Vs) and other determinants of venous return using a porcine model of hyperdynamic septic shock. Septicemia was induced in 10 anesthetized swine, and fluid challenges were started after the diagnosis of sepsis-induced arterial hypotension and/or tissue hypoperfusion. Norepinephrine infusion targeting a mean arterial pressure (MAP) of 65 mmHg was started after three consecutive fluid challenges. After septic shock was confirmed, norepinephrine infusion was discontinued, and the animals were left untreated until cardiac arrest occurred. Baseline Vs decreased by 7% for each mmHg decrease in MAP during progression of septic shock. Mean circulatory filling pressure (Pmcf) analogue (Pmca), right atrial pressure, resistance to venous return, and efficiency of the heart decreased with time . Fluid challenges did not improve hemodynamics, but noradrenaline increased Vs from 107 mL to 257 mL (140%) and MAP from 45 mmHg to 66 mmHg (47%). Baseline Pmca and post-cardiac arrest Pmcf did not differ significantly , but the difference between pre-arrest Pmca and post-cardiac arrest Pmcf was statistically significant . In conclusion, the baseline Vs decreased by 7% for each mmHg decrease in MAP during progression of hyperdynamic septic shock. Significant changes were also observed in other determinants of venous return. A new physiological intravascular volume existing at zero transmural distending pressure was identified, termed as the rest volume (Vr).The present work investigated the dynamic changes in stressed volume ( Vs, i.e., the volume in blood vessels when transmural distending pressure (Ptm) is above zero), while the remaining 70% is unstressed volume (Vu), i.e., the volume in blood vessels when Ptm equals zero.The traditional management of shock focuses on the regulation of left ventricular cardiac output (CO). However, it is the venous return theory that provides an understanding of the circulation, emphasizing that CO is associated with, and regulated by, the amount of blood returning to the heart. In general, venous return occurs because of a pressure gradient between the periphery and the right atrium. As a matter of fact, not all the blood leaving the venous system returns to the heart at the same time because the largest quantity remains within the veins to regulate venous return ; therefoVs to Vu, which decreases mean circulatory filling pressure (Pmcf) and venous return , an analogue of Pmcf can be derived using the mathematical model Pmca = (a × PRA) + (b × MAP) + (c × CO), where PRA is right atrial pressure and RVR is resistance to venous return ; (2) resistance to venous return was defined as the ratio of the pressure difference between Pmca and PRA and CO [RVR = (Pmca − PRA)/CO], a formula that is used to describe venous return during transient states of imbalances  [RA and Pmca [Eh = (Pmca – PRA)/Pmca]. This equation was proposed for the measurement of heart performance. During the cardiac stop ejection, PRA is equal to the Pmca, and Eh approaches zero [In addition, the following variables were determined: (1) pressure gradient for venous return (PGe heart) ,33; and hes zero ,34.Vs during septic shock, we used our extrapolation model in swine of the same age, weight, TBV, and baseline hemodynamics. The baseline Vs value and the hourly MAP values during progression of hyperdynamic septic shock were separately determined on a line plot. Using extrapolation lines and linear regression of MAP − Vs relationship, we estimated the hourly decrease in Vs considering that the total volume status was unchanged.So as to assess RA between 5 and 7.5 s after the onset of cardiac arrest, before the reflex response had significantly altered the measured plateau pressure [Significant changes in vasomotor tone occur after the onset of cardiac arrest. The arterial pressure falls and the venous pressure rises until they almost reach equilibrium ,36. Thuspressure ,40. ThenRA rose by less than one mmHg over the period from 5 to 7.5 s after the onset of cardiac arrest [As arteries are much less compliant than veins, transfer of the remaining arterial volume sufficient to equalize pressures throughout the vasculature could not significantly increase Pmcf or affect measurements in our study . In thisc arrest . In the p-values. The different subjects (swine) were included as random factor. p-values less than 0.05 were deemed significant.Statistical analysis was performed using R v4.1. Pearson’s method was used to correlate hemodynamic measurements with Pmca at baseline. Repeated-measures ANOVA was used to assess differences between groups. Linear mixed effects (LME) models were used when needed to assess coefficients additionally to Sepsis progressively evolved with time, and hyperdynamic septic shock was evident after the second hour from induction of septicemia. The progression of sepsis had a significant effect on hemodynamic  and metaVs during progression of septic shock are depicted in Vs was observed for each mmHg decrease in MAP during progression of sepsis and septic shock (The dynamic changes in ic shock .p < 0.001), along with PRA (p < 0.001) and RVR (p < 0.001). The PGVR also decreased, but the difference between time points was not statistically significant (p = 0.934). In addition, a statistically significant decrease in Eh was observed with time (p < 0.001).Mean circulatory filling pressure analogue decreased with time (−1 were administered within the first three hours from diagnosis of septic shock. The infusion of the first 50 mL of isotonic sodium chloride increased MAP from 61 mmHg to 64 mmHg (5%) and Vs from 221 mL to 243 mL (10%). However, neither this nor the subsequent amount of isotonic sodium chloride significantly affected hemodynamics, implying an increase in Vu and Vr  and MAP from 45 mmHg to 66 mmHg (47%). In addition, most systemic hemodynamic variables and determinants of venous return significantly improved after the onset of noradrenaline infusion , but the difference between pre-arrest Pmca and post-cardiac arrest Pmcf was statistically significant .Post-cardiac arrest Pmcf was 14.75 ± 1.5 mmHg. The change in Pmcf during the first minute after cardiac arrest is depicted in Vs and other determinants of venous return during progression and resuscitation of hyperdynamic septic shock in a swine model that closely resembles human hemodynamics. The main findings of the present analysis are: (1) the baseline Vs was estimated at 420 mL and decreased by 7% for each mmHg decrease in MAP during progression of septic shock; (2) we revealed a new physiological volume existing at Ptm ≈ 0, the Vr, which has important physiological significance and cannot be mobilized without the use of an external vasopressor or without decreasing arterial and/or venous resistance; (3) during septic shock, Pmca, PRA, RVR, and Eh significantly decreased with time, while PGVR also decreased but did not reach statistical significance; (4) fluid challenges  did not improve systemic parameters or determinants of venous return, while the infusion of noradrenaline significantly improved hemodynamics except for CO, Eh, and RVR; and (5) post-cardiac arrest Pmcf did not differ significantly from baseline Pmca, but the difference between pre-arrest Pmca and post-cardiac arrest Pmcf was statistically significant. The present study investigated for the first time the dynamic changes in intravascular volumes and venous return during progression of sepsis to hyperdynamic septic shock and cardiac arrest, providing novel insights into the evolution of cardiovascular dynamics during the condition.The aim of this experimental study was to investigate the dynamic changes in Vs estimation in healthy state and sepsis is limited. Ogilvie et al. reported mean Vs values of 812 mL (43% of TBV), 952 mL (50% of TBV), and 1148 mL (60% of TBV) for three different ways of inducing circulatory arrest [Vs from a preload reduction maneuver reported an average Vs of 486 mL (22.4% of TBV) in swine [Vs ranging between 322–653 mL (15–45% of TBV) [Vs was determined by extrapolating the mean systemic filling pressure –volume curve to zero pressure intercept after inspiratory holds and arm stop-flow maneuvers and was estimated to be 1265 mL (≈30% of the predicted TBV) [Vs was estimated with inspiratory hold maneuvers at 1677 mL (26% of TBV) [Vs can be explained by the physiological characteristics of species and the method used for its estimation. The evidence on y arrest . A modelin swine . Studies of TBV) ,43,44. I53 mL 15–% of TBV  of TBV) . The difVs was estimated at 420 mL and had decreased by 17% after 60 min from the onset of sepsis , and by 50% after 120 min from the onset of sepsis (100 mL of isotonic sodium chloride had been infused but did not affect Vs). Murphy et al. used a three-chambered cardiovascular system model to identify Vs in swine and reported that it decreased by 29% after 30–40 min from the infusion of E. coli endotoxin [E. coli endotoxin shock, Uemura et al. reported a decrease in Vs of 50% after the end of 60 min endotoxin infusion [Vs and Vu are virtual values, not separated, and they change their names and function depending on Ptm at every moment [Vs may lead to distinct shock phenotypes requiring distinct hemodynamic management. Considering the close resemblance between the Landrace–Large White swine and human hemodynamics, this species seems suitable for studying venous return and its determinants in steady and shock states [In the present experimental study, ndotoxin . Howeverinfusion . In eithy moment . Neverthk states ,49,50.Vr as the volume that cannot be mobilized/converted without the use of an external vasopressor or without decreasing arterial and/or venous resistance, e.g., by decreasing the dose of pure α-adrenergic agonists, such as phenylephrine. The utilization of Vr in research and clinical practice is extremely intriguing and helpful. Brengelmann has proposed the same term for the volume (Vu) beyond which further addition (in volume) would result in stretching of the vessel walls (distending volume or Vs) [Vr is different from Vu, although they both exist at Ptm ≈ 0. In normal conditions, Vu can be mobilized, if required, but Vr cannot be without external intervention. In particular, Vr seems to have dual main functions at the steady state, i.e., to prevent an increase in venous resistance and maintain critical closing pressure, which is the pressure below which small vessels collapse and effective capillary blood flow ceases. As critical closing pressure is related to vascular tone, the Vr exerts the peripheral venous pressure required to sustain a vasomotor reflex, resulting in the maintenance of critical closing pressure [Vr mandate that it should not be iatrogenically deranged or should be only minimally affected, even in patients with shock. A severe derangement of Vr could explain the devastating effects of exogenous adrenergic agonists, especially when administered in hypovolemic individuals and/or at high doses. One of the most significant findings to emerge from this study is the identification of e or Vs) . Howeverpressure ,53. Indepressure ,54,55. TVs until cardiac arrest occurred . In severe septic shock with low Vs, the use of exogenous vasopressors may not be sufficient to completely convert the increased amount of Vu (baseline Vu plus the converted part of Vs) to Vs, implying an increase in Vr (baseline Vr plus part of Vu that is not converted to Vs) and thus a lower Vc. In such a case, increasing vasopressor doses will result in arterial vasoconstriction, increased exit resistance from the arterial compartment, and decreased capillary perfusion [Vs, CO, and tissue perfusion. In our animals, the evolving vasoplegia decreased erfusion ,56. In cVr, a drug that stimulates both the α- and β-adrenergic receptors is expected to more effectively maintain systemic hemodynamics than one that activates either α- or β-adrenergic receptors [Vu to Vs and facilitate flow through the splanchnic system [Based on the aforementioned characteristics of eceptors . Indeed,c system ,57, and c system .VR of 6.2 ± 0.8 mmHg [VR [E. coli endotoxin infusion and reported an increase in CO concomitantly with a decrease in MAP and Pmsa; however, volume loading (20 mL·kg−1) significantly increased Pmsa above baseline values [VR (RVR and Eh did not change), but neither these nor the total amount of administered fluids (30 mL·kg−1) significantly improved hemodynamics. In addition, post-cardiac arrest Pmcf was 14.75 ± 1.5 mmHg in our animals, which was similar to their baseline Pmca, but significantly higher than the Pmca value before the onset of cardiac arrest, implying an increase in Vu and Vr. In humans, Pmcf measured one minute after death from septic shock was 12.7 ± 5.7 mmHg [Vr and its characteristics in the healthy state and disease state, as previously discussed in this section.Accurate data on Pmcf in septic patients are also scarce. A meta-analysis investigating the effects of vasopressor-induced hemodynamic changes in adults with shock reported that vasopressor infusion increased Pmsf analogue (Pmsa) from 16 ± 3.3 mmHg to 18 ± 3.4 mmHg, but had variable effects on central venous pressure, Eh, and CO . Guarrac0.8 mmHg . In bothmmHg [VR ,63,64,65mmHg [VR . In the mmHg [VR . Of notee values . The impe values . In the 5.7 mmHg , which i5.7 mmHg , our fin5.7 mmHg ,68. MostAlthough the clinical and pathophysiological understanding of septic shock has progressed in the previous decades, many questions still exist. Fluid resuscitation in septic shock is an effective intervention to increase venous return; however, timely fluid resuscitation is critical, and many patients do not respond to treatment ,70,71. AVs during hyperdynamic septic shock, which increases our understanding of sepsis-induced vasoplegia. As the currently available methods for assessing fluid responsiveness have limitations [Vs may further support the assessment of the procedure in patients with septic shock. Moreover, our findings can aid in the decision to start vasopressor support according to the decrease in vasomotor tone, a common characteristic of sepsis-related hypotension. Assessment of Vs can be also helpful in starting vasopressors simultaneously with fluids or following a very limited fluid resuscitation, which can improve Pmcf/Pmca, venous return, and CO, and decrease net fluid balance, incidence of complications, and mortality [The present study revealed the hourly decrease in itations ,73,74,75ortality ,78,79,80Vr. This volume cannot be mobilized/converted without the use of an external vasopressor or without decreasing arterial and/or venous resistance. The Vr seems to have a dual function, i.e., to prevent an increase in venous resistance and maintain critical closing pressure. These findings suggest that fluid management and administration of vasopressors in patients with shock should be considered only if they do not affect or minimally affect the Vr. The Vr seems extremely important for maintaining hemodynamic homeostasis both in the steady state and disease state.In addition, our analysis identified a new circulatory volume, the The present study provides a deeper physiological understanding of hyperdynamic septic shock and new information on how to optimize fluid administration and the use of vasoactive drugs within an individualized treatment strategy. Furthermore, our findings may help in identifying novel phenotypes of septic shock patients.RA during the cardiac cycle and vascular buffering minimize this effect [The major strength of this experimental study was the resemblance of the hemodynamic and biochemical/metabolic changes during hyperdynamic septic shock between Landrace–Large White swine and humans ,81. We as effect ,33.Vs was estimated at 420 mL and decreased by 7% for each mmHg decrease in MAP during progression of hyperdynamic septic shock. Significant changes were also observed in other determinants of venous return. A new physiological intravascular volume existing at Ptm ≈ 0 was identified, termed as Vr, which cannot be mobilized/converted without vasopressor support or without decreasing arterial and/or venous resistance.The baseline


ICS did not seem to modify the risk of cancer. In conclusion, in our study, asthma-COPD overlap was not associated with an increased risk of cancer events.Chronic inflammation such as asthma may lead to higher risks of malignancy, which may be inhibited by anti-inflammatory medicine such as inhaled corticosteroids (ICS). The aim of this study was to evaluate if patients with asthma-Chronic Obstructive Pulmonary Disease (COPD) overlap have a higher risk of malignancy than patients with COPD without asthma, and, secondarily, if inhaled corticosteroids modify such a risk in a nationwide multi-center retrospective cohort study of Danish COPD-outpatients with or without asthma. Patients with asthma-COPD overlap were propensity score matched (PSM) 1:2 to patients with COPD without asthma. The endpoint was cancer diagnosis within 2 years. Patients were stratified depending on prior malignancy within 5 years. ICS was explored as a possible risk modifier. We included 50,897 outpatients with COPD; 88% without prior malignancy and 20% with asthma. In the PSM cohorts, 26,003 patients without prior malignancy and 3331 patients with prior malignancy were analyzed. There was no association between asthma-COPD overlap and cancer with hazard ratio (HR) = 0.92, CI = 0.78–1.08,  COPD is a chronic pulmonary condition often linked to current or previous smoking. It shares many risk factors with cancer development, and the two are frequently found together ,2,3,4.Patients with asthma seem to have an elevated level of chronic low-grade inflammation with elevated pro-inflammatory biomarkers such as high sensitivity C-reactive protein (hsCRP) ,6, whichInhibition of Interleukin-1-beta with canakinumab has been shown to reduce the risk of cancer, especially lung cancer death, by 70% in a sub-study to a randomized controlled trial . The subIt seems plausible that asthma per se increases systemic inflammation and could increase the risk of malignancy ,22,23,24We aimed to find out whether the risk of cancer events is higher in patients with asthma-COPD overlap, as compared to those with COPD alone in a large nationwide epidemiological study, as well as to examine if ICS had a cancer-preventive effect in this population.The Danish Register of Chronic Obstructive Pulmonary Disease (DrCOPD), which contains nationwide information on COPD outpatients since 2008 .The Danish Civil Registration System with unique personal identification of all Danish citizens .The Danish National Patient Registry holds information on all admissions to Danish hospitals and outpatient clinic visits .The Danish National Health Service Prescription Database holds information on all prescriptions dispensed in Danish pharmacies since 2004 including date of dispensation, formulation, strength, and quantity .A multi-center retrospective cohort study was conducted by combining data from the following registries:We included all Danish residents > 30 years of age  with COP1%) [In both the group with and the group without previous malignancy, patients with asthma-COPD overlap were propensity score-matched to two controls with COPD without asthma. The propensity score matching was performed based on the following known and likely confounders: age, gender, tobacco exposure, body mass index (BMI), medical research council (MRC), and forced expiratory volume in first second as percent of predicted (FEV1%) . We registered the demographic variables, comorbidities, prior exacerbations of COPD, and medical therapy .Patients were followed for 2 years after study entry, during which time they were eligible to develop an event. The 2-year follow-up time was chosen to capture the developed cancer events, while still anticipating mortality as a not too dominant of a competing risk.Cancer events were defined and registered as all diagnoses of cancer (except non-melanoma skin cancer): malignant neoplasms of lip, oral cavity and pharynx: C00–C14; digestive organs: C15–C26; respiratory and intrathoracic organs: C30–C39; bone and articular cartilage: C40–C41; malignant melanoma of skin: C43; Merkel cell carcinoma: C4A; mesothelial and soft tissue: C45–C49; breast: C50; female genital organs: C51–C58; male genital organs: C60–C63; urinary tract: C64–C68; eye, brain and other parts of central nervous system: C69–C72; thyroid and other endocrine glands: C73–C75; ill-defined, other secondary and unspecified sites: C76–C80; neuroendocrine tumors: C7A; lymphomas: C81–C88; and leukemia: C90–C96 .1% as well as exacerbations in the year prior to inclusion , medium dose , and high dose . Treatment with ICS was defined as total redeemed prescriptions of ICS recalculated to daily dose. All patients included in this analysis suffered from both asthma and COPD. However, there was a clear relation between the dosage of daily ICS use and possible confounders including older age, male sex, and lower FEVnclusion . Hence, Our primary endpoint was time to cancer events as analyzed by Cox regression ana-lysis. As a few patients had more than one event during the follow-up period, only the first event was counted in Cox regression analysis and incidence plots.We performed adjusted Cox regression analysis to evaluate the effect of comorbidities by Charlson Comorbidity Index while adjusting for gender and asthma.We performed a sensitivity analysis by an unadjusted Cox regression analysis of the entire included population on the parameters included in the propensity score match, as well as by exacerbations within the year before inclusion.1% (as a continuous variable) at inclusion.Patients with asthma-COPD overlap were propensity score matched  to patiBaseline characteristics were compared by chi-square test. Cox regression model was used to assess the risk of cancer events before and after propensity score matching.Incidence plots were calculated with mortality due to any other cause than cancer as a competing risk, corresponding to significance by unadjusted Cox analysis and as determined by Gray’s K-sample test examining cancer events among propensity score-matched groups.1%).Inverse probability of treatment weighting using generalized boosted models was employed to balance covariates between the ICS treatment groups . PropensThe relative risk of cancer events or death by any other cause was estimated using inverse probability of treatment-weighted Cox proportional hazards models. Risk of cancer events was analyzed by right-censoring competing risks. Results were presented as hazard ratios (HR) with 95% confidence intervals (CI) and cause-specific HRs with 95% CI.1%).An adjusted Cox proportional hazard model in the unmatched population with a follow-up period of 730 days served as sensitivity analysis. The analysis was adjusted for the variables included in the propensity score match . Model control investigating the proportional hazards assumption was performed to validate the Cox proportional hazards regression on the following parameters; age, gender, tobacco exposure, MRC, BMI, and FEV1%. In all cases yielding p-values > 0.05.An adjusted Cox proportional hazards analysis was performed on the group of propensity-matched patients, with adjustment for the above-mentioned parameters . In Denmark, retrospective use of register data does not require ethical approval or patient consent.A total of 50,897 patients were included in the study. Of these, 88.0%  had no prior malignancy within 5 years before study entry. In this group, 19.7% (8828 patients) had asthma-COPD overlap compared to 18.3% (1116 patients) in the group of patients with known malignancy prior to study entry.p < 0.0001 and with prior malignancy: 14.0% vs. 3.7%, p < 0.0001), and there was a slightly higher prevalence of patients with asthma-COPD overlap diagnosed with osteoporosis/osteopenia. Additionally, patients with asthma-COPD overlap were to a clinically relevant degree more likely to have had an admission due to an exacerbation within the year before inclusion, and of having been treated with oral corticosteroids, ICS, and long- and short-acting β2-agonists (LABA and SABA) within the year before inclusion than patients with COPD without asthma.Baseline data of the cohorts are shown in p = 0.31) and neither in patients with prior malignancy   .p = 0.12; and prior malignancy: HR 0.68, CI 0.42–1.10, p = 0.11). In addition, there was no clinically relevant difference dependent on concomitant asthma for any other subtypes of cancer shown in p-values not shown).The risk of a lung cancer event was also not increased in patients with asthma-COPD overlap , and HR 0.89 in the groups with prior malignancy .Two-year mortality from non-malignancy causes was not statistically different: HR 1.04 in the groups without prior malignancy  by Grays test.Cumulative incidence plots similarly showed no difference in risk of cancer events  (no priop = 0.65), and the sensitivity analysis evaluating the effect of exacerbations in the last year prior to inclusion also showed no interaction with risk of all cancer events .The adjusted Cox regression analysis evaluating the effect of comorbidities showed no interaction between Charlson Comorbidity Index score and risk of all cancer events  were available for analysis of ICS dosage association to cancer. Their baseline data are shown in p = 0.01) and a slightly higher mortality from non-malignancy causes   . There wN = 66 (0.2%) were lost to follow-up and no meaningful differences were observed among groups.Loss to follow-up was seldom; 1%) yielded the following results by Cox multivariate analysis: Age: HR 1.00, CI 1.00–1.01, and p = 0.83; gender: HR 0.96, CI 0.90–1.01 and p = 0.14; tobacco exposure: HR 1.12, CI 1.08–1.17, and p < 0.0001; MRC: HR 1.08, CI 1.05–1.11, and p < 0.0001; BMI: HR 0.99, CI 0.98–0.99, and p < 0.0001; and FEV1%: HR 1.00, CI 1.00–1.00, and p = 0.64.The sensitivity analysis of the entire included population on the parameters included in the propensity score match  for use of cigarettes quantified similar to our method and as lifetime use. In contrast to cigarettes, use of other types of tobacco was less consistently reported both as current use and lifetime use at the different timepoint . AdditioWe did not add all baseline variables as matching variables in the matched cohort and as adjusting variables in the Cox analyses, since not all these variables were judged to have confounding potential, and since adding too many may have weakened the power of the models. Further, we could have overfitted the model. We conducted subgroup analysis of all endpoints, which may have caused us to miss minor differences depending on asthma status among less-frequent secondary endpoints in the small subgroups, such as the risk of pulmonary cancer among patients with prior cancer.In conclusion, asthma in patients with COPD does not seem to be associated with an increased risk of cancer events. ICS did not, to a clinically relevant degree, influence the risk of cancer events in patients with COPD-patients asthma. Hence, our results suggest that neither a concomitant diagnosis of asthma nor use of ICS should be considered independent risk or protective factors when assessing a patient with COPD and possible cancer. As a consequence, our data do not support a different approach for cancer diagnostic workup or screening among patients with asthma-COPD-overlap as compared to patients with COPD without asthma.


Sleep duration has been proposed to be associated with high blood pressure. However, nationwide studies regarding this association in adolescents remain limited. This study aimed to explore the national prevalence of high blood pressure among Thai adolescents and to determine the association between sleep duration and high blood pressure.Data from adolescents aged 10–19 years from the Thai National Health and Examination Survey V were included. We collected demographic data (including age and gender), height, weight, waist circumference, blood pressure, fasting blood chemistries and sleep duration data. Sleep durations were categorized as short, normal or long for each age group based on the United States National Sleep Foundation’s recommendations. High blood pressure was diagnosed using the 2017 guidelines of the American Academy of Pediatrics. Factors associated with high blood pressure were analyzed using multivariate logistic regression.A total of 3505 adolescents  were included. The prevalence of high blood pressure was 9.4% (95% CI 8.5–10.4%). The high blood pressure group had higher BMI z-score, LDL-C, triglyceride and lower HDL-C than the normotensive group. In the multivariate analysis, BMI z-score, LDL-C and HDL-C were independently associated with high blood pressure. However, there was no association between sleep duration and high blood pressure.High blood pressure risk was increased in adolescents with high BMI z-score. Neither short nor long sleep duration was associated with an increased risk of high blood pressure.The online version contains supplementary material available at 10.1186/s12889-022-14430-z. Over the past few decades, the prevalence of elevated blood pressure in children has been rising . The preApart from obesity, sleep duration has been reported to be one of the factors associated with high blood pressure in adults. However, little is known about the association between sleep duration and hypertension in adolescents. Wells et al. reported that short sleep duration was associated with increased systolic blood pressure in a cross-sectional survey of 4452 Brazilian adolescents . Bal et N = 54) were excluded. A total of 3505 adolescents were included in the final analysis.This study was conducted with approval from the Ramathibodi Hospital Ethics Committee for Human Research (MURA 2019/917). The participants included in this study were recruited from the database of the Thai National Health and Examination Survey V (NHES-V), conducted in the year 2014. The NHES-V was a nationwide cross-sectional survey using a multistage, stratified sampling of the Thai population. The method of sampling was previously described in detail . In brie2. BMI was categorized using BMI z-score based on the World Health Organization growth reference for age and gender  / 7, as used in the previous study . RecommeFasting blood samples were taken for chemistry analysis including plasma glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). An abnormal lipid profile was defined as LDL-C ≥ 130 mg/dl, TG ≥ 130 mg/dl or HDL-C < 40 mg/dl, according to the recommendations for adolescents from the National Heart, Lung, and Blood Institute .p-value of ≤ 0.05 was considered statistically significant. Institutional licensed SPSS software version 22 was used for statistical analysis.Demographic data are presented as frequency and medians (inter-quartile ranges). The Mann–Whitney U test was used to detect differences in continuous data between two groups; the Chi-square test was used to detect the differences in categorical data between two or three groups. Multivariate analysis was used to evaluate the parameters associated with high blood pressure in two models. The independent variables in model 1 included BMI category (BMI z-score < 2 vs. each 1 z-score increase), HDL-C (> 40 vs. each 5 mg/dl decrease), LDL-C (< 130 vs. each 10 mg/dl increase), and TG (< 130 vs. each 10 mg/dl increase), and the variable of average sleep duration model was added in model 2. A A total of 3505 participants  aged 10–19 years were included in this study. The overall prevalence of high blood pressure was 9.4% (95% CI 8.5–10.4%). Demographic and other data in the high blood pressure and the normotensive groups for all participants and separated by gender are presented in Table Overall, there were no significant differences in weekday, weekend and average sleep durations between the high blood pressure and normotensive groups. No differences in the disparity of sleep duration on weekdays and weekends were detected between the two groups Table . There wThe multivariate logistic regression for factors associated with high blood pressure is presented in Table The present study demonstrates that the prevalence of high blood pressure in adolescents aged 10–19 years in Thailand, based on the cutoff values from the 2017 AAP guidelines [This is the first study to represent the national prevalence of high blood pressure in Thai adolescents. The prevalence of high blood pressure in the present study was higher than in previous national-level studies conducted before the year 2017 in Iran, Australia and China, which reported the prevalence as 6.8%, 5.8% and 6%, respectively –20. ThisThe present study showed that in male participants, TC, LDL-C and TG levels were significantly higher and HDL-C levels were significantly lower in the high blood pressure group than the normotensive group. Among female participants, TG levels were significantly higher and HDL-C levels were significantly lower in the high blood pressure group than in the normotensive group. These results are consistent with the study reported by Garí-Llanes M et al., who found that among 373 children in Cuba aged 8–11 years, the high blood pressure group had higher levels of TC, LDL-C, TG and lower levels of HDL-C than those in the normotensive group . In the Apart from the BMI z-score and lipid profile, sleep duration was found by previous studies to be another independent factor associated with high blood pressure –11. The The present study represents the first identification of the national prevalence of high blood pressure in Thai adolescents. This study also demonstrated that BMI z-score as well as higher LDL-C and TG and a lower HDL-C were associated with high blood pressure after adjustment for the other parameters. Nonetheless, this study has some limitations. First, the cause-effect relationship between the risk factors and high blood pressure could not be determined from this cross-sectional survey. Second, high blood pressure was determined based on BP measurement at a single visit, not on three occasions as is recommended by the current guidelines; therefore a true diagnosis of hypertension could not be made in the context of this study. Data regarding awareness of hypertension, sleep-disordered breathing and co-morbidities were not available among these participants. Additionally, the sleep duration recommended by the NSF remains controversial, and therefore careful interpretation of the sleep duration results from the present study is warranted. Lastly, sleep duration was not measured using a validated self-reported tool specifically designed to measure adolescents’ sleep, such as the Adolescent Sleep–Wake Scale . TherefoIn conclusion, the overall prevalence of high blood pressure among adolescents in Thailand was 9.4%. BMI z-score was an important factor associated with high blood pressure. We found neither short nor long sleep duration to be associated with high blood pressure in the present study.Additional file 1: Table S1. The numbers of participants stratified by the sleep duration groups on Table S2. The numbers of participants with and without high blood pressure stratified by the sleep duration groups on weekdays and weekends


Chronic kidney disease (CKD) is a debilitating progressive illness that affects more than 10% of the world's population. In this literature review, we discussed the roles of nutritional interventions, lifestyle modifications, hypertension (HTN) and diabetes mellitus (DM) control, and medications in delaying the progression of CKD. Walking, weight loss, low-protein diet (LPD), adherence to the alternate Mediterranean (aMed) diet, and Alternative Healthy Eating Index (AHEI)-2010 slow the progression of CKD. However, smoking and binge alcohol drinking increase the risk of CKD progression. In addition, hyperglycemia, altered lipid metabolism, low-grade inflammation, over-activation of the renin-angiotensin-aldosterone system (RAAS), and overhydration (OH) increase diabetic CKD progression. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend blood pressure (BP) control of <140/90 mmHg in patients without albuminuria and <130/80 mmHg in patients with albuminuria to prevent CKD progression. Medical therapies aim to target epigenetic alterations, fibrosis, and inflammation. Currently, RAAS blockade, sodium-glucose cotransporter-2 (SGLT2) inhibitors, pentoxifylline, and finerenone are approved for managing CKD. In addition, according to the completed Study of Diabetic Nephropathy with Atrasentan (SONAR), atrasentan, an endothelin receptor antagonist (ERA), decreased the risk of renal events in diabetic CKD patients. However, ongoing trials are studying the role of other agents in slowing the progression of CKD. Chronic kidney disease (CKD) is a fatal progressive illness and a major cause of mortality worldwide ,2. The n2, and 3) albuminuria of ≥30 mg per day [CKD patients may present with various symptoms, including generalized weakness, pain, sleep disorders, anxiety, depression, and itching . CKD is  per day . There a per day .CKD can be complicated by health conditions that can be prevented and treated early in the disease course. Measures to manage CKD include screening high-risk groups  by testing for albuminuria, GFR, urine sediment, and serum creatinine (Cr); treating specific renal diseases; controlling progression; preventing and treating complications; and educating and preparing patients for renal replacement therapy (RRT) . In thisLifestyle modificationsWeight Loss2 and the risk of end-stage renal disease (ESRD) [There is a graded causal relationship between central (waist circumference) and general obesity and CKD incidence; a retrospective cohort study observed a significant relationship between high body mass index (BMI) starting from 25.0 kg/me (ESRD) -10. A sye (ESRD) . Howevere (ESRD) ,13.DietThe National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) established that adherence to low-protein diet (LPD) can slow the progression of ESRD and can improve the quality of life in CKD patients . A studyPhysical ActivityThe Physical Activity Guidelines for Americans recommends that adults have at least 150 minutes weekly of moderate-intensity physical activity or 75 minutes weekly of vigorous exercise for substantial benefit. Physical activity was controversial in CKD because of the risk of increased proteinuria and renal function impairment. On the contrary, a meta-analysis by Villanego et al. found that low-intensity physical activity improves the quality of life and does not impact renal function . But thiChen et al. conducted an observational study on patients with stage 3-5 CKD (mean age: 70 years), out of which most patients reported walking as the most common form of exercise. The study found that walking was associated with lower overall mortality and rates of RRT independent of age, renal function, and comorbidities of the patients . The finSmoking2 [It is difficult to assess the cause and effect of smoking. However, smoking is associated with a worse progression in patients with established CKD. A prospective cohort study conducted in Korea found that smoking is associated with a greater risk of CKD progression during a follow-up of three years. The results were most evident in patients with eGFR of <45 mL/minute/1.73 m2 . The sam2 ,26. Some2 .Limitation of Alcohol IntakeStudies reported that persistent moderate alcohol drinking is not related to the progression of CKD compared to not drinking. However, binge alcohol drinking increases the risk of CKD progression ,28.Stress, Working Hours, and SleepStress increases the risk of DM, HTN, and vascular diseases (major risk factors for CKD) by stimulating the sympathetic nervous system and elevating inflammatory cytokines . A cohorNutritional interventionsProtein consumption is one of the most-often addressed concerns in the dietary therapy of CKD. It has been shown that a high-protein diet, defined as >1.2 g/kg/day, significantly impairs kidney function . LPD proA caloric intake of 25-35 kcal/kg/day is advised to counterbalance the increased resting energy expenditure caused by inflammation and comorbidities and to maintain a neutral or positive nitrogen balance .Acidosis is one of the major risk factors for CKD progression. A study showed that fruits and vegetables are an option for oral alkali that may minimize the risk for volume retention and hypertension associated with bicarbonate supplementation. In this study, dieticians recommended 2-4 cups of fruits and vegetables per day . AnotherBlood sugar controlThe kidneys significantly impact glucose homeostasis via glucose glomerular filtration, reabsorption through sodium-glucose cotransporters (SGLT), and generation . HemogloA shift in the treatment of CKD associated with type 2 diabetes mellitus (T2DM) has been made since the first clinical trial showing the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors was published in 2015. Before this discovery, glycemic and blood pressure (BP) control were the mainstay for delaying the progression of CKD and cardiovascular diseases associated with T2DM. SGLT2 inhibitors were found to reduce the major risk of cardiovascular events and the advancement of chronic kidney disease in T2DM patients . ClinicaA prospective cohort study established a relationship between overhydration (OH), measured using bioimpedance assay (BIA), and CKD progression in patients with T2DM. The study found that OH is an independent risk factor for CKD progression in patients with T2DM. The authors hypothesized that OH was a predictor, while pigment epithelium-derived factor (PEDF) was a modifiable risk factor for the progression of CKD . PatientBlood pressure controlUncontrolled HTN adversely affects the prognosis in patients with CKD; therefore, strict BP control is mandatory . HypertePatients with CKD have a high prevalence of nocturnal hypertension . Higher The Systolic Blood Pressure Intervention Trial (SPRINT) have shown that intensive BP control (systolic BP of less than 120) in individuals with an increased cardiovascular risk and mild-to-moderate CKD significantly decreases the risk of cardiovascular events and all-cause mortality. However, the intensive BP management effect on CKD progression, acute kidney injury (AKI), and CKD incidence needs further evaluation . In non-Figure Medical managementCKD is a progressive illness that leads to the loss of nephrons. Current therapies for CKD aim to control its progression by targeting epigenetic alterations Figure , fibrosiRenin-Angiotensin System (RAS) InhibitorsAngiotensin-converting enzymes (ACEIs) and angiotensin receptor blockers (ARBs) are the first-line medications in proteinuric CKD patients. They delay the progression of CKD and lower the risk of cardiovascular outcomes in diabetic and non-diabetic CKD patients. Also, ACEIs were found to reduce all-cause mortality in these patients . HoweverSGLT2 InhibitorsSGLT2 inhibitors have a nephroprotective effect by reducing albuminuria. They increase the delivery of sodium to distal tubules, inhibit tubuloglomerular feedback, and minimize intraglomerular pressure and albuminuria via afferent vasoconstriction. Also, SGLT2 inhibitors have an anti-inflammatory effect by decreasing profibrotic factors, interleukin-6, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This drug class inhibits the progression of albuminuric CKD in diabetic and non-diabetic patients, including those with heart failure . HoweverFinerenoneMineralocorticoid receptor (MR) gene expression is involved in electrolyte balance and fluid homeostasis. Also, MR is over-activated in patients with chronic diseases such as CKD and T2DM. This over-activation leads to increased inflammation, fibrosis, and end-organ damage. In contrast to spironolactone and eplerenone as steroidal MR blockers, finerenone is a nonsteroidal MR blocker. This nonsteroidal structure reduces inflammation and fibrosis by inhibiting the recruitment of transcriptional factors. In comparison to spironolactone, finerenone causes less hyperkalemia . AccordiPentoxifylline (PTF)Pentoxifylline (PTF) is a nonspecific phosphodiesterase inhibitor demonstrating a kidney-protective effect through its anti-inflammatory effect; PTF reduces high-sensitivity C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and fibrinogen levels. Also, it improves kidney function by increasing the eGFR at 12 months. As a result, PTF decreases the progression of CKD to ESRD, particularly in albuminuric patients, regardless of the presence of diabetes mellitus and reduces the risk of cardiovascular mortality in CKD patients . On the Atrasentan Endothelin receptor antagonist (ERA) protects the kidney via its antihypertensive, anti-albuminuric, anti-inflammatory, and anti-fibrotic effects. Also, it reduces hyperfiltration and endothelial injury while increasing podocyte number. This class of drugs demonstrates its anti-inflammatory effect via reducing NF-κB, transforming growth factor-β (TGF-β), and extracellular matrix (ECM) accumulation. The anti-albuminuric impact is related to increasing the number of podocytes and reducing the permeability of albumin (endothelin-1 (ET-1) stimulates angiotensin II production, thus increasing albumin permeability) . AccordiPirfenidone Pirfenidone is an anti-fibrotic agent that has both anti-fibrotic (via inhibiting the expression of TGF-β1) and anti-inflammatory (via tumor necrosis factor (TNF) expression) effects. Those effects were seen in animal models. Pirfenidone was approved for the management of idiopathic pulmonary fibrosis (IPF). It is renally excreted, and the Food and Drug Administration (FDA) recommends using it cautiously when creatinine clearance is <80 mL/minute. Also, it is contraindicated in dialysis patients. Pirfenidone has side effects, including transaminitis, gastrointestinal symptoms, and photosensitivity. Currently, the Trial of Pirfenidone to Prevent Progression in Chronic Kidney Disease (TOP-CKD) is an ongoing phase II trial that will be finished in December 2024. It involves 200 patients and aims to study pirfenidone's role in CKD .CKD is a growing worldwide health burden. As a result, active efforts have been made to study CKD progression; this literature review summarizes the role of DM and HTN control, nutritional and therapeutic interventions, and lifestyle modification, including weight loss, diet, physical activity, smoking, and alcohol, in delaying the progression of CKD. Obesity, smoking, binge alcohol drinking, uncontrolled DM, and hypertension tend to worsen CKD. However, RAAS blockade, SGLT2 inhibitors, pentoxifylline, and and finerenone are the currently approved medications for managing CKD progression. The role of other agents is being studied through completed and ongoing clinical trials.


Neuroimaging markers of cerebral small vessel disease (SVD) are common inolder individuals, but the pathophysiological mechanisms causing theselesions remain poorly understood. Although hypertension is a major riskfactor for SVD, the direct causal effects of increased blood pressure areunknown. The Hyperintense study is designed to examine cerebrovascular andstructural abnormalities, possibly preceding SVD, in young adults withhypertension. These patients undergo a diagnostic work-up that requirespatients to temporarily discontinue their antihypertensive agents, oftenleading to an increase in blood pressure followed by a decrease onceeffective medication is restarted. This allows examination of the effects ofblood pressure increase and decrease on the cerebral small vessels.T = 1), when patients have restarted medication(T = 2) and reached target blood pressure and 1 yearlater (T = 3). The 3T MRI protocol includes conventionalstructural sequences and advanced techniques to assess various aspects ofmicrovascular integrity, including blood-brain barrier function usingDynamic Contrast Enhanced MRI, white matter integrity, and microperfusion.Clinical assessments include motor and cognitive examinations and bloodsampling.Hyperintense is a prospective observational cohort study in 50 hypertensiveadults (18–55 years) who will temporarily discontinue antihypertensivemedication for diagnostic purposes. MRI and clinical data is collected atfour timepoints: before medication withdrawal (baseline), onceantihypertensives are largely or completely withdrawn(The Hyperintense study will improve the understanding of thepathophysiological mechanisms following hypertension that may cause SVD.This knowledge can ultimately help to identify new targets for treatment ofSVD, aimed at prevention or limiting disease progression. SVD can be clinically covert, but is associated with cognitive decline,dementia, and disturbances in gait and mood. Moreover, most hemorrhagic strokes and a fourth of all ischemic strokes arecaused by SVD.Cerebral small vessel disease (SVD) is an umbrella term covering a variety ofpathologies that affect the small arteries, arterioles, and capillaries in the brain. However, these MRI markers are likely the result of long ongoing pathologicalprocesses and studying them provides limited insights into their (early)pathogenesis. Endothelial dysfunction is hypothesized to play a key role in thepathophysiology of SVD and may explain the various pathologies seen in SVD patients,including loss of integrity of the Blood Brain Barrier (BBB), vessel wallstiffening, impairments in vasodilation, reduced cerebral blood flow, and increased inflammation. The relation between these pathological processes, the order in which theyoccur and the role they play in the etiology of SVD remains largely unknown.Small vessel pathology cannot be visualized in vivo with standard 1.5 or 3T MagneticResonance Imaging (MRI). SVD is therefore usually defined by tissue alterations onMRI thought to be a consequence of small vessel pathology, such as white matterhyperintensities (WMH), lacunes, and microbleeds. Higher blood pressure in midlife is shown to lead to higher SVD burden andsmaller brain volumes at later age. Moreover, the presence of cardiovascular risk factors, includinghypertension, at a young age (18–40 years), is associated with changes in vesselmorphology  and higher WMH volume. This suggests that small vessel changes precede end-stage MRI markers and theaccompanying clinical symptoms for decades, but the underlying mechanisms areunknown. In addition, the causal relation with hypertension is predominantly basedon prospective cohort studies and trials that have shown slower SVD progressionamong those with lower blood pressure or active treatment with anti-hypertensives,but no studies have examined the actual effect of increasing bloodpressure on MRI markers of SVD.To advance our understanding of SVD etiology and progression, research in young- andmiddle-aged adults at risk or with early-stage SVD is crucial. Hypertension is themost established risk factor for SVD, but evidence is based on prospective andcross-sectional studies.In this paper we describe the protocol of the Hyperintense study. We will apply anadvanced MRI protocol to examine early functional and (micro)structural changes inyoung-and middle-aged adults with hypertension, the most important cardiovascularrisk factor of SVD. Specifically, we will examine the effects of blood pressureincreases in patients with hypertension who undergo a routine diagnostic work upwhich includes temporary withdrawal of their antihypertensives, followed bysubsequent decrease after reinstatement of therapy. The design of this study, thatis, temporal withdrawal of antihypertensive drugs in patients with refractoryhypertension, allows assessment of the pathological mechanisms following bloodpressure increase. At four time-points, advanced MRI sequences will be applied toprobe potential changes in BBB integrity, microvascular perfusion, microstructuralintegrity, and functional connectivity.n = 50) will be recruited at theoutpatient clinic of the Department of Internal Medicine of the RadboudUniversity Medical Center (Radboudumc), which is a national referral center forpatients with complex hypertension. Approximately 120 patients aged 18–55 yearswith hypertension are referred to the Radboudumc annually. These patients areoften referred by general practitioners or other hospitals when blood pressureis not well-controlled (>140/90 mmHg) despite the use of three or moreantihypertensive drugs or when there is clinical suspicion for secondary formsof hypertension. To determine if high blood pressure is caused by anoverproduction of aldosterone in the adrenal gland , the plasma aldosterone/renin ratio (ARR) can be determined.Because many common hypertensive drugs interfere with this ratio, patients oftenhave to discontinue antihypertensive drugs prior to screening or switch to drugsthat are known not to affect ARR  according to local protocols. Medication has to be stopped for at least 4 weeks  or 2 weeks  inhibitors, Angiotensin Receptor Blockers (ARBs)). This often leads to atemporary increase in blood pressure. After diagnostics are completed,medication is adjusted accordingly, and blood pressure levels drop again. Thisdiagnostic protocol with temporary withdrawal of antihypertensive medication hasbeen proven to be safe.Patients with hypertension . This is based on self-report and subsequent verificationof available medical documentation.a. Large-artery disease, defined as stenosis >50% in theinternal carotid artery or vertebral artery based onultrasound collected at baseline and medical recordsb. Cardioembolism, defined as atrial fibrillation or otherhigh risk cardioembolic conditions c. VasculitisConditions leading to similar appearance of MRI markers as SVD,including: Major neurological/psychiatric diseases or other diseases that preventlong-term follow-upa. Renal insufficiency b. PregnancyContraindications for 3T MRI Inability to give informed consent.T = 0). The second study visit (T = 1)will take place approximately 2–6 weeks after antihypertensive medicationwithdrawal when blood pressure is increased. T = 2 is scheduledwithin 2–4 months once patients have reached their target blood pressure andblood pressure is stable. The final study visit takes place approximately 1 yearafter T = 2 (T = 3). After the final studyvisit, long-term future incident clinical events will be monitored by contactingthe GP or treating physician of the participants. Participants will be requested to complete four study visits, combined withroutine visits to the outpatient clinic when possible . The basT1-weighted MP2RAGE, FluidAttenuated Inversion Recovery (FLAIR), susceptibility-weighted imaging (SWI),multi-shell Diffusion Weighted Imaging (DWI), resting-state functional MRI(rs-fMRI), Intravoxel Incoherent Motion (IVIM), and Dynamic Contrast Enhanced(DCE) MRI. In addition, a B0 field map and a diffusion-weighted sequence withreversed phase-encoding direction were acquired for distortion correction ofDWI, IVIM, and rs-fMRI scans. Acquisition parameters for all sequences are shownin Supplemental Table 1. DCE-MRI consists of successive slow, fast,and slow T1-weighted saturation recovery spoiled GRE pulse sequences. Gadobutrol contrast agent (0.1 mmol/kg) will be injected at a 3 ml/s ratefollowed by a 20 ml saline flush during the fast sequence. This macrocyclicagent is shown to be more stable than other gadolinium-base contrast agents andcan therefore safely be used for multiple MRI assessments.During each study visit, a brain MRI scan will be performed on a 3T MRI system using a 20 channelhead-neck coil. The total imaging protocol will take approximately 75 min andincludes the following sequences: 3D  WMH volume will be calculated using an in-house developed andvalidated technique that has previously been described.Conventional MRI markers of SVD, such as WMH, lacunes, microbleeds,enlarged perivascular spaces, and recent infarcts will be examinedfollowing the STRIVE guidelines. In short, images will be visually inspected to exclude majorartifacts. The following preprocessing steps will be applied: denoising,removal of Gibbs artifacts and correction for head motion,susceptibility-induced distortions, and eddy current-induceddistortions. To do this we will use the Functional Magnetic ResonanceImaging of the Brain (FMRIB) software library and MRtrix3 .14 BET (FSL) is usedto extract brain tissue, after which the diffusion tensor metrics (FAand MD) will be calculated using DTIFIT (FSL).Diffusion-weighted images will be processed according to a previouslydescribed protocol. This approach is suggested to improve detection of subtlediseases in the brain.16 PSMD will becalculated using a fully automated pipeline that was previously described.Next to these common DTI-derived measures, the Peak Width of SkeletonizedMean Diffusivity (PSMD) will be calculated. PSMD is based onskeletonization and histogram analysis and is calculated as thedifference between the 95th and 5th percentiles of MD values within themasked skeleton. Processing of IVIM images has been previously described. In short, preprocessing steps will include visual inspection ofimage quality, distortion corrections and head motion correction. Tomodel the diffusion-attenuated signal, a two-compartment diffusion modelis used that describes vascular and nonvascular compartments. Fitting of the model will be performed on a voxel-by-voxel basisusing a previously described two-step method. Measures derived from this model include: the perfusion volumefraction f, the diffusion coefficient of parenchymalwater D, and the pseudodiffusion coefficient ofcirculating blood D*. Furthermore, fD*is a blood perfusion related measure that will be calculated.IVIM is a DWI-technique that is used to study both microvascularperfusion and changes in microstructural tissue properties, which isespecially useful in SVD research since both are impaired in this disease. Images are segmented into white and gray matter using theT1-weighted image and WMH are segmented on FLAIRimages. After coregistration of T1-weighted images andFLAIR, Normal Appearing White Matter (NAWM), WMH, cortical gray matter,and deep gray matter are selected as regions of interest (ROI).DCE-MRI images will be processed according to previously describedprotocol by performing pharmacokinetic modeling and histogram analyses.T1 maps derived fromthe MP2RAGE sequence will be used. The vascular input function used to calculate the contrastconcentration in blood plasma will be derived from the superior sagittal sinus. The slope and intercept of the graphical Patlak model will beused to calculate the leakage rate (transfer constant Ki). A histogram is created for the Ki values in each ROIin a voxel-wise manner. Two measures to quantify BBB leakage are derivedfrom these histograms: the mean transfer constant Ki as ameasure of leakage rate and the area under the histogram curve as ameasure of tissue volume of leaking microvessels (Vl). Thesemeasures will be calculated for all ROIs. T1 values inthese ROIs will be computed at the individual level to evaluate theinteraction between hypertension and T1, a marker ofwater mobility.To calculate the concentration of the contrast agent in tissue, therelative signal enhancement and  In short, 264 functional areas will be used as network nodes inthe cerebral cortex, subcortical structures, and cerebellum. We will define five functional networks: a global brain network,the default mode network, the fronto-parietal task control network, thesomatosensory-motor network of the hand, and the visual network. For these networks, we will calculate the weighted globalefficiency and the weighted clustering coefficient, since these measureshave previously been shown to be sensitive to structural networkabnormalities in SVD patients.Processing of resting-state functional MRI (rs-fMRI) includes thefollowing steps: removal of artifacts, correction for slice time andhead motion, co-registration of functional and structural images,normalization of subject brain to Montreal Neurological Institute (MNI)space and spatial filtering. Graph theory will be used to examinefunctional brain networks using a previously described protocol.Primary outcomes of this study will be the changes in MRI outcomes afterwithdrawal of antihypertensive medication (highest blood pressure) andsubsequent restart (lowest blood pressure). MRI outcomes include WMH volume,PSMD, BBB leakage rate and volume, IVIM outcomes , PSMD, network globalefficiency, and clustering coefficients and are described in more detail in the“Imaging Protocol” section.Secondary study outcomes include:‒ Effects of antihypertensive medication withdrawal and restart oncognitive and motor functioning‒ Baseline associations between cardiovascular risk factors and MRImarkers of cerebral structure and vascular functioningT = 1 and bloodpressure and brain MRI parameters‒ Association between circulating markers of inflammation, includingcytokines and chemokines, measured at ‒ Changes in MRI parameters of brain structure and vascular function at1.5-year follow-up‒ Number of future incident clinical events. This includes all-causemortality, death due to vascular causes, non-fatal strokes (ischemic andhaemorrhagic), and TIAs.T = 2 and T = 3 patients willundergo a 60-min cognitive assessment covering six domains: processing speed,attention, executive functioning, verbal memory, working memory, and psychomotorfunctioning . All administered tests are validated andwidely used. To minimize intra-individual variability, we use standardized testswith high test-retest reliability. Parallel versions will be used to taketask-specific practice effects into account. Furthermore, participants willperform the Alertness subtask of the Test of Attentional Performance on a laptopduring each study visit. The Alertness subtask is a sensitive test forprocessing speed and attention, during which participants have to press a buttonas quickly as possible then a target stimulus is shown.At baseline, Gait speed (m/s) will be determined over a 6-m distance during each study visitto examine motor functioning. Gait and balance of participants will be assessedusing the Timed Up & Go Test, measuring the time a participant needs to getup from a chair, walk 3 m, turn around, and sit back down. Medical history includes age of hypertension onset and medication use. Ateach follow-up visit, changes in medication use and lifestyle behavior, andincident clinical events are assessed.A structured questionnaire will be used at baseline to assess demographic data,medical history and lifestyle behavior . Educational level is determined using a seven-point Dutch ratingscale, the Verhage scale.T = 1 and T = 2 todetermine levels of circulating inflammatory markers, such as cytokines afterovernight fasting. We will collect 45 ml of blood . Samples will bestored in the Hyperintense BioBank at the Radboudumc for future analyses.Blood will be collected at We will measure height and weight and calculate the Body Mass Index (BMI). Bloodpressure will be measured three times while participant is in seatedposition.Because the effects of blood pressure increase and decrease on MRI outcomesassessed here have never been examined, there is no information available aboutthe size of these possible effects. A formal sample size calculation istherefore not feasible. Instead, we based our sample size on the number ofpatients referred to the Radboudumc annually that are eligible for participationin this study within the limited time period of 2.5 years.To analyze primary outcome measures, MRI outcomes at different timepoints will becompared. MRI outcomes are discussed in the imaging analysis section andinclude: WMH volume, PSMD, BBB leakage rate, BBB leakage volume, IVIM outcomes,FA, MD, network global efficiency, and clustering coefficients. All outcomemeasures are continuous measures and data will be log-transformed in case ofnon-normality. We assume a linear (or parametric) relationship between bloodpressure and MRI parameters and will therefore run linear mixed models,including all time points. These will be adjusted for age, sex, education, andother conventional MRI markers of SVD. We will not correct for multiple analysissince different MRI measures probe different aspects of the brain in terms ofbrain structure, physiology, and function. Missing data will be described in ourscientific reports.Z-scores using available normative data,32 adjustingfor age, sex, and educational levels when possible. The association betweenblood pressure and incident clinical events will be investigated using Coxproportional hazard analyses, adjusted for age, sex, education, and SVD MRImarkers where appropriate.To examine the association between changes in blood pressure and cognitive andmotor functioning, individual cognitive test scores will be adjusted toLittle is known about the pathophysiological mechanisms underlying SVD. Research intoSVD pathogenesis is hampered by difficulties with visualizing the smallest cerebralvessels with conventional MRI, allowing only the detection of end-stage diseasecerebral lesions. Most of the knowledge about SVD is derived from studies conductedin individuals older than 60 years in whom SVD most likely has been present fordecades. To advance the understanding of key mechanisms implicated in SVD, studiesconducted in young- and middle-aged adults that are able to catch the first signs ofSVD, before the occurrence of widespread irreversible tissue damage, are needed. TheHyperintense study is the first serial MRI study designed to examine the effects ofchanges in blood pressure on cerebral microvasculature in young- and middle-agedadults with hypertension, the strongest risk factor for SVD. Furthermore, we combine several advanced MRI techniques to examine earlymicrovascular changes. We use DCE-MRI to examine BBB integrity, which is associatedwith clinical and imaging features of SVD. Since both microstructural integrity and cerebral perfusion are suggested tobe diminished in SVD patients, we use multi-shell DWI and IVIM to examine this simultaneously. We also use rs-fMRI to examine functional connectivity since(micro)structural damage in SVD patients can lead to disturbed connectivity bothbetween and within brain networks. These MRI techniques allow analysis of early pathological mechanisms and theorder in which they occur before MRI markers of SVD become visible. Another strengthof this study is the extensive amount of cognitive, motor, and biobank data that iscollected in a structured and standardized way. MRI outcomes can therefore be linkedto cognitive functioning, measured by tests that are widely accepted and shown to besensitive to SVD-related brain changes. Assessment of circulating inflammatorymarkers will help identify ongoing inflammatory responses that may play a centralrole in SVD pathogenesis. We expect the external validity of this study to be high. Since the patientsincluded in this study are highly likely to develop SVD later in life, abnormalitiesin vascular functioning observed here are presumably also present in otherpopulations at risk of SVD. Findings of this study will therefore have implicationsfor treatment optimization in patients at risk of cerebrovascular damage; reachingconventional target blood pressure may not be sufficient and additional treatment tofurther lower blood pressure or reduce inflammation and BBB leakage can havebeneficial effects on clinical outcomes.One of the main strengths of this study is the unique design that includes inducedhypertension due to temporary withdrawal of antihypertensive medication, followed byblood pressure lowering due to medication restart as part of routine clinicalpractice, without the need for an intervention study. This design allows analysis ofthe effects of both increases as well as decreases in blood pressure. Previousstudies have examined the effects of blood pressure lowering on SVD measures, butthe effects of blood pressure increase have never been studied.In conclusion, the Hyperintense study is a unique serial MRI project that has thepotential to further unravel the association between early-life hypertension andSVD. Although hypertension is considered a main risk factor for developing SVD, itremains unknown how hypertension exerts an effect on brain structure and vascularfunction. This study will help to identify early-life pathological mechanisms of SVDcaused by hypertension. Improved understanding of the pathological mechanismsdriving SVD pathogenesis and progression will contribute to identification of newtargets for treatment.Click here for additional data file.Supplemental material, sj-docx-1-eso-10.1177_23969873221100331 for TheHyperintense study: Assessing the effects of induced blood pressure increase anddecrease on MRI markers of cerebral small vessel disease: Study rationale andprotocol by Esther Janssen, Annemieke ter Telgte, Esmée Verburgt, Joost JA deJong, José P Marques, Roy PC Kessels, Walter H Backes, Marnix C Maas, FrederickJA Meijer, Jaap Deinum, Niels P Riksen, Anil M Tuladhar and Frank-Erik de Leeuwin European Stroke Journal


Patients with a failed kidney allograft have steadily increase in recent years and returning to dialysis after graft loss is one of the most difficult transitions for chronic kidney disease patients and their assistant physicians. The management of these patients is complex and encompasses the treatment of chronic kidney disease complications, dialysis restart and access planning, immunosuppression withdrawal, graft nephrectomy, and evaluation for a potential retransplant. In recent years, several groups have focused on the management of the patient with a failing renal graft and expert recommendations are arising. A review of Pubmed, ScienceDirect and the Cochrane Library was performed focusing on the specific care of these patients, from the management of low clearance complications to concerns with a subsequent kidney transplant. Conclusion: There is a growing interest in the failing renal graft and new approaches to improve these patients’ outcomes are being defined including specific multidisciplinary programs, individualized immunosuppression withdrawal schemes, and strategies to prevent HLA sensitization and increase retransplant rates. The last decade has seen a marked improve in short-term kidney transplantation outcomes, but long-term graft survival remains sub-optimal over the last 30 years . This haReturning to dialysis after graft loss is one of the most difficult transitions for chronic kidney disease (CKD) patients and their assistant nephrologists, as the conditions of these patients are complex and they face several complications. Patients with allograft loss have lower quality of life scores, a higher burden of depression, increased hospitalization, and significantly higher mortality rates ,5. From Despite the large number of patients affected by the deleterious consequences of graft loss, the only available recommendations on the care of the patient with a failing graft are the 2014 guidelines from the British Transplantation Society .The management of the failing graft has become a growing concern in the kidney transplantation community and several groups are arising to address this complex issue. The development of multidisciplinary teams and a paradigm shift focusing on long term patient outcomes, combined with advances in immunosuppressive drugs and modern immunogenetic techniques are contributing to provide the best care to patients with graft loss. In the current review we aim to address the challenges in managing patient with a failing graft and review recent recommendations on this growing group of CKD patients.This narrative review is based on an extensive literature research accessed between January and July 2022 from the following databases: NCBI Pubmed, ScienceDirect, the Cochrane Library and the websites clinicaltrails.org and uptodate.com. Full articles were accessed and reviewed. For the included articles, we used the tools “reference lists” and “related articles” of PubMed to increase our search. We used MeSH terms and free text, according to the specific chapter and in different combinations. The main keywords used were “allograft failure”, “chronic kidney disease”, “end stage renal disease”, “failing allograft”, “graft embolization”, “graft intolerance syndrome”, “graft nephrectomy”, “highly sensitized”, “immunosuppression”, “kidney transplant”, “retransplantation”, “sensitization”, “taper”, “withdrawal”. There were no restrictions on publication date but articles published in the last five years were prioritized. Only articles in English were selected.The definition of a failing allograft is the beginning of the challenge in managing KT recipients with decreased glomerular filtration rate (GFR). The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines suggest that KT recipients with CKD stage 4T, in evidence of progression, should be prepared for kidney replacement therapy . However2 [A combined approach that includes eGFR trends, proteinuria, the presence of donor-specific antibodies (DSA), recurrent disease and transplant glomerulopathy might be the best predictor of graft failure ,13. A mu2 . The sam2 .Another issue is the heterogeneity of causes of allograft failure and difficulty in defining the cause of graft loss. A recent study that thoroughly analyzed the cause of death-censored graft failure in 303 recipients, concluded that 51.2% of the patients had more than one cause contributing to graft loss and that the causes varied over time . FocusinA group of experts proposed in 2021 that the failing allograft definition should include patients with stable but low allograft function; irreversible and progressive decline in kidney function with anticipated graft loss in less than 1 year; and a return to renal replacement therapy, maintenance dialysis, new wait-listing or repeat transplantation . Figure There are important dichotomies in CKD management between transplant-naïve patients and transplanted patients. The main focus of transplant nephrologists is to prolong allograft survival, which comes at the expense of a worst control of CKD-associated complications and a less organized beginning of dialysis. Higher blood pressure, anemia, CKD—mineral bone disorder (CKD-MBD) and worst nutrition contribute not only to higher morbimortality, but also play an important role in allograft dysfunction progression .A large multicenter study from the UK Renal Registry investigated the prevalence of CKD-related complications in 1797 KT recipients with CKD stage 4 and 5. They concluded that renal allograft recipients had lower standards in anemia, CKD-MBD, blood pressure and nutrition than prevalent dialysis patients . Another2. The ESA group showed significantly higher levels of hemoglobin (12.5–13.5 g/dL vs. 10.5–11.5 g/dL) and a significantly slower rate of eGFR decline, without significant side effects [Focusing on anemia, the benefit of using erythropoiesis-stimulating agents (ESA) and the optimum target hemoglobin remain uncertain in transplant patients . A rando effects . A recen effects .The diagnosis and management of CKD-MBD in KT is very complex as it encompasses bone disease before KT, bone disease after KT, and the influence of immunosuppressant drugs, especially steroids . KT reci2 did not reach target levels regarding blood pressure or LDL levels [Volume overload and dyslipidemia may also be important contributors to the progression of graft dysfunction and cardiovascular mortality. Data from the UK renal registry showed that the majority of KT recipients with eGFR < 30 mL/min/1.73 mL levels .A definitive dialysis access, especially for hemodialysis (HD), is another important issue in KT recipients returning to dialysis. Several authors have reported that KT recipients start HD by a CVC more frequently than arteriovenous fistula, and a large registry study concluded that 65% of patients restart dialysis using a CVC ,32. ConsThe British Transplantation Society recommends the development of dedicated low clearance transplant Clinics, which provide multidisciplinary tailored care from both a transplant and a low clearance perspective, including specialized nephrologists, nurses, dietitians and pharmacists . Two stuThis individualized multidisciplinary approach is more focused on long-term outcomes and brought some novelties with regard to differing eGFR decline, prolonging residual renal function and improving patients’ quality of life .2) and found a significant increase in eGFR (32 ± 13 mL/min/1.73m2), improvement in serum bicarbonate levels, better CKD-MBD control, and an increase in albumin levels [2, was only beneficial in a subgroup of patients with less time post-transplant, low proteinuria, and less HLA sensitization [Focusing on stabilizing eGFR, calcineurin inhibitor (CNI)-free regimens could be beneficial considering their nephrotoxicity and metabolic side effects, despite a higher risk of acute rejection and HLA sensitization ,40,41,42n levels . In a latization . Anothertization . These rIncremental HD strategy is another novelty with the goal of preserving residual renal function on patients with a failing graft. Although there are no published RCT studies available, recent recommendations believe that it might be beneficial by extrapolation of native kidney CKD patients ,48.Studies on the optimal timing of dialysis initiation after graft failure are lacking. A cohort study that evaluated 4741 patients with graft failure showed that higher eGFR at dialysis restart was associated with higher mortality . HoweverThe majority of patients with graft loss who resume dialysis opt for HD, but when compared to native kidney patients, there are more KT recipients choosing peritoneal dialysis (PD), probably due to age and autonomy bias ,53. A laKidney palliative care is an emerging subspecialty of palliative care and nephrology, but for KT recipients, the utility of kidney palliative care has not been explored nor well-delineated. A recent small trial published by a group of inpatient kidney palliative care service  showed that providing a trained and multidisciplinary team of palliative care to patients with graft failure increased the adherence of patients to palliative care and time-limited trial dialysis, resulting in a more active role of the patient to decide their future after graft loss .Decisions on tapering immunosuppressive medications in patients returning to dialysis are complex, without a strong evidence base or universally accepted recommendation, resulting in widely clinical practice variance. The Kidney Recipient with Allograft Failure Transition of Care (KRAFT) group distributed an online questionnaire to 92 KT centers to evaluate the patterns of management of patients with renal allograft, concluding that practices in the US vary greatly . SeveralThe first prospective multicenter study on IS withdrawal was recently published and included 269 patients with graft loss from 16 Canadian centers. Two groups were compared at a two-year follow up period: group 1—continuation of IS with CNI and/or antiproliferative and/or prednisone versus group 2: discontinuation of all IS or use of prednisone only. In multivariable models, group 1 patients had a lower risk of death and no differences in hospitalization due to infection. Group 1 presented less HLA antibodies determined by Luminex, especially class 2, but did not reach significance. There were no differences in virtual panel reactive antibody (PRA) or GIS .Despite the conflicting results presented by the available studies, groups of experts are proposing strategies to IS withdrawal in patients with a graft loss .These recommendations mainly focus on three aspects: the possibility of a retransplantation; the adverse effects of IS, including cardiovascular disease, infection and neoplasia; and the preservation of residual renal function.A major difficulty in maintaining IS after graft loss is the adequate dosing of CNI. In a study by Augustine and colleagues, the majority of the patients who continued IS had a functioning pancreas graft and maintained higher levels of CNI, which might explain the lower HLA sensitization . AdditioInnovative approaches to IS withdrawal after graft loss in order to decrease sensitization are arising. A pilot RCT published in 2021, randomized 13 patients with failed allograft upon reinitation of dialysis to belatacept versus IS discontinuation and evaluated HLA antibody formation 36 months after randomization. Overall, the breadth and depth of HLA antibody formation was greater in the withdrawal group relative to belatacept treated patients, with similar adverse events . These pThere are formal indications for graft nephrectomy that the majority of the centers follow , but forWhen an established indication of graft nephrectomy is not present, the reported rate of surgical allograft nephrectomy after graft failure varies from 9 to 74%, depending on the center policy rather than compelling data . The potA recent meta-analysis explored the impact of allograft nephrectomy in 2256 patients with subsequent kidney retransplantation, concluding that a prior allograft nephrectomy increased the risk of higher PRA, delayed graft function, acute rejection and primary non-function but had no significant association with five-year graft or patient survival . While oAnother interesting approach that bypasses the surgical risk of allograft nephrectomy is the embolization of the renal artery. A recent meta-analysis showed that renal artery embolization successfully treated GIS in the majority of the patients, with lower morbidity and mortality, but 20% of the patients required nephrectomy at follow-up . Post-emIn selected patients with appropriate clinical conditions to receive a new graft, retransplantation offers the largest survival benefit, with a mortality rate reduction ranging from 20% to 88%, depending on specific comorbidities and transplant era ,85,86. TWith the increasing number of KT recipients returning to dialysis, the nephrology community is shifting towards a better paradigm and most transplant centers are now driven to deliver long-term, individualized care. The patient with a failing graft encompasses several issues that are similar to native kidney CKD patients, but longer dialysis vintage and exposure to IS make this population management more complex. New data on IS withdrawal management, impressive progresses in immunogenetics and new pharmacological therapies are arising and bringing a new hope to CKD-5 patients with a failing graft.