When safe to do so, avoiding blood transfusions in cardiac surgery can avoid the risk of transfusion-related infections and other complications while protecting a scarce resource and reducing costs. This protocol describes a kidney substudy of the Transfusion Requirements in Cardiac Surgery III (TRICS-III) trial, a multinational noninferiority randomized controlled trial to determine whether the risk of major clinical outcomes in patients undergoing planned cardiac surgery with cardiopulmonary bypass is no greater with a restrictive versus liberal approach to red blood cell transfusion.The objective of this substudy is to determine whether the risk of acute kidney injury is no greater with a restrictive versus liberal approach to red blood cell transfusion, and whether this holds true in patients with and without preexisting chronic kidney disease.Multinational noninferiority randomized controlled trial conducted in 73 centers in 19 countries (2014-2017).Patients (~4800) undergoing planned cardiac surgery with cardiopulmonary bypass.The primary outcome of this substudy is perioperative acute kidney injury, defined as an acute rise in serum creatinine from the preoperative value (obtained in the 30-day period before surgery), where an acute rise is defined as ≥26.5 μmol/L in the first 48 hours after surgery or ≥50% in the first 7 days after surgery.2).We will report the absolute risk difference in acute kidney injury and the 95% confidence interval. We will repeat the primary analysis using alternative definitions of acute kidney injury, including staging definitions, and will examine effect modification by preexisting chronic kidney disease (defined as a preoperative estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 mIt is not possible to blind patients or providers to the intervention; however, objective measures will be used to assess outcomes, and outcome assessors will be blinded to the intervention assignment.Substudy results will be reported by the year 2018.This substudy will provide generalizable estimates of the risk of acute kidney injury of a restrictive versus liberal approach to red blood cell transfusion in the presence of anemia during cardiac surgery done with cardiopulmonary bypass.www.clinicaltrials.gov; clinical trial registration number NCT 02042898. Initiating transfusions at a lower level of hemoglobin substantially reduces the number of transfusions performed with no adverse impact on clinical outcomes; however, uncertainty remains in the setting of cardiac surgery where patients may have less ability to tolerate anemia.This substudy of Transfusion Requirements in Cardiac Surgery III (TRICS-III), a multinational noninferiority randomized controlled trial, will provide new knowledge on the risk of acute kidney injury of a restrictive versus liberal approach to red blood cell transfusion in the presence of anemia during cardiac surgery done with cardiopulmonary bypass.2 When safe to do so, avoiding blood transfusion in this setting protects a scarce resource, reduces costs, and avoids the risk of transfusion-related infection and other complications, which can include myocardial infarction, stroke, and acute kidney injury.4 However, the risks of transfusion must be balanced against the risks of untreated anemia, which can compromise tissue oxygenation and also increase the risk of myocardial infarction, stroke, and acute kidney injury.5Almost 20 million cardiac surgeries are performed worldwide each year, and the period during and shortly after cardiac surgery consumes 15% to 20% of the red blood cell supply available for transfusion.2 Emerging evidence suggests that initiating transfusions at a lower level of hemoglobin substantially reduces the number of transfusions performed with no adverse impact on clinical outcomes.6 These data come from randomized controlled trials as it is impossible to reliably disentangle the adverse effects of anemia and red blood cell transfusion in observational studies. In controlled trials, patients were randomized to receive a restrictive versus liberal approach to transfusion initiation, where initiation occurred at a lower versus higher level of hemoglobin, typically 75 g/L versus 95 g/L, respectively.6 Meta-analyses of trials examining these approaches have been done in the nonsurgical and surgical setting, including small trials of patients undergoing cardiac surgery. While these studies suggest that a restrictive versus liberal approach to red blood cell transfusion is safe,69 uncertainty remains in the setting of cardiac surgery where patients may have less ability to tolerate anemia, and where trials conducted to date have been too small to determine whether there are meaningful differences in outcomes between the 2 groups.10Avoiding unnecessary red blood cell transfusions in cardiac surgery has been identified as a critical area for research.Prompted by the need for better evidence, the Canadian, Australian, and New Zealand governments provided funding for a noninferiority multicenter randomized controlled trial to test the hypothesis that the risk of adverse clinical outcomes from cardiac surgery with cardiopulmonary bypass is no greater with a restrictive versus liberal approach to red blood cell transfusion. The Transfusion Requirements in Cardiac Surgery III (TRICS-III) trial (NCT02042898) was launched in 2013 and includes over 4800 patients. The primary outcome of adverse events from cardiac surgery is a composite of all-cause mortality, myocardial infarction, new focal neurological deficit, and new kidney failure treated with dialysis, as assessed within 28 days of surgery or at hospital discharge, whichever comes first.1113 that is not treated with dialysis but is still associated with short- and long-term mortality, a longer hospital stay, and higher health care costs.1417 This evidence prompted us to develop a kidney substudy of the TRICS-III trial. Our substudy will test the hypothesis that the risk of perioperative acute kidney injury is no greater with a restrictive approach to red blood cell transfusion during cardiac surgery than a liberal approach. We also want to know whether this holds true in patients with and without preexisting chronic kidney disease. This protocol describes our plan to conduct these kidney substudy analyses in TRICS-III.Approximately 1% of patients who undergo cardiac surgery will develop severe acute kidney injury and receive dialysis in the perioperative period. Many more patients (over 15%) will develop an important degree of acute kidney injuryAmong patients undergoing planned cardiac surgery with cardiopulmonary bypass, is a restrictive approach to red blood cell transfusion noninferior to a liberal approach with respect to the risk of perioperative acute kidney injury?2. Does the presence of preexisting chronic kidney disease modify the effect of a restrictive versus liberal approach to transfusion with respect to the risk of acute kidney injury?18 Briefly, this parallel group, pragmatic, noninferiority trial was designed to evaluate whether a restrictive approach to transfusion is no worse than a liberal approach with respect to a composite primary outcome of all-cause mortality, myocardial infarction, new focal neurological deficit, and new kidney failure treated with dialysis. The primary outcome will be assessed up to postoperative day 28 or at hospital discharge, whichever comes first. Planned enrollment was 5000 patients, and the trial accrual ended in March 2017 with 5028 randomized patients across 73 centers in 19 countries . The data are currently being prepared for analysis .TRICS-III (NCT02042898) is a multinational, open-label randomized controlled trial testing 2 commonly used red blood cell transfusion approaches in high-risk patients undergoing planned cardiac surgery with cardiopulmonary bypass . The prespecified methods of this large international trial are described elsewhere (available from the authors upon request).Patients were identified in the preoperative anesthesia or cardiac surgery clinic or in the in-patient unit at each hospital, where informed consent was obtained. Enrolled patients were randomized to receive a restrictive or liberal approach to red blood cell transfusion. Randomization was generated centrally online by the Applied Health Research Centre at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital . Randomization was stratified by center using random permuted blocks of varying sizes. For the restrictive approach, transfusion was not initiated until a patient’s hemoglobin concentration fell below 75 g/L intraoperatively and/or postoperatively in the intensive care unit or on the hospital ward. For the liberal approach, transfusion was initiated once a patient’s hemoglobin concentration fell below 95 g/L intraoperatively or postoperatively in the intensive care unit or if it fell below 85 g/L on the ward. For each group, transfusion occurred within the following time frames of the hemoglobin trigger: within 2 hours for patients in the operating room, within 18 hours for patients in the intensive care unit, and within 40 hours for patients on the hospital ward.Ethics approval was obtained for additional renal data collection at all 73 participating centers (in 19 countries). Key aspects of the TRICS-III protocol that are relevant to the proposed kidney substudy are described below.Inclusion criteria for the TRICS-III main trial were as follows: adults aged 18 years or older undergoing a planned cardiac surgery with cardiopulmonary bypass, and a Preoperative European System for Cardiac Operative Risk Evaluation (EuroSCORE I) of 6 or more. Exclusion criteria were patient refusal or inability to receive blood products, involvement in the autologous predonation program, having a heart transplant, having a type of surgery solely for an insertion of a ventricular assist device, and the presence of pregnancy or lactation. Patients who were randomized but who did not undergo cardiac surgery will be excluded from the analysis (we expect ~3% of randomized patients did not undergo surgery).The following additional exclusions will be applied to the TRICS-III kidney substudy:2 .Patients with preoperative end-stage kidney disease, defined as previous chronic dialysis, receipt of a kidney transplant, or an estimated glomerular filtration rate (eGFR) <15 mL/min per 1.73 mPatients missing a preoperative serum creatinine value .emergency cardiac surgery will be excluded for 2 reasons: (1) They frequently have acute kidney injury or other complications prior to surgery, and so the preoperative serum creatinine may not be stable at baseline and (2) unfortunately many die, either in the operating room or shortly thereafter, before postoperative acute kidney injury develops (we expect <1% of randomized patients will have undergone emergency cardiac surgery).Patients having Preoperative serum creatinine was obtained within the 30-day period before surgery, where the most recent value before surgery will serve as the baseline value. Participating sites received study funds to measure the postoperative serum creatinine on days 1, 2, 3, and 5 after surgery. To our knowledge, at participating sites, serum creatinine measurements were traceable to isotope dilution mass spectrometry. No urine output data will be used in the primary analysis of this substudy given difficulties with accurately measuring this variable outside of the intensive care unit.20 Results from an earlier cardiac study with similar enrollment criteria as TRICS-III suggests that our data collection schedule will capture most perioperative acute kidney injury events in the first 5 days of surgery; in this previously published prospective surgery study of 1219 cardiac patients, 15% of patients developed perioperative acute kidney injury (as per our definition); 13.9% of events were observed in the hours following surgery and 38.7%, 38.7%, and 8.7% of events were observed on postoperative days 1, 2 and 3, respectively.21 For this reason, our protocol provides each center funding for serum creatinine measures on days 1, 2, 3, and 5 to encourage measurement on these days in all patients; as well, any other serum creatinine measures obtained in the perioperative period as part of routine care are recorded in the trial database . We will compare the number of serum creatinine measurements (and the postoperative days of these measurements) in each intervention group during the hospital stay to examine the potential for ascertainment bias. While health care providers in TRICS-III are aware of the intervention received, this was also the case in our analyses of acute kidney injury within a large randomized trial where coronary artery bypass surgery was done with and without a bypass pump (where there was no difference in the frequency of serum creatinine measurement between the 2 groups given how ubiquitous serum creatinine measurements are in routine care in the perioperative setting19). We expect that less than 2% of patients will be missing serum creatinine values in the first 2 days of surgery as a result of death.The primary outcome of the TRICS-III kidney substudy is perioperative acute kidney injury, defined as an acute rise in serum creatinine from the preoperative baseline value, where an acute rise is defined as ≥26.5 μmol/L in the first 48 hours after surgery or ≥50% in the first 7 days after surgery.19The TRICS-III study is designed to test whether a restrictive approach to transfusion is noninferior to a liberal approach. The total required sample size for the TRICS-III kidney substudy is 3378 based on a noninferiority margin of 3.5% for an absolute risk increase in acute kidney injury with the restrictive versus liberal approach, a 1-sided alpha of 0.025, and 85% power, assuming a baseline rate of acute kidney injury of 15%, <2% missing data due to death, and ~85% meeting our eligibility criteria. Thus, our projected available sample size of 4074 patients for this substudy will be adequate. A noninferiority margin of 3.5% is a reasonable minimal clinically important difference; for example, in our prior analyses of acute kidney injury within a large randomized trial, coronary artery bypass surgery done without a bypass pump reduced the relative risk of acute kidney injury by 17%  compared with surgery done with a bypass pump, but without evidence of better preserved kidney function, mortality, or any other relevant clinical outcome 1 year later .23; however, the per-protocol analysis will be considered primary. We will report the stability of the noninferiority conclusion between the per-protocol and intention-to-treat results,23 and congruence in results between these analyses will increase confidence in our interpretation of the findings. Per-protocol analyses are often preferred for addressing questions of noninferiority because compared with intention-to-treat analyses they reduce the risk of falsely declaring noninferiority when a meaningful difference between the effects of 2 interventions in truth exists. In contrast, intention-to-treat analyses are preferred for questions of superiority because they reduce the risk of falsely declaring superiority when the effects of the interventions are, in truth, similar. As outlined in the TRICS-III main protocol, the per-protocol analyses will exclude (1) patients whose adherence to the assigned transfusion strategy is less than 90% and/or (2) patients who withdraw from the study at any time . Currently, we anticipate an estimated 10% of randomized participants will be excluded from the per-protocol analysis; this subgroup of patients will be examined carefully to assess the potential for bias in the per-protocol analysis. In the intention-to-treat analyses (described below), all participants will be analyzed according to their original randomized group assignment regardless of whether transfusion occurred or which transfusion approach was followed. We will report the unadjusted absolute risk difference between the 2 groups with a 95% confidence interval using the large-sample normal approximation for a difference in proportions. We will accept noninferiority if the upper limit of the 2-sided 95% confidence interval for the difference in proportions of acute kidney injury  is less than the noninferiority margin of 3.5%. We expect that data on postoperative serum creatinine will be missing for <2% of participants due to death and <5% due to missing data. For patients who were randomized but are missing at least 1 postoperative serum creatinine value, we will use recommended model-based multiple imputation methods using all available data to impute acute kidney injury status.2426As recommended, we will conduct both per-protocol and intention-to-treat analyses2732 We will examine whether the presence of preexisting chronic kidney disease  modifies the effect of a restrictive versus liberal approach to transfusion with respect to the risk of acute kidney injury.30 The P value for the interaction will be assessed by including the type of transfusion approach, an indicator variable for chronic kidney disease, and an interaction term (chronic kidney disease × type of transfusion approach) as independent variables in a regression model for binary outcome data. We will also present the absolute risk difference between intervention groups within each subgroup.Compared with patients with preserved kidney function, patients with chronic kidney disease have a higher risk of acute kidney injury, as well as higher rates of anemia, perioperative mortality, and cardiovascular events.2426 We will also examine death as a competing outcome and examine alternative definitions of acute kidney injury.As outlined below, we will perform several supporting analyses including a complete-case analysis, an inverse probability weighted analysis, an intention-to-treat analysis, and an adjusted analysis, examining whether there is concordance with the primary analysis.We will perform a complete-case analysis (no use of postoperative serum creatinine imputation) restricted to patients with at least 1 postoperative serum creatinine measurement . We may also perform an analysis restricted to those centers with over 90% of patients with complete serum creatinine measurements.The intention-to-treat analysis will follow the same analytic approach as the primary analysis, but all participants will be analyzed according to their original randomized group assignment regardless of whether transfusion occurred or which transfusion approach was followed. In addition, if noninferiority is shown, an intention-to-treat superiority comparison will be performed using a 2-sided alpha of 0.05.26 the unadjusted and adjusted results were virtually identical; nonetheless, we will conduct the following mixed-effects model for binary outcome data, considering center as a random effect (randomization stratum), adjusted for several prespecified factors (measured before randomization) based on their known association with acute kidney injury in the cardiac surgery setting: age (per year), sex, hemoglobin (per 10 g/L), left ventricular systolic ejection fraction categories, diabetes mellitus, treated hypertension, and eGFR (above or below 60 mL/min/1.73 m2).3335 We will report the adjusted absolute risk difference with a 95% confidence interval (the latter estimated using bootstrap methods).36In our experience with CORONARY and POISE kidney substudies,To determine whether the primary result is robust when the competing event of death is considered (which may influence serum creatinine measurements after surgery), we will also examine a composite outcome of acute kidney injury or death within 5 days of surgery.38 and assess the consistency of effect across stages of acute kidney injury based on visual inspection of point estimates and 95% confidence intervals. Despite the large sample size, these supplementary analyses for severe stages of acute kidney injury will have limited statistical power for small effects.We will repeat the primary analysis using alternative definitions of perioperative acute kidney injury including staging definitions,20 While virtually all prevention trials of acute kidney injury follow this definition, this outcome is a surrogate endpoint that may not directly impact how a patient feels, functions, or survives. Detailed information on long-term permanent kidney function after hospital discharge will not be available in this trial. Nonetheless, our primary outcome follows the current recommended standard of diagnosis of acute kidney injury.20 We will also examine whether intervention effects are consistent across stages of acute kidney injury; despite being less frequent, events of Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 and stage 3 acute kidney injury are more relevant to patients and health care providers. Although it is not possible to blind patients or providers to the intervention allocation, any resulting ascertainment bias should be minimal as we have the same prespecified serum creatinine measurement schedule for patients in both groups. Furthermore, our outcomes will be objectively measured by laboratory technicians unaware of group allocation.The primary outcome in this kidney substudy of TRICS-III is perioperative acute kidney injury .Acute kidney injury is a common and important complication of cardiac surgery. The TRICS-III kidney substudy will efficiently and reliably assess the renal effects of a restrictive versus liberal approach to red blood cell transfusion in the presence of acute anemia. It will also assess whether the effects of these approaches differ in patients with and without preexisting chronic kidney disease. Finally, this trial will provide some insights on the interplay between acute anemia, transfusions, and the risk of acute kidney injury.


Raised blood pressure is an important risk factor for cardiovascular diseases and chronic kidney disease. We estimated worldwide trends in mean systolic and mean diastolic blood pressure, and the prevalence of, and number of people with, raised blood pressure, defined as systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure of 90 mm Hg or higher.For this analysis, we pooled national, subnational, or community population-based studies that had measured blood pressure in adults aged 18 years and older. We used a Bayesian hierarchical model to estimate trends from 1975 to 2015 in mean systolic and mean diastolic blood pressure, and the prevalence of raised blood pressure for 200 countries. We calculated the contributions of changes in prevalence versus population growth and ageing to the increase in the number of adults with raised blood pressure.We pooled 1479 studies that had measured the blood pressures of 19·1 million adults. Global age-standardised mean systolic blood pressure in 2015 was 127·0 mm Hg  in men and 122·3 mm Hg (121·0–123·6) in women; age-standardised mean diastolic blood pressure was 78·7 mm Hg (77·9–79·5) for men and 76·7 mm Hg (75·9–77·6) for women. Global age-standardised prevalence of raised blood pressure was 24·1% (21·4–27·1) in men and 20·1% (17·8–22·5) in women in 2015. Mean systolic and mean diastolic blood pressure decreased substantially from 1975 to 2015 in high-income western and Asia Pacific countries, moving these countries from having some of the highest worldwide blood pressure in 1975 to the lowest in 2015. Mean blood pressure also decreased in women in central and eastern Europe, Latin America and the Caribbean, and, more recently, central Asia, Middle East, and north Africa, but the estimated trends in these super-regions had larger uncertainty than in high-income super-regions. By contrast, mean blood pressure might have increased in east and southeast Asia, south Asia, Oceania, and sub-Saharan Africa. In 2015, central and eastern Europe, sub-Saharan Africa, and south Asia had the highest blood pressure levels. Prevalence of raised blood pressure decreased in high-income and some middle-income countries; it remained unchanged elsewhere. The number of adults with raised blood pressure increased from 594 million in 1975 to 1·13 billion in 2015, with the increase largely in low-income and middle-income countries. The global increase in the number of adults with raised blood pressure is a net effect of increase due to population growth and ageing, and decrease due to declining age-specific prevalence.During the past four decades, the highest worldwide blood pressure levels have shifted from high-income countries to low-income countries in south Asia and sub-Saharan Africa due to opposite trends, while blood pressure has been persistently high in central and eastern Europe.Wellcome Trust. Raised blood pressure is the leading global risk factor for cardiovascular diseases and chronic kidney disease.The prevalence of raised blood pressure measures the number of high-risk people irrespective of treatment status, and is the indicator used in the global NCD target. However, blood pressure has a log-linear association with cardiovascular diseases and chronic kidney disease that continues well below the threshold for raised blood pressure, and treatment provides similar proportional risk reductions irrespective of pretreatment blood pressure.We pooled population-based data to estimate national, regional, and global trends from 1975 to 2015 in mean systolic and mean diastolic blood pressure, and in the prevalence of raised blood pressure, for adults aged 18 years and older in 200 countries and territories. We also estimated trends in the number of adults with raised blood pressure, and calculated how much these trends are attributable to changes in prevalence versus changes in population size and age structure.Evidence before this studyWe searched MEDLINE (via PubMed) for articles published in English, Spanish, Portuguese, Chinese, Italian, French, or Farsi between Jan 1, 1950, and Feb 19, 2014, using the search terms (“blood pressure”[Mesh:NoExp] OR “hypertension”[Mesh:NoExp]) AND (“Humans”[Mesh]). We screened articles according to the inclusion and exclusion criteria described in the Some studies, including the MONICA Project, have reported on blood pressure change or trends in one or more countries. Two previous global analyses, done more than a decade ago, pooled data from different countries and reported mean systolic blood pressure or prevalence of hypertension in the year 2000 for the world and its major regions. A more recent analysis published in 2016 pooled 135 studies to estimate global and regional hypertension prevalence in 2000 and 2010, but did not report changes in mean blood pressure, which reflect shifts in the population distribution of blood pressure. None of these studies provided consistent estimates for all countries or accounted for the fact that the data used were collected in different years. The only analysis of trends at the country level reported mean systolic blood pressure from 1980 to 2008 but did not report mean diastolic blood pressure or prevalence of raised blood pressure, which is of clinical relevance and needed for monitoring progress towards the global target.Added value of this studyThis study provides the most complete picture of trends in adult blood pressure for all countries in the world with the longest observation period of any global blood pressure study to our knowledge, and includes trends in mean diastolic blood pressure and prevalence of raised blood pressure, which were not included in previous studies and are of clinical, public health, and health systems significance. We also estimated trends in the number of adults with raised blood pressure, and how much these trends are driven by changes in prevalence versus population size and age structure.Implications of all the available evidenceDuring the past four decades, the highest levels of blood pressure worldwide have shifted from high-income countries to low-income and middle-income countries in south Asia and sub-Saharan Africa, while blood pressure has been persistently high in central and eastern Europe. The global target of reducing raised blood pressure prevalence by 25% by 2025 is unlikely to be achieved in these regions. The number of people with raised blood pressure has risen worldwide, with the increase happening mainly in low-income and middle-income countries. Population-based interventions throughout the life-course and pharmacological treatment for people with high absolute risk or people with substantially raised blood pressure should be a part of any effort to address the global burden of non-communicable diseases, especially in the poorest countries.For this pooled analysis, we included data collected from samples of a national, subnational , or community  population in which participants' blood pressure had been measured. Our methods for identifying and accessing data sources are described in the 292 (20%) of the 1479 data sources we analysed (2298 [16%] of 14 391 age-sex-study-specific data points) that were from a previous global poolingThe statistical model used to estimate means and prevalence by country, year, and age is described in detail in a statistical paper and related substantive papers.The model incorporated non-linear time trends and age patterns. It allowed the age association of blood pressure to vary across populations, and the rise in means and prevalence over age to be steeper where blood pressure is higher.We fitted the statistical model with the Markov chain Monte Carlo algorithm, and obtained 5000 post-burn-in samples from the posterior distribution of model parameters, which were in turn used to obtain the posterior distributions of primary outcomes. The reported credible intervals (CrI) represent the 2·5th to 97·5th percentiles of the posterior distributions. Each primary outcome was analysed separately, and all analyses were done separately by sex to allow blood pressure, its trends, and age associations to differ among outcomes and between men and women.We calculated mean change in mean blood pressure and the prevalence of raised blood pressure across the 41 years of analysis (reported as change per decade). We also report the posterior probability (PP) that an estimated trend represents a true increase or decrease. We generated age-standardised estimates using the WHO standard population,We calculated the contribution of population growth and ageing to the change in the number of adults with raised blood pressure by fixing age-specific prevalence at its 1975 levels while allowing age-specific population to change as it did. We calculated the contribution of change in prevalence by fixing age-specific population at its 1975 level while allowing age-specific prevalence to change as it did. The interaction between the two contributions is the residual change in the number of adults with raised blood pressure after accounting for the two forementioned components.The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Country and Regional Data Group members and BZ had full access to the data in the study. The corresponding author had final responsibility for the decision to submit for publication.We included 1479 population-based measurement surveys and studies, with 19·1 million participants aged 18 years and older for whom blood pressure was measured. We had at least one data source for 174 (87%) of the 200 countries we made estimates for, covering 97·5% of the world's population in 2015 , and at Globally, age-standardised adult mean systolic blood pressure remained virtually unchanged from 1975 to 2015 in men  and decreased slightly in women  to 24·1% (21·4–27·1) in men (PP=0·9482) and from 26·1% (21·7–31·1) to 20·1% (17·8–22·5) in women (PP=0·9884). The largest decrease was seen in high-income super-regions, followed by Latin America and the Caribbean, central and eastern Europe, and central Asia, Middle East, and north Africa . ElsewheSouth Korea and Canada had the lowest age-standardised mean systolic blood pressure in 2015 for both men (117–118 mm Hg) and women . The estimates were very similar with correlation coefficients between the estimates from the main and sensitivity analyses being 0·94 or higher in 1990 and 0·98 or higher in 2015 . Third, Blood pressure is a multifaceted trait, affected by nutrition, environment, and behaviour throughout the life course, including fetal and early childhood nutrition and growth,The partly unexplained nature of these favourable trends necessitates speculation about their drivers, which might include unmeasured improvements in early childhood nutrition and year-round availability of fruits and vegetables, which might increase the amount and regularity of their consumption. Our results show that similar decreasing trends in mean blood pressure and prevalence of raised blood pressure might have begun in some middle-income regions, although at a slower rate than trends in high-income regions, but not in the poorest populations, including those in south Asia and sub-Saharan Africa, and in populations affected by major social and economic changes in central and eastern Europe. These populations have low consumption of fresh fruitsmajid.ezzati@imperial.ac.ukCorrespondence to: Prof Majid Ezzati, Imperial College London, London W2 1PG, UK


Post-transplantation hypertension is prevalent and is associated with increased cardiovascular morbidity and subsequent graft dysfunction. The present study aimed to identify the factors associated with arterial stiffness as measured by the ambulatory arterial stiffness index.The current study used a prospective, observational, analytical design to evaluate a group of adult heart transplantation patients. Arterial stiffness was obtained by monitoring ambulatory blood pressure and using the ambulatory arterial stiffness index as the surrogate outcome. Multivariate logistic regression analyses were performed to control confounding.In a group of 85 adult heart transplantation patients, hypertension was independently associated with arterial stiffness  as well as systolic and diastolic blood pressure averages and nighttime descent.Measurement of ambulatory arterial stiffness index is a new, non-invasive method that is easy to perform, may contribute to better defining arterial stiffness prognosis and is associated with hypertension. Globally, heart transplantation is indicated for the treatment of heart failure refractory to clinical, surgical and interventional treatments. Transplantation survival has improved significantly in recent decades, mainly due to the emergence of new immunosuppressants However, post-transplantation hypertension is a major cardiovascular problem. The vasoconstrictor effect of immunosuppressants, including cyclosporin, plays an important role in generating this hypertension Data from the International Society for Heart and Lung Transplantation (ISHLT) show that hypertension is present in 50–90% of transplantation patients and is associated with increased cardiovascular morbidity and mortality Pulse wave velocity (PWV) and the augmentation index (AIx) are the standard methods of assessing arterial stiffness. However, the ambulatory arterial stiffness index (AASI), derived from the ABPM GVD remains the main late complication after heart transplantation and is responsible for many deaths after the first year post-transplantation. Furthermore, its association with hypertension and arterial stiffness is well demonstrated This work aims to identify the factors associated with arterial stiffness as measured by the AASI, thereby identifying the prognostic utility of this methodology.This study used a prospective, observational, analytical design to measure arterial stiffness using a surrogate outcome index, AASI, as measured by ABPM in heart transplantation patients.The present study was conducted at the Messejana Heart and Lung Hospital, Ceará, Northeast Brazil. Data were collected from March 2012 to June 2013. The patients included in the study were followed until December 2014.The study participants were adult patients who had undergone heart transplantation before June 2013. Although there is information available in the literature on arterial stiffness in hypertensive patients, most studies Clinical and laboratory data were stored in a special clinical record and transported to a specific database. All patients underwent clinical examination from March 2012 to June 2013 before being included in the study protocol. The examination included a routine laboratory evaluation, a clinical protocol with biochemical and hematological examination and an evaluation of the dosage of immunosuppressants  obtained at time “0” from use.Transthoracic echocardiography was performed for all transplantation patients to evaluate graft function. Endomyocardial biopsy was performed at 1, 2, 3 and 6 months post-transplantation, when the patient completed their first year of transplantation, or at any time there was suspicion of graft rejection. All analyses were conducted by the same pathologist in the study institution following the ISHLT classification.Coronary angiography was performed on completion of the first year after transplantation or at any time suspicion of GVD arose. If more than 6 months elapsed since the participant’s last coronary angiography, the procedure was repeated. GVD was indicated by coronary angiography showing at least a 50% lesion in a coronary artery. All procedures were conducted at the study institution.ABPM was performed for all patients for a 24-hour period. The monitor used was a Meditech® ABPM 04 , with a program specific for the calculation of AASI. The measurement protocol followed the American Hypertension Guidelines with 15/15-minute measurements during the monitoring period and 30/30-minute measurements during sleep, with monitoring starting at 7:00 hours and ending at 22:59 hours. Abnormality criteria were mapped according to the guidelines. Analysis of ABPM and AASI data was performed by a single doctor, who was blinded to patient identification.Distributions of continuous variables were described using mean values and standard deviations. Categorical variables were described by relative frequency categories. The normality of all numeric variables was tested using the Kolmogorov-Smirnov test. The variables that showed an abnormal distribution were transformed with Tukey’s ladder and the best possible transformation was chosen.p values up to 0.1 in the bivariate analysis.An interaction test was used to identify possible multiplicative interactions between transplantation and hypertension in the development of arterial stiffness through a logistic regression model. A bivariate analysis was performed with parametric tests and simple regression models using arterial stiffness as a binary variable. Finally, multiple logistic regression was performed to control confounding between determinants with variables having The present study obtained approval from the Ethics and Research Committee of the study institution under the number 826/2011 and all enrolled patients provided written informed consent.versus 3.4%, 20.3%, 0, and 16.1% if not). Patient gender and age did not appear to be related to arterial stiffness , as well as levels of urea (p=0.006) and of high-density cholesterol (p=0.015)  .p<0.001). Systolic descent also showed significance, as shown in Analysis of the ABPM data showed that average systolic and diastolic blood pressure measurements were related to the development of arterial stiffness  and with an absence of diastolic nighttime descent. Additionally, GVD , diabetes  and elevated creatinine levels  were highly associated with arterial stiffness. All variables identified as significant in the regression are presented in In recent years, arterial stiffness has been shown to be an important marker of cardiovascular events and CVA in the general population, especially in patients with chronic kidney disease or diabetes Our transplantation patients presented higher average diastolic blood pressure and smaller nocturnal systolic descents and diastolic levels than the normal population. These factors are probably secondary to cardiac denervation and the use of immunosuppressants and can lead to worsening endothelial function in the transplantation population.The literature shows that patients who have a normal decrease in blood pressure during sleep have a reduction in cardiac output with maintenance of peripheral resistance, while heart transplantation patients have lower reductions in cardiac output and in peripheral resistance due to a relative absence of nighttime descent p<0.001) In a cohort of 330 renal transplantation patients, Mitchell et al. observed significant increases in PWV  with age, systolic blood pressure and pulse pressure. They concluded that PWV is a strong predictor of all-cause mortality in the renal transplantation population (A number of publications and reviews of various physiopathological conditions have reported associations between age, genetic factors, physical inactivity, smoking Hypertension is strongly associated with an increased risk of arterial stiffness Routine clinical applications for measuring arterial stiffness may be expanded, as many studies have demonstrated the predictive value of arterial stiffness for the risk of cardiovascular events and its mitigation through the use of antihypertensive, antidiabetic and cholesterol-lowering drugs, among others Our multivariate analysis showed that the association between hypertension and arterial stiffness was not confounded by other factors. Additionally, other independent factors were identified, including diabetes mellitus, GVD and elevation of creatinine levels The loss of renal function, measured as increased creatinine and urea levels, was the most important laboratory factor identified for increased risk of arterial stiffness in transplantation patients. This finding is consistent with the literature Multiple factors are involved in generating hypertension in heart transplantation patients; these include immunosuppressive therapy, increased sensitivity of beta-adrenergic receptors due to donor heart denervation, worsening of endothelial function and drug nephrotoxicity GVD is the main complication of heart transplantation. Identified risk factors for GVD include hypertension, obesity, diabetes, and smoking. In our study, GVD was related to arterial stiffness, and its determinants were also associated Arterial stiffness is an independent predictor of cardiovascular events and all-cause mortality. The main risk factors for arterial stiffness include hypertension, diabetes, dyslipidemia, and chronic kidney disease. Heart transplantation patients who have these risk factors should be screened for early development of arterial stiffness.The data in the current study highlight the need for early detection of hypertension and routine indication of ABPM in heart transplantation patients with risk factors. Based on our results, arterial stiffness should be analyzed using the AASI or a similar evaluation method with the goal of early intervention to reduce adverse events.The present study was limited by the small number of transplantation patients included. However, this is a unique population, which by nature is difficult to select. Another limitation was the lack of comparison between AASI arterial stiffness measurements and another group measured using standard methods such as the PWV or AIx, which may have improved the accuracy of the analysis. However, for heart transplantation patients as a specific group, our study reached its goals of identifying a method of analysis for arterial stiffness that is non-invasive, simple to perform and easily adaptable for future studies.This study concluded that hypertension was independently associated with estimated arterial stiffness in a group of adult heart transplantation patients. Renal dysfunction, diabetes and absence of diastolic descent were identified as determinants of arterial stiffness. Measuring the AASI offers a new, non-invasive method that is easy to perform and is indicative of hypertension. This method may assist in defining therapeutic strategies for transplantation patients and could contribute to improving prognosis.Souza-Neto JD, Oliveira IM, Bacal F, Lima-Rocha HA and Oliveira-Lima JW provided substantial contributions to the conception and design of the study and to critically revising the manuscript for important intellectual content. Souza-Neto, Oliveira IM and Lima-Rocha HA were responsible for the analysis and interpretation of data and for drafting the manuscript. All of the authors read and approved the final version of the manuscript.


To assess whether circadian patterns of temperature correlate with further values of intracranial pressure (ICP) in severe brain injury treated with hypothermia.24).We retrospectively analyzed temperature values in subarachnoid hemorrhage patients treated with hypothermia by endovascular cooling. The circadian patterns of temperature were correlated with the mean ICP across the following day  and the preceding diurnal period (6:00–18:00) [temperature variability (TV)] ranged from 0.274 to 1.97. Regression analysis showed that TV correlated with ICP24 , and that ICP24 = 6 (4–TV) mmHg or, for 80% prediction interval, 24 higher than 20 mmHg is unlikely after a day with TV ≥1.0.We analyzed data from 17 days of monitoring of three subarachnoid hemorrhage patients that underwent aneurysm coiling, sedation and hypothermia due to refractory intracranial hypertension and/or cerebral vasospasm. ICPTV correlates with further ICP during hypothermia regardless the strict range that temperature is maintained. Further studies with larger series could clarify whether intracranial hypertension in severe brain injury can be predicted by analysis of oscillation patterns of autonomic parameters across a period of 24 h or its harmonics.The online version of this article (doi:10.1186/s12967-017-1272-y) contains supplementary material, which is available to authorized users. Severe brain injury may lead to a progressive worsening of neurological status and consequently to poor outcome. Nonetheless, the intensity of neurological deterioration varies widely in each case and frequently is unpredictable. Such poor outcome occurs in part because an effective neuroprotective therapy is missing and the currently available therapies may lead to significant side effects. Therefore, the treatment of patients with severe brain injury could be improved by the development of new methods to predict neurological status worsening –3, whichWe have previously shown that the adult human brain displays a potential novel mechanism of plasticity that involves a neurogenic system orchestrated in a broad brain area . This syWe performed retrospective analysis from subarachnoid hemorrhage patients enrolled in the ongoing project named “ICU Cockpit”, which has been approved from local institutional review boards. Regarding the patients analyzed in this study, ICP and brain temperature  were used for brain monitoring. Body temperature was monitored by intra-arterial thermistors . Hypothermia (target core body temperature 33.0–33.9 °C) was induced and maintained using endovascular cooling  according to a standardized protocol if intracranial hypertension and/or delayed cerebral ischemia refractory to conventional treatment occurred . Glasgow® Delta Monitor  were conveyed to and synchronized in Component Neuromonitoring System (CNS) monitor . Continuous parameters were stored at 1–10 Hz. Next, files obtained from CNS monitors were converted into Matlab files  for statistical analysis. We selected the cases with ICP monitoring registered during more than 5 days. Because we suspected that the circadian rhythms could be a primary factor that correlates with brain injury, we built a spreadsheet in Excel  containing the mean and standard deviation of all parameters in diurnal (6:00–18:00) and nocturnal (18:00–6:00) periods, encompassing all days of monitoring. We used this time to define diurnal and nocturnal periods based on the pattern of intrinsic circadian rhythms, which are related to endogenous oscillation of suprachiasmatic nucleus activity and observed through parameters such as serum level of melatonin and core body temperature [Neuromonitoring and systemic data obtained with Infinity diurnal :00–18:00From the initial series containing 11 enrolled patients in the ICU Cockpit Project, we obtained data from 17 days of monitoring during hypothermia induced in three patients with subarachnoid hemorrhage that were treated with aneurysm coiling and sedation Table .Table 1C24) ranged from 11.5 ± 3.1 to 24.2 ± 6.2 mmHg  .The ratio between the coefficient of variation (standard deviation/mean) of temperature during the nocturnal period 18:00–6:00) and the preceding diurnal period (6:00–18:00) (TV) ranged from 0.274 to 1.97 (Table 8:00–6:0024 = 23.9–6.22 TV mmHg. A simplified manner to write this formula and facilitate its memorization is ICP24 = 6 (4–TV) mmHg. This formula determines the regression line. Complementary, to calculate the range of expected ICP24 with 80% of certainty for a certain day, one might use TV  in the formula From regression analysis, we obtained the formula ICPmentclass2pt{minimThe analysis of the ICP curve in head injury patients has been allowed the development of prediction models with up to 30 min of antecedence , 8.The present results indicate that an alteration in the circadian rhythm may anticipate intracranial hypertension. One should bear in mind that the period during which a neurological patient undergoes therapeutic hypothermia is the most critical period of treatment, when episodes of intracranial hypertension are likely to occur. The results of this study seem to be particularly useful during this period, in cases in which a strict temperature control is maintained (please note that the maximum standard deviation of temperature in 12 h periods was 0.2).24 formula may guide the therapy in severe cases of subarachnoid hemorrhage. A caveat in this analysis is that ICP24 is a mean ICP value, and along a 24 h period it is possible that intracranial hypertension episodes take place. However, in our results we found a variability in ICP that in general did not exceed 20% of ICP24. For example, the third quartile of the coefficients of variability of the 17 analyzed days equals 0.192, which means that in 75% of the analyzed days the standard deviation of ICP24 did not exceed 19.2% ICP24. In this manner, it is highly probable that the patient will experience a day with episodes of intracranial hypertension after a day with TV ≤0.333. On the other hand, a day without episodes of intracranial hypertension is highly probable after a day with TV ≥1. These predictions are suitable while the patient undergoes a relatively constant treatment and a strict mild hypothermia. Therefore, a clinical implication of this study may be that endovascular catheter-induced hypothermia may lead to more predictable ICP [The analysis of the ICPable ICP .It remains to be determined whether the circadian patterns of temperature correlate with further ICP under normothermia. A further parameter that could be tested regarding ICP prediction under normothermic conditions is the ratio between mean temperature during night and the preceding diurnal period. This parameter was not suitable for ICP prediction due to the strict temperature ranges used to treat the enrolled patients. Nonetheless, this parameter could be assessed in a further study to investigate whether in determined circumstances it may serve to predict intracranial hypertension in the same way it predicts seizure in epileptic patients with 24 h of antecedence .Likewise, perhaps other autonomic parameters correlate with further ICP in a manner not revealed in this study . Blood pA major caveat of this study is that the method proposed here remains to be improved after confirmation of the results with the analysis of larger series with patients under different conditions, inclusion of other predictive factors, determination of confounders, and technical improvement of data acquisition and analysis. Accordingly, we studied data from a total of only 17 days of monitoring of three patients. To validate our findings with a retrospective study design, it would be necessary to make up a development cohort and a validation cohort sufficiently large to yield statistically significant results , 14.In conclusion, the analysis of circadian patterns of autonomic functions may be a paradigm to predict intracranial hypertension in acute brain injury. Temperature seems to be the most remarkable autonomic function to this end, even when maintained in a strict range in patients under deep sedation.Additional file 1. Data regarding heart rate, blood pressure, and ICP. This Table shows the values obtained for the variables derived from heart rate (HR) and mean blood pressure (mBP) that are the counterpart of the variables obtained for temperature. HR and mBP data from day 6 of monitoring of patient #2 and HR data from day 3 of monitoring of patient #3 displayed artifact and were not included in the Table. Legend: BPV, blood pressure variability, defined as the ratio between the standard deviation of mean blood pressure during the nocturnal period (18:00 to 6:00) and the preceding diurnal period (6:00 to 18:00); HRV, heart rate variability; HRVd, standard deviation of NN interval during the diurnal period; HRVdn, standard deviation of NN interval during 24 h; HRVn, standard deviation of NN interval during the nocturnal period; HRVn/d, ratio between standard deviation of NN interval during the nocturnal and preceding diurnal periods; ICP24, mean intracranial pressure during 24 h after the monitoring day of HR and BP; mBP, mean blood pressure during 24 h.Additional file 2. Statistical analysis  regarding correlation between heart rate and blood pressure variables with ICP24. This Table shows that there is no statistical correlation between heart rate and blood pressure variables and intracranial pressure across the following day. Legend: BPV, blood pressure variability, defined as the ratio between the standard deviation of mean blood pressure during the nocturnal period (18:00 to 6:00) and the preceding diurnal period (6:00 to 18:00); HRVdn, standard deviation of NN interval during 24 h; HRVn/d, ratio between standard deviation of NN interval during the nocturnal and preceding diurnal periods; ICP24, mean intracranial pressure during 24 h after the monitoring day of heart rate and blood pressure.


In severe asthma, high doses of inhaled corticosteroids (ICS) are used in order to achieve clinical and functional control. This study aimed to evaluate lung function in outpatients (children and adolescents) with severe asthma in Brazil, all of whom were treated with high doses of ICS. We evaluated all spirometry tests together and by ICS dose: 800 and > 800 µg/day.This was a 3-year longitudinal study in which we analyzed 384 spirometry tests in 65 severe asthma patients (6–18 years of age), divided into two groups by the dose of ICS : 800 and > 800 µg/day.1) and the FEV1/forced vital capacity (FVC) ratio were both < 80% of the predicted values in 50.8% of the patients. The median age of the patients was 10.4 years (interquartile range 7.8–13.6 years). In the sample as a whole, there were significant increases in FEV1% and in the FEV1/FVC% ratio  over the course of the study. In the > 800 µg/day group, there were no statistical increases or decreases in FEV1, the FEV1/FVC ratio, or forced expiratory flow between 25 and 75% of the FVC (FEF25–75%), when calculated as percentages of the predicted values. However, the z-score for FEF25–75% showed a statistically significant reduction, in the sample as a whole and in the > 800 µg/day group. Also in the > 800 µg/day group, there was a significant reduction in the post-bronchodilator FEV1% (p = 0.004).At baseline, the forced expiratory volume in one second  remained constant in the > 800 µg/day group, whereas there was a gain in lung function in the sample as a whole, suggests an early plateau phase in the > 800 µg/day group. However, there was some loss of lung function in the > 800 µg/day group, as evidenced by a decrease in the z-score for FEF However, approximately 5% of such children present with severe asthma that is uncontrolled or obtain asthma control only with the use of high doses of ICS, in combination with a long-acting βsteroids –3. In thsteroids . Pediatrsteroids .1) can help identify pediatric patients at risk for abnormal lung function and irreversible airflow obstruction. Careful follow-up evaluation can identify the plateau phase and a subsequent decline [The finding of an abnormal trajectory through monitoring of the forced expiratory volume in one second , the FEV1/FVC ratio, and forced expiratory flow between 25 and 75% of the vital capacity (FEF25–75%), has been described in longitudinal studies [1 as a percentage of the predicted value (FEV1%), which persisted into adult life. The authors also identified an early decline in lung function in 52% of the patients. Among children with moderate asthma in Europe [25–75% [25–75% can express airway obstruction better than can FEV1 and the FEV1/FVC ratio, both of which are often normal in children with asthma [The evolution of lung function in asthma patients, as determined by monitoring FEV studies . In a stn Europe , the use [25–75% . In chil1%. Because those patients entered treatment between 5 and 12 years of age, the authors suggested that an irreversible loss of lung function might have occurred prior to the initiation of treatment [1/FVC ratio, FEV1, and FEF25–75% observed at 2 months of age persist at 22 years of age, suggesting that reduced lung function is a risk factor for early airway obstruction in adulthood [1 %, was observed only in the first year of follow-up. That gain was not progressive, reaching a plateau, with a mean FEV1 below 80% of the predicted value, that was maintained over the following 3 years [The scope of ICS treatment in preventing a loss of lung function in children and adolescents with asthma has also been a concern. In a study involving children with mild to moderate asthma in the United States, the use of budesonide was not found to increase the post-bronchodilator FEVreatment . It has dulthood . In a stdulthood , a gain  3 years . In pediThere have been few longitudinal studies of lung function in pediatric patients with severe asthma. Therefore, the objective of the present prospective study was to analyze the evolution of lung function over a 3-year period in a cohort of children and adolescents with severe asthma treated using high doses of ICS, considering all of the spirometry tests together and by dose of ICS: 800 and > 800 µg/day.Centro Multidisciplinar de Asma de Difícil Controle , a university center in the city of Belo Horizonte, in southeastern Brazil. The methods of evaluation and therapeutic management of this cohort have previously been described [This was a prospective cohort study in which 384 spirometry tests of 65 patients with severe asthma, obtained over a period of 3 years, were referred by pediatric pulmonologists affiliated with the Wheezing Baby Program , which oescribed . We exclSevere asthma is defined as asthma which requires treatment with high doses of ICS, plus a second controller  to prevent it from becoming “uncontrolled”, or which remains “uncontrolled” despite this therapy –3. High Patients were recruited into the study between September 2010 and July 2015. At enrollment, all were in step 4 or 5 of the Global Initiative for Asthma (GINA) treatment plan and were using ≥ 800 µg/day of budesonide or equivalent . All of The patients were evaluated periodically according to a standardized protocol that follows the recommendations of an expert panel convened by the World Health Organization to discuss severe asthma, in 2009 .1, FVC, the FEV1/FVC ratio, and FEF25–75%. Increases of 200 mL or 12% were considered significant post-bronchodilator variations in FEV1. The bronchodilator response was evaluated according to the proportional post-bronchodilator increase in FEV1 in relation to the baseline value [All spirometry tests were performed at the same place and time, with a spirometer . The tests were performed in accordance with the recommendations of the American Thoracic Society . Before ne value .The parameters are expressed as percentages of the values predicted value for age, gender, and height , as wellIn all patients, the fraction of exhaled nitric oxide (FeNO) was measured prior to spirometry and only when the patients were free of upper airway infections. Using a portable analyzer , we obtained the FeNO values at an expiratory flow rate of 50 ml/s .At each visit, the level of asthma control was evaluated on the basis of the following parameters: daytime and nighttime symptoms; the ability to perform physical activities; and the need for rescue medication . We alsoAll medications were provided free of charge to the patients by the pharmacies of secondary referral centers . Over thThe patients were receiving one of two types of treatment: dry-powder inhalers delivering a combination of budesonide and formoterol—Symbicort  or Alenia ; or dry-powder or metered-dose inhalers containing fluticasone, combined with salmeterol , montelukast , oral prednisolone (generic), or omalizumab .Every patient used a dry-powder inhaler or a metered-dose inhaler with a spacer fitted to the mouthpiece. The inhalation technique was evaluated at each visit, and the interventions proposed were reviewed at subsequent visits , 20.We determined the rate of adherence to the use of the ICS by calculating the proportion of doses used in relation to the expected number of doses for each time period, on the basis of the dose counters of the devices or counting the empty capsules  and the records of the dates on which the medicines were dispensed , 21.In accordance with the criteria of the Allergic Rhinitis and its Impact on Asthma guidelines , the diaDermatophagoides pteronyssinus, Dermatophagoides farinae, Blomia tropicalis, Alternaria alternata, Aspergillus fumigatus, cat dander, dog dander, and cockroach allergens (from Periplaneta americana and Blattella germanica). We determined total immunoglobulin E by fluorescence enzyme immunoassay , considering reference values by age group [We performed forearm skin prick tests using allergens obtained from ALK-Abelló , and positivity for allergic sensitization was defined as a wheal 3 mm larger than that observed for the negative control. The positive and negative controls were histamine and saline solution, respectively. We tested the following allergens : Dermatoge group .At each visit, we reviewed the level of environmental control in the home, considering reports of exposure to mold, passive smoking, household dust, and domestic animals, and the recommended interventions were reevaluated in subsequent visits , 20.Patients with symptoms suggestive of gastroesophageal reflux disease were followed by specialists and underwent diagnostic assessment as necessary . PatientDescriptive analyses were performed by calculating frequencies, means, medians, and standard deviations. Because of the considerable variability observed in the individual profiles, we employed a mixed-effects linear regression model, with a random intercept and a random slope, in our evaluation of lung function over time. The inclusion of the random effects allowed us to estimate a specific intercept for each patient, and the random slope evaluated the estimated trend for individual patients to gain or lose lung function over time.The graphics for the longitudinal profiles were then constructed, considering all of the spirometry tests together and by treatment group: 800 µg/day of ICS; and > 800 µg/day of ICS. To smooth the longitudinal profiles and determine the mean behavior among the groups, we adopted the locally weighted scatter-plot smoothing method.1, FEF25–75%, and FEV1/FVC ratio. The post-bronchodilator variation in FEV1 was expressed in mL and in percentage. For each of these variables, we constructed two models. An initial model included only the length of follow-up (in months) and allowed us to infer the longitudinal trend (slope) for the sample as a whole. A second model was constructed in order to determine the influence that an ICS dose > 800 µg/day has on the mean behavior of lung function over time. To identify factors associated with pulmonary function, we also created a third model, which included the following covariates: gender; age at first spirometry; duration of illness; self-reported exposure to passive smoking; ACT score; occurrence of exacerbation since the previous consultation; FeNO; and length of follow-up. The models were initially adjusted for all of the covariates listed above. The covariates were selected manually: at each step, the least significant covariant  was removed, and the process was repeated until all non-significant covariates had been excluded. Covariates for which the estimated p value was less than 0.05 were considered significant. The suitability of the model was determined by visual inspection of residual plots, which did not indicate major deviations from the distributional assumptions. Data were analyzed with the program R (R Development Core Team—www.r-project.org). The level of significance was set at p < 0.05.Separate models were adjusted for the pre- and post-bronchodilator values of each of the response variables, calculated as percentages of the predicted values and as z-scores: FVC, FEVTable D. pteronyssinus, D. farinae, and B. tropicalis being the most common aeroallergens to which they were sensitized.The median FeNO was 22.5 ppb at enrollment and 13.5 ppb at the end of the follow-up period. The majority of the patients were allergic, During the study, we addressed the factors that influence asthma control, such as allergic rhinitis (the median score for which dropped from 9.5 at baseline to 6.0 at the end of the study) and exposure to secondhand smoke within the home, adopting measures for its elimination. The patients with gastroesophageal reflux disease were treated by specialists, and two of those patients underwent fundoplication. All patients were reminded of the importance of correct inhalation technique and treatment adherence, both of which showed improvement over the course of the study. During the study, the median dose of ICS increased from 800 to 876.1 µg/day and the maximum dose increased from 1600 to 2400 µg/day. At enrollment, all of the patients were using a LABA in combination with the ICS. During the study, the proportion of patients using leukotriene receptor antagonists increased from 16.9 to 61.5%, whereas there was a reduction in the proportion of patients on a regimen of continuous oral corticosteroid use. Omalizumab was started in 7.8% of the patients. During the follow-up period, there was improvement in the median ACT score (which increased from 15.5 at enrollment to 22.0 at the end of the study), a reduction in the frequency of severe exacerbations, and no intensive care unit admissions, showing that treatment optimization provided clinical improvement.Table 1%, in the FEV1/FVC ratio, and in FEF25–75% (% predicted). In the > 800 µg/day subgroup, the intercept values were lower and no gain in lung function was observed for any of the parameters evaluated. However, we observed a significant reduction in the z-score for FEF25–75%. That phenomenon was observed in the cohort as a whole and in the > 800 µg/day subgroup.In the cohort as a whole, statistically significant increases were observed in the pre-bronchodilator FEV1/FVC ratio, which showed a statistically significant increase. In the > 800 µg/day subgroup, most of the parameters remained constant, with no gain or loss of function, although there was a reduction in the FEV1%. Over the course of the study, there was a significant reduction in the FEV1 response to bronchodilator administration in the cohort as a whole. In the > 800 µg/day subgroup, the post-bronchodilator variation in FEV1 remained unchanged over the 3 years of follow-up.In the longitudinal evaluation, the post-bronchodilator lung function parameters remained constant throughout the study in the cohort as a whole, with the exception of the z-score for the FEVFigure 1 and FEF25–75%, for which the values were below the lower limit of the normal range at several points.The evolution of the pre- and post-bronchodilator spirometry parameters, in z-scores, can be seen in Fig. 25–75%. The covariates that remained in the final model were the length of the follow-up period (p < 0.001), age (p < 0.001), and the FeNO (p = 0.001).Table 1%, has been shown to be characterized by a phase of elevation during childhood and adolescence, a plateau in young adulthood, and a subsequent decline after 30 years of age [1% in patients with mild to moderate asthma in a cohort studied in the United States [In individuals without lung disease, a normal pattern of growth and decline in lung function, based on the FEVs of age . A patted States . The aut1, the FEV1/FVC ratio, and FEF25–75% (% predicted). However, in the > 800 µg/day subgroup, FEV1, the FEV1/FVC ratio, and FEF25–75% remained constant over time, a behavior that suggests an early plateau. At the end of the study, the median age of our patients was 13.5 years, when they would be expected to be in the FEV1 gain phase.During follow-up at our referral outpatient clinic, the patients in our cohort showed a statistically significant increase in lung function, as determined by measurements of FEV1 of 2.6% only in the first year, with a plateau in the following 3 years.In a four-year longitudinal study involving 47 children and adolescents  with severe asthma that was refractory to treatment with 1600 µg/day of budesonide or equivalent, an early plateau phase was also observed [In the Tucson birth cohort , which c1/FVC ratio, showed the same tendency in percentage of predicted and in z-score—an increase in the cohort as a whole and stability in the > 800 µg/day subgroup. In our study, the z-scores revealed a statistically significant reduction in the pre-bronchodilator FEF25–75%, in the cohort as a whole and in the > 800 µg/day subgroup.The interpretation of lung function in the transition from childhood to adolescence is complex and is influenced by the multitude of predictive equations of normal values and the differences among the various age groups. Unlike the majority of biological indices in medicine, such as plasma concentrations of chemical analytes or hormones, lung function varies with age, height, gender, and ethnicity. Few equations take into account the changing relationship between lung function and height during the adolescent growth spurt . The per25–75% is a sensitive indicator of small airways disease and has been shown to be useful in distinguishing patients with persistent symptoms from those with transient symptoms [25–75%, could function as a predictor of persistent asthma and of difficult-to-control asthma. Unlike FEV1, FEF25–75% is independent of abnormalities indicative of alterations in large airways [25–75% in childhood is predictive of asthma in adult life, whereas it is not necessarily the case for FEV1 [A low FEF airways . Studiesfor FEV1 .25–75% as a diagnostic tool has limitations related to its reproducibility and interindividual variability, which are usually greater than those associated with FEV1 and FVC. The coefficient of variation for FEF25–75% is approximately 6%, which is high but acceptable [25–75% is more sensitive to detecting increased airway resistance because the growth of the pulmonary parenchyma can be disproportionate or because of “distal displacement” of the middle portion of the forced expiratory curve when there is lung deflation [25–75% were the length of follow-up, age, and FeNO. These findings are consistent with those of a study involving patients with severe asthma with a median age of 10 years , in whom changes in the obstructive pulmonary function pattern and elevated FeNO persisted over time despite high doses of ICS. This suggests that persistence of airway inflammation defines a subpopulation of pediatric patients with severe asthma [1/FVC ratio and FEF25–75% both being lower at 14–15 years of age than at 8–9 years of age, whereas the persistent wheezing phenotype has been associated with higher ratios of FeNO at 14–15 years of age [The use of FEFeflation . In our e asthma . The pros of age . Childres of age .1% over the course of the study, in comparison with the placebo and nedocromil sodium. The authors stated that, as a measure of lung function, post-bronchodilator FEV1% presents less variability over time than do pre-bronchodilator values.In a 4-year, placebo-controlled study of the use of budesonide and nedocromil sodium in children with mild persistent asthma , conducted by the Childhood Asthma Management Program Research Group [The use of pre- or post-bronchodilator spirometry values to determine the degree of airway obstruction is open to discussion. Although post-bronchodilator spirometry is recommended in patients with chronic obstructive pulmonary disease, its use in asthma patients, especially in younger patients, is more controversial . A high 1% in the group of asthma patients that required even higher doses of ICS. In a study involving adults with severe asthma [1 % over time (p < 0.001) and asthma severity was associated with a greater decline in lung function, supporting the concept that there is a specific endotype of progressive airway remodeling.Among the post-bronchodilator parameters evaluated in the present study, we observed a decrease in FEVe asthma , there wIn a study involving children with moderate asthma in Europe , the gro1 response is a characteristic of asthma, and the magnitude of that response can decrease over the course of treatment [The post-bronchodilator FEVreatment . In the reatment .1/FVC ratio indicated that a reduction in lung function occurs in early childhood [In one long-term study, the slopes for changes in the FEVhildhood . Among ahildhood .25–75% z-score and post-bronchodilator FEV1%, was not due to insufficient doses of ICS, lack of other controllers, or potentially modifiable factors.The patients in our study used high doses of ICS, always in combination with a LABA. Other controllers, such as leukotriene receptor antagonists and oral corticosteroids, were prescribed as needed. Omalizumab was prescribed for patients over 6 years of age who had a serum immunoglobulin E level of 30–1500 IU/mL and in whom asthma was uncontrolled despite treatment with high doses of ICS and a LABA. Over the course of the study, the mean treatment adherence rate was 93.2%. The inhalation technique, reviewed at all visits, was found to be adequate. In addition, after initial efforts to educate the patients and their relatives, exposure to secondhand smoke in the home was reportedly eliminated and the comorbidities were addressed. All of our patients were treated within the public health care system, via the CEMAD and Wheezing Baby Program, which is the first of its kind in Brazil . Since 1The high treatment adherence rates observed in the present study were likely due to the fact that the CEMAD is a referral center structured for the treatment of asthma patients. A study involving adult patients with severe asthma in the city of Salvador, Brazil, also showed high treatment adherence rates, which the authors suggested was attributable to the fact that those patients were under treatment at specialized centers .Our study has certain limitations. The results might have limited external validity, because the patients with severe asthma were recruited from among those who had been referred to our university center and had already been followed for a median of 6 years. Our patients, all of whom were referred by pediatric pulmonologists, had not achieved control despite being in GINA treatment step 4 or 5. Nevertheless, we believe that our sample was representative of this specific patient population.It has been postulated that an irreversible loss of pulmonary function occurs early in life . Our 3-y1%. We observed an early plateau phase in an age group in which the majority of individuals should be gaining lung function. In the group of patients studied here, higher doses of ICS doses > 800 µg/day of budesonide or equivalent did not improve lung function parameters and the decrease in FEF25–75% might reflect remodeling of the smaller airways.Our results indicate that the need for higher doses of medication is associated with greater asthma severity. Over the course of our study, we observed an improvement in asthma control, as evaluated by the ACT score, although functional alterations in the distal airways persisted, as did low post-bronchodilator FEV25–75%. Nevertheless, in the > 800 µg/day subgroup, there was also a significant reduction in the post-bronchodilator FEV1%. The significant reduction in FEF25–75% in the cohort as a whole and, more clearly, in the > 800 µg/day subgroup, suggests small airway impairment that is unresponsive to ICS and to the other controllers used. It is possible that the FEF25–75% z-score is a more sensitive measure of asthma obstruction. The behavior of lung function in the > 800 µg/day subgroup (no significant gain over the 3-year follow-up period) suggests an early plateau phase. The results of our study corroborate those of previous studies showing an abnormal pattern of growth or a decline in lung function among children with asthma, provide new evidence that treatment with ICS, even at very high doses, is insufficient to prevent the problem, and underscore the fact that low FEF25–75% might be a sensitive biomarker of asthma severity, potentially indicating a subpopulation of pediatric patients with severe asthma.In conclusion, among children and adolescents with severe asthma undergoing treatment in a referral outpatient clinic in Brazil, our longitudinal evaluation evidenced a gain in lung function, based on the majority of the spirometric variables evaluated. However, there was a decline in the z-scores for pre-bronchodilator FEF


Physiologic determinants, such as pulse pressure [difference between systolic blood pressure (SBP) and diastolic BP (DBP)], mean arterial pressure (2/3 DBP + 1/3 SBP), and double product [beats per minute (bpm) × SBP], are linked to cardiovascular outcomes. The effects of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on pulse pressure, mean arterial pressure, and double product were assessed in patients with type 2 diabetes mellitus (T2DM).This post hoc analysis was based on pooled data from four 26-week, randomized, double-blind, placebo-controlled studies evaluating canagliflozin in patients with T2DM (N = 2313) and a 6-week, randomized, double-blind, placebo-controlled, ambulatory BP monitoring (ABPM) study evaluating canagliflozin in patients with T2DM and hypertension (N = 169). Changes from baseline in SBP, DBP, pulse pressure, mean arterial pressure, and double product were assessed using seated BP measurements (pooled studies) or averaged 24-h BP assessments (ABPM study). Safety was assessed based on adverse event reports.In the pooled studies, canagliflozin 100 and 300 mg reduced SBP (−4.3 and −5.0 vs −0.3 mmHg) and DBP (−2.5 and −2.4 vs −0.6 mmHg) versus placebo at week 26. Reductions in pulse pressure (−1.8 and −2.6 vs 0.2 mmHg), mean arterial pressure (−3.1 and −3.3 vs −0.5 mmHg), and double product (−381 and −416 vs −30 bpm × mmHg) were also seen with canagliflozin 100 and 300 mg versus placebo. In the ABPM study, canagliflozin 100 and 300 mg reduced mean 24-h SBP (−4.5 and −6.2 vs −1.2 mmHg) and DBP (−2.2 and −3.2 vs −0.3 mmHg) versus placebo at week 6. Canagliflozin 300 mg provided reductions in pulse pressure (−3.3 vs −0.8 mmHg) and mean arterial pressure (−4.2 vs −0.6 mmHg) compared with placebo, while canagliflozin 100 mg had more modest effects on these parameters. Canagliflozin was generally well tolerated in both study populations.Canagliflozin improved all three cardiovascular physiologic markers, consistent with the hypothesis that canagliflozin may have beneficial effects on some cardiovascular outcomes in patients with T2DM.Trial registration ClinicalTrials.gov Identifier: NCT01081834 (registered March 2010); NCT01106677 (registered April 2010); NCT01106625 (registered April 2010); NCT01106690 (registered April 2010); NCT01939496 (registered September 2013) Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular morbidity and mortality . T2DM haArterial stiffness is also an established risk factor of cardiovascular events and mortality –7. In paCanagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor approved to treat adults with T2DM . SGLT2 iIn a pooled analysis of four placebo-controlled, Phase 3 studies, canagliflozin treatment was associated with reductions in SBP at 26 weeks in both the overall population of patients with T2DM and a subgroup of patients with elevated SBP at baseline (≥140 mmHg) . A separThis post hoc analysis was based on data from two study populations: a pooled population consisting of four 26-week, randomized, double-blind, placebo-controlled, Phase 3 studies evaluating canagliflozin in patients with T2DM (N = 2313) and a 6-week, randomized, double-blind, placebo-controlled study evaluating canagliflozin in patients with T2DM and hypertension (N = 169).2. The dual and triple therapy studies included patients with HbA1c ≥7.0 and ≤10.5% and eGFR ≥55 mL/min/1.73 m2. Patients were required to be on a stable antihypertensive medication regimen for ≥4 weeks prior to randomization; adjustments to antihypertensive medication considered clinically necessary were to be made during the pretreatment phase in order to avoid adjustments during the double-blind period. Key exclusion criteria common to all four studies included fasting plasma glucose (FPG) ≥15 mmol/L (≥270 mg/dL) during the pretreatment phase; history of type 1 diabetes mellitus (T1DM); history of myocardial infarction, unstable angina, revascularization procedure, or a cerebrovascular accident within 3 months of screening; and uncontrolled hypertension . Details of the study design, including randomization and blinding, and glycemic rescue criteria have been previously reported for the individual studies included in the pooled analysis  × SBP.In the pooled, placebo-controlled studies, each seated BP measurement was based on an average of three BP readings taken manually with a mercury sphygmomanometer or an automated BP monitor at intervals of ≥1 min. In the ABPM study, BP recordings were collected over a 24-h period using an ABPM device every 20 min during the day and every 30 min during the night. Additional details regarding the methods used to measure BP have been previously reported for both study populations , 17.Medical Dictionary for Regulatory Activities (MedDRA). The overall incidence of AEs and the incidence of volume depletion–related AEs were evaluated.Safety and tolerability were assessed based on adverse event (AE) reports through week 26 in the pooled, placebo-controlled studies and through week 6 in the ABPM study. AEs were reported spontaneously by patients or in response to non-directed questioning and were coded using the Analyses were performed using data from all randomized patients who received ≥1 dose of study drug. The last observation carried forward (LOCF) approach was used to impute missing data. Endpoints were analyzed using an analysis of covariance (ANCOVA) model, with treatment and stratification factor (ABPM study) or study  as fixed effects and the corresponding baseline value as a covariate. Least squares (LS) mean differences and 2-sided 95% confidence intervals (CIs) were estimated for the comparisons of each canagliflozin dose versus placebo. Safety analyses included all reported AEs , and included all randomized patients who received ≥1 dose of study drug. Statistical analyses were performed using SAS, version 9.2 .2, and SBP of 128 mmHg. Of the 2313 patients included in the pooled studies, 1332 (57.6%) were taking antihypertensive medication at baseline. In the ABPM study, the mean baseline age was 59 years and patients had a mean baseline HbA1c of 8.1%, BMI of 33 kg/m2, and SBP of 139 mmHg. Mean baseline SBP and DBP were lower in the pooled, placebo-controlled studies, which included patients with and without hypertension, compared with the ABPM study, which enrolled only patients with hypertension.Baseline demographic and disease characteristics were generally similar across treatment groups in both study populations Table . In the In the pooled, placebo-controlled studies, canagliflozin 100 and 300 mg provided reductions in SBP and DBP compared with placebo at week 26  were low across groups . Among patients treated with canagliflozin, no volume depletion–related AEs were considered serious or led to study discontinuation. In the ABPM study, 2 patients (3.6%) experienced a volume depletion–related AE with canagliflozin 300 mg; none were reported with canagliflozin 100 mg or placebo. Rates of significant orthostasis [defined as symptoms on standing  or a reduction in office SBP ≥20 mmHg or DBP ≥15 mmHg 2 min after standing] at week 6 were 3.8, 7.1, and 3.9%, with canagliflozin 100 and 300 mg and placebo, respectively.In the post hoc analysis of pooled data from four Phase 3 studies, canagliflozin 100 and 300 mg provided reductions in SBP and DBP, as well as pulse pressure, mean arterial pressure, and double product compared with placebo over 26 weeks in a broad population of patients with T2DM. Responses were generally similar in the post hoc analysis of data from a smaller, 6-week ABPM study in patients with T2DM and hypertension. Both canagliflozin doses reduced mean 24-h SBP and DBP over 6 weeks compared with placebo. Canagliflozin 300 mg provided reductions in pulse pressure and mean arterial pressure compared with placebo, while canagliflozin 100 mg had more modest effects on these parameters. In both study populations, canagliflozin was generally well tolerated, with an increase in AEs related to the mechanism of SGLT2 inhibition , consistent with previous Phase 3 studies of canagliflozin .The findings from this analysis are consistent with those reported for the SGLT2 inhibitor empagliflozin in a study that evaluated changes in BP and markers of arterial stiffness and vascular resistance in patients with T2DM . EmpagliThe favorable effects of canagliflozin treatment on pulse pressure, mean arterial pressure, and double product are expected to translate into reduced arterial stiffness, improved blood flow, and a lower cardiac workload. Furthermore, as these markers have been shown to be predictive of cardiovascular events , 25–27, Limitations of the study include the post hoc nature of the analysis and the relatively small number of patients in the ABPM study population. In addition, double product may be best assessed using ABPM and many not accurately predict cardiovascular risk in some patient populations . HoweverCanagliflozin provided reductions in pulse pressure, mean arterial pressure, and double product over 26 weeks in a general population of patients with T2DM and in a 6-week ABPM study in patients with T2DM and hypertension. The improvements in cardiovascular physiologic markers seen with canagliflozin in this analysis are consistent with the hypothesis that canagliflozin may have beneficial effects on some cardiovascular outcomes in patients with T2DM. Results from the ongoing CANVAS and CANVAS-R trials may help to better define the cardioprotective effects of canagliflozin in patients with T2DM.


The endocan levels were inversely correlated with the estimated glomerular filtration rate . An endocan cutoff concentration of 7.0 ng/mL identified pediatric RT patients who had hypertension and a loss of renal function with 100% sensitivity and 75% specificity. In conclusion, the endocan concentrations were significantly elevated in pediatric RT patients who had both hypertension and a loss of renal function. The correlations between the endocan levels and the hemodynamic variables and the markers of renal function strengthen the hypothesis that it is an important marker of cardiorenal risk.Endocan is an important biomarker of inflammation and endothelial dysfunction that increases in association with several chronic diseases. Few published data have described the role of endocan in pediatric renal transplant (RT) patients. We evaluated the endocan concentrations in 62 children who underwent renal transplantation and assessed their relationships with the patients' blood pressure and loss of renal function. The endocan levels were significantly elevated in the pediatric RT patients who had hypertension and a loss of renal function. We determined positive correlations between the endocan concentrations and the hemodynamic variables (systolic blood pressure:  Renal transplantation is one of the most effective options for the treatment of chronic renal failure in children , 2. ChilDespite a positive prognosis, concerns continue to exist about the progressive loss of renal function and the development of cardiometabolic diseases among pediatric RT recipients –7. The fThe findings from recent research indicate that endocan could be an important predictive marker of arterial HT and renal failure –14. Endo (Protocol Number: 354.875). All parents and children signed written informed consent/assent forms.This study was conducted at the Renal Transplant Unit of the Nephrology Division from Kidney & Hypertension Hospital  on pediatrics patients, who were recruited between August 2013 and July 2014. The study was carried out on 62 RT children (43 boys and 19 girls). Inclusion criteria were as follows: RT patients of either sex; patients who were between 6 and 24 months after transplant. On the other hand, patients were excluded for the following reasons: presence of systemic infection or acute rejection clinically diagnosed and biopsy proven. None of the children who underwent renal transplant received vitamin D supplementation. All patients provided a blood sample, which was collected in the morning, following an overnight fast. After that, the body weight and height were measured using a standard balance beam scale. The local ethics committee approved the study protocolSystolic (SBP) and diastolic (DBP) blood pressure were measured with appropriate cuff size by auscultation after the child was seated for 10 min. We defined HT in accordance with the Fourth National Task Force on High Blood Pressure in Children and Adolescents . An HT d2)  = mL/min/1.73 m2) .The serum endocan levels were measured using a magnetic bead-based immunoassay kit , according to the manufacturer's protocol. The assay's concentration range was 0.02–9.6 ng/mL. The intra-assay and interassay coefficients of variation for the endocan assay were <2.43% and <5.57%, respectively. Neither significant cross-reactivity nor interference between human endocan and the breakdown product, which is a p14 peptide fragment, has been reported.2, and the presence or absence of HT [P < 0.20 in the univariate model were included in the multivariate analysis. A receiver operating characteristic (ROC) curve was applied to identify the best endocan cutoff point. All of the statistical tests were two-tailed, and the significance level was set at P < 0.05. The statistical analyses were performed using IBM®SPSS® software .The categorical variables are presented as the frequencies and the percentage distributions. The continuous variables were assessed for normality before the data were analyzed, and they are summarized as the means, standard deviations, and the 95% confidence intervals (CIs). The analyses were performed by stratifying the pediatric RT patients according to the chronic kidney disease (CKD) cutoff point, namely, an eGFR of <60 mL/min/1.73 mce of HT , 22. To 2. HT was detected in 44 of the children before renal transplantation, and HT persisted in 29 of the children after transplantation. Sixteen children had both HT and CKD after renal transplantation, and 20 children had neither HT nor CKD. Seventeen children (26%) were given steroid-free immunosuppressive therapy and seven children (25%) were given single agent antihypertensive therapy that comprised calcium channel blockers (CCBs). Demographic, anthropometric, and clinical data are presented in Tables Our study cohort comprised 62 pediatric RT patients, and 67% of the patients were boys. The mean age of the recipients at transplantation was 12.8 years (range: 3–17 years), and the mean age of the donors was 12.7 years (range: 2–43 years). Six of the donors were adults and 56 donors were younger than 18 years of age. The causes of renal failure were defined as uropathy in 22.6% and glomerulonephritis in 17.7% of the patients, and the etiologies were undetermined or the renal failure was associated with other causes in 59.7% of the RT patients . After rP = 0.252). There were no correlations between the endocan levels and age  or the body mass index (BMI) . We found positive correlations between the endocan levels and the SBP  and the PP  . The serum endocan levels did not change significantly when immunosuppressive or antihypertensive agents were administered (both P > 0.05). Inverse correlations were detected between the eGFR and the SBP  and the PP . Interestingly, endocan levels were inversely correlated with the eGFR .The mean endocan concentration was 12.2 ng/mL (range: 4.3–15.4 ng/mL), and there was no significant difference between the genders with respect to the endocan concentration  and CKD  on the serum endocan concentrations (n = 16) had a significantly higher mean serum endocan concentration  compared with that in the pediatric RT patients who did not have either of these conditions (n = 20)  (P < 0.001) and the mean serum endocan concentration in those with HT only (n = 13)  (P = 0.002). There was no significant difference with respect to the mean serum endocan concentration between the pediatric RT patients with HT and CKD and those with CKD only (n = 13)  (P = 0.342) (P = 0.007)  . The mea= 0.007) .P < 0.20) (P < 0.001)  . The end < 0.20) . The mul < 0.20) . The ROC< 0.001) .The main finding of present study is that serum endocan levels were significantly elevated in RT children with both HT and loss of renal function and that the serum endocan concentration was an independent predictor of the presence of HT and a loss of renal function in pediatric RT patients, after adjusting for multiple confounders. In addition, we found positive correlation of endocan with SBP and pulse pressure, and the serum levels of this biomarker were inversely correlated with eGFR among RT children.Endocan is a soluble proteoglycan that is detected in the blood and is expressed by endothelial cells of the vasculature, lung, and kidney , 17. TheSome mechanisms could explain the high endocan levels in the pediatric RT patients with HT and the loss of renal function. The findings from recent studies have shown links between the endocan levels and endothelial dysfunction and inflammation , 18, 19.The limitations of the present study include the small number of patients recruited, its cross-sectional design, and the single rather than multiple measurements of the serum endocan concentrations. In conclusion, pediatric RT patients with both HT and a loss of renal function have elevated endocan levels. The presence of correlations between the endocan levels and the SBP, the PP, and the eGFR strengthens the hypothesis that endocan is an important marker of cardiorenal risk. Although the pathological implications are not completely understood, the data from this study may help to explain the kidney damage and the increased risks of HT and other cardiovascular diseases that occur in pediatric RT patients. Further studies are necessary to clarify the importance of these correlations and to elucidate the clinical significance of endocan.