Fractional exhaled nitric oxide (FeNO) is a surrogate marker of eosinophilic airway inflammation and good predictor of corticosteroid response.To evaluate how FeNO is being used to guide primary care asthma management in the United Kingdom (UK) with a view to devising practical algorithms for the use of FeNO in the diagnosis of steroid-responsive disease and to guide on-going asthma management.Eligible patients (n = 678) were those in the Optimum Patient Care Research Database (OPCRD) aged 4–80 years who, at an index date, had their first FeNO assessment via NIOX MINO® or Flex®. Eligible practices were those using FeNO measurement in at least ten patients during the study period. Patients were characterized over a one-year baseline period immediately before the index date. Outcomes were evaluated in the year immediately following index date for two patient cohorts: (i) those in whom FeNO measurement was being used to identify steroid-responsive disease and (ii) those in whom FeNO monitoring was being used to guide on-going asthma management. Outcomes for cohort (i) were incidence of new ICS initiation at, or within the one-month following, their first FeNO measurement, and ICS dose during the outcome year. Outcomes for cohort (ii) were adherence, change in adherence (from baseline) and ICS dose.In cohort (i) (n = 304) the higher the FeNO category, the higher the percentage of patients that initiated ICS at, or in the one month immediately following, their first FeNO measurement: 82%, 46% and 26% of patients with high, intermediate and low FeNO, respectively. In cohort (ii) (n = 374) high FeNO levels were associated with poorer baseline adherence (p = 0.005) but greater improvement in adherence in the outcome year (p = 0.017). Across both cohorts, patients with high FeNO levels were associated with significantly higher ICS dosing (p < 0.001).In the UK, FeNO is being used in primary practice to guide ICS initiation and dosing decisions and to identify poor ICS adherence. Simple algorithms to guide clinicians in the practical use of FeNO could improved diagnostic accuracy and better tailored asthma regimens. Inhaled anti-inflammatory  therapy is the cornerstone of asthma management with the ultimate goal of maintaining control of the clinical manifestations of the disease for prolonged periods . InitiatAchieving optimum asthma control requires an understanding of the nature and extent of the airway inflammation present. In the Gaining Optimum Asthma controL (GOAL) study, for example, over 30% of patients failed to achieve totally controlled asthma despite receiving maximum doses of fluticasone propionate. While drug delivery and/or treatment adherence may have played a part in their failure to achieve control, it may also have been partially attributable to the presence of steroid unresponsive asthma in these patients ,5.ICS dosing decisions (starting dose and subsequent dose adjustments) are typically symptom-driven and reliant on patient or carer/parental reports . Yet resApproximately 50% of asthma cases are attributable to eosinophilic airway inflammation -19. EosiThe role of FeNO as a diagnostic and decision-support tool is relatively well documented -26. IndeYet despite the body of evidence underpinning the potential uses of FeNO, its uptake within primary care remains limited. This is, in part, due to a lack of clear, practical guidance on its appropriate use in routine asthma care and how it can be best utilized to aid diagnosis and support decision making with respect to ICS dose optimization and the need for non-ICS therapies.Against this backdrop, we designed a study to identify patterns of use of FeNO assessment in routine primary care in the United Kingdom (UK) and the effects of this assessment on clinical parameters and physician and patient behaviour with a view to informing algorithms for the use of FeNO in primary care practice.This observational study analyzed clinical data from the Optimum Patient Care Research Database (OPCRD). The OPCRD is a UK respiratory dataset containing anonymized, longitudinal, research-quality clinical records and patient-reported outcome data from practices that subscribe to the Optimum Patient Care (OPC) respiratory review service. At the time of the study, the OPCRD included 341,000 patients at 176 practices . The OPCEligible patients were those aged 4–80 years who, at an index date, had their first FeNO measurement via NIOX MINO® or Flex®. Patients had to be managed at practices routinely measuring FeNO, defined as those that measured FeNO in at least ten patients over the study period. All eligible patients had to have at least one (baseline) year of continuous practice data before the index date, and one complete (outcome) year of data after the index.During baseline, all patients were characterised in terms of demography, clinical management, exacerbation history, risk and control status. Patients were defined as controlled in baseline if they used little symptom relief medication (average SABA use of ≤200 μg daily) and high risk if they had multiple (i.e. at least two) exacerbations over the baseline year. Normal, intermediate and high FeNO levels were categorised as: low/normal: <25 ppb (adults), <20 ppb (children); intermediate: 25–50 ppb (adults), 20–35 ppb (children); or high: >50 ppb (adults), >35 ppb (children)  those in whom FeNO measurement was being used to identify possible steroid-responsive disease (i.e. in patients not receiving ICS therapy during the baseline year) and (ii) those in whom FeNO monitoring was being use to support clinical management of asthma (i.e. in patients who received at least one prescription for ICS therapy during the baseline year).In patients in whom FeNO measurement was being used to help identify possible steroid-responsive disease, the percentage of patients initiating ICS at, or in the one month immediately following their first FeNO measurement was evaluated and split by FeNO category  to explore the effect of FeNO measurement on physician prescribing behaviour.In the cohort of patients in whom FeNO monitoring was being use to support asthma clinical management, the association between adherence to ICS in the baseline and outcome years (and change in ICS adherence between baseline and outcome) was evaluated, and split by FeNO category, to explore the effect of FeNO level on subsequent patient behaviour. Adherence was assessed in terms of medication possession ratio .Across both cohorts, the association between FeNO level and prescribed ICS dose was evaluated, with ICS dose being a marker of FeNO’s effect on physician prescribing behaviour.Analyses were conducted using SPSS version 18 , SAS version 9.2 , and Microsoft Office Excel 2007 . Statistical significance was defined as p < 0.05. Descriptive analysis was used to investigate patterns of FeNO assessment and the effect on physician prescribing. Plots and statistical tests were used to explore the relationships between FeNO levels and ICS consumption/patient adherence using, namely Kruskal Wallis Test for variables measured on the interval/ratio scale and Chi Square Test for categorical variables.A total of 678 eligible patients were identified in the database. The median (interquartile range) age of the study population was 46 26–60) years, 46% of patients were male, 45% had comorbid rhinitis and 6% of patients were current smokers. During baseline, 7% of the patients experienced multiple exacerbations, classifying them as high risk (12% had 1 exacerbation and 81% had no exacerbations during baseline)  of whom, 56% had low/normal FeNO levels, 27% had intermediate levels and 17% had high levels. Across all patients, the higher the FeNO category, the higher the median prescribed ICS dose in the outcome year – a sign that FeNO measurement/monitoring was informing rationale prescribing decisions (see Table FeNO measurement was being used to help identify possible steroid-responsive disease in 304 patients. ICS was initiated within one month of the index date (i.e. first FeNO measurement) in 82% of patients with high FeNO levels, 46% of those with intermediate FeNO levels and approximately one quarter (26%) of patients with low/normal FeNO  prior to their first FeNO measurement  as a complementary diagnostic tool to aid diagnosis in patients in whom traditional assessment tools may have been inconclusive. It appears to be being used to guide decisions around ICS initiation or step up.While FeNO can provide useful information about the nature and presence (or absence) of eosinophilic airway inflammation and about the likelihood (or not) of ICS responsiveness, it can also be used to identify poor adherence. These data suggest that a high FeNO level appears to drive improved ICS adherence in routine care. Using FeNO in this way has the potential to optimize existing therapy and minimize inappropriate use of ICS in patients unlikely to respond.number of participants who had asthma exacerbations during follow-up as the primary endpoint, which does not take into consideration the fact that some patients may have multiple exacerbations during the course of a study. Indeed, the National Institute for Health (NIH) considers time to first asthma exacerbation and/or asthma exacerbation rates to be the most meaningful outcomes for assessing asthma exacerbations [rate of exacerbations was significantly lower in patients receiving a FeNO-based asthma management strategy, in both adults and children [This real-life study adds to a rather limited evidence base on the role of FeNO monitoring in asthma management. At one point, the combined findings of a Cochrane systematic review of FeNO-based asthma management and a meta-analysis of studies evaluating the role of FeNO or sputum eosinophils in asthma management of patients concluded FeNO-guided asthma management could not be recommended (for adults or children) and that further studies were needed ,29. Thisrbations . A re-anrbations -30 usingchildren -35.Pooling the evidence from the existing literature and the results of this real-life study together with our own experience of using FeNO in clinical practice, we have devised two clinical practice algorithms to aid primary care practitioners in the practical use of FeNO monitoring. The first algorithm is an “Initial Evaluation Algorithm”, which aims to provide guidance on the use of FeNO at the time of initial asthma diagnosis where traditional tools are inadequate Figure . The secThe Initial Evaluation Algorithms build on an understanding that FeNO cannot be used to diagnose asthma (as asthma is defined by symptoms and variable airflow obstruction), but that it can be used to indicate elevated FeNO levels, the presence of eosinophilic airway inflammation and likely steroid response. Indeed, it can be a valuable complementary diagnostic tool and guide to therapeutic decision-making in patients with non-specific respiratory symptoms that are difficult to diagnose using conventional tools ,10,24,25The presence of low FeNO levels in untreated patients with normal spirometry can help to rule out asthma  indicate that eosinophilic airway inflammation is present and that the likelihood of ICS response is high. Consequently initiation of ICS therapy is recommended. However, specialist referral may still be necessary for symptomatic patients with lung function impairment and high FeNO levels if they do not respond to treatment with an ICS  to provide supplementary information about a patient’s disease state and to help tailor asthma therapy appropriately. FeNO can be particularly useful when trying to identify patients who may be at increased risk of asthma exacerbations -38; thosOur recommendations on how FeNO can be used as a decision-support tool once a diagnosis of asthma has been established are summarised in Figure In the case of maintenance ICS patients who have low FeNO levels yet remain symptomatic, care must be taken to understand the reason for the persistence of symptoms. Alternative diagnoses and/or the presence of comorbidities  should be explored. Patients’ smoking habits should also be discussed. Not only can smoking reduce FeNO levels (possibly an early indicator of smoking’s impact on the lungs), but it can also drive management with higher ICS doses, both of which can increase the chance of a “false low” FeNO reading. Chronically reduced levels of FeNO have been demonstrated due to habitual smoking, but acute effects have also been shown immediately after cigarette smoking -46. WhilIn patients with low FeNO levels in whom the diagnosis of asthma appears valid (e.g. confirmatory spirometry and bronchodilator response) increasing ICS is unlikely to result in an improvement in symptoms or other asthma outcomes. Instead, addition of a non-ICS therapy (e.g. an LTRA or LABA) should be considered. Also, as FeNO is highly ICS responsive (and low FeNO levels could indicate good adherence to ICS therapy) it is worth exploring whether there has been any recent change in a patient’s usual adherence pattern (e.g. an improvement in adherence in response to a recent exacerbation) that may have led to a short-term reduction in FeNO levels.Where patients are asymptomatic, have low FeNO levels and have stable, well-controlled disease, a reduction in ICS dose (or ICS cessation if existing dose is low) should be considered. The chances of loss of control are much lower in patients with a low FeNO. Those selected for step-down should be followed-up  within 4 weeks, especially where the step-down is to low-dose ICS or where the ICS is being discontinued. If FeNO levels rise during the follow-up period, it may be a precursor to future loss of control and indicates the need to restart or increase ICS therapy. The 4-week follow-up recommendation is based on data from studies in both children and adults demonstrating that a 4-week period is adequate to identify individuals who are likely to experience an increase/decrease in their level of asthma control (based on increased/decreased FeNO levels) and be at increased/decreased risk of having an exacerbation -51. A chWe recommend no initial changes to existing ICS therapy, in asymptomatic patients with intermediate FeNO levels. Such patients should be followed for an additional 3–6 months and if they remain asymptomatic and their FeNO levels remain stable, a reduction in ICS dose can be considered with a follow-up in 4 weeks including an evaluation of symptom control, lung function and FeNO. However, it is important to recognize that in apparently stable patients, a rise in FeNO may indicate the possibility of a future loss of control. Thus, patients who have had an increase in FeNO levels to the intermediate zone, even in the absence of symptoms, should be followed more closely as they may be at risk of reduced asthma control. In all cases, medication adherence, trigger factors and inhaler technique should be carefully assessed.On occasion, a patient with a high FeNO level and otherwise apparently well-controlled asthma and no history of frequent exacerbations will be encountered. The high but stable FeNO level may represent the “normal baseline” for some patients, but a trial of increased ICS  to definitively establish their “normal” baseline may be appropriate. Once a patient’s baseline has been established, and if they remain asymptomatic with stable FeNO levels, a reduction in ICS dose can be cautiously considered with follow-up in 4 weeks.The presence of elevated (intermediate or high) FeNO levels in patients who remain symptomatic despite maintenance ICS therapy indicates sub-optimal control. For such patients, it is imperative to assess medication adherence, trigger factors and inhaler technique before any changes in treatment are considered. Where the patient remains symptomatic with elevated FeNO levels despite an evaluation and optimization of these factors, improved control may be possible by increasing the ICS dose or by addition of LTRA to improve anti-inflammatory management. Or specialist referral should be considered.In conclusion, FeNO monitoring should be viewed as a complementary assessment and monitoring tool when traditional assessment techniques prove inadequate or inconclusive. It can offer added advantages for clinicians (and patients) in terms of: (1) detecting the presence of eosinophilic airway inflammation, (2) determining the likelihood of ICS responsive (and lack thereof), (3) monitoring of airway inflammation to determine the potential need for a corticosteroid, and (4) unmasking (otherwise unsuspected) non-adherence to corticosteroid therapy.Using FeNO to guide asthma management may not only benefit patients and reduce pressures on healthcare professionals, but could also reduce asthma-related healthcare costs -54. FeNOWhile some studies based in academic medical centres have found that physician-based treatment decisions are non-inferior to biomarker- or symptom-based ICS adjustments in mild-moderate asthma,  we belieDP has consultant arrangements with Almirral, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Medapharma, Novartis, Napp, Nycomed, Pfizer, Sandoz, Takeda and Teva. He or his research team have received grants and support for research in respiratory disease from the following organisations in the last 5 years: UK National Health Service, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Mundipharma, Novartis, Nycomed, Orion, Pfizer, and Teva. He has spoken for Almirral, AstraZeneca, Activaero, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Novartis, Merck, Mundipharma, Pfizer and Teva. He has shares in AKL Ltd which produces phytopharmaceuticals. He is the sole owner of Research in Real Life Ltd (RiRL) and its subsidiary social enterprise Optimum Patient Care. MT spoke for Aerocrine at the 2012 European Respiratory Society Annual Conference, he has no other conflicts of interest to declare. CG has participated in respiratory and primary care advisory and educational events organised by GlaxoSmithKline, Almirall and AstraZeneca and has received support from Aerocrine for Niox Mino mouthpiece provision. A Copland has spoken for Almirral, AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Merck Novartis and Pfizer. DF has spoken for Napp, Chiesi and Boehringer Ingelheim. At the time the data and opinions in this paper were analysed and formulated: AB, SG and JvZ are employees of RiRL; A Chisholm is a consultant to RiRL. DR and K G-J have with no conflicts of interests to declare.DP, MT, DR, K G-J, A Copland, CG, conceived and designed the study. AB conducted the analyses, with help from JvZ and SH. A Chisholm wrote the initial draft of the paper. All authors contributed to the data collection and/or interpretation, the writing of the manuscript, and review of the final draft. DP is the study guarantor. All authors read and approved the final manuscript.


Background: A sympathetic shift in heart rate variability (HRV) from high to lower frequencies may be an early signal of deterioration in a monitored patient. Most chronic heart failure (CHF) patients receive β-blockers. This tends to obscure HRV observation by increasing the fast variations. We tested which HRV parameters would still detect the change into a sympathetic state.Methods and results: β-blocker (Carvedilol®) treated CHF patients underwent a protocol of 10 min supine rest, followed by 10 min active standing. CHF patients (NYHA Class II–IV) n = 15, 10m/5f, mean age 58.4 years (47–72); healthy controls n = 29, 18m/11f, mean age 62.9 years (49–78). Interbeat intervals (IBI) were extracted from the finger blood pressure wave (Nexfin®). Both linear and non-linear HRV analyses were applied that (1) might be able to differentiate patients from healthy controls under resting conditions and (2) detect the change into a sympathetic state in the present short recordings.Linear: mean-IBI, SD-IBI, root mean square of successive differences (rMSSD), pIBI-50 , LF, HF, and LF/HF ratio.Non-linear: Sample entropy (SampEn), Multiscale entropy (MSE), and derived: Multiscale variance (MSV) and Multiscale rMSSD (MSD). In the supine resting situation patients differed from controls by having higher HF and, consequently, lower LF/HF. In addition their longer range (τ = 6–10) MSE was lower as well. The sympathetic shift was, in controls, detected by mean-IBI, rMSSD, pIBI-50, and LF/HF, all going down; in CHF by mean-IBI, rMSSD, pIBI-50, and MSD (τ = 6–10) going down. MSD6–10 introduced here works as a band-pass filter favoring frequencies from 0.02 to 0.1 Hz.Conclusions: In β-blocker treated CHF patients, traditional time domain analysis  and MSD6–10 provide the most useful information to detect a condition change. Heart rate variability (HRV) analysis has seen an increasing interest since the early work of B.McA. Sayers in the 1970's  have different HRV patterns compared to matched healthy controls , SD-IBI (standard deviation), rMSSD (root mean square of successive differences of IBI's), pIBI-50 (proportion of pairs of successive IBI's that differ by more than 50 ms) and from the frequency domain: LF, HF and LF/HF . In view of earlier studies where the use of short recordings for non-linear analysis has been analyzed  as well as detect the sympathetic shift (Question 2) within the limits of the 20 min recordings that were available.2-receptor subtype that was present in the patient. In a double-blind cross-over design they received the non-selective β-blocker Carvedilol®  or the selective metoprolol succinate  as β-blocker for 6 weeks. Both drugs were titrated to equipotent dosages, additionally checked by resting heart rate. Since recordings made under Carvedilol showed fewer extrasystoles and other rhythm disturbances, we have restricted our study to the recordings made after 6 weeks on this drug. It should be mentioned here that Carvedilol is known to also have α1-blocking properties, without intrinsic sympathetic activity , age 62.9 ± 7.3 BMI 26.1 ± 4.2 for analysis. There are no significant differences in age and BMI distribution between healthy controls and CHF patients.Subjects had been recruited by advertisement and selected to match the patient group by gender, age and βContinuous non-invasive blood pressure was measured from a finger by the volume-clamp technique. A Nexfin®  hemodynamic monitor was used with instantaneous display of reconstructed upper arm blood pressure, heart rate, pulse contour derived cardiac output and systemic vascular resistance. This enabled proper monitoring during the stand test. To prevent hydrostatic errors the hand was held at heart level in both positions by a sling around the neck.Patients and controls underwent a test protocol which included blood draws for clotting factors in the supine position as described earlier , and substituted any IBIi outside the range 80–120% of IBImean−glb by that value. Next, a 10-beat window would slide over the recording, replacing any newly added IBIj outside the 80–120% range around the IBImean−local by the value of the local mean. The first step deletes sharp spikes globally, making it easier for the second step which is required to preserve continuity of the time series.In view of dysrhythmias like PVC's, other rhythm disturbances and, occasionally, movement artifacts that were present in the IBI-recordings, they had to be pre-processed before analyses could be performed. We used a two-step spike-removal procedure. First we established the global mean value IBISince we derived heart periods from blood pressure recordings rather than from an ECG, we cannot call them NN-intervals  since, strictly spoken, we have no information on the origin of the heartbeat, whether it originates from the sinus node or from some other pacemaking site in the heart. Although all patients underwent a test-ECG just prior to the present recording, where normal sinus rhythm had been established, we will use the more general term “IBI”  instead.After data pre-processing as described above we calculated mean-IBI, SD-IBI, rMSSD, pIBI-50  following the usual methods ] from the series X, where τ is the scale factor. Next, the SampEn  at the next point in the data set. A high SampEn value implies low regularity, i.e., few repetitions of the same pattern. Details on how to calculate SampEn can be found in references . By taking τ consecutive values together, the original signal is progressively “smoothed” and more and more beat-to-beat “noise” is averaged out. This process is visualized in Figure In short, MSE aims to measure the complexity of the system. In a totally random sequence, SampEn will decrease to zero with increasing τ; in a sequence that has been generated by a system with some degree of complexity, like heart rate over time, it tends to find a stable non-zero value.We also computed a side-product of the coarse-graining process, i.e., the  variance (MSV) and multiscale rMSSD (MSD) of the newly constructed series Y(τ). We reasoned that these might show in a simple way the variability of heart rate at medium-scale time-intervals.t-test or Mann–Whitney u-test where appropriate. For the change to a sympathetic state within one subject, we used the computed supine value to normalize the upright value. The resulting quotient upright/supine was then linearized by a log-transformation before statistical testing.All computations were done by use of SPSS®. After testing for normality, comparisons between groups were done by pairwise testing using Student's p-value. This allows the reader to judge the significance of observed changes, taking into account the type I/type II error as well as the biological significance of the change , yet in view of the narrow distribution and the exact p-value of 0.015 we do consider this difference significant.To further analyze the internal structure of the variability we computed, first, the MSE-curves for τ = 1–10, results shown in Figure p-values are shown in Table We computed the 11 parameters again for the upright condition, and expressed the upright value as fraction of the individual supine one. For statistical testing the values have been log-transformed, to obtain values which follow a normal distribution with mean = 0 if the supine and upright values are equal. The averages and 6−10, MSV6−10, and MSD6−10 did not change.As to be expected, mean-IBI has significantly decreased, i.e., heart rate goes up on standing. All short-term variability measures go down as well: rMSSD, pIBI-50 and HF. The increase in LF did not reach statistical significance; LF/HF increased in line with the decreased HF. SampEn and the coarse grained measures, MSEGenerally speaking, the sympathetic change in CHF-patients followed the same pattern as in healthy control subjects, without statistically significant differences between the two groups. However, there were a few notable within-group exceptions, as shown in Table 6−10 decreased significantly, the other ones did not change appreciably.In the patients mean-IBI decreased significantly, so did rMSSD, pIBI-50, but none of the frequency analysis measures. Of the non-linear and coarse-grained parameters only MSDFourier analysis of HRV may be analyzed in many ways; we chose to look at the individual normalized powers of LF and HF and the LF/HF quotients. However, if the underlying (absolute) data are very much changed by the intervention (standing up in this case) these numbers may be misleading. Therefore, we checked the absolute powers and in addition those in the VLF band (very low frequency band: from the lowest observed frequency in the 5–10 min recording to 0.04 Hz). The results are given in Table post-hoc study tried to establish the numbers that could aid in fast diagnosis of a β-blocker treated patient's “slipping off” into a more sympathetic state. We chose a stand-test as model for this condition; no one can stand very well for 10 min without sympathetic system involvement in view of the induced drop in blood pressure at the level of the carotid sinuses and the relative hypovolemia that is observed by pressure sensitive receptors in the low-pressure area  , rMSSD, pIBI-50 and MSD6−10 (decreased). None of the other parameters would indicate a shift into a sympathetic state. Our results in the healthy control group tally well with those of Turianikova et al.  , thus mainly spanning the LF-band and slightly lower, as illustrated in Figure rMSSD has peculiar properties, acting as a high-pass filter to the original heart rate signal. It has been proven  to 10 rather than going to 20. At τ = 10 we have in a 10 min recording about 60 points for the coarse grained series. Since our τ-MSE curves reached stable levels for the data sets that we used, we considered this choice appropriate.None of the authors has any relevant disclosures to make. Ms. Zhang, PhD is the recipient of a post-doc training grant from the Department of Physiology.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Systemic arterial hypertension is an important risk factor for cardiovascular disease that is frequently observed in populations with declining renal function. Initiation of renal replacement therapy at least partially decreases signs of fluid overload; however, high blood pressure levels persist in the majority of patients after dialysis initiation. Hypervolemia due to water retention predisposes peritoneal dialysis (PD) patients to hypertension and can clinically manifest in several forms, including peripheral edema. The approaches to detect edema, which include methods such as bioimpedance, inferior vena cava diameter and biomarkers, are not always available to physicians worldwide. For clinical examinations, the presence of pitting located in the lower extremities and/or over the sacrum to diagnose the presence of peripheral edema in their patients are frequently utulized. We evaluated the impact of edema on the control of blood pressure of incident PD patients during the first year of dialysis treatment. Patients were recruited from 114 Brazilian dialysis centers that were participating in the BRAZPD study for a total of 1089 incident patients. Peripheral edema was diagnosed by the presence of pitting after finger pressure was applied to the edematous area. Patients were divided into 2 groups: those with and without edema according to the monthly medical evaluation. Blood arterial pressure, body mass index, the number of antihypertensive drugs and comorbidities were analyzed. We observed an initial BP reduction in the first five months and a stabilization of blood pressure levels from five to twelve months. The edematous group exhibited higher blood pressure levels than the group without edema during the follow-up. The results strongly indicate that the presence of a simple and easily detectable clinical sign of peripheral edema is a very relevant tool that could be used to re-evaluate not only the patient's clinical hypertensive status but also the PD prescription and patient compliance. Cardiovascular disease is the most common cause of morbidity and mortality in patients with chronic kidney disease (CKD) The reduction in blood pressure levels observed in peritoneal dialysis (PD) patients can be attributed to the continuous effective control of fluid balance and, consequently, extracellular volume Despite the fact that some patients present SAH independently of volemic status, it is recognized that hypervolemia, with or without the presence of edema, is one of the principal factors responsible for the resistance of PD patients to SAH treatment We hypothesized that the presence of pitting edema is associated with the worsening of SAH, which leads to the cardiovascular impact observed in fluid-overloaded patients. Thus, in the present study, we evaluated the impact of peripheral edema on hypertensive control in incident PD patients with SAH during the first year of dialysis treatment.PDnet, which was designed specifically to collect data for this study. From a total of 3439 incident patients, 239 were excluded because they were less than 18 years old, 1650 were excluded for not completing 12 full months of follow up , 430 were excluded because they were normotensive with or without previously using any antihypertensive drugs and because they did not have peripheral edema at the beginning of the PD treatment, and 31 were excluded due to missing data. After exclusion criteria were applied, 1089 hypertensive patients were included in the analysis.Each consecutive incident patient recruited from 114 Brazilian dialysis centers participating in the BRAZPD study from December 2004 through October 2007 was included, totaling 3439 patients. Incident patients were defined as patients who originated from pre-dialysis conservative treatment or HD, who started treatment with PD during the study period and who remained on the therapy for at least 90 days. In Brazil, 60% of the patients start treatment in APD and 40% in CAPD. Details of the BRAZPD study design and characteristics of the cohort are described elsewhere The variables analyzed included anthropomorphic data, comorbidities, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), erythropoietin use, PD modality (CAPD or APD), and physical examination. During the physical examination, peripheral edema was characterized by the presence of pitting after finger pressure was applied to the edematous area for at least five seconds. The nephrologists graded pitting edema on a scale from 1+ to 4+. The urea and plasma creatinine, serum potassium, and hemoglobin values of the patients were measured to be used as annual means.For all patients, the dialysis nurse or the nephrologist measured blood pressure during their monthly visits to the dialysis clinic. For the diagnosis of systemic hypertension, the following WHO/ISH criteria were applied: SAP≥140 mmHg and/or DAP≥90 mmHg, with or without the use of hypertensive medication. SAP levels were verified using an oscillating method. Mean arterial pressure was calculated using the formula MAP = (2DAP+SAP)/3. The number of anti-hypertensive drug classes used monthly by the patients (NAC) was also reported. The classes considered were diuretics, beta-blockers, ACE inhibitors, angiotensin II receptor blockers, centrally and peripherally acting alpha-blockers, and calcium channel blockers. Each class listed was counted as one unit, and the NAC represented the mathematical mean of the number of anti-hypertensive drug classes used per patient for each subgroup.After the exclusion criteria were applied, the final sample consisted of 1089 hypertensive patients. These patients were subdivided into those with (E+) and without (E−) clinically detectable pitting edema, according to the monthly medical evaluation at both the beginning of the observation period and during the twelve months of follow up. The number of patients in each subgroup varied monthly depending on the presentation of edema at that particular evaluation . In ordeCategorical variables are presented as frequencies and percentages. Continuous variables are presented as the mean ± standard deviation (mean ± SD). In the figures, continuous variables are presented as the mean ± standard error. The chi-squared test and analysis of variance (ANOVA), with repeat measures and measures of position and distribution, were utilized for the comparison between the E+ and E− subgroups. The parallelism analysis of both groups was performed to verify the trends and similarities between the groups, for the initial defined groups at month 1. For all analyses, a p-value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 8.0 .2. The correlation between BMI and the number of patients with edema was negative and significant (r = −0.83). The increase of blood pressure  correlated with the number of patients with edema: 0.76; 0.69 and 0.52 respectively (p<0.001).Overall, 42.6% of study participants were diabetic, and the mean number of anti-hypertensive class drugs (NAC) used was 2.1±1.0 drugs/patient. Forty-three percent of patients were on APD using Homechoice™  as the cycler, and all patients were prescribed only glucose-based PD solutions .Descriptive data at baseline PD treatment level (after the first month on PD) for all patients included in this study are shown in Analysis of groups divided by the presence of clinically detectible edemast and 5th month , and SAP remained constant from the 5th month until the end of the study . DAP did not change significantly between the 1st and 12th month . SAP decreased significantly between the 1st and 5th month , and MAP remained constant from the 5th month through the 12th month . NAC did not change between the 1st and 12th months . The number of patients with edema decreased between the 2nd and 6th months from 307 to 245 individuals; this number varied through the end of the evaluation period, at which point 243 patients were clinically diagnosed with edema   presented a decrease in SAP between the 1th edema . BMI inc p<0.05) .th month through the 12th month . NAC did not vary throughout the study period; the mean at the 1st month was 2.0±0.7, and the mean at the 12th month was 2.1±1.1 (p>0.05). For subgroup E−, there was no difference in BMI during the 12 months of follow-up (Subgroup E− (n = 782) presented a significant decrease in SAP between the 1st and 5th month . After this initial period, SAP remained constant until the end of the study period . DAP did not change between the 1st and 12th months . MAP decreased significantly between the 1st and 5th months  and then remained constant from the 5ollow-up  and 4).The descriptive characteristics of the two subgroups defined by the presence of edema at the start of dialysis are shown in et al.et al.It is well known that the expansion of extracellular volume with or without detectible edema is one of the principal factors responsible for the increase in SAP in patients with CKD th month (et al. et al.et al. Upon separate analysis of the E+ and E− groups, we observed a monthly variation throughout the study period in the number of patients. This variation was a consequence of bi-directional flow between these groups. Despite this, the number of patients in the E+ subgroup decreased significantly after 12 months, from 307 to 243 patients . Among tth month  and 4, wth month  and 4. GOur data demonstrated that the NAC in the E+ subgroup, despite not varying throughout the study, was significantly greater than in the E− subgroup during the months evaluated. This observation may suggest a greater difficulty in SAH control in the E+ group. Furthermore, BMI in the E+ group increased progressively over the 12 month period. A strong and negative correlation between BMI and the number of patients with edema was observed. This association could be explained in two ways: a worsening of the edema status during PD therapy or a real gain of body mass. We believe that future studies with adequate designs will help to answer this question.The progressive increase in body weight, likely caused to a large extent by the presence of edema, can be attributed to a water and salt imbalance, the patient's failure to follow medical recommendations, and/or an inadequate PD prescription. The progressive increase in body weight among PD patients might also be attributed to a gain of fat mass due to glucose absorption from the peritoneal cavity, as the patients may have been prescribed more hypertonic PD solutions to improve UF.In the E− subgroup, blood pressure patterns followed the trend observed in the E+ group and decreased in the first months of PD before subsequently stabilizing . In the The present study presents several limitations. Edema evaluation cannot be easily standardized, and the influence of expansion or retraction of volume on the systemic pressure levels could be better analyzed if it was evaluated by other methods, such as bio-impedance, inferior vena cava diameter Hypertensive CKD patients experienced a significant reduction in blood pressure levels after the initiation of PD, which was more pronounced in the first few months of therapy. However, most patients do not achieve normalization during the first year of treatment. This difficulty in reducing arterial blood pressure to normal levels is aggravated by the presence of edema, which points to a pivotal role of fluid overload in the hypertension of CKD patients on dialysis. The presence of clinically detectible pitting edema can be a useful clinical sign that could be used to guide the optimization of SAH treatment in patients undergoing continuous peritoneal dialysis.In summary, volume status is of major importance to outcomes in patients undergoing PD. The lack of a robust edema evaluation and the limited availability of BIA and other objective measures of quantifying volume status make clinicians highly dependent on clinical evaluation. Clinically detectable pitting edema remains the most readily used clinical assessment tool. This study is the first to give a large-scale systematic description of pitting edema in the context of arterial hypertension in PD patients and to assess the effects of edema resolution in blood pressure values with PD initiation.The results presented here strongly indicate that the presence of such a simple and easily detected clinical sign as pitting edema should be considered to be a relevant observational tool to assess a patient's clinical status, PD prescription and compliance with treatment. The term “back to basics" could mean, “examine your patients, look for edema and observe the blood pressure" and to do this sophisticated technologies are not needed.


Hypertension is a major health problem worldwide. Its attendant morbidity and mortality complications have a great impact on patient's quality of life and survival. Optimizing blood pressure control has been shown to improve overall health outcomes. In addition to pharmacological therapies, nonpharmacological approach such as dietary modification plays an important role in controlling blood pressure. Many dietary components such as sodium, potassium, calcium, and magnesium have been studied substantially in the past decades. While some of these nutrients have clear evidence for their recommendation, some remain controversial and are still of ongoing study. Dietary modification is often discussed with patients and can provide a great benefit in blood pressure regulation. As such, reviewing the current evidence will be very useful in guiding patients and their physician and/or dietician in decision making. In this review article of nutritional factors in hypertension management, we aim to examine the role of nutritional factors individually and as components of whole dietary patterns. In adults aged 18 years and older, hypertension is defined as a systolic blood pressure (SBP) equal or more than 140 mmHg and/or diastolic blood pressure (DBP) equal or more than 90 mmHg based on the mean of 2 or more properly measured seated blood pressure readings on each of 2 or more office visits by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) [Clinical and population-based studies show that several components of the diet such as sodium, potassium, calcium, magnesium, fiber, and fish oil affect blood pressure, and modification of these nutritional factors provide an important strategy to control blood pressure especially in the prehypertensive stage (SBP 120–139 mmHg and/or DBP 80–89 mmHg) or stage I hypertension (SBP 140–159 mmHg and/or DBP 90–99 mmHg). The role of these dietary factors singly or in combination in blood pressure regulation and to what extent each contributes has been a subject of research for many decades, and despite this, it remains controversial. Modifying one's diet can be a difficult and significant change in life, and many patients oppose this or fail despite several attempts. Given how frequently clinicians have to provide patients with this recommendation and the potential impact on the overall outcome in patient health, it is of great benefit to study the current evidence in nutritional approach to hypertension management. In this paper, we aim to review the role of each individual dietary factor as well as whole dietary patterns.The relationship between sodium intake and blood pressure changes has been a topic of discussion for decades. Hypertension is predominantly observed in societies with average sodium chloride intake >100 mmol/day and very rare in populations consuming <50 mmol/day , 4. HoweAs a brief review of physiology, sodium homeostasis is maintained by glomerular filtration and tubular reabsorption. Sixty-five to seventy-five percent of sodium reabsorption is mediated by neurohumoral hormone in the proximal (angiotensin II and norepinephrine) and collecting tubules , whereas 30–35% occurs in the loop of Henle and distal tubules and this is flow dependent. A parallel adaptation in renal tubular activity in response to alterations in glomerular filtration of sodium keeps little variation in urinary sodium excretion . This exSalt sensitivity has been found to have a higher prevalence in certain populations: older age , 12, blaDietary sodium restriction is strongly advocated as a lifestyle behavioral change for prevention and treatment of hypertension and consequently cardiovascular morbidity and mortality by several professional organizations , 26–28. Evidence from several clinical studies shows that a reduction in sodium intake leads to modest to large reduction in blood pressure in normotensive and hypertensive participants –36 as weThe INTERSALT study, a population-based study across 52 centers from 32 countries, examined the relationship between sodium excretion and blood pressure among over 10,000 participants. Sodium excretion was highly variable (0.2–242 mmol/24 hour (hr)), with 4 centers having very low levels (0.2–51.3 mmol/24 hr). A significant positive association between sodium excretion and blood pressure in individuals was reported overall. However, with exclusion of data from the 4 centers with the lowest excretion, no relation could be found [The Dietary Approaches to Stop Hypertension (DASH)-sodium trial randomized subjects to either the DASH diet  or a control diet  diet which is high in fat and low in fruits, vegetables, and dairy products) with participants consuming a graded sodium intake  within each group during the study period. The study demonstrated significant dose-response decreases in SBP and DBP overall and blunting of the age-related increase in blood pressure with sodium restriction. The DASH diet and sodium restriction each lowered blood pressure substantially, but the effect was greater when combined , 36.Investigators on a prospective followup study of participants in the trials of hypertension prevention phase I and II for 10–15 years found a 30% and 20% risk reduction of cardiovascular disease  and cardiovascular death, respectively, but the reduction in death was not statistically significant .In contrast, several studies demonstrate harmful effects of lower salt intake on important clinical outcomes including MI , all-cauAll together, despite several years and high magnitude of population-based studies and clinical research, the evidence supporting the recommendation of dietary sodium restriction should be interpreted with caution.Given that salt restriction is not a “one size fits all” approach, differentiating individuals with salt sensitive and salt resistant hypertension would be beneficial. However, subjecting all hypertensive patients to salt sensitivity testing as in research protocols seems inconvenient and unfeasible. Thus, the question appears to be how physicians can clinically determine salt sensitivity. To address this query, a couple of studies have suggested ambulatory, however, indirect methods in evaluating salt responsiveness. De la Sierra and coinvestigators reported that patient's performance on ambulatory blood pressure monitoring could be a useful tool to assess salt sensitivity . In theiCurrently, based on available evidence, the WHO strongly recommends the restriction of daily sodium intake to less than 2000 mg  , while tThe association of potassium and blood pressure has been described in many studies. Potassium intake was found to be inversely related to both DBP and SBP in a population-based study including 685 men and women who were predominantly Caucasian in Southern California, United States of America (USA) . SimilarSeveral interventional studies have shown the positive effects of potassium supplementation on blood pressure reduction. Cappuccio and MacGregor reviewed 19 clinical trials in which oral potassium supplements significantly lowered SBP , −6.6 to −5.2 mmHg) and DBP  . A meta-The benefit of potassium intake on blood pressure reduction appears to be greater in patients with hypertension , 60, lonThe magnitude of blood pressure reduction seems small in number but might be translated into a benefit in mortality from complications of hypertension. In a study of 6 different populations, the relative increase in 25-year mortality risk due to coronary heart disease was 1.17  per 10 mmHg increase in SBP and 1.13  per 5 mmHg increase in DBP. After adjustment for within-subject variability in blood pressure, this relative risk was 1.28 . A 5 mmHIt is worth mentioning that some protective effects of high potassium intake on cardiovascular health might be independent of blood pressure. An analysis of sodium and potassium intake and mortality among US adults based on data from the third National Health and Nutrition Examination Survey (NHANES) showed that higher sodium intake was associated with increased all-cause mortality, while higher potassium intake seemed to be associated with lower mortality. Of note, this finding was independent of sex, age, hypertension, physical activity, and body mass index (BMI) . In a 12The antihypertensive effect of potassium supplementation might be from various mechanisms: (1) natriuresis by inhibiting sodium reabsorption in the proximal renal tubules  and suppBased on available data, the Institute of Medicine has recommended a potassium intake of 4700 mg (120 mmol) a day as adequate intake for all adults . A similIn reality, the average intake of dietary potassium in many countries is relatively lower than recommended. As in a report from the third NHANES 1988–1994 study, estimated mean potassium intakes of adults in the USA ranged from 2900 to 3300 mg in men and 2200 to 2400 mg in women . The NHAFoods rich in potassium are vegetables, fruit, dairy products, nuts, and so forth. Natural source of potassium is preferable. Currently, pharmacological potassium supplementation is not recommended as a method to obtain the advised daily intake of potassium.The relationship between calcium intake and hypertension is a complex and difficult one to isolate largely because of the interaction with other nutrients in the diets and difficulty in reliably collecting calcium intake data and important unmeasured confounding variables.Despite an abundance of studies on the effect of dietary or supplemental calcium on blood pressure, the evidence on its benefit is inconclusive and remains controversial. An inverse relationship between dietary calcium intake and blood pressure has been reported in many studies –89. SimiTwo meta-analyses assessed the relationship between dietary calcium supplementation and blood pressure. The authors found small reductions in SBP (1-2 mmHg), and results were even smaller and insignificant for DBP , 105.Similar results were reported in another meta-analysis by van Mierlo et al., effect on SBP of −1.86 mmHg  and DBP of −0.99 mmHg , however, the impact on SBP was larger in people with relatively low calcium intake of ≤800 mg/day . A CochrCurrently, the evidence on the benefit of calcium supplementation in prevention or treatment of hypertension is weak; therefore, there is no justification to increase the intake of calcium above the recommended dietary allowance of 1000–1300 mg/day based on age and gender. Foods rich in calcium are mainly dairy products (preferably low fat) such as milk, cheese, and yogurt.Proposed mechanisms by which calcium intake regulates blood pressure include alteration in intracellular calcium which in turn affects vascular smooth muscle contraction , effect Magnesium deficiency has been found to result in increased blood pressure in single studies , 130. HoThe evidence of a causal association between magnesium supplementation and blood pressure reduction was weak in a meta-analysis including 12 randomized trials with followup ranging from 8 to 26 weeks . In anotOn the basis of these data, the relationship between magnesium and hypertension seems inconsistent and not convincing. Currently, magnesium supplementation is not recommended as a means of hypertensive treatment.A standard drink in the USA is equal to 14 g (6 ounces (oz)) of pure alcohol. This amount is present in 12 oz of regular beer, 5 oz of wine , 8 oz of malt liquor, and 1.5 oz of 80-proof distilled spirits . This seModerate alcohol intake, defined as a maximum of 2 alcoholic drinks/day in men and 1 alcoholic drink/day in women and lighter-weight persons, is supported by the AHA 2006 scientific statement of hypertension management . In a prOn the other hand, heavy drinking, generally referred to as any amount of alcohol use above the moderate level, is associated with a higher risk of hypertension in a dose-dependent manner. This has been demonstrated in various populations: Japanese men , US womeFiber is the indigestible portion from plant-based food. How exactly fiber might affect blood pressure is not entirely understood. An inverse association between blood pressure and fiber intake has been described. Among 30,681 predominantly white US male health professionals, 40–75 years old, those with a fiber intake of less than 12 g/day were at higher risk of developing hypertension compared to those taking more than 24 g/day, relative risk 1.57  . This reDaily dietary fish consumption as a part of weight reduction regimens has shown benefits in blood pressure fall . A body Mercury is a chemical element of which fish living in contaminated water can contain a high level in their body. Some cross-sectional studies have mentioned the possibility of increasing blood pressure caused by mercury. Would this go against the above findings of a positive correlation between daily fish meal and blood pressure reduction? Recently, two large prospective cohort studies on 6045 US men and women, do not support any effects of methylmercury on the risk of incident hypertension .Garlic is one of the most commonly used natural herbs. Its role in hypertension has also been explored by researchers. In patients with baseline elevated blood pressure, compared with placebo, garlic significantly reduced SBP by 16.3 mmHg  and DBP by 9.3 mmHg  . The effBeing the main ingredient in stimulant drinks, caffeine is found in coffee, tea, sodas, and many energy drinks. Acutely, caffeine can elevate blood pressure in nonhabitual caffeine users , whereasThere is evidence that other ingredient than caffeine might be responsible for the stimulating effect of coffee on blood pressure. An increase in blood pressure was observed in decaffeinated coffee drinkers . The useLicorice has been long used as a flavoring agent in chewing tobacco, candies, spices, and as a medical product in some gastrointestinal and upper respiratory disorders. It contains glycyrrhetinic acid which inhibits 11-beta-hydroxysteroid dehydrogenase enzyme type 2 isoform, allowing cortisol to bind to the mineralocorticoid receptors creating a status of mineralocorticoid excess and subsequently blood pressure elevation. The use of licorice can be potentially dangerous in hypertensive individuals .The DASH diet is a diet rich in fruits and vegetables (4-5 servings/day) and low-fat dairy products (2-3 servings/day) and includes whole grains, poultry, fish, and nuts. This diet is rich in potassium, magnesium, calcium, dietary fiber, and protein and has reduced fat  and cholesterol (<25%), red meat, sweets, and sugar-containing beverages. Two controlled clinical trials established its efficacy in lowering blood pressure , 155. ThThe DASH-sodium trial  was a crAfrican Americans with hypertension derive the most benefit from the blood pressure lowering effect of the DASH diet , howeverOther potential benefits of the DASH diet include reduction in cardiovascular morbidity , 161, moThe DASH and low sodium diet has been endorsed by professional organizations including the AHA , the JNCYour Guide to Lowering your Blood Pressure with DASH, which is a great resource to guide patients in preparation of meals in accordance with the DASH diet [Barriers to compliance with the DASH diet include cost, availability, accessibility, lack of information, and cultural dietary preferences. The US Department of Health and Human Services published a guidebook, ASH diet .The PREMIER trial studied 810 adults with SBP ranging from 120 to 159 mmHg and DBP 80 to 95 mmHg . PatientEarly observation has described lower blood pressure in vegetarians compared to patients on regular diets . It seemIt appears that a vegetarian diet might reduce blood pressure by several factors: increased vegetables, fiber and fruit intake, low protein, and so forth.Dietary modification has important therapeutic roles in blood pressure control. Strong evidence supports the recommendation of a diet containing high potassium, moderate alcohol, and high fiber intake. As a whole, a DASH pattern diet rich in fruits, vegetables, low-fat dairy products, whole grains, nuts, and fish with reduced amount of red meat, fat, sugar-sweetened food and beverages, and/or a vegetarian diet, which is also high in vegetables and fruits and low in animal protein should be considered. The use of pharmacological supplements to achieve these dietary goals is not advised. Sodium restriction is strongly recommended by professional organizations, however, this needs to be carefully interpreted and individualized given the evidence of associated potential harmful effects and its unequal efficacy in various patient populations. The recommendation is not quite definite in terms of increased intake of calcium, magnesium, fish oil, and garlic. Irregular coffee drinkers and licorice consumers face a possibility of inducing hypertension; thus, these habits need to be avoided in patients at risk. Established nutrition recommendations are proven to be helpful in reducing blood pressure and thus hypertension-related complications and overall mortality. However, in view of the heterogeneity in risk factors, patient features, and pathogenesis of hypertension, the approach should be individualized and discussed in detail between the patient and their physician and/or dietician, based on the understanding of each patient's distinct disease characteristics.The importance of dietary modification in hypertension management has been substantially studied for past decades with encouraging findings. Additional studies are warranted to further explore the role of these nutrient factors in preventing and treating this condition in special populations.


C), was evaluated. Total RNA was extracted from leukocytes of C (n = 8) and of HF patients  with a PAXgene Blood RNA Kit. An increase as a function of clinical severity was observed in each AR . The mRNA expression of the ectonucleoside triphosphate diphosphohydrolase (CD39) and the ecto-5′-nucleotidase (CD73) were also evaluated. They resulted up-regulated. These findings show that components of adenosine metabolism and signalling are altered to promote adenosine production and signalling in HF patients. Thus, HF may benefit from adenosine-based drug therapy after confirmation by clinical trials.In this study the transcriptomic profiling of adenosine receptors (ARs) in human leukocytes of heart failure (HF) patients as a function of clinical severity, assessing the possible changes with respect to healthy subjects ( Adenosine is a potent extracellular messenger produced in high concentrations under metabolically unfavorable conditions . Adenosi2aR receptors can contribute to tissue repair by enhancing paracrine adaptive mechanisms, by improving engraftment of circulating progenitor cells, or by promoting proliferation and differentiation of bone marrow mesenchymal stem cells in vivo [In particular, adenosine receptors such as A in vivo . MoreoveThe ability of adenosine to inhibit cardiac fibroblast proliferation and collagen synthesis may help attenuate cardiac remodelling and fibrosis of ischemic or failing hearts , 4, thusDespite great advances in the field of pharmacological and nonpharmacological treatment, at present , the ris1R, A2aR, A2bR, and A3R mRNA expression was evaluated in human whole blood of normal subjects [Based on previous studies showing that in cardiovascular disease human circulating blood cells may mirror the same abnormalities occurring in the heart , studiessubjects . The fousubjects , providiThe aim of this study was to evaluate the transcriptomic profiling of ARs in human leukocytes of HF patients as compared to healthy subjects and to assess whether this profiling is related to the clinical severity of the disease.The study conforms with the principles outlined in the Declaration of Helsinki approved in 1964. The study was approved by the local Ethical Committee, and all patients provided signed informed consent.n = 9 and NYHA III-IV: n = 14) were collected into PAXgene Blood RNA system (DIALAB ITALIA Srl) tubes.Human whole blood samples (2.5 mL) from eight healthy adults and from 23 HF patients  to obtain total RNA.In all cases, the integrity of total RNA was detected by electrophoresis on Gel-Star  stained 1.5% Agarose  gel; total RNA purity and concentration were evaluated spectrophotometrically . The RNA samples were stored at −80°C.In μg of total RNA obtained from each sample was reverse-transcribed with iScript cDNA Synthesis Kit  according to the manufacturer's instructions.A quantity of 0.5 1R (Hs_ADORA1_2_SG Quantitect Primer assay), A2aR (Hs_ADORA2a_1_SG Quantitect Primer assay), A2bR (Hs_ADORA2b_1_SG Quantitect Primer assay), and A3R (Hs_ADORA3_2_SG Quantitect Primer assay), while the ectonucleoside triphosphate diphosphohydrolase (CD39) and the ecto-5′-nucleotidase (CD73) designated for the dephosphorylation of extracellular ATP to AMP were synthesized by sigma-Aldrich  candidate reference genes , and sterile water. Amplification protocol started with 95°C for 3 min followed by 39 cycles at 95°C for 10 s and 60°C for 30 s. To assess product specificity, amplicons were checked by melting curve analysis. Melting curves were generated from 65°C to 95°C with increments of 0.3°C/cycle. An interrun calibrator was used to allow comparison of Ct values obtained in different runs. The mean standard deviation for Ct values was 0.09. All reactions were performed in duplicate.RT-PCR reactions were performed in a 96-well CFX96 RT-PCR system (Bio-Rad). The reaction was carried out in a total volume of 25 TOP2b, YWHAZ, and SRP14) was used for normalization of each gene mRNA expression in the samples [Ct method using iQ5 software (BioRad). Differences between more than two independent groups were analyzed by Fisher's test after ANOVA. Differences between two independent groups were assessed by un-paired t-test. Relations between variables were assessed by linear regression.GeNorm software was used to define the most stably expressed gene set, as previously described , 15. The samples . The relP value was considered significant when <0.05.The results are expressed as mean ± SEM, and A260/A280 nm) of all preparations was between 1.9 and 2.1. All samples were subject to gel electrophoresis to prove the integrity of 18 and 28 S ribosomal RNAs. The amount and purity of RNA were evaluated by absorption wavelengths of 260 nm and 280 nm, and the absorption ratio .CD39 and CD73 transcript levels resulted upregulated in human leukocytes of HF patients as a function of clinical severity, although not significantly , angiotensin receptor blockers, or aldosterone analogs have been proven effective for the treatment of HF in large-scale clinical trials [Adenosine attenuates the release of catecholamines, l models , 29. Alll trials , 31, butl trials , 33. The2aR [2aR pathway in order to prevent exacerbations of cytotoxic leukocytes functions.Moreover, an increasing body of evidence suggests an amplification of oxidative stress in circulating leukocytes of patients with HF, implying a contribution to the oxidative damage. Adenosine may have the potential to limit the oxidative stress response of leukocyte through an upregulation of A2aR , 29, 34 The results of this study are in line with previous ones performed in normal and failing minipig hearts , 36 and RT-PCR is the benchmark method for measuring mRNA expression levels, but the accuracy and reproducibility of its data greatly depend on appropriate normalization strategies. In order to avoid a confounding effect due to reference gene variability between samples, of the many strategies suggested , 41, theThe findings of this study show that components of adenosine metabolism and signalling are altered to promote adenosine production in HF patients as a function of clinical severity. These changes include the upregulation of CD39-CD73 and elevations in each of the four AR subtypes. These data provide proof of the concept that adenosine-based drugs may play a role in the treatment of HF patients, after confirmation by randomized clinical trials.


The aim of the present study was to assess the tolerance and safety of a high-dose adenosine protocol (210mcg/kg/min) in patients with inadequate hemodynamic response to the standard adenosine dose (140mcg/kg/min) when undergoing CMR perfusion imaging.Adenosine is the most widely used vasodilator stress agent for Cardiovascular Magnetic Resonance (CMR) perfusion studies. With the standard dose of 140 mcg/kg/min some patients fail to demonstrate characteristic hemodynamic changes: a significant increase in heart rate (HR) and mild decrease in systolic blood pressure (SBP). Whether an increase in the rate of adenosine infusion would improve peripheral and, likely, coronary vasodilatation in those patients is unknown.98 consecutive patients with known or suspected coronary artery disease (CAD) underwent CMR perfusion imaging at 1.5 Tesla. Subjects were screened for contraindications to adenosine, and an electrocardiogram was performed prior to the scan. All patients initially received the standard adenosine protocol (140 mcg/kg/min for at least 3 minutes). If the hemodynamic response was inadequate (HR increase <10bpm or SBP decrease <10mmHg) then the infusion rate was increased up to a maximum of 210 mcg/kg/min .All patients successfully completed the CMR scan. Of a total of 98 patients, 18 (18%) did not demonstrate evidence of a significant increase in HR or decrease in SBP under the standard adenosine infusion rate. Following the increase in the rate of infusion, 16 out of those 18 patients showed an adequate hemodynamic response. The hemodynamic parameters at rest and during adenosine stress are shown on table 2. Two patients of the standard infusion group and one patient of the high-dose group developed transient advanced AV block. Significantly more patients complained of chest pain in the high-dose group  .On multivariate analysis, age > 65 years and ejection fraction <57% were the only independent predictors of blunted haemodynamic responsiveness to adenosine.A substantial number of patients do not show adequate peripheral hemodynamic response to standard-dose adenosine stress during perfusion CMR imaging. Age and reduced ejection fraction are predictors of inadequate response to standard dose adenosine. Our initial experience with a high-dose adenosine protocol (up to 210 mcg/kg/min) shows that it is well tolerated and results in adequate hemodynamic response in nearly all patients.


Non-invasive measurements of 24 hour ambulatory central aortic systolic pressure (24 h-CASP) and central pulse pressure (24 h-CPP) are now feasible. We evaluate the relationship between 24 h central blood pressure and diabetes-related complications in patients with type 1 diabetes.The study was cross-sectional, including 715 subjects: 86 controls (C), 69 patients with short diabetes duration (< 10 years), normoalbuminuria (< 30 mg/24 h) without receiving antihypertensive treatment (SN), 211 with longstanding diabetes (≥ 10 years) and normoalbuminuria (LN), 163 with microalbuminuria (30-299 mg/24 h) (Mi) and 186 with macroalbuminuria (> 300 mg/24 h) (Ma).24 h-CASP and 24 h-CPP was measured using a tonometric wrist-watch-like device  and derived using N-point moving average.p < 0.001); and 24 h-CPP: 38 ± 8, 38 ± 7, 44 ± 10, 46 ± 11 and 46 ± 11 mmHg, (p < 0.001).In C, SN, LN, Mi and Ma mean ± SD 24 h-CASP was: 114 ± 17, 115 ± 13, 121 ± 13, 119 ± 16 and 121 ± 13 mmHg (p ≤ 0.031).Following rigorous adjustment , 24 h-CASP and 24 h-CPP increased with diabetes, albuminuria degree, previous cardiovascular disease (CVD), retinopathy and autonomic dysfunction  were for CVD: 3.19 (1.68-6.05), 1.43 (1.01-2.02) and 2.39 (1.32-4.33), retinopathy: 4.41 (2.03-9.57), 1.77 (1.17-2.68) and 3.72 (1.85-7.47) and autonomic dysfunction: 3.25 (1.65-6.41), 1.64 (1.12-2.39) and 2.89 (1.54-5.42).vs. controls and increased with diabetic complications independently of covariates. Furthermore, 24 h-CASP was stronger associated to complications than 24 h-SBP.24 h-CASP and 24 h-CPP was higher in patients The prognostic significance of 24 h-CASP and 24 h-CPP needs to be determined in follow-up studies.NCT01171248.ClinicalTrials.gov ID  Blood pressure (BP) control is of paramount importance in prevention of complications in type 1 diabetes . DespiteRoutinely, seated BP measurements are recorded over the brachial artery in the physician’s office. However, increasing evidence points towards superior predictive value of out-of-office measurements such as 24 hour ambulatory BP (AMBP)  and homeCentral and brachial pressures are mutually influenced by cardiac output, vascular resistance and conduit artery rigidity. Whilst mean arterial pressure (MAP) is relatively constant across large arteries, systolic pressure waves are amplified as they move from the aortic root to the brachial artery. This amplification results in a higher brachial systolic BP (SBP) relative to the corresponding CASP . With agMeasurement of ambulatory 24 h-CASP and 24 h-CPP are now feasible, and a recent study showed a difference in central and brachial diurnal patterns, which could imply that central BP possess additional prognostic value . We invevs. 54 ± 13 years and 56% males (p < 0.001 and 0.62). In addition, a control group of 51 non-diabetic subjects from Copenhagen, Denmark and 46 non-diabetic subjects from Leichester, UK were included.Between September 2009 and June 2011, Caucasian patients with TIDM, were recruited to enter a cross-sectional study at Steno Diabetes Center, Copenhagen, Denmark. Recruitment was in sequential order according to date of birth from a list of all patients attending the outpatient clinic. For power calculations we used an α-value of 5%, a β-value of 20%, and an estimated variance of 9.5 mmHg. For the comparison between controls and patients we estimated a 24 h-CASP-difference of 4 mmHg between groups, which implied that we needed a minimum of 45 participants in each group. For the comparisons between patient groups , we estimated a 24 h-CASP-difference of 2 mmHg, indicating a need for 177 patients in each group. Thus, we intended to include at least 45 controls and 576 patients. Of 1285 patients invited, 676 (52.6%) agreed to enter the study. Patients declining participation were younger but with similar gender distribution compared to participating patients  patients and 90 (92.9%) controls had adequate ambulatory AMBP available, with 46 ± 7 and 18 ± 3  recordings during day and night, respectively. Four controls and 25 patients with normoalbuminuria and short diabetes duration received AHT and were excluded in order to create two comparable groups not treated for hypertension. The remaining groups of patients had no restriction regarding AHT , and all participants gave written informed consent.Participant attended one single study visit, during which all clinical and laboratory measurements were performed. For office BP, 15 minutes supine rest was followed by recording and averaging of three separate left brachial measurements .AMBP were recorded non-invasively, using a validated system consisting of a radial arterial tonometer embedded in an articulating strap of a wrist-watch device . The device was calibrated to brachial BP and variations in pulse waveform height over the subsequent measurement period used to calculate brachial AMBP . CalibraFollowing 15 minutes supine rest, office measurements of central BP were obtained with the SphygmoCor device  by trained laboratory technicians according to guidelines.Electrocardiographs (ECG) were recorded with Cardiosoft V6.51  and LVH defined according to Sokolow-Lyon, Cornell and/or Romhilt-Estes score  by the i1c was measured by high-performance liquid chromatography , urinary albumin excretion rate (UAER) was measured in 24 h sterile urine collections by enzyme immunoassay, and plasma creatinine concentration by an enzymatic method .All participants had blood samples and phenotypic characteristics collected. HbAPatients were stratified as normoalbuminuric if two out of three consecutive measurements contained normoalbuminuria with UAER < 30 mg/24 h, and micro- or macroalbuminuric if UAER was or previously recorded between 30–299 mg/24 h or above 300 mg/24 h, in two out of three consecutive measurements, respectively. Estimated GFR (eGFR) was calculated by the four variable Modification of Diet in Renal Disease (MDRD) formula. Based on standardized questionnaires, current daily use of ≥ 1 cigarettes/cigars/pipes classified smokers. Previous of CVD was myocardial infarction, stroke, or peripheral arterial disease based on standardized WHO questionnaires and patient records from Steno Diabetes Center.Normally distributed variables are given as mean ± SD. The non-normally distributed variable (UAER) is given as median (range) and log10 transformed before analysis. Comparisons between groups were performed by unpaired Student’s t-test or analysis of variance (ANOVA).1c, smoking and antihypertensive treatment. In comparisons including controls HbA1c and antihypertensive treatment was left out.Univariate and mulitivariate linear regression compared hemodynamic variables with covariates. Analysis of covariance (ANCOVA) was applied for multivariable adjustment when comparing hemodynamic variables in different groups and in patients with or without complications. Adjustments were made for gender, age, 24 h-MAP, 24 h-HR, eGFR, HbAThe multivariate logistic regression between hemodynamic variables and diabetic complications also included UAER and office CASP, CPP or SBP. Although for LVH the analyses were only adjusted for gender, age and 24 h-MAP.p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows, version 20.0 .A two-tailed 1c, total cholesterol, eGFR, UAER, pulse wave velocity, HRV, frequency of previous CVD, retinopathy status and presence of LVH (p > 0.11). Table 1c, smoking and antihypertensive treatment.Characteristics of the analysed cohort consisting of 629 patients and 86 controls are shown in Tables 1c or body mass index.Correlations between covariates and 24 h-CASP, 24 h-CPP and 24 h-SBP in all participants are shown in Table p ≤ 0.001).In adjusted analyses only age, diabetes duration, 24 h-MAP, 24 h-HR and UAER correlated with 24 h-CASP, 24 h-CPP and 24 h-SBP . For comparison, the correlation between office CASP measured by SphygmoCor and supine brachial SBP was also high , indicative of an overall close relation between CASP and brachial SBP. However, despite the close correlation, there was a scatter between central and brachial measurements as seen in Figure p < 0.001 for 24 h, daytime and nighttime BPs). As was the correlation between 24 h-CASP and office CASP .Correlations between 24 h-CASP and 24-SBP were high  (Tables p ≥ 0.61). Controls compared to all normoalbuminuric patients (SN and LN) had lower 24 h-CASP and 24 h-CPP  . Additional adjustment for body mass index and total cholesterol did not alter these results (p = 0.016 and 0.018).C and SN had similar 24 h-CASP and 24 h-CPP (unadjusted p = 0.19), while 24 h-CPP was almost similar between groups (p = 0.14) (Table p < 0.001 for both) (Table p ≤ 0.001)Between the groups with LN, Mi, and Ma, 24 h-CASP was lowest in Mi albeit not statistically significant (h) Table . If invevs. without a history of CVD was 121 ± 14, 49 ± 11 and 127 ± 16 vs. 119 ± 14, 43 ± 10 and 129 ± 16 mmHg . Following adjustment, 24 h-CASP, 24 h-CPP and 24-h SBP was higher in patients with a history of CVD . Per 1 standard deviation (SD) increase in 24 h-CASP, 24 h-CPP and 24-h SBP the odds ratio (OR) for previous CVD was 3.2 (1.7-6.1), 1.4 (1.0-2.0) and 2.4 (1.3-4.3)  ) vs. without LVH were 125 ± 11, 48 ± 11 and 132 ± 15 vs. 119 ± 14, 44 ± 10 and 128 ± 16 mmHg . Following adjustment for gender, age and 24 h-MAP the significance attenuated . Per 1 SD increase in 24 h-CASP, 24 h-CPP and 24 h-SBP, the OR for LVH was 2.5 (1.0-6.5), 1.5 (1.0-2.3) and 2.1 (0.9-5.0)  ) vs. without retinopathy, 24 h-CASP, 24 h-CPP and 24 h-SBP was 121 ± 14, 46 ± 11 and 130 ± 15 vs. 115 ± 14, 39 ± 8 and 124 ± 15 mmHg . Following adjustment all three BP’s were higher in patients with retinopathy . Per 1 SD increase in 24 h-CASP, 24 h-CPP and 24 h-SBP, the OR for presence of retinopathy was 4.4 (2.0-9.6), 1.8 (1.2-2.7) and 3.7 (1.9-7.5)  ) vs. without autonomic dysfunction had 24 h-CASP, 24 h-CPP and 24 h-SBP of 121 ± 14, 47 ± 11 and 130 ± 16 vs. 117 ± 12, 40 ± 8 and 126 ± 13 mmHg . Following adjustment, 24 h-CASP, 24 h-CPP and 24 h-SBP remained significantly higher in patients with autonomic dysfunction . Per 1 SD increase in 24 h-CASP, 24 h-CPP and 24 h-SBP the OR for presence of autonomic dysfunction was 3.3 (1.7-6.4), 1.6 (1.1-2.4) and 2.9 (1.5-5.4)   of 587 assessed patients. Patients with p ≤ 0.045) associated with all complications except albuminuria (data not shown), suggesting additional risk information of 24 hour measurements as compared to office measurement. Furthermore, 24 h-CASP was closer associated to diabetic complications as compared to 24 h-SBP.This is the first study to measure 24 h-CASP and 24 h-CPP in patients with type 1 diabetes. The adjusted values of 24 h-CASP and 24 h-CPP was lower in controls compared to normoalbuminuric patients, and associated with increasing degree of albuminuria. Furthermore, 24 h-CASP and 24 h-CPP was higher in patients with a history of CVD, retinopathy and autonomic dysfunction, but similar in patients with and without LVH on ECG. Importantly, the positive associations were present despite rigorous adjustment for baseline characteristics including brachial 24 h-MAP. If we further included office CASP or office CPP in the adjustments, both 24 h-CASP and 24 h-CPP remained significantly  in type 2 diabetes to influence development of retinopathy  and highLonger diabetes duration with presence of autonomic dysfunction does affect BP regulation. This is partly due to autonomic dysfunction being associated with altered vascular adrenoceptor sensitivity and catecholamine release ,34, alteThe close correlation between 24 h-CASP and 24 h-SBP is understandable, as both were calculated from the same radial pulse wave. Given this close correlation, 24 h-CASP may not be superior to 24 h-SBP. However, we show that measurements of 24 h-CASP are feasible, and that values are strongly associated with diabetic complications, independently of brachial 24 h-MAP. Furthermore, we also exposed 24 h-CPP to be associated with diabetic complications, and the correlation between 24 h-CPP and 24 h-SBP was much weaker. Thus, despite the correlations between central and brachial BPs, the former may offer additional risk predictive value. This is in accordance with other studies, which have documented central BP to be closer associated with end organ damage  and supeIn a future perspective, the 24 h-CASP and 24 h-CPP may offer additional predictive value to 24 h-SBP in patients with type 1 diabetes. However, whether these methods of evaluating central stiffness will add prognostic information or, if there is any prognosis superiority between them, can only be determined in prospective studies. If subtle differences in 24 h-CASP and 24 h-SBP impact on outcome, targeting control of CASP rather than SBP may be more efficient in prevention of complications. The CAFE study, a sub-study of the ASCOT trial, investigated the effect of reducing CASP, and showed calcium blockers and beta blockers to exhibit different effect on CASP despite similar effect on SBP . AnotherWe suggest that CASP and CPP may supplement the predictive value of brachial BP in patients with type 1 diabetes. Moreover, central BP could be a future target for BP monitoring and control. Although, follow-up of this and other future prospective studies are required to verify if modifying CASP and/or CPP may supplement or even exceed the predictive value of modifying brachial BP on diabetic complications.vs. without LVH were different in size, which limits the statistical power of these analyses. Furthermore, the diagnosis of LVH was solely based on ECG’s, which has a lower specificity and sensitivity than cardiac imaging.The 24 h-CASP and 24 h-CPP was measured by a wrist bound tonometric device. This device has previously been validated with other non-invasive and invasive measurements ,21,22. MWe did adjust for antihypertensive treatment in general. However, it was not possible to compare patients receiving different single agent regiments, as most patients received several different agents.Major strengths are the remarkably high sample size, and the study being from a single center, why the cohort was likely rather homogenous and receiving similar treatment. The majority of patients had been followed at the Steno Diabetes Center for more than a decade, rendering the information on diabetic complications very reliable.This is the first study to measure 24 h-CASP and 24 h-CPP in patients with type 1 diabetes. The 24 h-CASP and 24 h-CPP was increased in patients with type 1 diabetes compared to controls and increased with albuminuria, CVD, retinopathy and autonomic dysfunction independently of covariates. Furthermore, 24 h-CASP appeared to be stronger associated with complications as compared to 24 h-SBP. As measurement of 24 h ambulatory central BP is now feasible, further studies are required to determine its prognostic significance in patients with diabetes.AHT: Antihypertensive treatment; AMBP: 24-hour ambulatory blood pressure; BPro: BPro HealthStats; CVD: Cardiovascular disease; CASP: Central aortic systolic pressure; CPP: Central pulse pressure; DBP: Diastolic blood pressure; ECG: Electrocardiogram; eGFR: Estimated glomerular filtration rate; HR: Heart rate; MAP: Mean arterial pressure; PP: Pulse pressure; SBP: Systolic blood pressure; UAER: Urinary albumin excretion rate.Williams is a National Institutes for Health Research (NIHR) Senior Investigator, supported by the University College London NIHR Biomedical Research Centre, London UK. Williams and Lacy have worked in scientific collaboration with HealthStats, Singapore developing methods for non-invasive derivation of central pressures from radial artery wave forms. Theilade, Lajer, Hansen, Joergensen, Persson, Andrésdottir, Reinhard, Nielsen and Rossing have received no grants/support and have nothing to disclose and no conflicts of interest.ST researched and analysed the data, contributed to the discussion, wrote and edited the manuscript. ST is the guarantor for the manuscript. ML researched the data, contributed to the discussion and reviewed the manuscript. TWH analysed the data, contributed to the discussion, edited and reviewed the manuscript. CJ, FP and HR researched the data and reviewed the manuscript. GA and SEN researched the data. PL and BW contributed to the data analyses, and the discussion and edited the manuscript. PR researched and analysed the data, contributed to the discussion and reviewed the manuscript. All authors read and approved the final manuscript.


In addition, there is no consensus whether these variables are interchangeable. The objective of this study was to evaluate the influence of tissular perfusion on the correlation between the central venous (SvcO2), the mixed venous (SvO2) and the atrial oxygen saturations (SvaO2) by the analysis of arterial lactate.Even though there has been quite a discussion on whether venous oxygen saturations are useful to guide treatment during initial resuscitation of sepsis, using mixed and central venous oxygen saturations as goals is still advised in the Surviving Sepsis Campaign under strong recommendation but a low level of evidence (1C). According to these guidelines, SvOA prospective observational study; the populations from three ICUs of the Hospital São Paulo were evaluated from October 2011 to November 2012 and patients diagnosed with severe sepsis or septic shock monitored by pulmonary artery catheter (PAC) were included. Hyperlactatemia was defined as an arterial lactate value >28 mg/dl and the correct location of the PAC was confirmed by chest radiography and pulmonary artery pressure tracings. For the statistical analysis, samples were allocated into two groups: normal lactate levels (Group 1) and hyperlactatemia (Group 2). Results were expressed in mean ± standard deviation or median (25 to 75% percentiles) or percentages.2 and SvO2 were shown not to be acceptable surrogates by the analysis of the Bland-Altman plots, but bias and limits of agreement were narrower in Group 1 (Figures Twenty-one patients were included; altogether, 65 paired blood samples were obtained Table . A highe Figures .2, but also on the SvcO2. There was no agreement between those variables either.In patients with hyperlactatemia, a global tissular perfusion marker, venous oxygen saturations presented a higher correlation and narrower bias and limits of agreement, suggesting, perhaps, that under high arterial lactate levels there is a generalized hypoperfusion that reflects not only on the SvO


Introduction. Diabetes and its vascular complications are main noncommunicable chronic diseases and major global health issues. Peripheral arterial disease (PAD) is highly prevalent in diabetes with nephropathy. We evaluated the associations of variables of arterial stiffness and the decline in estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. Materials and Methods. A total of 577 type 2 diabetic patients  were enrolled. A rapid decline in eGFR was defined as progressively lower eGFR detected at both the 6- and 12-month follow-up visits, plus a reduction in eGFR more than 3 mL·min−1per 1.73 m2 per year. Results. Higher glycated hemoglobin (HbA1c), systolic blood pressure (SBP), pulse pressure (PP), and brachial-ankle pulse wave velocity (ba-PWV) at baseline were independently associated with a rapid decline in eGFR. The adjusted odds ratios  for a rapid decline in eGFR for ba-PWV, SBP, and PP were 1.072 (1.011–1.136), 1.014 (1.004–1.025), and 1.025 (1.008–1.041), respectively, after adjustment for gender, age, body mass index, smoking, HbA1c, and baseline eGFR in separated models. Conclusions. Ba-PWV may serve as a simple and noninvasive predictor of rapid renal function progression in type 2 diabetic patients. With rapid growth in patients with type 2 diabetes, a varying degree of renal complications caused by chronic kidney disease (CKD) has imposed a high burden of disease-related morbidity and mortality . In fact−1per 1.73 m2), malignancy, acute myocardial infarction, amputations, or arrhythmia. Those with an ABI of >1.3 or <0.95 were also excluded. An ABI of >1.3 indicates calcification in the lower limbs, and it is difficult to assess for possible obstructive lesions [−1per 1.73 m2) = 186 × Cr−1.154  × age−0.203 ×  ×  [Data were adapted from a retrospective cohort study conducted at an outpatient clinic in central Taiwan. We enrolled type 2 diabetic patients who regularly visited the outpatient departments of our hospital for at least 1 year and underwent ABI, TBI, and brachial-ankle pulse wave velocity (ba-PWV) examinations between October 2008 and August 2009. In addition, the renal function of all enrolled patients was evaluated at the 6 and 12 months after baseline at follow-up visits. These values were used to derive the slope of the eGFR. In addition, baseline clinical characteristics and measurements of the ABI, TBI, and ba-PWV were collected. Patients were excluded if they were undergoing dialysis or had a history of stroke, stage V chronic kidney disease  , eGRF waABI, TBI, and ba-PWV were measured using the Vascular Profiler 1000 , while patients were in the supine position and after resting for at least 5 min in an air-conditioned room (approximately 25°C). SBP, DPP, ba-PWV, and electrocardiogram data were recorded simultaneously. The equation used to calculate ba-PWV is as follows: ba-PWV = (La − Lb)/Tba, where La represents the length from the suprasternal notch to the ankle (La = 0.8129 × height (cm) + 12.328), Lb represents the length from the suprasternal notch to the right brachium (Lb = 0.2195 × height (cm) − 2.0734), and Tba is the time interval between the brachial and ankle arteries measured between the front wave of the brachial and ankle waveforms . ABI wasClinical data  were entered into the profiler. The device measured these data simultaneously. SBP refers to the highest brachial SBP of the patient, and DBP is the brachial DBP measured on the same side as the SBP. PP was calculated as SBP minus DBP. We reviewed patients' medical records to obtain their history of smoking  and medications at baseline. Overnight fasting blood samples were collected for measurement of plasma glucose, HbA1c, and serum cholesterol levels. HbA1c levels were measured by boronate affinity high-performance liquid chromatography . Fasting plasma glucose levels were measured by the glucose oxidase-peroxidase method. Serum cholesterol levels were assayed using the enzymatic method, and triglyceride levels were assayed with the enzymatic GPO-Trinder. The homogeneous method was used to measure high-density lipoprotein cholesterol and low-density lipoprotein cholesterol concentrations, and the UniCel DxC 800 Chemistry Analyzer  was used to determine serum creatinine concentration. Spot urinary albumin was measured by turbidimetric method and urine creatinine was measured using the modified kinetic Jaffé method .−1·1.73 m−2 per year [−1per 1.73 m2 in the overall population and 1.51 mL·min−1per 1.73 m2 per year in south Asian patients [−1per 1.73 m2 per year [−1per 1.73 m2 per year, were defined as having a rapid decline in eGFR; those who did not show such changes were considered to be patients without a rapid decline in eGFR.The Kidney Disease Outcomes Quality Initiative guidelines developed by the National Kidney Foundation state that eGFR should normally decrease by 1 mL·minper year , 22. A rpatients . Based oper year , 25. In t-tests to detect differences between patients with and without a rapid decline in eGFR. Chi-square tests were used to assess differences based on gender, smoking status, and the use of medications. The adjusted odds ratios (OR) of risk factors for a rapid decline in eGFR were determined by multivariate logistic regression analysis. Receiver operating characteristic curves for ba-PWV, PP, SBP, and TBI levels were constructed, and the area under each curve (AUC) was calculated. Statistical significance was defined as P < 0.05. The linear correlations between arterial functional markers at baseline and the change of eGFR were determined by Pearson correlation. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 19.0 for Windows .All descriptive data are presented as mean ± standard deviation (SD). Statistical analyses were performed using independent sample −1per 1.73 m2; 116 patients (20.1%) experienced a rapid decline in eGFR, whereas the remainder  did not. P < 0.05). Although TBI values were lower and the fasting plasma glucose levels were higher in patients with rapid renal function decline, the differences were not significant. The distributions of each medication profile were similar between the 2 groups, except that sulfonylurea was used more commonly in those with rapid eGRF decline (P = 0.004) (−1per 1.73 m2. Those patients with a rapid decline in eGFR (n = 52) had significantly higher baseline UACR  than those without rapid decline of eGFR (n = 163). We also detected that higher baseline baPWV levels were associated with progression of UACR during one-year period .A total of 577 type 2 diabetic patients fulfilled the inclusion criteria with medical records containing at least 3 eGFR measurements at baseline, 6 months, and 12 months. Patients had a mean age of 63 ± 11 years . The mean baseline value of eGFR was 92 ± 28 mL·min= 0.004) . The basP values for the AUC of these arterial functional markers were all < 0.05, indicating statistical significance (AUC > 0.5) (The effects of aging on eGFR are well known . TherefoC > 0.5) .Results of the correlation analysis between several arterial functional indexes and eGFR are shown in P) for a rapid decline in eGFR for ba-PWV, SBP, PP, and TBI were 1.072 , 1.014 , 1.025 , and 0.338 , respectively (t-test P = 0.004) and found that markers of arterial stiffness remained independent risk factors for a rapid decline in eGFR, whereas the effects of HbA1C on rapid renal function progression became nonsignificant  and blood pressure (both SBP and PP), arterial compliance (measured by ba-PWV) was associated with a rapid decline in eGFR during a 1-year follow-up period in type 2 diabetic outpatients without apparent cardiovascular disease or peripheral arterial occlusive disease .The presence of arterial stiffness in patients with cardiovascular pathology may be observed even at an early stage of the disease. Previous studies have demonstrated that ba-PWV is a predictor of the future development of coronary artery disease, major cardiovascular events, and heart failure and that it is a factor in the short-term prognosis of type 2 diabetes in patients with coronary artery disease , 28. In −1per 1.73 m2during a 5-6-year follow-up period [The ba-PWV value reflects the stiffness of peripheral muscular arteries and is simpler and more convenient to perform . In addip period . Our stup period . BecausePrevious studies reported that peripheral arterial occlusive disease, measured by ABI or TBI, is more prevalent in diabetic patients with CKD , 37–39. The ba-PWV values obtained from our cohort with type 2 diabetes were higher than those reported previously in studies conducted in healthy populations  and simiA recent study that followed patients with type 2 diabetes for 10 years reported that the predictors of a decline in eGFR included hypertension, increased HbA1c levels, and insulin use . PreviouThe main limitation of our study is the retrospective nature of the study design. The ba-PWV was only measured once (at enrollment); however, the validation of these methods has been described previously . This stIn conclusion, our results demonstrated that, in addition to traditional and vascular functional markers such as HbA1c, SBP, and PP, values of ba-PWV were independently associated with rapid renal function decline in a group of type 2 diabetic patients without symptomatic cardiovascular disease. Screening type 2 diabetic patients using ba-PWV, a simple and noninvasive marker, may help identify patients at high risk for a short-term decline in renal function.