were the results when UA was treated as a continuous variable (data not shown). Significant cause of death in both survival analysis with UA level and hyperuricemia, age , male gender , BMI , infection episode  and intriguing, meanwhile, unexpectedly TG level .We observed that 3-month eGFR was statistically confined by UA level, gender, age and BMI collected at 1-monthpost-transplant. And the variables in the regression equations for medium-long renal function were different in number at different time points. One possible explanation: early stage of recovery from long-term dialysis and allograft compatibility issue could switch body metabolism pathway, therefore, more factors undergoing transform at early stage post-transplant might impact eGFR and more stabilized diet and lifestyle came along with less influencing factors. As previous reports , 38, obeWith controversial results, reports in the literature that focus on UA level on graft function/survival of renal transplantation are limited. Opposite to our observation, some investigators claim that UA level is generally irrelevant to renal function or allograft survival. Akgul et al.  did not 2. Haririan et al. [On the contrary, Akalin et al.  investign et al.  publishen et al. . They enn et al. compositeThe major advantage is that we did a relatively overall analysis with a reasonable sample size in the literature. Moreover, the hyperuricemia definition was designed for long-time exposure for transplanted kidney which is more convincing that the hazard factor influenced the recipient the whole time since operation. Additionally, we always compare UA, as a continuous variable and hyperuricemia, as a categorical variable with the outcomes of our interest to decline statistical bias. Another distinguishing aspect is that we introduced infection episode and rejection episode in our survival analysis. Though these two elements are known risk factors for poor outcomes, we still acquired the independent association between hyperuricemia and poor outcomes after adjusting these major risk factors, which intensifies our result. Interestingly, higher TG level, according to our results, is correlated with death and graft loss which contradicts the results of Gerhardt et al. .The findings of our study should be interpreted with cautiousness. Because of its retrospective design, residual confounding cannot be excluded. Despite these limitations, this study has notable strengths and unique characteristics as detailed above.In summary, we observed a significant association between serum UA level and poor outcomes after adjustment for confounders including infection and rejection episode. And early-stage post-transplant UA level can act as a predictor for renal function at multiple time points after transplant. Also, hypertriglyceride could lead to poor outcomes. Our findings bring up a question whether hyperuricemia management can be treated as a way to improve long-term prognosis of renal transplantation. And it may suggest that syndrome X leads to bad prognosis of renal transplantation. Further investigation are needed to examine if treatment for hyperuricemia, or maybe expand to syndrome X, could improve the outcome.S1 FileThe original form is provided by the Red Cross Society of China. The Red Cross Society coordinator will have a patient conversation with the potential donor’s immediate family about human organ donation with this file when unfortunate accident occurs. We translated it into English version.(DOCX)Click here for additional data file.S2 FileWe made this consent form (Chinese and English version) to not only inform the living-related donor the risks he/she may confront but also rights and obligations of both sides of health care.(DOCX)Click here for additional data file.


The associations between visit-to-visit blood pressure (BP) variability and cardiac function and carotid atherosclerosis is not clear.Study subjects were 144 subjects  who underwent echocardiography and cervical ultrasonography. The ratio of early ventricular filling velocity to early diastolic mitral annular velocity (E/e’), ejection fraction, left ventricular mass index (LVMI), and maximum intima-media thickness (max-IMT) of the carotid artery were compared between the highest (high variability) and lowest (low variability) tertiles of the standard deviation of systolic BP (9.9 ± 3.5 mmHg).E/e’ and max-IMT were significantly greater in the high variability group than in the low variability group after adjusting for age, sex, baseline systolic BP, and other covariates  = 1.82, 95% confidence interval 0.06–3.58; max-IMT: 1.65 ± 0.43 mm vs. 1.42 ± 0.46 mm, β = 0.20 mm, 95% confidence interval 0.03–0.36 mm). There were no significant differences in LVMI or ejection fraction.These results indicate that high visit-to-visit BP variability is associated with diastolic function and carotid atherosclerosis, and is a possible risk factor for diastolic dysfunction and atherosclerosis. Blood pressure (BP) variability is now considered to be an important risk factor for cardiovascular diseases (CVD) . Visit-tThis study was performed in 144 consecutive subjects  who underwent echocardiography and cervical ultrasonography at the same time between September 2011 and August 2013 at Okada Medical Clinic in Nagoya, Japan. These data were collected during routine care and were extracted from medical charts, thus the patients for the examinations were not randomly collected for this study. The study subjects were; 15 with the history of coronary heart diseases, 10 with the history of stroke, 42 with diabetes, 118 with hypertension, and 46 with hyperlipidemia. Systolic and diastolic BP, heart rate, height, and weight at the time of echocardiography were used as baseline variables. Blood samples were also taken in the morning after an 8-h overnight fast to measure laboratory variables. Fasting plasma glucose, hemoglobin A1c, and serum low-density lipoprotein cholesterol, uric acid and creatinine were measured using standard laboratory techniques, and the estimated glomerular filtration rate was calculated as previously described [We retrospectively reviewed the subjects’ medical records to retrieve BP values recorded over 1 year before the echocardiographic examination. BP was measured in an outpatient clinic every 1 to 3 months using the conventional cuff method using the standard protocol of BP measurement by the Japanese Society of Cardiovascular Disease Prevention. BP variability was retrospectively assessed. The standard deviation (SD) of systolic BP from 4 to 13 BP measurements was used as an index of BP variability, as reported in earlier studies , 9–11. SEchocardiographic examinations were performed by a single sonographer who assessed cardiac structural changes and cardiac function. Two-dimensional (2D) echocardiography and M-mode echocardiography were performed using high-resolution ultrasound . Left ventricular (LV) diastolic function was assessed by transmittal pulse-wave Doppler to measure mitral inflow early (E) and late (A) diastolic filling velocities, E/A ratio, and tissue Doppler imaging parameters, including the early diastolic mitral annular velocity (e’), which was measured on the lateral side of mitral annulus. The E/e’ ratio was measured as an index of LV filling pressure. Diastolic dysfunction was defined as E/e’ ≥15 . The lefArterial stiffness was assessed by measuring the carotid intima-media thickness (IMT) just after echocardiography by high-resolution ultrasound, as described above, with a 7.5-MHz linear array transducer. The maximum IMT (max-IMT) was defined as the single thickest wall of the near and far right or left walls of the common carotid artery, bulbus, and internal carotid artery, including plaques, as a marker of carotid atherosclerosis .Clinical, echocardiography, and cervical ultrasonography variables were compared among the tertile groups of BP variability using analysis of variance for continuous variables or χ2 tests for dichotomous variables. Variables that showed statistically significant differences among the three groups were then included in multivariate analyses. β coefficients (the differences between the highest or middle tertile and the lowest tertile) and 95% confidence intervals (CI) were calculated for each variable by linear regression with adjustment for age (continuous), sex, baseline systolic BP (continuous), use of antihypertensive drugs, and history of CVD. Odds ratios and 95% CIs were calculated for the prevalence of diastolic dysfunction and carotid atherosclerosis by unconditional logistic regression with adjustment for the same covariates. Values of P < 0.05 in adjusted models were considered statistically significant. All analyses were performed using STATA software version 9 .BP was measured for 9.5 ± 2.9 times during one year (range 4 to 13 times), and mean systolic BP was 130 ± 10 mmHg; the lowest tertile (SD <8.29 mmHg), the middle tertile (SD 8.29-10.99 mmHg), and the highest tertile (SD >10.99 mmHg). The clinical, echocardiography, and cervical ultrasonography variables for the study subjects are summarized by BP variability level in Tables Because E/e’ and max-IMT were significantly different between the BP variability groups (P <0.05 by Tukey method), multivariate analyses were performed to examine the associations between BP variability and E/e’ and max-IMT. Both E/e’ and max-IMT were significantly greater in the high BP variability group than in the low BP variability group also in the multivariate models  = 1.82, 95% CI 0.06–3.58 for high BP variability and β = 0.92, 95% CI −0.44–2.29 for middle BP variability; max-IMT 1.65 ± 0.43 mm, 1.36 ± 0.37 mm vs. 1.42 ± 0.46 mm, β = 0.20 mm, 95% CI 0.03–0.36 mm for high BP variability and β = −0.02 mm, 95% CI −0.17–0.13 mm for middle BP variability).Additionally, the prevalence rates of diastolic dysfunction and carotid atherosclerosis were greater in the high BP variability group than in the low BP variability group. The risk of carotid atherosclerosis was significantly greater in the high BP variability group compared with the low variability group  in the multivariate model. Also, the risk of diastolic dysfunction was greater in the high BP variability group compared with the low variability group although it was not statistically significant after adjustment  (Table To the best of our knowledge, this was the first study to reveal that greater visit-to-visit BP variability is significantly associated with both decreased diastolic function and carotid atherosclerosis independently of mean BP. These findings may provide new insights into the mechanism underlying the relationship between visit-to-visit BP variability and CVD.Recent data suggest that BP variability is a strong prognostic factor for stroke, coronary heart disease, and all-cause mortality –4. ThereThis study showed that visit-to-visit BP variability was associated with carotid IMT. Carotid IMT is a well-established marker of subclinical atherosclerosis, and it is strongly associated with the risk of future CVD events including coronary heart disease and stroke . Recent Diastolic dysfunction is believed to be the main cause of heart failure with preserved ejection fraction . PreviouThe LVMI was greater in subjects with higher BP variability, which was consistent with the former study , althougSeveral limitations of this study should be mentioned. First, because of the relatively small number of subjects, we could not perform analyses after stratifying the subjects according to their age or the presence of hypertension. Most of the prior studies that showed associations between BP variability and diastolic function or IMT were performed in elderly subjects with hypertension , 7, and Visit-to-visit BP variability recorded over 1 year was associated with cardiac diastolic function and carotid atherosclerosis. In addition to other well-defined risk factors, we suggest that visit-to-visit BP variability is considered as a marker for the development of diastolic dysfunction and atherosclerosis. Measurements of cardiac function and carotid atherosclerosis may be warranted in subjects with high BP variability.


Background: Due to the loss of autonomic nervous system, precise control of the hemodynamic status in dead brain potential donors presents a clinical dilemma. In these patients, due to head trauma and cerebral edema, fluids administration is restricted. Moreover, the decreased central venous pressure may put the viability of the organs at risk.Objective: To investigate hemodynamic factors affecting the suitability of the donated heart and kidney for transplantation.Methods: Data were retrospectively collected from the maintained databases of all dead-brain donors (DBDs) admitted to our organ procurement unit (OPU) ICU between 1999 and 2008. In this study, laboratory variables in addition to demographic data were collected. The time between donor entrance to the DBD ICU and organ procurement, vital signs, hourly urine output, amount of IV fluid administered, and the dosage of vasopressor and desmopressin were recorded. The end-point of the study was organ suitability for organ retrieval. Results: A total of 132 dead brain donors were studied. The mean±SD age of the donors was 26.3±12.2 years. The main cause of brain death was multiple trauma (53%). The organ retrieval rate was 82.6% for the kidney, 59.8% for the liver, and 53% for the heart. 83 (63%) and 106 (80.3%) donors had suitable hearts and kidneys, respectively. 66 cases did not receive desmopressin (50.4%) at all. The mean±SD dose of desmopressin the donors received was 7±1 µg. There was a significant association between the suitability of these two organs for transplantation and the dosage of the administered desmopressin and volume of IV solution the donors received.Conclusion: Fluid therapy and administration of desmopressin can improve the number and quality of retrieved organs from dead brain donors. The demand for donor organs is increasing continuously. Iran is among the countries that try to increase the rate of dead-brain donors (DBDs). However, a potential DBD should be transferred to the ICU of organ procurement units (OPUs) by the coordinating team, for lack of technical expertise and human resources for managing the donor’s medical conditions. Brain death is associated with immunological and endothelial activation, cytokine and catecholamine storm which may provoke delayed graft function. The main responsibility of the management team is to maintain the arterial blood pressure and hemodynamic status of the donor to preserve as many organs as possible for retrieval. The balance between the least dose of vasopressors and optimal amount of volume therapy needs effective supervision and although there are various guidelines, the rate of hemodynamic and metabolic abnormalities in DBDs is still high. This issue is much more important when the management is separated in two ICUs of the hospital of origin and referral OPU -3.Hemodynamic control in DBD is a serious clinical challenge not only due to the donor’s physiologic situations but also because of the involvement of a high number of specialties in decision making. The usual practice in patients with multiple trauma, before declaration of the brain death, is to restrict free fluid administration. Furthermore, administration of diuretics is sometimes inevitable for cerebral protection. Insufficient volume therapy, central venous hypotension and high-dose vasopressors may cause vital organs damage. Moreover, one strategy that may be helpful for preservation of one organ may not be useful for the other. For example, the high rate of lung recovery may be affected by the restrictive volume balance, which is in sharp contrast with what has been recommended for kidney transplantation .et al, showed that longer delays between donor brain death and cross-clamp time are associated with a higher-risk of mortality in cardiac transplant recipients. The mean±SD cross-clamp time in their study was 13.2±3.96 hours [For impaired hemodynamics in DBDs, the efficacy of different protocols to maintain the patient’s hemodynamics including fluid infusion, administration of vasopressor and desmopressin, is variable and may lead to changes in cardiac index, arterial blood pressure, heart rate and even organ recovery rate , 7. Furt96 hours .We conducted this study to determine the hemodynamic factors affecting the suitability of the donated heart and kidney for transplantation.Data were retrospectively collected from the databases of all DBDs admitted to our OPU ICU between 1999 and 2008. In this study, BUN and creatinine, and demographic data were collected. The time between donor entrance to our DBD ICU and organ procurement, vital signs, 24-hour urine output before organ procurement, amount of IV fluid administered, and dosage of vasopressor and desmopressin were recorded. The end-point of the study was organ suitability for organ retrieval. Potential suitability for transplantation of kidneys was defined by the last serum creatinine level before the organ procurement, 24-hour urine output before retrieval and approval of a nephrologist. Potential suitability for heart transplantation was defined by the dose of vasopressor administered and the mean blood pressure in during the last 24 hours, history of cardiac arrest and duration of CPR, and approval of a cardiologist. ® for Windows® ver 19.0 . Descriptive data at the time of admission and during the follow-up are presented as mean±SD. Continuous and categorical variables were compared between the two groups using the Student’s t test for independent samples, and χ2 test, respectively. A p value <0.05 from 2-sided tests was considered statistically significant. This study was exempted from the assessment and approval by the University Ethics Committee due to its retrospective nature. Brain death was diagnosed according to the protocol practiced in Iran . StatistThis study included 132 cases of DBDs. The male to female ratio was 1.8 (85/47); they had a mean±SD age of 26.3±12.2 (range: 7–60) years. Two donors (1.5%) had a history of hypertension. The main causes of brain death were head trauma due to traffic collisions (53%), falling down (13.6%), and cerebrovascular accidents (11.4%). The donors’ characteristics with respect to their hemodynamics and the dose of administered inotrope are summarized in The mean±SD time from the onset of coma to the clinical diagnosis of brain death was 61.7±55.7 hours; the duration from the entrance to the OPU ICU until organ procurement was 20.1±5.5 hours. Thirty-five donors (26.5%) received only crystalloid IV solutions, while 55 (41.7%) received dextrose/crystalloid IV fluids. Th donors received a mean±SD of 52.7±25.8 (range: 8–98) mL/h fluid. Thirty-three donors (25%) did not receive bicarbonate in their volume therapy.Seven (5.3%) donors needed packed RBC, 13 (9.8%) received fresh frozen plasma (FFP), 15 (11.4%) received both packed RBCs and FFP, and two received platelets. Twenty-two (16.7%) DBDs experienced cardiac arrest; the mean±SD duration of CPR was 2.1±0.65 (range: 0–8) minutes.Inotropic agents used included dopamine in 95 (72%), and dobutamine and epinephrine each in one (0.8%).No record was found in 27 donors (4.20%). Sixty-six cases did not receive desmopressin (50.4%) at all. The mean±SD dose of desmopressin administered was 7±1 µg; the urine output 12 h before organ recovery was 217.1±153.9 (range: 11.5–942) mL/h. Seventy-four cases (70.5%) had polyuria (urine output >125 mL/h).The utilization rates were 82.6% for the kidneys, 59.8% for the liver, 53% for the heart, 3% for the lungs and 0.8% for the pancreas. Seventy (53%) hearts were recovered. Potential suitability for transplantation of hearts in each donor was optimal in 83 (62.9%), moderate in 33 cases (25%), and unsatisfactory in 11 (8.3%) cases; no reliable data were available for the analysis in five cases (3.8%). The reasons for non-retrieval of suitable heart from DBDs were lack of supportive services to prepare the operating room, transplant team or potential recipients. Potential suitability for transplantation of hearts was not associated with age, sex, cause of brain death, changes in mean arterial blood pressure and heart rhythm, fluid intake in 24 hours before the surgery and dose of the administered desopressin in 24 hours prior to the organ harvesting procedure. The uitability was associated with administration of desmopressin (p=0.009) and type of the IV fluid received (p=0.03).Kidneys were recovered from 109 DBDs (82.6%). Potential suitability for transplantation of kidneys in each donor was optimal in 106 cases (80.3%), moderate in 10 (7.6%), and unsatisfactory in six cases (4.5%); no reliable data were available for the analysis in 10 cases (7.6%). Regarding renal function, we found that the mean serum level of creatinine was 1.2 (range: 0.5–3.2) mg/dL at the time of admission and 1.1 (0.4–4.8) mg/dL prior to organ procurement.There was no significant association between kidney suitability for transplantation and age, gender, cause of brain death, chnges in blood pressure, heart rate and dose of the administered vasopressor . However, we found a significant correlation between successful kidney recovery with the volume of the administered IV fluid (p=0.006), the type of IV fluid which could provide a better hemodynamic status (p<0.001), and administration of desmopressin (p=0.002) within 24 hours prior to organ recovery and its dose (p=0.008).et al, in their study on 299 cases, found two main factors predicting the higher risk of kidney graft failure: cerebrovascular accident (CVA) as the cause of brain death and history of hypertension which is in contrast with our study. In their study, 43% (128/299) of the donors had the two mentioned criteria—CVA as the cause of death or history of hypertension [The main purpose of potential DBD care is to stabilizing and controlling the hemodynamic status of DBD to protect organs as best as possible. Two findings in our study require attention. The first was the young age of our donors, which was similar to other studies in Iran and other developing countries; this is in sharp contrast with many western countries discussed thoroughly elsewhere , 8. The The mean±SD duration between arriving at the OPU ICU and organ procurement was 20.1±5.5 hours—more than some other studies [et al, in their study on 57 kidney recipients from DBDs, found that the serum creatinine level on the 7th day and before discharging from the hospital (after transplantation) correlated significantly with the donor’s urine volume , and serum sodium level , respectively [et al, by using the Organ Procurement and Transplantation Network database, studied 10,431 donors and found that those who received desmopressin  had a significantly higher yield of organ procurement than those who did not  [The next issue, which is believed by all researchers involved in DBD management, is the administration of desmopressin. Diabetes insipidus may cause a rapid reduction in intravascular volume, hypotension and abnormal serum electrolytes. Therefore, the main steps in DBD management are volume therapy and administration of desmopressin. Increasing the intravascular volume with colloids or crystalloids is required in DBD management which is routinely adjusted by CVP , 10, 11.ectively . Plurad,In the present study, we did not find any correlation between suitability of heart and kidney for transplantation and the dose of the administered inotropes, which may be due to the younger age and more stable hemodynamic state of the donors studied. The main variable that correlated with a higher rate of organ suitability was higher fluid therapy and the administration of inotropic agents. As administration of desmopressin and IV fluid has a positive impact on the suitability of organs for transplantation, it seems necessary to follow the recipients to further confirm these results.


A post-hoc analysis was performed on the data from a 54 weeks phase III study  to measure changes in the health-related quality of life (HRQoL) of 2,690 patients aged ≥18 with moderate-to-severe hypertension who received one of six doses of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ), using the MINICHAL and EQ-5D instruments.Descriptive statistics were used to assess blood pressure and HRQoL scores over the study period. Analysis of covariance (ANCOVA) was used to identify those factors that could possibly have influenced HRQoL. Linear regression was used to assess the relationship between changes in blood pressure and HRQoL scores.Patients’ baseline MINICHAL mood and somatic domains scores were 5.5 and 2.6. Over the study period HRQoL improved as both MINICHAL scores decreased by 31-33%. Patients’ baseline EQ-5D index and VAS scores were 0.9 and 73.4 respectively, increasing by 6% and 12% over the study period. Patients’ QALY gain over the 54 weeks study period was estimated to be 0.029 QALYs. The ANCOVA showed that changes in patients’ HRQoL was likely to have been influenced by patients’ achievement of blood pressure control, the amount of concomitant medication and patients’ last used dosage strength of antihypertensive. Linear regression showed that blood pressure improvement may have been associated with improved HRQoL.This study showed that OLM/AML/HCTZ reduced blood pressure and significantly increased blood pressure control whilst improving patients’ HRQoL. Achieving blood pressure control, amount of concomitant medication and dosage strength of antihypertensive impacted on patients’ HRQoL. The risk of cardiovascular disease among hypertensive individuals has been well documented , and hypIt has been estimated that 15–20% of hypertensive patients are not adequately controlled on a dual antihypertensive combination and that three or more different antihypertensive drug classes are required to achieve blood pressure control -8. The tIn a phase III, multicentred, double-blind, parallel-group design study , 2,690 patients aged ≥18 years with moderate-to-severe hypertension were randomised to receive placebo, OLM/AML (20 mg/5 mg), OLM/AML (40 mg/5 mg) or OLM/AML 40 mg/10 mg) for a period of 2 weeks , over-weight [>25 kg/m2 to ≤30 kg/m2] and obese [>30 kg/m2]);Weight based on BMI at baseline ;Smoking status (Non-Smoker/Ex-Smoker/Current Smoker);Country ;Concomitant cardiovascular risk using concomitant medications as a proxy;Mental disorder using concomitant medications as a proxy;Number of concomitant medications per patient during the study;Baseline hypertension grade ;Blood pressure goal control at week 54 .The first step involved the generation of descriptive statistics for the following quantitative factors:The second step involved performing analysis of covariance (ANCOVA) for each target variable and factor, to assess if these factors possibly influenced HRQoL changes during the study. Factors with p-value of >0.2 were omitted in the third step. Any factors with a p-value for effect of 0.2 or lower were used in the third step for the respective target covariate. The third step involved stepwise ANCOVA that included treatment and all pre-selected factors for each target variable based on second step findings until all remaining factors had p-values ≤0.05.The outputs of the analyses were a descriptive summary of the results. P-values between 0.05 and 0.01 were considered a trend and p-values of 0.01 or lower were considered to be indicative. Since multiple tests were performed without any adjustment, the p-values even if statistically significant, should only be considered to be indicative of trends or possible hypotheses.Since blood pressure changes from baseline to week 54 were initially not included in the ANCOVA models, a separate linear regression model was calculated to assess the relationship between changes in blood pressure and HRQoL scores from baseline.Of the 2,690 patients who were randomised into the double-blind study , 2,679 pThe efficacy and safety of the alternative antihypertensive combinations have been described elsewhere ,11. HoweAt baseline patients’ MINICHAL mood domain and somatic domain scores were 5.5 and 2.6 respectively. Over the 54 weeks study period patients’ HRQoL improved as both MINICHAL scores decreased by 31-33%  have not been included in the ANCOVA model and thus it was not possible to control for their effect. Nevertheless, achievement of blood pressure target was found to be an influencer for HRQoL. Both these variables have been shown to be independent predictors of HRQoL among hypertensive patients [The ANCOVA model showed that multiple factors influenced HRQoL changes. However, individual categorical variables (as identified in step 3) would seem to have only accounted for up to 40% of the variation in patients’ HRQoL (measured using the MINICHAL), since Rpatients ,21. Alsopatients ,23. Therpatients . Furtherpatients . Consequpatients . MoreoveThe mean EQ-5D index and VAS baseline scores for the whole study cohort was 0.9 and 73.4 respectively. These baseline scores are high, probably due to the fact that patients with major concomitant cardiovascular risk factors and co-morbidities were excluded by the clinical trial protocol. Nonetheless, these scores increased by 6% and 12% respectively over the study period. In comparison, the international population norm for the EQ-5D index across the 18 to 75+ age group has been reported to range from 0.74 to 0.95 and that of the EQ-5D VAS has been shown to range from 71.1 to 83.7 . These cNotwithstanding this, the analysis showed that age, gender, BMI, whether patients were taking cconcomitant medication for cardiovascular disease and/or mental disorder and whether they achieved hypertension control by week 54 all influenced the EQ-5D index score. Additionally, gender, co-morbid diabetes, co-morbid cardiovascular disease, country of origin, whether patients were taking concomitant medication for mental disorder and their hypertension grade at baseline influenced their EQ-5D VAS score. The effect of concomitant cardiovascular diseases on HRQoL has been much debated in the published literature. For example, the epidemiological study ESTHER showed that in a large cohort of hypertensive patients being managed by general practitioners, additional cardiovascular risk factors did not seem to be related to a substantial worsening of their HRQoL measured using the SF-12. Nonetheless, the physical component score (PCS) reported in the ESTHER study was found to be significantly decreased by cardiovascular risk factors such as BMI, macroalbuminuria, diabetes and circulatory disorders . In our The Step 3 analyses identified multiple factors that were likely to have influenced HRQoL simultaneously. Blood pressure control was the only blood pressure-related factor modelled in Step 3. However, linear regression showed that blood pressure improvement may have been associated with improved HRQoL.This post-hoc analysis is subject to several other limitations. The statistical analysis protocol for the post-hoc HRQoL analysis was prepared after the clinical report had been completed. Multiple statistical tests were performed without any adjustment. Hence, the p-values can only be viewed as being exploratory and indicative of trends or possible hypotheses. Furthermore, the large sample size may have resulted in small, statistically significant p values for changes that may have marginal clinical significance. Factors that may have influenced patients’ HRQoL, such as educational level, marital status, job status, income and residency, were not collected during the phase III trial. Exclusion of these factors should be considered as an additional limitation. Moreover, the large sample size of this non-comparative study has only generated small effects. Hence, the reproducibility of the HRQoL impact of OLM/AML/HCTZ seen in this study needs to be studied further in a controlled study design.In conclusion, this present study showed that OLM/AML/HCTZ reduced blood pressure and significantly increased blood pressure control whilst improving patients’ HRQoL. Achieving blood pressure control, amount of concomitant medication and dosage strength of antihypertensive all impacted on patients’ HRQoL. Hence, when prescribing antihypertensive agents physicians should consider the impact of all these factors on patients’ HRQoL and on their adherence to treatment.


Of all patients, 207 (43.9%) were diabetic and 240 (50%) had fluid overload. For non-diabetic CKD, fluid overload was associated with being female , heart disease , high baPWV , low hemoglobin , and low serum albumin  in multivariate analysis. For diabetic CKD, fluid overload was associated with diuretics use , high mean arterial pressure , low bPEP/ET , low hemoglobin , and low serum albumin . In conclusion, baPWV is associated with fluid overload in non-diabetic CKD and bPEP/bET is associated with fluid overload in diabetic CKD. Early and accurate assessment of these associated cardiovascular risk factors may improve the effects of entire care in late CKD.Fluid overload is one of the characteristics in chronic kidney disease (CKD). Changes in extracellular fluid volume are associated with progression of diabetic nephropathy. Not only diabetes but also fluid overload is associated with cardiovascular risk factors The aim of the study was to assess the interaction between fluid overload, diabetes, and cardiovascular risk factors, including arterial stiffness and left ventricular function in 480 patients with stages 4–5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. Brachial-ankle pulse wave velocity (baPWV), as a good parameter of arterial stiffness, and brachial pre-ejection period (bPEP) Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The presentation of fluid overload is often noticed in patients with CKD, and excess fluid status induces elevated arterial pressure, left ventricular hypertrophy, and associated cardiovascular sequelae On the other hand, diabetic CKD patients have a greater risk of commencing dialysis, and higher all-cause and cardiovascular mortality than non-diabetic CKD patients 2; CKD stage 4, eGFR: 15∼29 ml/min/1.73 m2; CKD stage 5, eGFR<15 ml/min/1.73 m2) All 612 of CKD stages 4–5 patients were invited to participate in the study from January 2011 to December 2011 at one hospital in Southern Taiwan. The study protocol was approved by the Institutional Review Board of the Kaohsiung Medical University Hospital. All patients had been enrolled in our integrated CKD program for more than 3 months (30.9±27.0 months). CKD was staged according to K/DOQI definitions and the estimated glomerular filtration rate (eGFR) was calculated using the equation of the 4-variable Modification of Diet in Renal Disease (MDRD) Study . Informed consents were obtained in written form from patients and all clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. The patients gave consent for the publication of the clinical details.th percentile for the normal reference population when the fluid status was measured with the same technology Fluid status was measured once by a bioimpedance spectroscopy method, Body Composition Monitor  at enrollment. BCM has been validated extensively against all available gold-standard methods in the general and dialysis populations Brachial-ankle pulse wave velocity (baPWV), as a good parameter of arterial stiffness, was measured by the ABI-form device, which automatically and simultaneously measured blood pressures in both arms and ankles using an oscillometric method The bET was automatically measured from the foot to the dicrotic notch  of the pulse volume waveform. The total electromechanical systolic interval (QS2) was measured from the onset of the QRS complex on the electrocardiogram to the first high-frequency vibration of the aortic component of the second heart sound on the phonocardiogram. The bPEP was also automatically calculated by subtracting the bET from the QS2 Demographic and clinical data of patients were obtained from interviews and medical records at enrollment. Blood and urine samples were obtained at the same time of fluid status measurement. Patients were asked to fast for at least 12 hours before blood sample collection for the biochemistry study. Protein in urine was measured using an immediate semiquantitative urine protein dipstick test and graded as negative, trace, 1+, 2+, 3+, or 4+. The body mass index was calculated as the ratio of weight in kilograms divided by square of height in meters. Blood pressure was recorded as the mean of two consecutive measurements with 5-minute intervals, using one single calibrated device. Mean arterial pressure was calculated as 2/3 diastolic blood pressure plus 1/3 systolic blood pressure. Diabetes was defined as those with a medical history through chart review. Cardiovascular disease was defined as a history of heart failure, acute or chronic ischemic heart disease, and myocardial infarction. Information regarding patient’s medications including diuretics, HMG-CoA reductase inhibitors (statins), anti-hypertensive drugs, including calcium channel blocker, β-blocker, and angiotensin converting enzyme inhibitor, and angiotensin II receptor blocker within 3 months before enrollment was obtained from medical records.th, 75th percentile), as appropriate, and categorical variables were expressed as percentages. Skewed distribution continuous variables were log-transformed to attain normal distribution. The significance of differences in continuous variables between groups was tested using independent t-test or the Mann-Whitney U analysis, as appropriate. The difference in the distribution of categorical variables was tested using the Chi-square test. Linear regression models were utilized to evaluate the determinants of fluid overload in diabetes and non-diabetes. All the variables in The study population was further classified into two groups according to the presence or absence of diabetes. Continuous variables were expressed as mean ± SD or median (252), mean arterial pressure (98.8±12.0 mmHg), fat tissue index (10.7±4.5 kg/m2), TBW (34.1±7.2 L), ECW (16.7±4.1 L), ECW/TBW (48.9±3.5%), and OH (1.7 L) than non-diabetic patients. Diabetic patients with fluid overload received more diuretics, statin, and anti-hypertension treatment. Higher baPWV, and lower bPEP/bET were found in diabetic patients than non-diabetic patients. Uric acid levels and the degree of proteinuria were higher and serum albumin was lower in diabetic patients than in non-diabetic patients.The comparison of clinical characteristics between groups based on the presence or absence of diabetes is shown in Different zones can be identified in the plot of mean arterial pressure (Y-axis) versus relative hydration status (ΔHS) (X-axis), of normovolemic and normotensive patients , fluid-overloaded and hypertensive patients , fluid-overloaded but normo- or hypotensive patients , hypertensive and normovolemic patients , in The aim of this study was to evaluate the relationship between fluid overload, diabetes and baPWV or bPEP/bET in patients with stages 4–5 CKD. Fluid overload was associated with baPWV, a clinical indicator of arterial stiffness, in non-diabetic CKD. Conversely, instead of baPWV, fluid overload was associated with bPEP/bET, a marker of left ventricular systolic function, in diabetic CKD.Fluid overload may have an influence on vasculature and lead to vascular remodeling, characterized by dilatation of muscular and elastic type arteries and increased wall thickness, thereby inducing arterial stiffness and consequent cardiovascular sequelae Interestingly, instead of baPWV, low bPEP/bET, which has a significant correlation with impaired left ventricular ejection fraction Cardiovascular dysfunction progresses with arterial-cardiac interactions Due to the strong association of fluid overload and adverse outcomes The present study has some limitations that must be considered. This study was conducted at a single center. Fluid status, baPWV, bPEP/bET, clinical parameters, and the use of drugs were measured only once at enrollment. The association of time-varying baPWV, bPEP/bET, clinical parameters, and the use of drugs with time-varying fluid status could not be estimated. Additionally, our findings show the relative weak correlation between bPEP/bET and fluid overload in diabetic CKD. The weak correlation between fluid overload and bPEP/bET is probably related to the relatively small sample size of diabetic patients. Based on the association of bPEP/bET with cardiac function, we performed subgroup analysis to analyze the relationship between bPEP/bET and fluid overload in the heart disease group and the result was consistent . However, there was no significant correlation between bPEP/bET and fluid overload in the non-heart disease group. We need a large population study to evaluate the interaction between bPEP/bET, cardiac function and diabetes in a CKD cohort.In conclusion, our study evaluates a relationship between fluid overload, diabetes, and arterial stiffness or cardiac function in late CKD patients. Fluid overload is correlated with arterial stiffness in non-diabetic CKD, and with left ventricular dysfunction in diabetic CKD. Fluid overload probably has distinct arterial-cardiac influences on CKD patients in the presence or absence of diabetes. Early and accurate assessment of these associated cardiovascular risk factors may improve the effects of entire care in late CKD patients.