Renin‐angiotensin‐system blockers (RASB) improve clinical outcomes in patients with chronic heart failure with reduced fraction; however, there remains ambiguity whether RASB therapy should be continued during the treatment of acute decompensated heart failure (ADHF).In comparison to patients with RASB use, RASB discontinuation in ADHF will be associated with worsening renal function, hypotension, and adverse long‐term clinical outcomes.Patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE) trial were separated into four groups based on RASB use at baseline and discharge: continuation (n = 316), discontinuation (n = 21), initiation (n = 42), and nonuse (n = 23). Post‐discharge outcomes were validated in an independent ADHF cohort admitted to the Cleveland Clinic (n = 253).P < .001 for both), but not with serial potassium and systolic blood pressure measurements. No other clinical parameter changes were significant. In comparison to RASB continuation, RASB discontinuation and nonuse was associated with ~75% increased risk of a 180‐day composite of death, transplant, or rehospitalization . Post‐discharge outcomes were similar in the validation cohort.RASB discontinuation and nonuse were associated with higher serial creatinine and blood urea nitrogen levels than RASB continuation or initiation (Compared to RASB continuation, RASB discontinuation and nonuse were associated with higher baseline and serial creatinine levels during treatment for ADHF, but not with changes in SBP and potassium levels. Furthermore, RASB discontinuation and nonuse in ADHF were associated with an increased risk of adverse clinical outcomes. ACEIACE‐inhibitorADHFacute decompensated heart failureARBangiotensin‐receptor blockerBUNblood urea nitrogenCCCleveland ClinicESCAPEEvaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization EffectivenessLVEFleft ventricular ejection fractionPACpulmonary arterial catheterizationRASBrenin‐angiotensin‐system blockersSBPsystolic blood pressureWRFworsening renal function1Renin‐angiotensin‐system blockers (RASB) are cornerstones in the treatment of chronic heart failure with reduced left ventricular ejection fraction, leading to a reduction in morbidity and mortality.22.1The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial tested whether pulmonary arterial catheterization (PAC) improved outcomes in patients hospitalized with acute decompensated heart failure. Criteria for study inclusion were left ventricular ejection fraction ≤30%, symptomatic heart failure for at least 3 months prior despite ACEI and diuretic therapies, a systolic blood pressure (SBP) of ≤125 mm Hg and at least one sign and one symptom of congestion. There were 215 patients assigned to the PAC arm of the 433 randomized patients. This trial was conducted at 26 sites in the United States and Canada from 2000 through 2003. The main findings of this trial have been previously published.2.2This cohort is three data sets pooled together from consecutive patients admitted to a specialized heart failure intensive care unit with ADHF at the Cleveland Clinic (CC) from 2000 to 2005, 2006 to 2007, and 2010 to 2011. The assembly and characteristics of this cohort have been previously described.2.3Renin‐angiotensin system blockers (RASB) included ACE‐inhibitors (ACEI) or angiotensin‐receptor blockers (ARB). Their use was determined daily by on‐site research personnel in ESCAPE and by chart abstraction in the Cleveland Clinic (CC) cohort. Subjects with a ventricular ejection fraction (LVEF) >40% and in whom RASB could not be determined were excluded (n/N = 31/433 in ESCAPE and n/N = 190/443 in the CC cohort). The remaining cohort  was then categorized into one of groups based on RASB use at baseline and discharge: RASB at baseline and discharge [“continuation”], RASB only at discharge [“initiated”], RASB only at admission but not discharge [“discontinuation”], and no RASB use [“nonuse”].2.4P‐values <.05 were considered statistically significant. All statistical analyses were performed using Stata version 13.1 software .Continuous variables were expressed as median (interquartile range) and categorical variables as percent. The Kruskall‐Wallis and Pearson's Chi‐square tests were used to test differences across RASB use categories for continuous and categorical variables, respectively. The association of RASB use category and serial serum creatinine levels, blood urea nitrogen (BUN) levels, SBP measurements, and serum potassium levels were determined by a mixed effects model assuming unequal variance. Survival analyses were completed via the Kaplan‐Meier method and log‐rank test to compare cumulative incidence curves across RASB categories. Cox‐proportional hazards models were used to test the association between RASB and time to clinical outcomes after adjusting for potential confounders. The combined endpoint included death, transplant, or all‐cause rehospitalization. The proportional hazards assumption was verified by generalized linear regression of scaled Schoenfeld residuals over time. The model covariates were selected a priori because of their potential to confound the RASB use‐risk relationship. These included age, sex, systolic blood pressure amount < 140 mm Hg, serum potassium, and serum creatinine. All time‐to‐event analyses were landmarked at the time of discharge for each subject. Two‐sided 33.1P < .0001 for both). Similar findings were seen in the CC cohort. Notably, there were no significant differences among sex, systolic blood pressure, sodium, potassium, hemoglobin or hemodynamic characteristics across the four groups.Baseline characteristics for the ESCAPE and CC cohorts are shown in Tables 3.2P = .02). However, diuretic efficiency measures and changes in serum sodium, hemoglobin, cardiac output or filling pressures were not significantly different among RASB groups.The changes in key clinical parameters, stratified by RASB classification, are shown in Table P < .001 for all groups). Furthermore, RASB discontinuation was associated with rising creatinine by days 5 (P‐interaction = .02) and 7 (P‐interaction = .002). On the other hand, there was no significant difference in serial serum creatinine over time between the RASB continuation or initiation groups (P = .6). In comparison to RASB continuation, RASB initiation, discontinuation, and nonuse were not associated with serial systolic blood pressure measurements or potassium levels.Figure 3.3Figure 3.4P < .001). RASB discontinuation during hospitalization was associated with a 4‐fold increase in 180‐day death (hazard ratio (HR) 4.12, 95% confidence interval (CI) 2.00‐8.47, P < 0.001), whereas RASB nonuse had a trend towards increased 180‐day death risk . In the ESCAPE cohort, RASB discontinuation and nonuse during hospitalization was significantly associated with death and the composites of death, transplant, or all‐cause rehospitalization at 6 months in comparison to RASB continuation .In ESCAPE, there were 402 patients followed for 180‐day outcomes. A total of 68 deaths occurred: 14% (n/N = 42/300) in those with RASB continuation, 14% (n/N = 6/43) in those initiated, 57% (n/N = 12/21) in those discontinued and 35% (N = 8/23) in those with nonuse (Log‐rank P = .005). Similar trends were seen with worsened outcomes in those with RASB discontinuation and nonuse in respect to the composite endpoint of death, transplant or all‐cause hospitalization at 6 months after multivariable adjustment , as illustrated in Supplemental Figure In the Cleveland Clinic cohort, there were 43 deaths, including 14.9% (n/N = 23/154) in RASB continuation, 6.7% (n/N = 2/30) in those with initiation, 35.7% (n/N = 10/28) in those with discontinuation and 19.5% (n/N = 4/21) in those with nonuse , hypotension (23.3%), and hyperkalemia (10%).Although the clinical benefits of RASB use persist across the spectrum of renal function, individuals with renal insufficiency are less likely to be prescribed RASB.Our study must be interpreted in the context of several limitations inherent to its design. As a post hoc analysis, the direct impact of RASB discontinuation or nonuse in ADHF on outcomes remain uncertain. Yet, these findings highlight a high‐risk group that might benefit from further investigation. Secondly, we cannot exclude selection bias for those treated for ADHF in the context of a clinical trial. However, the generalizability of these findings is supported by comparable findings with respect to long‐term clinical outcomes in the CC cohort. Thirdly, whether there was active uptitration or downtitration of RASB during the hospitalization was unknown. While RASB uptitration has been associated with favorable clinical outcomes,5In comparison to RASB continuation, RASB discontinuation and nonuse was associated with higher baseline and serial serum creatinine and BUN during treatment for ADHF, but not with changes in SBP or other key clinical parameters. Furthermore, RASB discontinuation and nonuse in ADHF were associated with an increased risk of adverse clinical outcomes. These findings further highlight the implications of RASB use at the time of discharge. Prospective study determining the cardiorenal and clinical impacts of continuing RASB therapy in the face of renal insufficiency in individuals ADHF is warranted.The authors declare no potential conflict of interest.Supplementary Figure S1. Kaplan–Meier Estimates of the Cumulative Incidence of the Composite Endpoints Stratified by RASB Use. The composite endpoint was death, transplant or all‐cause rehospitalization at 6 months for the ESCAPE cohort (A) and death, LVAD/transplant or all‐cause rehospitalization at 6 months for the Cleveland Clinic cohort (B).Click here for additional data file.


Trichuris trichiura (whipworm) infection; higher vegetable consumption was associated with lower systolic BP. Results for diastolic BP were similar, except higher fruit, rather than higher vegetable consumption was associated with lower diastolic BP and there was no association with waist circumference or Trichuris trichiura infection. In summary, life-course exposures were associated with adolescent BP in this tropical birth cohort. Malaria early in life could impact later BP. Interventions initiated early in life targeting individuals with family history of hypertension, aiming to reduce adiposity (in pregnancy and adolescence) and promoting fruit and vegetable consumption might contribute to reducing the risk of high BP and subsequent cardiovascular diseases.We aimed to investigate life-course factors associated with blood pressure (BP) among Ugandan adolescents. Between 9th April 2003 and 24th November 2005, 2507 pregnant women from Entebbe municipality and Katabi sub-county were enrolled into a deworming trial. The resulting 2345 live-born offspring were followed to age 10 or 11 years, when between 20th May 2014 to 16th June 2016, BP was measured following standard protocols. Factors associated with BP were assessed using multivariable linear regression. BP was measured in 1119 adolescents with a median age of 10.2 years. Mean systolic BP and diastolic BP was 105.9 mmHg (standard deviation (SD) 8.2) and 65.2 mmHg (SD 7.3), respectively. Maternal gestational body mass index (BMI), higher maternal education status and family history of hypertension were positively associated with adolescent BP. Childhood (age ≤5 years) malaria was associated with lower adolescent systolic BP. Factors measured at time of BP measurement positively associated with systolic BP were age, BMI, waist circumference and  Once uncommon in Africa , high blAlthough high BP is less common in children and adolescents than in adults, it initiates early in life, persists into adulthood  and predSevere persistent high BP is associated with increased risk of stroke and heart failure ; treatmeEarlier studies, mainly in adults, have demonstrated the role of established risk factors for high BP such as obesity  and physChildhood and adolescence are opportune periods for high BP control or prevention before clinical manifestation of hypertension or related CVDs. Identification of life-course BP risk factors unique to Africa is needed for the development of appropriate BP control strategies. We used longitudinally collected data from the Entebbe Mother and Baby Study (EMaBS), a large tropical birth cohort, to describe factors associated with adolescent BP.This longitudinal observational study investigated perinatal and life-course factors associated with BP among adolescents born in Wakiso district, Uganda. The EMaBS was a randomised double-blind placebo-controlled factorial trial [ISRCTN32849447], designed to investigate effects of worms and their treatment in pregnancy and childhood on response to childhood vaccines and on infections .The study was conducted in Entebbe municipality and Katabi sub-county (a peninsula on the northern shores of Lake Victoria). In 2003–2005, 2507 women attending Entebbe Hospital antenatal clinic, in their second or third trimester were invited, enrolled and randomised to receive albendazole (400 mg) or placebo and praziquantel (40 mg/kg) or placebo .Data were collected prenatally from women and resulting 2345 live-born offspring followed from birth. As previously described , at 15 m2). Trained clinicians examined and performed Tanner staging as described elsewhere . Briefly, participants stood barefooted on the posterior electrode base while holding two anterior electrodes handles of the SBCAM. Fat mass index = FMI (kg)/height  ova and Strongyloides larvae using Kato-Katz [Mansonella perstans. Maternal HIV status at enrolment and children’s HIV status after 18 months of age were assessed using a rapid serial testing algorithm described elsewhere [Stool and blood samples were collected from women at enrolment and annually from children. Stool was examined for helminth  were taken after 5 min rest using automated devices (Omron M6), with appropriate sized cuffs .For clinical care purposes, means of the three systolic BP and three diastolic BP measurements were calculated and BP percentiles determined using Centre for Disease Control height charts and 2004 updated National Health and Nutrition Examination Survey BP tables specific for sex, age and height , 10. ThoFor data analysis purposes, the means of the second and third systolic/diastolic BP readings on day 1 were used: day 1 second and third BP readings were lower than the first BP reading but similar to each other .Ethical approval was granted by the Uganda Virus Research Institute Science and Ethics Committee; the Uganda National Council for Science and Technology; and the London School of Hygiene and Tropical Medicine. Written informed assent and consent were obtained for study participation.t-tests (for continuous variables) were used to compare characteristics of cohort members who participated and did not participate in the BP study.Data were collected on pre-coded questionnaires and analysed with Stata 14.2 . Chi-squared tests  and Study outcomes were mean systolic BP and mean diastolic BP, based on the second and third day-one measurements. The decision was made to model these two continuous BP outcome variables rather than to dichotomise outcomes  as an analysis using these binary outcomes would be underpowered. Maternal, perinatal and offspring life-course factors considered as exposures and potential confounders were: maternal and adolescent socio-demographic and anthropometric characteristics; EMaBS trial interventions ; sickle-cell trait; illnesses and infections from birth to time of BP measurement; and body composition, puberty stage, diet, sleep pattern and physical activity at time of BP measurement. Area of residence was grouped into urban versus rural area using zones based on topography and settlements generated from geographical positioning system data . HousehoLinear regression analysis was used. Data satisfied the assumptions for linear regression. Crude associations were examined for each covariate and a 20% significance level was used for selecting covariates for multivariable models. Adolescents’ sex, age and BMI were confounders a priori. Multivariable analysis followed a hierarchical causal approach adding factors sequentially Fig. .Fig. 1CoBecause of a large proportion of missing data, puberty and body composition variables were not included in model building for other exposures but their effects were each adjusted for variables included in the final multivariable model. Multicollinearity was assessed by considering the change in standard error, when potentially multicollinear variables were included in the same model.A total of 1119 EMaBS participants were enrolled into the BP study: 583 (52%) were males; 1100 (98.3%) singletons; 18 (2%) HIV positive; and 344 (31%) mixed feeding by 6 weeks. EMaBS adolescents participating in the BP study were similar to non-participants, except that mothers of participants were more likely to be of higher education status or married/cohabiting; offspring were less likely to be HIV positive or of a multiple birth, details published earlier .2 (standard deviation (SD) 1.9) and mean waist circumference 58.1 cm (SD 4.9). Body composition data were available for 176 (16%) participants, with mean fat mass index 2.9 kg/m2 (SD 1.2), fat-free mass index 12.8 kg/m2 (SD 1.4) and total body water mass index 9.5 kg/m2 (SD 0.9).At age 10/11 (median participant age 10.2 years (interquartile range (IQR): 10.0–10.9)), 117 (11%) were attending boarding schools, 441 (72%) were pre-pubertal stage for pubic hair development and 178 (65%) of girls were pre-pubertal stage for breast development. Mean BMI was 15.8 kg/mOver the previous month, starchy staple foods, animal proteins, fruit, vegetables and sugar drinks were consumed on average for 6.9 days/week (SD 0.8), 2.2 days/week (SD 1.7), 3 days/week (SD 2.2), 3.4 days/week (SD 2.3) and 1.7 days/week (SD 2.1), respectively. Nearly all adolescents (98%) reported adding salt to cooked food.P-value = 0.971) or diastolic BP  between males and females. None of the adolescents had had a prior BP measurement or high BP diagnosis.Mean systolic BP was 105.9 mmHg (SD 8.2) and mean diastolic BP was 65.2 mmHg (SD 7.3). There was no difference in mean systolic BP  and 42 (7.2%), respectively, among males, and 54 (10.1%) and 52 (9.7%), respectively, among females. After extra measurements on the second and third visits and taking loss to follow-up into account, pre-hypertension prevalence was estimated as 2.2% in males and 0.7% in females; high BP prevalence was 0.4% in males and 1.8% in females.Tables β = 1.84  after adjustment for maternal and childhood factors. Body composition and puberty stage covariates were no longer associated with systolic BP on adjusting for adolescents’ age, BMI and waist circumference.Characteristics at the time of BP measurement showing a crude positive association with systolic BP were age, BMI, waist circumference, family history of high BP, body composition variables and puberty stage covariates. In multivariable analysis, systolic BP increased, on average, by 1.35 mmHg, 95% CI  for each 1-year increase in adolescents’ age; by 0.78 mmHg  per unit increase in BMI; and by 0.21 mmHg  per centimetre increase in waist circumference. Family history of high BP remained associated with increased systolic BP, Lifestyle factors crudely associated with increased systolic BP were increased animal-protein consumption, increased consumption of sugared drinks and attending a boarding school rather than a day school. Increased fruit and vegetable consumption were associated with reduced systolic BP. After adjusting for confounders, systolic BP reduced on average by 1.13 mmHg  among adolescents who consumed vegetables for 3–7 days/week (versus 0–2 days/week).Trichuris trichiura was positively associated with systolic BP after adjusting for confounders ). Systolic BP dropped by 1.24 mmHg  among adolescents who had malaria in childhood compared to those who had not. Both clinical and asymptomatic malaria were independently associated with lower BP in multivariable analysis. Weight and height at 10 and 11 years of age were reduced among adolescents with childhood clinical and or asymptomatic malaria . Systoβ = −0.28 mmHg ), even after adjusting for age and sex. HbAS was inversely associated with malaria .Genetic data were available for 802 (72%) participants of whom 141 (18%) had sickle-cell trait (HbAS) and 661 (82%) normal haemoglobin (HbAA). Sickle-cell trait was not associated with systolic BP  on adolescent BP and no associations between prior helminth infection (in pregnancy or childhood) and adolescent BP.Our findings are consistent with several earlier studies , 26. We Malaria parasitaemia in childhood was associated with lower BP in early adolescence, consistent with findings from a cross-sectional study among 5–18-year-old Ugandan students, which reported that current asymptomatic malaria was associated with lower BP . Our stuSub-microscopic malaria was most likely misclassified as negative in this population, since in malaria-endemic areas, asymptomatic malaria often presents as sub-microscopic in individuals with past malaria infection . We founSimilar to earlier studies , 31, chiTrichuris trichiura  was associated with increased systolic BP in early adolescence. To our knowledge, no study has previously reported such an association. This may reflect short-term effects  or it could be a spurious finding due to the many exposures included in the analysis. The effect of current Trichuris trichiura infection on BP is likely not mediated through increasing BMI (weight or height); there was no difference in these measures between adolescents with and without current Trichuris trichiura infection.Current but not previous infection with Unlike previous studies , we founPrevious studies have linked hypertension to socioeconomic determinants (socioeconomic status (SES), education, income, urbanisation) , 36. OurStrengths of this study included its longitudinal design with prospectively collected data reducing recall and reporter bias, the use of robust BP procedures and the measurement of BP on up to two extra occasions in those with BP ≥95th percentile at the initial visit, to avoid overestimation of high BP. It is unlikely that white-coat phenomenon was an issue as participants regularly attend this clinic for scheduled and/or illness visits. The use of digital machines reduced differences in BP reading between operators which can occur with auscultation.Study limitations include the possibility of residual confounding by unmeasured factors (such as glomerular filtration rate (GFR)). The GFR could not be estimated as creatinine was only measured for a subgroup of the participants. The use of digital BP machines may overestimate BP; however, digital devices used in this study were calibrated twice annually. A large number of statistical tests were undertaken; thus, some findings may be due to multiplicity. However, it is reassuring that most findings are consistent with previous literature, albeit from different settings. Not inviting all adolescents  for up to two extra BP measurements might have resulted in an underestimation in the overall prevalence of pre-hypertension and hypertension. We modelled BP as a continuous outcome, since analysing high or pre-hypertensive BP versus normal BP as a binary outcome (or outcomes) would be underpowered, consequently our findings may not necessarily reflect associations with hypertensive disease.In summary, routine BP screening which is seldom conducted for adolescents at health care visits remains vital in the control and prevention of CVDs later in life. Similar life-course factors to those observed in high-income settings (such as adiposity and diet) affect both systolic BP and diastolic BP among African adolescents. Interventions during pregnancy, childhood and early adolescence could be vital in the control and prevention of later high BP. Multiple intervention strategies initiated during pregnancy and the early postnatal period and continued across a lifetime could be fundamental in the control of adulthood hypertension and CVDs.High blood pressure and cardiovascular diseases are increasing in Africa.Scarcity of data on blood pressure risk factors among African children and adolescents.The risk factors for high blood pressure may differ from those seen in high-income non-tropical settings.Malaria infection in childhood is associated with reduced blood pressure among adolescents. Effects of childhood malaria on later blood pressure may be partially mediated through chronic reduction in weight and height.Trichuris trichiura is associated with increased blood pressure.Current infection with Interventions during pregnancy, childhood and early adolescence could be vital in the prevention of high blood pressure later in life.Supplementary tables


Acute respiratory distress syndrome (ARDS) patients may present impaired in lung function and structure after hospital discharge that may be related to mechanical ventilation strategy. The aim of this study was to evaluate the association between functional and structural lung impairment, N-terminal-peptide type III procollagen (NT-PCP-III) and driving pressure during protective mechanical ventilation. It was a secondary analysis of data from randomized controlled trial that included patients with moderate/severe ARDS with at least one follow-up visit performed. We obtained serial measurements of plasma NT-PCP-III levels. Whole-lung computed tomography analysis and pulmonary function test were performed at 1 and 6 months of follow-up. A health-related quality of life survey after 6 months was also performed.p < 0.01). At 6 months driving pressure was associated with lower FVC independently on tidal volume, plateau pressure and baseline static respiratory compliance after adjustments . There was a significant correlation between driving pressure and lung densities and nonaerated/poorly aerated lung volume after 6 months. Driving pressure was also related to general health domain of SF-36 at 6 months.Thirty-three patients were enrolled, and 21 patients survived after 6 months. In extubation day an association between driving pressure and NT-PCP-III was observed. At 1 and 6 months forced vital capacity (FVC) was negatively correlated to driving pressure (Even in patients ventilated with protective tidal volume, higher driving pressure is associated with worse long-term pulmonary function and structure. Acute respiratory distress syndrome (ARDS) is a rapidly progressive illness associated with high mortality and morbidity –3. Up toAbout 25% of ARDS survivors present some reduction in the forced vital capacity (FVC) and in diffusion capacity 6 months after discharge [The risk factors for a reduced long-term lung function in ARDS patients are unknown. As protective mechanical ventilation is an important intervention to reduce mortality of ARDS, probably by decreasing lung inflammation, we hypothesized that the parameters used during the ventilation strategy could be related to long-term lung fibrosis, impairing the lung function among ARDS survivors.During a recent ARDS trial  comparinWe conducted a prospective longitudinal cohort study of 22 survivors of moderate/severe ARDS, recruited from six different ICUs located in Hospital das Clínicas, São Paulo, Brazil, from November 2008 to January 2012.Patients were enrolled in this study in conjunction with a clinical trial in mechanical ventilation, the “ARDSnet Protocol versus Open Lung Approach in ARDS” trial (NCT 00431158) . The insA/C, tidal volume of 4–8 mL/kg PBW, plateau pressure ≤ 30 cmH2O, PEEP/FIO2 adjustments using ARDSnet table, and ventilator rate to keep PaCO2 = 35–60 mmHg. During the 12–36-h  period, PaO2/FIO2 must remain < 200 mm Hg for an ABG obtained 30 min after placement on the following specific ventilator settings: volume A/C, tidal volume = 6 mL/kg PBW, plateau pressure ≤ 30 cmH2O, inspiratory time ≤ 1 s, PEEP ≥ 10 cmH2O, FIO2 ≥ 0.5, ventilator rate to keep PaCO2 = 35–60 mmHg. No lung recruitment maneuvers or adjunct therapy. Total time on mechanical ventilation < 96 h at time of randomization.The inclusion criteria for the study were as follows: Patients intubated and mechanically ventilated, with diagnosis of ARDS using American–European Consensus Criteria and enrollment in study < 48 h since diagnosis of ARDS. For 12–36 h , after diagnosis of ARDS, patient must be ventilated as follows: volume Patients were excluded if they presented one of the following criteria: age < 18 years or > 80 years, weight < 35 kg PBW, body mass index > 60, intubated 2° to acute exacerbation of a chronic pulmonary disease, acute brain injury (ICP > 18 mmHg), immunosuppression 2° to chemo- or radiation therapy, severe cardiac disease (one of the following): New York Heart Association Class 3 or 4, acute coronary syndrome or persistent ventricular tachyarrhythmias, positive laboratory pregnancy test, sickle cell disease, neuromuscular disease, high risk of mortality within 3 months from cause other than ARDS, e.g., cancer, more than 2 organ failures (not including pulmonary system), documented lung barotrauma, i.e., chest tube placement other than for fluid drainage, persistent hemodynamic instability or intractable shock, penetrating chest trauma, enrollment in another interventional study. Randomization in the pivotal study was stratified by center, age and APACHE II scores.2/FIO2) with a positive end-expiratory pressure (PEEP) of at least 10 cmH2O and FIO2 > 0.5, and static compliance (respiratory system) 30 min before protocol enrollment. Twenty-four hours after patient enrollment, we collected respiratory variables, including tidal volume (mL/kg of predicted body weight), PEEP and plateau pressure. Airway driving pressure was defined as plateau pressure minus total PEEP. To measure the plateau pressure we used neuromuscular blocking agents and volume-controlled ventilation.Baseline data collected at enrollment included age, sex, height, severity of illness measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score, ratio between arterial oxygen tension and fraction of inspired oxygen (PaOBlood samples were obtained on the day of randomization (day 0) and on days 1, 3, 7, and the day of extubation. Blood samples were centrifuged, and plasma was stored at 70 C. NT-PCP-III was assayed by a sandwich ELISA method according to the methodology specifications of the manufacturer . The normal range of serum levels of nonsmoking individuals was determined to be 1.6–4.0 ng/L.Pulmonary function testing (PFT) was performed at 1 and 6 months after the onset of ARDS using the MedGraphics Cardiorespiratory Diagnostic System . All tests were done according to Brazilian guidelines . ReferenHigh-resolution computed tomography (HRCT) scan of the lungs was also performed 1 and 6 months after the onset of ARDS in supine position during inspiration, close to total lung capacity. All CT scans were segmented by applying the region growing algorithm to select the lung parenchyma using OsiriX . After the segmentation, the original images (DICOM files) as well as each respective ROI were exported and analyzed with a purpose-built routine (QALI-DV software) written in MATLAB . Manual correction was applied to the segmented images containing peripheral atelectasis. Total lung volume (TLV), total air volume (TAV) and total lung mass (TLM) were extracted from the segmented whole lung in 3D , 12. TheSix months after ARDS onset, we also performed a standardized 6MWT  and fulft test or the Mann–Whitney test for dependent or independent data. The Friedman test was used for one-way repeated-measures analysis. The strength of the association between two variables was measured using correlation coefficient (r). We used Pearson correlation to parametric variable and Spearman correlation to nonparametric variable. We used linear regression to get r2 in parametric variable. In order to determine clinical variables independently associated with lung function, we performed a multivariable linear regression. For NT-PCP-III regression we used log10 transformations as is commonly performed for biomarkers with a right-tailed distribution. Statistical significance was set at a two-tailed p value of ≤ 0.05, and analyses were performed with R, version 3.0.2 (http://www.r-project.org).Categorical values are described as frequency and percentages, and continuous variables as the mean and SD, or median and interquartile range. The Fisher exact test was used to compare independent categorical variables. Continuous variables were compared with the Student Over the 58-month 2007–2012) recruitment period, we enrolled 33 patients. The patients in cohort were predominantly male. Mortality at 28th day was 33%  and 72 h  after randomization. The descriptive baseline and hospital data for all randomized patients and for survivors are described in Table CO after 6 months  patients showed a reduced DLCO after 6 months of follow-up (Table Pulmonary function tests showed a mildly reduced FVC and a moderately reduced DLhs Table . The FVCeas four 9% patienr = 0.65) and 6-month (r = 0.67) follow-up  and APACHE II (r = 0.59) were correlated with DLCO at month-1. Of note, tidal volume and respiratory system compliance were very weakly correlated with pulmonary function tests.Driving pressure was the only ventilation variable significantly correlated with FVC at 1-  = 4.66, p = 0.022), the association between driving pressures and FVC at month-6 remained the only statistically significant one , P = 0.002).After testing for the confounding effects of tidal volumes, plateau pressures and baseline static respiratory compliance (P = 0.06), representing 96 ± 20% versus 86 ± 15% of predicted, respectively (P = 0.32).When comparing the effects of the randomized treatments (OLA vs. ARDSnet) on FVC at month-6, there was a marginal difference between arms, with FVC of 4.54 ± 0.93 L versus 3.41 ± 1.04 L  was 72 g/L (42–117).Twenty-one patients were performed a HRCT at month-1 of follow-up. The median and interquartile range of the total lung volume (TLV) was 3.54 L (2.29–4.37); the total lung weight (TLW) was 1194 g (861–1873), and the mean pulmonary density (MPD) was 451 g/L (243–610). The PP = 0.01) to 4.99 L (3.73–6.20), the TLW decreased (P = 0.01) to 762 g (652–934 g), the MPD decreased (P < 0.001) to 164 g/L (133–183), and P15 decreased (P = 0.02) to 49 g/L (23–65). Those longitudinal reductions in MPD, TLM and percent of nonaerated/poorly aerated lung volumes were all significant, as well as the increase in TLV.At month-6, 16 patients were performed a HRCT. The median and interquartile range of TLV increased , but not with respiratory system compliance (P = 0.95). Consistently, FVC at month-6 strongly correlated with CT parameters: MPD , % of nonaerated/poorly aerated volume , TLV  and air/tissue volume ratio .Lung image parameters were significantly correlated with driving pressure and pulmonary function. After 6 months, individual MPD was significantly correlated with individual driving pressure , MDP was higher in HDP group  or low (LDP) driving pressure groups (≥ 13 and < 13 cmHP = 0.92). There was no difference in terms of TLV (P = 0.38) and TLW (P = 0.35).When comparing the effects of the randomized treatments (OLA vs. ARDSnet) on MPD at month-6, there was no difference, with MPD of 175 (131–176) g/L versus 171 (138–195) g/L .From the 28 patients, 106 blood specimens were available for analysis of NT-PCP-III levels. All plasma samples had elevated levels, considering normal values, and considering the samples collected after 24 h from inclusion, after 3 days, and after 7 days or weaning time, the level increased over time , r2 = 0.35, F = 8.55, p = 0.011; Fig. 10NT-PCP-III difference.Individual increments in log10NT-PCP-III level during the first week of mechanical ventilation: at day 0 , r2 = 0.35, F = 8.06, p = 0.014), day 1 , r2 = 0.34, F = 8.84, p = 0.010), day 3 , r2 = 0.25, F = 5.38, p = 0.038).Mean pulmonary density (MPD) at month-6 was related to log2O, respectively), LDP group did not change levels over time (P = 0.15), while HDP group increased  or low (LDP) driving pressure groups , day 1 (P = 0.55), day 3 (P = 0.19) and on extubation (P = 0.65). There was a difference in terms of log10NT-PCP-III at day 7 . There was no difference in the change between day 0 to day 1 (p = 0.69), to day 3 (p = 0.23), to day 7 (p = 0.31) and to extubation (p = 0.18).When comparing the effects of the randomized treatments (OLA vs. ARDSnet) on logr = − 0.69, p = 0.02).A standardized 6MWT was performed in 11 patients, but we could not observe any relationship between the walked distance and the ventilation variables selected. In terms of HRQoL, 10 patients completed SF-36 survey and we found a correlation between driving pressure (24 h after randomization) and the general health domain  measured after 6 months of ARDS onset. This early measurement of driving pressure was representative of the applied strategy of protective ventilation, adjusted right after randomization and persisting at similar levels during the following days , and didSeveral studies involving ARDS survivors have shown a significant reduction in long-term lung function in a substantial proportion of patients, with a quarter of the patients presenting a FVC lower than 70% of predicted , 21. In Some investigators had previously correlated the total duration of mechanical ventilation and the levels of plateau pressure with the long-term results of pulmonary function tests and high-resolution CT studies, suggesting a relationship between mechanical ventilation and pulmonary dysfunction , 23. ThiA pro-fibrotic response to ARDS might be responsible for the physiologic abnormalities observed. Biomechanical interactions between cells and the extracellular matrix (ECM) proteins may be associated with the reorganization and remodeling of the ECM . CollageDiffuse alveolar damage (DAD) is considered absent in approximately half of patients undergoing lung biopsy for nonresolving ARDS. The main alternatives to DAD were interstitial pneumonia and lung fibrosis, infections, cryptogenic organizing pneumonia and alveolar hemorrhage , 30. In In the general population, a low FVC has been associated with increased respiratory symptoms, functional limitation and mortality –35. ThusThe modest number of patients enrolled in a single center  may have compromised the power of this study to identify statistically significant relationships. The identified relationships, however, were consistent across different long-term variables, measured independently by CT, function tests and questionnaire, suggesting the strength of the association. The independent blood samples also added consistency to our results.Another limitation of our study was the unknown functional status of the enrolled patients, who were lost during follow-up. Additionally, though patients with an exacerbation of previous lung diseases were excluded before randomization, preexisting lung disease may have interfered in the results, as patients were not evaluated by pulmonary function tests prior to enrollment.Finally, driving pressure was measured at 24 h of the beginning of the protocol. Ideally, we should consider some average exposition during the whole mechanical ventilation period. In this study, however, similarly to the previous study of Amato et al. , the valIn patients surviving after a moderate to severe ARDS there is an association between driving pressure measured 24 h after enrollment and lung function measured at 1 and 6 months after the ARDS onset, and this relationship was independent of tidal volume and independent of baseline compliance. These results suggest that, even in the context of protective tidal volume and plateau pressure, mechanical ventilation can still promote lung injury and fibrosis, highlighting the possible role of driving pressure in long-term outcomes.


Patients with lower (<40 μg/L) and higher (≥40 μg/L) leptin levels were compared. Bravais-Pearson’s correlation, multiple linear regression, and logistic regression analysis were performed. A total of 112 morbidly obese patients were included. Serum leptin was significantly higher in females than in males . Leptin was positively correlated with body mass index , IL-6 , and ΔPaO2 . Leptin was negatively correlated with preoperative PaO2 . Preoperative PaO2 was lower, ΔPaCO2 was smaller, and ΔPaO2 was greater in the high leptin group than in the low leptin group. In multiple regression analysis, leptin was negatively associated with preoperative PaO2 . In logistic regression analysis, leptin was associated with improved ΔPaO2  and ΔPaCO2 . Leptin appears to have dual effects related to perioperative gas exchange in obese patients undergoing bariatric surgery. It is associated with worse preoperative oxygenation but improved respiratory function after surgery.Leptin has shown positive effects on respiratory function in experimental settings. The role of leptin on perioperative respiratory function in morbidly obese patients has not been established. We performed a retrospective analysis of morbidly obese patients undergoing laparoscopic sleeve gastrectomy. Fasting serum leptin and interleukin (IL)-6 were measured preoperatively, and arterial blood gases were obtained pre- and postoperatively. Outcome variables were arterial partial pressure of oxygen (PaO The incidence and prevalence of obesity continue to increase globally . Obesityob gene that interacts with receptors in the hypothalamus to inhibit eating. Its importance is clearly illustrated by the extreme obesity observed in the ob/ob mouse (C57BL/6J-Lepob), which cannot produce functional leptin [Adipose tissue is not only the main storage site for surplus food energy, but it is also an endocrine organ . It prodLeptin may also have respiratory effects. Evidence from animal models suggests that leptin stimulates ventilation. Acute leptin replacement significantly increases baseline ventilation –9. LeptiObesity has well-established effects on respiratory function, which are exacerbated by supine positioning, surgery, and anesthesia. Arterial blood gases are often abnormal in obesity, characterized by hypoxemia and, less frequently, hypercapnia –12. DataWe conducted a retrospective evaluation using our hospital database and medical records of morbidly obese patients who underwent laparoscopic sleeve gastrectomy under general anesthesia at our institution. We included only patients with obstructive sleep apnea (OSA) in whom fasting serum leptin was measured preoperatively and arterial blood gases were measured preoperatively and postoperatively. Patients were recruited consecutively until the sample size was achieved. An equal allocation strategy was used to include adequate numbers of patients with high (≥40 μg/L) and low (<40 μg/L) serum leptin values. We chose 40 μg/L as the cut-off based on previous studies ,15. No o2) at 35–40 mm Hg. Lung recruitment maneuvers were performed after tracheal intubation and immediately before tracheal extubation. Anesthesia was maintained with desflurane to ensure a bispectral index value of approximately 40. At the conclusion of surgery, sugammadex 2 mg/kg total body weight was administered to ensure full reversal (train-of-four ratio ≥1.0) of moderate neuromuscular blockade. Ketoprofen 100 mg and ondansetron 8 mg were also administered at this time to reduce postoperative pain, as well as nausea and vomiting.All patients underwent a standardized general anesthetic. Anesthesia was induced with propofol 2 mg/kg lean body weight (LBW), ketamine 1 mg/kg LBW, and fentanyl 3–4 μg/kg LBW, and neuromuscular blockade was achieved with rocuronium 1 mg/kg LBW . After t2) and PaCO2 were the primary outcome variables. Arterial blood was obtained for gas exchange analysis 15 minutes before anesthesia induction and 15 minutes after tracheal extubation. We computed changes in PaO2 and PaCO2 from before to after surgery as follows: ΔPaO2 = PaO2POST–PaO2PRE and ΔPaCO2 = PaCO2POST–PaCO2PRE. Sex, age, and body mass index (BMI) before surgery were recorded as potential confounding variables.Preoperative and postoperative arterial partial pressure of oxygen .Arterial blood was obtained for gas exchange analysis using a small caliber needle to minimize patient discomfort. Gas exchange analysis was performed immediately after sampling using the Rapidlab®, Reutlingen, Germany) according to the routine methodology used in our institution’s laboratory. The analytical sensitivity of the assay was 0.1 ng/mL and the intra-assay coefficient of variability was <5%. IL-6 was measured by electrochemiluminescence immunoassay  according to our laboratory’s standard procedures. The intra-assay coefficient of variability was <7%.Venous blood sample for leptin and IL-6 was collected into a 10-mL vacutainer before noon, after patients underwent a 12-hour overnight fast. The sample was maintained in a polystyrene container with ice packs and brought quickly to the laboratory for analysis; all analyses were performed within 2 hours of blood collection. Leptin was measured by radioimmunoassay  and 95% confidence interval (CI). The two-tail Student’ t-test or two-tail Mann-Whitney U test was used to compare low to high leptin groups for variables normally or non-normally distributed variables, respectively. Median, minimum, and maximum values are reported for non-normally distributed variables. Sex distribution is presented as number (percentage) and compared between groups using the chi-square test.We used multiple linear regression analysis to determine the relationship between one dependent normally distributed variable and one or more independent normally distributed variables. For non-normally distributed variables, we first dichotomized continuous variables, then conducted logistic regression analysis to determine odds ratios (ORs) with 95% CIs.P-values <0.05 were considered statistically significant.All statistical analyses were conducted using R version 3.4.0 (2017-04-21). All procedures in the study were performed in accordance with the ethical standards of our institutional research committee and the 1964 Helsinki declaration and its later amendments. Formal consent was not necessary for this type of study . The Ethics Committee for Clinical Research of Padova approved this study.2, p = 0.583). Females had significantly higher serum leptin levels  and PaO2POST  than males. No other significant sex-related differences were observed.The characteristics of the 112 consecutive morbidly obese patients included in this study are summarized in 2PRE, and ΔPaO2  was negatively associated with PaO2POST. Age (p = 0.005) and BMI (p = 0.003) were positively associated with PaCO2PRE. No variables were significantly associated with PaCO2POST , BMI (p = 0.004), and serum leptin (p = 0.023) were negatively associated with PaOaCO2POST .2, whereas only leptin (p = 0.021) was significantly associated with ΔPaCO2  and BMI (p = 0.024) were significantly associated with ΔPaOh ΔPaCO2 .2—and positively associated with postoperative respiratory function—as evidenced by improved gas exchange.This study demonstrated that leptin  was negatively associated with preoperative respiratory function—mainly associated with a reduced PaO2PRE, higher PaCO2PRE, and greater ΔPaO2. Zavorsky et al. found lower PaO2 , normal PaCO2, and higher alveolar-to-arterial oxygen partial pressure difference  in morbidly obese patients. Furthermore, morbidly obese men had poorer gas exchange at rest than morbidly obese women [2 difference and an 8-mm Hg P(A-a)O2 difference were observed between sexes, with women exhibiting superior gas exchange [Obesity is associated with worse gas exchange compared with normal-weight individuals . Even inse women . Among 4exchange . In obesexchange  and leadexchange ,23, and exchange . These cexchange –29.Adipose tissue can also affect respiratory function through pro-inflammatory adipokines, such as leptin ,30. Airw2POST observed in men in our study may likewise be explained by these differences in adipose tissue, as well as the lower serum leptin levels in men.Sex steroid hormones are likely involved in the sex-related serum leptin differences observed in the current study –40. In mob/ob mouse model, Yao et al. identified activation of the forebrain  as the mechanism through which leptin reduces upper airway obstruction during episode of sleep apnea [Obesity is one of the most important factors contributing to upper airway changes . Fat depep apnea .2, which is likely mediated by its action in hypothalamic and brainstem nuclei. In the hypothalamus, leptin's ventilatory effects appear to be mediated by the melanocortin system [ob/ob mouse model, Yao et al. identified the hindbrain (possibly the nucleus tractus solitarius) as the main site of leptin’s effects on ventilatory control [Leptin may also play a role in positively modulating respiration. Models of animals lacking the gene responsible for leptin production exhibit marked abnormalities in breathing control, leading to respiratory failure (hypoxemia and hypercapnia) . Althougn system . In the  control . In huma control . In hype control .This study has two main limitations. It is not a randomized controlled study and thereby has the drawbacks of all observational studies. Furthermore, several factors, including aspects of anesthetic care, may have influenced the postoperative data. Rapid, short-acting volatile anesthetics, low doses of opioids, sugammadex for reversing rocuronium-induced neuromuscular blockade, and prophylactic intraoperative lung-protective mechanical ventilation have been previously reported to improve postoperative respiratory function and gas exchange –48. HoweAlthough the precise mechanisms by which leptin affects respiratory function are not yet established, our data suggest that leptin is involved in respiration and may exert a stimulatory ventilatory effect in obese patients undergoing bariatric surgery. Leptin appears to have dual effects, as it is associated with worse preoperative oxygenation but improved respiratory function after surgery.S1 Data(PDF)Click here for additional data file.


The present study analyzed blood pressure responses after a single session of isometric handgrip exercise performed with different volumes and intensities by patients with hypertension.th min).This randomized crossover trial submitted 12 hypertensive patients (58±5 years old) to four isometric handgrip exercise sessions in a random order: 4 x 2 min at 30% of the maximal voluntary contraction (S30%); 4 x 2 min at 50% of the maximal voluntary contraction (S50%2min); 4 x 3 min at 30% of the maximal voluntary contraction (S30%3min); and a control session. The systolic and diastolic blood pressure, heart rate, and rate-pressure product were measured pre- and post-exercise . Similarly, individual analyses revealed heterogeneity in the responses, including increases in blood pressure observed in some sessions. Patients with reduced blood pressure after an isometric handgrip exercise session exhibited a higher body mass index, diastolic blood pressure and heart rate (p<0.05). They also tended to be younger (p=0.07).No significant changes were observed in cardiovascular variables after any session (Isometric handgrip exercise performed with different intensities and volumes did not reduce the blood pressure of hypertensive patients. Hypertension affects more than 1 billion adults worldwide Studies that analyzed the acute effects of isometric exercise observed increased Cardiovascular responses to exercise also exhibit intra- and inter-subject heterogeneity Therefore, the present study examined blood pressure changes following IHG protocols with different volumes and intensities in hypertensive patients.This randomized crossover trial included hypertensive patients of both sexes who were participating in an IHG program for six weeks. The following inclusion criteria were used: a) use of anti-hypertensive medications b) >18 years old, c) absence of diabetes or cardiovascular disease, d) no limitations for performing IHG, and e) no other regular physical activity programs. The ethics committee of the University of Pernambuco approved the study protocol, which was performed in compliance with the Declaration of Helsinki and Brazilian National Research Ethics System Guidelines.Demographic data, medical history and medication use were self-reported. Height and weight were measured using standardized protocols, and the body mass index was calculated.Participants were familiarized with testing procedures prior to data collection, and 1-2 additional familiarization sessions were performed to ensure satisfactory performance. Participants were seated with their elbow flexed at 90°, and a MVC was performed 3 times using their dominant hand and a handgrip dynamometer . The highest recorded trial was recorded as the MVC www.randomizer.org). The experimental session was performed as follows: a) four sets of 2-min isometric contractions at 30% MVC (S30%2min); b) four sets of 2-min isometric contractions at 50% MVC (S50%2min); c) four sets of 3-min isometric contractions at 30% MVC (S30%3min); and, d) remaining seated without performing the exercise (control session - CS). An interval of 1 min between sets was used in each session, except for the S30%3min session, which did not include a rest interval between sets to standardize the duration of the experimental sessions. Patients were instructed to eat a light meal and avoid exercise, alcohol and caffeine ingestion for 24 hours prior to the experiment. All sessions were performed in a temperature-controlled room, free from noises and external distractions.Each experimental session was performed at the same time of day (10:00 a.m. to 12 p.m.) and with a 48-hour interval between sessions to avoid circadian influence and residual effects of exercise, respectively. The order in which the patients performed each experimental session was determined using simple randomization . Participants remained in a seated position for at least 5 min in a temperature-controlled room for these measurements. The blood pressure was measured at least three consecutive times in the right arm, until the values were within 4 mmHg of the previous value, with 1-min intervals between measurements. The average of the last two measurements was used, which followed the procedures of VII Brazilian Guidelines on Hypertension p≤0.05 was considered statistically significant.The sample size calculation was performed using G*Power (version 3.1.0). The minimum sample size required was 12 patients per session considering an effect size of 0.25, a power of 80% and an alpha error of 5%. The normality and homogeneity of variance of the data were determined using the Shapiro-Wilk and Levene's tests, respectively. Comparisons of pre-intervention blood pressure, heart rate, and rate-pressure product among protocols were performed using one-way ANOVA. Two-way ANOVA for repeated measures was used for pre- to post-blood pressure, heart rate, and rate-pressure product comparisons among protocols, using time and protocol as factors. We compared the CS, S30%2min, and S50%2min sessions to examine the influence of exercise intensity and exercise volume. We used Chi-square and paired t-tests to examine whether the clinical characteristics differed between patients who did or did not exhibit reductions ≥4 mmHg in systolic or diastolic blood pressures in at least one exercise session. Individual analyses were performed by calculating the net effect (changes after each exercise session minus the changes in the CS for each patient) of systolic and diastolic blood pressures. All analyses were performed using STATISTICA (version 7.0) and SPSS (version 21.0), and a value of Twelve hypertensive patients (16.6% men) fulfilled the study criteria and participated in the study. p>0.05).p>0.05)  . The meaSeven patients exhibited increases ≥4.0 mmHg in systolic or diastolic blood pressure in one of the sessions. Three patients exhibited increased systolic and diastolic blood pressure after all sessions, with values varying between 5 and 18 mmHg for systolic blood pressure and between 4 and 10 mmHg for diastolic blood pressure. In addition, 57.1% of the patients who exhibited increases in blood pressure ≥4.0 mmHg showed the greatest increases after the S30%2min session.p<0.05), and they tended to be younger (p=0.07).The primary finding of the present study is that different IHG protocols did not reduce any of the measured cardiovascular parameters. Analyses of the individual data demonstrated heterogeneity in responses, including increases in blood pressure during some sessions. Patients with higher body mass index, diastolic blood pressure and heart rate were more likely to experience decreases in blood pressure ≥4 mmHg during at least one exercise session.The results of the present study indicated that IHG exercise did not acutely alter the systolic or diastolic blood pressure, heart rate or rate-pressure product of hypertensive patients. Although acute reductions in blood pressure after exercise were shown in several studies Patients in the current study had well-controlled cardiovascular parameters , which may be associated with the fact that these patients had already performed six weeks of isometric exercise training, which was sufficient to reduce blood pressure. Trained hypertensive patients are less responsive to acute effects Sample characteristics may explain the differences between responder and non-responder. Patients with reductions in blood pressure had a higher body mass index, diastolic blood pressure and heart rate than patients who did not exhibit reductions. These factors affect cardiovascular responses following exercise Notably, the greatest acute decreases in blood pressure occurred after the higher intensity session (approximately 60% of patients). The mechanisms underlying this response were not assessed. However, the mechanical contraction of the muscles around the vessels during the S50%2min session may have produced a higher occlusion of blood flow than the lower intensity exercise and increased shear stress, which stimulated nitric oxide production and vasodilation. Millar et al. IHG exercise performed with different intensities and volumes did not reduce blood pressure in trained hypertensive patients. The chronic effects of IHG exercise on clinical blood pressure are widely demonstrated in the literature This study has some limitations that should be considered. The small sample size precluded us from performing additional analyses, primarily to compare the clinical conditions. The specific characteristics of the sample population may limit the generalizability of the results to other populations that differ in age, sex, or health status. We included men and women, and the influence of sex differences on the mechanisms underlying the cardiovascular responses to exercise cannot be excluded. The patients were monitored for only 30 min, and whether the post-exercise duration influenced the results was not examined in this study.In conclusion, IHG exercise performed with different intensities and volumes did not reduce the blood pressure of controlled and trained hypertensive patients.Silva GO, Farah BQ and Ritti-Dias RM were responsible for the study conception and design, analysis and interpretation of data, draft of the manuscript, critical revision of the manuscript for important intellectual content and approval of the final version to be published. Germano-Soares AH, Andrade-Lima A, Santana FS and Rodrigues SL were responsible for the manuscript drafting, critical revision of the manuscript for important intellectual content and approval of the final version to be published.


Chronic kidney disease (CKD) has a rapidly rising global prevalence, affecting as many as one-third of the population over the age of 75 years. CKD is a well-known risk factor for cardiovascular disease and, in particular, there is a strong association with stroke. Cohort studies and trials indicate that reduced glomerular filtration rate increases the risk of stroke by about 40% and that proteinuria increases the risk by about 70%. In addition, CKD is also strongly associated with subclinical cerebrovascular abnormalities, vascular cognitive impairment and dementia. The mechanisms responsible for these associations are currently unclear. CKD is associated with traditional risk factors such as hypertension, diabetes mellitus and atrial fibrillation, but non-traditional risk factors such as uraemia, oxidative stress, mineral and bone abnormalities, and dialysis-related factors, such as changes in cerebral blood flow or cardiac structure, are also postulated to play a role. Kidney disease can also impact and complicate the treatments used in acute stroke and in secondary prevention. In this review, we will outline our current understanding of the epidemiology and pathophysiology of cerebrovascular disease in CKD. Chronic Kidney Disease (CKD) affects as many as 8-16% of the population worldwide.In this review, we will explore the risk, severity and mechanisms for stroke in CKD. Firstly, we will discuss the clinical associations between renal and cerebrovascular diseases, including ischaemic stroke, small-vessel disease (SVD), haemorrhagic stroke, vascular cognitive impairment and dementia. Secondly, we will highlight the mechanisms of susceptibility and injury, including shared pathophysiology and risk factors, secondary consequences of renal dysfunction, and diseases that can cause both CKD and stroke.2 had an incidence rate of 10.3 stroke events per 1000 person-years compared with 3.4 events per 1000 person-years in those without; however, this apparent excess risk of stroke was no longer statistically significant after adjusting for conventional vascular risk factors .There is conflicting evidence about whether CKD, specifically low estimated glomerular filtration rate (eGFR), is a risk factor for stroke independent of traditional cardiovascular risk factors. In a meta-analysis of 22 634 people from four population-based longitudinal studies, individuals with an eGFR of <60 mL/min/1.73 m2 had a 43% increased risk of stroke in a pooled multivariate-adjusted analysis that adjusted for conventional vascular risk factors,However, this attenuation of risk association may simply have been the result of inadequate statistical power, as a larger meta-analysis of 33 prospective studies with 284 672 participants experiencing 7863 stroke events reported that patients with an eGFR of <60 mL/min/1.73 m2 decrease in glomerular filtration rate (GFR).Similarly, in the most recent meta-analysis of 83 studies (over two million participants), there was an inverse linear relationship between eGFR and the risk of stroke, with risk of stroke increasing 7% for every 10 mL/min/1.73 mThere is a particularly strong and independent association between proteinuria and stroke. In a meta-analysis of 10 cohort studies , participants with proteinuria had a 71% greater risk of stroke compared with those without (95% CI 1.39% to 2.10%).Patients with CKD tend to suffer more severe strokes with worse functional outcomes, morbidity and mortality. This was demonstrated by the Fukuoka Stroke Registry multicentre study of 3778 patients with first-ever ischaemic stroke.2  had a 2.5 times greater risk of in-hospital mortality after acute ischaemic stroke compared with those with normal renal function, even after adjusting for comorbidities and initial NIHSS score.Functional outcomes and stroke mortality are worse in advanced CKD. In a cohort study of 232 236 patients, patients with an eGFR of <15 mL/min/1.73 m2, 60.5±37.1 vs 73.9±33.3 mL/min/1.73 m2 and 57.6±33.3 vs 73.9±32.9 mL/min/1.73 m2, respectively).CKD is also highly prevalent in patients with SVD. In a single-centre study of survivors of acute ischaemic stroke, patients with silent lacunar infarction, white matter lesion (WML) or cerebral microbleed (CMB) had significantly lower eGFR than those without such lesions  but not deep subcortical white matter in patients with acute ischaemic stroke.The Oxford Vascular Study highlighted an age-specific association between SVD and CKD in 1080 patients with transient ischaemic attack (TIA) and ischaemic stroke.Subclinical SVD has also been proposed to underlie the association between CKD and cognitive impairment, as patients with CKD have a tendency to develop a pattern of cognitive dysfunction with prominent deficits in executive function, attention, planning and information processing speed, which is typical for a vascular cognitive impairment profile.While intensive glycaemic control is known to reduce the incidence and progression of nephropathy in diabetic patients,2 and nearly half of patients with a urinary ACR of >300 mg/g.CKD is prevalent in nearly one-third of patients presenting with ICH, and it is associated with much worse mortality compared with those with normal renal function.Compounding the problem, CKD was predictive of poorer outcomes in acute ICH in a secondary analysis of INTERACT-2, although intensive BP reduction appears to be equally effective in those with reduced eGFR compared with those with normal renal function.2 decrease in eGFR <60 mL/min/ 1.73 m2 was associated with an 11% increase in prevalence of cognitive dysfunction.CKD is associated with a significant burden of cognitive impairment and dementia that increases with worsening renal function.Both vascular and neurodegenerative hypotheses for cognitive impairment in CKD have been proposed .29 TransNeurodegenerative mechanisms may also be augmented in CKD, and this may be partly attributable to hypertension, often comorbid in patients with CKD, and thought to potentiate Alzheimer’s pathology, lowering the threshold at which signs and symptoms manifest.The Sefuri study was a population-based cohort study of 560 non-demented elderly patients that explored the relationships between CKD, subclinical cerebrovascular abnormalities and cognition using structural equation modelling, and tests of global cognitive function  and executive function (modified Stroop test).Cognitive impairment is also associated with abnormal neuroimaging in dialysis patients.Proteinuria shares similar associations with cognitive abnormalities. In the Systolic Blood Pressure Intervention Trial–Memory and Cognition in Decreased Hypertension substudy, patients with higher urine ACR had worse global cognitive function, executive function, memory, attention and abnormal white matter volume, such that each doubling of urine ACR had the same association with cognitive performance as being 7, 10, 6 and 14 months older, respectively.There is a complex relationship between CKD and cerebrovascular disease with many potential contributing mechanisms . Some ofThe kidney and the brain share unique anatomical and physiological features that render them vulnerable to conventional cardiovascular risk factors such as hypertension, diabetes and smoking. They are both characterised by high blood flow rates and are dependent on local autoregulation. However, the kidney consumes twice as much oxygen as the brain and requires 20% of cardiac output to deliver a high GFR of 100–125 mL/min.Cardiovascular mortality doubles with every 20/10 mm Hg increment in systolic/diastolic BP in the general population.The ‘strain vessel hypothesis’, based on hypertensive vascular damage, has been suggested as a possible mechanism for the association between CKD and stroke  since boIn the kidney, the juxtamedullary afferent arterioles are small, short vessels that have to maintain a strong vascular tone in order to provide a large pressure gradient in a short distance.Strain vessels also exist in the central nervous system in the form of deep perforating arteries that arise directly from large high-pressure arteries, such as anterior, middle or posterior cerebral arteries, and then penetrate into the brain tissues.Thus, there are strain vessels common to the kidney and brain that seem to be preferentially damaged by hypertension, exacerbated by the haemodynamics of large arteries, particularly arterial stiffness.Injury of the juxtamedullary afferent arterioles (the ‘strain’ vessels) and glomeruli, of which microalbuminuria is a marker, may impair downstream medullary circulation through the vasa recta. As the medullary circulation has an important role in the mechanisms of pressure natriuresis to accomplish complete sodium balance ,It has been suggested that albuminuria not only reflects localised renal damage but also is a surrogate biomarker of more generalised endothelial dysfunction associated with increased risk of vascular events such as stroke. This is the basis of the Steno hypothesis.BBB dysfunction with altered permeability plays an important role in both acute and chronic cerebrovascular diseases.As the BBB and the glomerular barrier in the kidney share similar structural features with tight junction complexes, they may also share similar susceptibility to mechanisms of disruption, such as hypoperfusion, ischaemic and inflammatory stimuli.S1, S2 and clinical studies have shown CSF leakage of gadolinium in patients with CKD after contrast-enhanced brain MRI, consistent with impaired BBB function in these patients.S3 Although underlying mechanisms for this disruption are unclear, it may explain some of the association between CKD, particularly proteinuric disease, and SVD.Animal models of acute kidney injury and CKD have demonstrated loss of BBB integrity in the setting of uraemia,2, respectively.S4 Even after adjustment for age, hypertension and cardiac disease, patients with CKD with AF were still at much higher risk of stroke and death .Patients with CKD are at high risk of AF. From the recently published Stockholm Creatinine Measurements project, 13 412 (12%) of adult patients with CKD followed up for a mean of 3.9 years developed AF with increasing incidence rates with advancing kidney disease stages: from 29.4 to 46.3 per 1000 person-years in patients with eGFR=45–60 and <30 mL/min/1.73 mS5 In addition, CKD has been associated with a left atrial (LA) thrombogenic milieu  among patients with non-valvular AF undergoing transoesophageal echocardiography.S6 The prevalence of thrombogenic milieu increased with declining eGFR .To compound matters, rates of prescription of anticoagulant drugs have been found to be suboptimal in people with CKD.2DS2–VASc-R and CHA2DS2–VAK scores.S7, S8 Increasing CHA2DS2–VASc-R score correlated significantly with mortality, thromboembolism and incident AF. In the CHA2DS2–VAK score, CKD was substituted for female sex, and there was enhanced discrimination of low to intermediate thromboembolic risk patients with AF in a Korean population.Therefore, it has been suggested to incorporate a measure of renal function in thromboembolic risk prediction scores, including the CHA2 decrease).S9 This suggests that the association between CKD and carotid disease cannot be entirely explained by their common risk factors .Although carotid artery disease is a common cause of large-artery atherosclerotic stroke in the general population, it appears to have a particularly strong association with kidney disease. In a community-based cohort study of 3364 participants, kidney function was a strong predictor of greater carotid intima–media thickness, progression of subclinical atherosclerosis, and increased fatal and nonfatal vascular events independent of traditional and non-traditional cardiovascular risk factors in multivariable analysis  and unstable and ruptured plaques  compared with patients with normal renal function. The content of collagenous fibres was also significantly reduced in patients with CKD. It would seem therefore that patients with CKD have a greater susceptibility to carotid disease and its cerebrovascular complications via enhanced calcification and the lower collagenous content of their carotid plaques leading to plaque instability and rupture.It may be the case that the uraemic or the proinflammatory milieu causes CKD to impact on plaque composition, lesion stability and risk of rupture in patients with advanced carotid stenosis.S11 Patients with CKD again had more end-stage calcification, unstable and ruptured lesions, and lower collagenous content of their plaques. Relevant serum markers of inflammation, vascular calcification and vessel wall degradation were significantly elevated in patients with CKD compared with those with normal renal function, including enhanced levels of fibrinogen, parathyroid hormone, fetuin-A and matrix metalloproteinase-7. In accordance with this, patients with CKD experienced a higher prevalence of prior cerebrovascular events >6 months before carotid surgery .A similar German study analysed metabolic and chemical parameters, along with plaque composition in relation to stroke events and renal function in patients with advanced carotid disease.Thus, CKD is not only associated with progression of carotid atherosclerosis but also with an inflammatory milieu that creates a greater propensity for unstable plaques more likely to rupture and result in cerebrovascular embolic events.S12 This is particularly prominent in patients with type 1 diabetes where serum total cholesterol, VLDL, LDL cholesterol and triglycerides all rise with increasing albuminuria.S13Patients with CKD can develop a secondary form of dyslipidaemia that is similar to the atherogenic dyslipidaemia of insulin-resistant patients. In addition, progressive proteinuric kidney disease can interfere with lipoprotein transport causing an increase in serum triglycerides with elevated very-low-density lipoprotein (VLDL), small dense low-density lipoprotein (LDL) particles and reduced high-density lipoprotein (HDL) cholesterol, which have significant atherogenic potential.S14 Urinary losses of the enzyme lecithin–cholesterol acyltransferase also lead to low HDL with a poor maturation of HDL-3 to cholesterol-rich HDL-2.S15One of the mechanisms of this ‘renal dyslipidaemia’ may be the increase in hepatic LDL synthesis that results from urinary protein loss causing upregulation of 3-hydroxy-3-methylglutaryl CoA reductase with consequent hypercholesterolaemia.S16 Approximately 20%–30% of both type 1 and type 2 diabetics will have moderately increased albuminuria.S17, S18CKD prevalence in the diabetic population is much higher than that of the general population at 36%.S19 and progression of urinary protein loss in diabetic nephropathy.S20In addition to the associated dyslipidaemia that may result from urinary protein loss, albuminuria also appears to correlate with certain inflammatory biomarkers indicative of endothelial dysfunction, such as intercellular adhesion molecule-1. Increased levels of intercellular adhesion molecule-1, in turn, have been associated with greater burden of WMHS21 In an adjusted analysis, the presence of microalbuminuria was associated with an increased risk of stroke with an HR of 3.2 (95% CI 1.9 to 5.6). The HRs for patients with diabetic nephropathy with macroalbuminuria and end-stage kidney disease (ESKD) were 4.9 (95% CI 2.9 to 8.2) and 7.5 (95% CI 4.2 to 13.3), respectively, with similar risks for cerebral infarction, haemorrhage and lacunar stroke. Progression of diabetic kidney disease was associated with worse stroke outcomes.S22In the Finnish Diabetic Nephropathy Study, 4083 patients with type 1 diabetes were studied.S23Non-traditional CKD-related risk factors can promote cerebrovascular injury by triggering vascular injury and endothelial dysfunction. These factors include chronic inflammation, endothelial dysfunction, uraemic toxins, anaemia and mineral–bone disorder .4 A receS24 There is evidence that protein carbamylation may cause endothelial dysfunction as impaired acetylcholine-induced vasorelaxation has been described in mice with elevated urea levels. Carbamylated-oxidised LDL has also been shown to have proatherosclerotic effects on endothelial cells and macrophages, and to impair myocardial function.S25High levels of urea may contribute directly to stroke risk in patients with CKD via a reaction known as carbamylation, whereby urea dissociates to form cyanate, which, in turn, reacts irreversibly with proteins and free amino acids.S26 Disruption of the intestinal epithelial barrier due to substantial reductions in the tight junction proteins claudin-1, occludin and ZO-1 in the colonic mucosa has been observed in animal models of CKD,S27, S28 and this may cause gut bacterial toxins to translocate into the systemic circulation.S29 It is proposed that this translocation of gut toxins may promote systemic inflammation and adverse cardiovascular outcomes. In keeping with this theory, patients with CKD have different gut microbiome patterns, and uraemic toxins such as p-cresol sulfate, indoxyl sulfate and trimethylamine-N-oxide are derived from this colonic microbiome. Increased circulating levels of these uraemic solutes have been associated with a higher risk of cardiovascular morbidity and mortality in patients with ESKD.S30The gut microbiome is also emerging as a potential source of uraemic toxins.S31 The mechanisms of impaired platelet function in CKD include impaired platelet adhesiveness and abnormal platelet endothelial interaction. There is an imbalance between platelet agonists, ADP and serotonin, and its inhibitor, cyclic adenosine monophosphate (cAMP) resulting in an activation defect. There is also a deficiency in platelet cytoskeletal proteins that can impair motility and secretory function. Binding of both von Willebrand factor and fibrinogen to the platelet receptor glycoprotein, GPIIb/IIIa, is reduced in uraemia, leading to impaired platelet adhesion to the subendothelium.Platelet dysfunction in the setting of uraemia may also increase the risk of haemorrhagic stroke in patients with advanced CKD.S32The kidney is the one of the most important sources of antioxidant enzymes, such as glutathione peroxidases, and thus, levels of pro-oxidants increase with in CKD. There was a significant elevation in malondialdehyde levels (a biomarker of oxidative stress) in patients with CKD with cardiovascular disease compared with patients with CKD without cardiovascular disease, suggesting that oxidative stress potentiates atherosclerosis in CKD.S33Iron therapy, frequently required to treat anaemia in advanced CKD, may also contribute to oxidative stress. Supersaturation of iron sequestration proteins such as transferrin and ferritin following the administration of intravenous iron may result in elevated levels of free iron with damaging oxidative properties.S34 Inflammation is initiated by innate immune reactions to modified lipoproteins and is perpetuated by TH1 cells that react to autoantigens from the apolipoprotein B100 protein of LDL. In addition, patients with CKD have higher levels of haemostatic factors, particularly factor VIII and von Willebrand factor, which may also augment their risk of thrombotic events.S35CKD accelerates atherosclerosis by enhancing inflammation and dyslipidaemia.S36Dialysis-dependent patients are particularly prone to chronic inflammation resulting from exogenous factors such as dialysis membranes and central venous catheters, cellular factors such as oxidative stress, tissue factors such as hypoxia and salt and fluid overload, and microbial factors such as immune dysfunction, and from the retention of uraemic toxins.S37 ‘Adynamic’ bone disease may also occur with low bone turnover, decreased bone buffering capacity, higher serum calcium and higher risk of extraskeletal, particularly vascular, calcification. Arterial calcification and stiffness can lead to left ventricular hypertrophy and increased cardiovascular morbidity and mortality.S38Hyperphosphataemia complicates advanced CKD as a result of reduced urinary phosphate excretion, ongoing intestinal phosphate absorption and the development of secondary hyperparathyroidism.S39 Phosphate balance is regulated by fibroblast growth factor-23 (FGF-23), a protein secreted primarily by bone tissue. FGF-23 signalling requires the presence of the coreceptor Klotho.S40 CKD is characterised by Klotho deficiency and increased FGF-23 levels, which are independently associated with cardiovascular mortality.S41 In mouse models of Klotho deficiency, an accelerated ageing syndrome results with vascular calcification that resembles features of uraemia.S42Hyperphosphataemia contributes to arterial medial calcification by inducing an osteogenic phenotype change of vascular smooth muscle cells.S43 However, there was substantial discrepancy and heterogeneity in results with better evidence to support this association in dialysis patients than in predialysis patients.From a systematic review of the risk of all-cause mortality, cardiovascular mortality and cardiovascular events associated with bone–mineral abnormalities in CKD, the findings suggest a higher mortality risk with phosphate, followed by calcium and parathyroid hormone.S44 CKD impairs uric acid excretion and the problem is compounded by often coexistent diuretic use, insulin resistance and increased renal vascular resistance.S45Under normal conditions, two-thirds of the uric acid that is produced in the body is excreted in the urine and one-third is removed by the biliary tree.S46 In an analysis of the Losartan Intervention for Endpoint Reduction in Hypertension Study, baseline serum uric acid was significantly associated with cardiovascular complications. Losartan's reduction of uric acid accounted for 29% of its treatment effect on the primary composite end point  compared with atenolol.S47Results from a meta-analysis of 15 studies with 22 571 cases of stroke and 1 042 358 participants indicate that hyperuricaemia may modestly increase the risks of both stroke incidence and mortality.S48 A discrepancy in line with this suggestion is that in patients with acute ischaemic stroke, there is a 12% increase in the odds of good clinical outcome for each milligram per decilitre increase of serum uric acid,S49 and the administration of uric acid therapy to patients post-thrombolysis has been associated with lower rates of early ischaemic worsening.S50 It has been postulated that uric acid may act as a neuroprotectant in the acute phase of stroke due to its efficient antioxidant capacity.However, some propose that hyperuricaemia is simply a marker for other risk factors such as hypertension or diabetes, rather than a casual factor itself.S51 The hypothesis follows that any decrease in nephron number would be accompanied by glomerular hyperfiltration and glomerular enlargement, and would culminate in systemic hypertension. An individual’s total nephron composition, combined with a susceptibility to confounding disease factors (‘second hit’), may lead to increased risk of cardiovascular and renal diseases later in life.S52There is a large natural variation in nephron numbers between typical two-kidney individuals, and there is an association between nephron number and BP.S53 Polygenic scores correlating with higher eGFR using serum creatinine were associated with lower risk of large-artery atherosclerosis. Their results also indicate a possible polygenic overlap between microalbuminuria and SVD.Polygenic models derived using genome-wide association studies’ meta-analysis results for three kidney traits suggest that some of the risk association between CKD and cerebrovascular disease may be related to shared genetic factors. This association may vary depending on the ischaemic stroke subtypes, being particularly strong for large-vessel stroke.S54, S55 Missense mutations of COL4A1 are also implicated in kidney disease such as hereditary angiopathy, nephropathy, aneurysms and cramps (HANAC) syndrome.S56 COL4A1 mutations have also been recently reported as a potential novel cause of autosomal-dominant congenital anomalies of the kidney and urinary tract (CAKUT) in humans (the most common cause of kidney disease under the age of 30).S57COL4A1 mutations have been identified as a monogenic cause of cerebral SVD and are associated with stroke .S54, S55S58 APOE allelic variation is also a risk factor for CKD progression that is independent of established CKD risk factors such as diabetes and hypertension.S59Apolipoprotein E (APOE) allelles ε2 and ε4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology.S60 and thus are less able to tolerate acute BP dips during ultrafiltration on dialysis.S61 Myocardial stunning can develop during haemodialysis, resulting in or worsening any pre-existing cerebral hypoperfusion.S62 It has been hypothesised that such circulatory stress could produce cumulative ischaemic brain insults .S63 In this UK study of a small group of haemodialysis patients (n=73), brain MRI and BP variability were examined to assess the impact of haemodialysis on brain white matter microstructure. Increased intradialytic haemodynamic instability was associated with ischaemic white matter changes, but patients who were treated with cooled dialysate (0.5°C below core body temperature) showed improved haemodynamic tolerability and demonstrated complete protection against white matter changes at 1 year.Haemodialysis patients appear to have abnormal autonomic function as evident from their lower baroreflex sensitivity values compared with the general populationS64 In a study of 58 haemodialysis patients, every 10 mm Hg decrease in mean arterial pressure(MAP) was associated with a 3% increase in ischaemic events, and the incidence of ischaemic events was particularly marked below an absolute MAP of 60 mm Hg.S65 In 23.5% of haemodialysis sessions, patients developed some evidence of transient cerebral ischaemia , and this intradialytic cerebral ischaemia correlated with decreased executive dysfunction 1 year later.BP control is more complex in dialysis patients, and several studies have linked lower BP to adverse outcomes, including increased mortality, especially in older or diabetic patients, or in those with pre-existing cardiac disease.S66 Decline in MFV also correlated significantly with progression of white matter burden and cerebrovascular disease at 12 months’ follow-up. Haemodialysis is thus capable of inducing transient ‘cerebral stunning’, analogous to myocardial stunning, and may be a major mechanism of cerebral injury and accelerated cognitive decline in ESKD.In a prospective observational cohort study of 97 maintenance haemodialysis patients, cerebral arterial mean flow velocity (MFV) was shown to decline significantly during dialysis, and this decline correlated with intradialytic decline in cognitive function.S67 Greater BP variability has been shown to increase the risk of ICH in patients with CKD.S68 Arterial stiffness is a particularly prominent cardiovascular risk factor in haemodialysis patients. In a study examining the prognostic significance of ambulatory brachial BP, central BP, pulse wave velocity (PWV) and heart rate-adjusted augmentation index in this population, 48 hours PWV was the only vascular parameter independently associated with the primary composite cardiovascular outcome in a multivariate analysis  .S69CKD is associated with increased BP variability partly due to arterial stiffness.S70 Renal involvement, in the form of a thrombotic microangiopathy, may occur in as many as 25% of those with primary APS.S71 In patients with APS associated with SLE, renal disease may result from microthrombi and/or deposits of immune complexes.S72 An ischaemic stroke occurring in a young patient with renal dysfunction and no obvious risk factors for cerebrovascular disease is an important setting in which to suspect APS.There are certain genetic and acquired conditions that can be complicated by both renal and cerebrovascular sequelae. These are outlined in S73 There is a need to better understand the epidemiology of cerebrovascular risk in renal disease and particularly to what extent prior hypertension may confound this relationship. There may be different mechanisms underlying the association between low GFR versus proteinuria with stroke. Better aetiological classification of stroke outcomes in future studies may help provide mechanistic insights. Preventing stroke in patients with CKD may also be a potential strategy to protect against important downstream consequences such as vascular cognitive impairment or dementia.Patients with CKD clearly represent a high-risk group for stroke that warrant clinical prioritisation and further research focus. CKD has already been incorporated into risk prediction models such as QRISK3.Additional web references are found in the online 10.1136/jnnp-2019-320526.supp1Supplementary data