IntroductionHypertension is one of the leading causes of mortality worldwide. Fifty-four percent of strokes and forty-seven percent of cardiovascular deaths are caused by suboptimal control of blood pressure. Economically developing countries like Pakistan are heavily burdened with an ever-rising epidemic of cardiovascular disease and stroke morbidity and mortality. Therefore, urgent steps are required to treat, as well as modify, risk factors for cardiovascular disease, including hypertension.PurposeThe objective of this study was to ascertain the knowledge of hypertension and other sociodemographic variables and their impact on controlling blood pressures in the hypertensive population belonging to the low socioeconomic strata.MethodsThis cross-sectional study was conducted in the general medicine and cardiology outpatient clinics of a tertiary care charity hospital. Three-hundred thirty-five hypertensive patients of age >24 years were selected and informed consent was obtained. Hypertension-related knowledge was assessed using the Modified "Hypertensive Knowledge-Level Scale (HK-LS)" via a 15-20 min interview. Secondary variables in the questionnaire included social demographics, medical history, and assessment of body mass index (BMI) and blood pressure average values, which were measured during the interview. Knowledge was recorded based on the 33-point modified HK-LS scale, whereas secondary variables were not counted toward the assessment of knowledge.ResultsThe frequencies of low, moderate, and high levels of hypertension-related knowledge were recorded as 2.1%, 79.4%, and 62%, respectively. Among 335 patients, (57.3%) were male, the mean age was 52.5 ± 11.5 years, and 63.6% were professionally active. Median systolic blood pressure (SBP) and diastolic blood pressure (DBP) in hypertensive patients were 140 and 86 mmHg, respectively. Sixty-nine percent of patients reported existing comorbidities, 54% had diabetes, 20.7% had cardiovascular disease, and 24% reported renal disease. No significant association was observed between the levels of knowledge of hypertension and gender, blood pressure (BP) status, professional activity, and age groups .ConclusionThe majority had adequate knowledge of hypertension but only 64.8% had controlled BP status. This depicts not a lack of knowledge and awareness but rather a lack of prevention of risk factors related to hypertension. Thus, further studies are advised to look into the preventive strategies employed by patients to control their BP and assess their effectiveness. Non-communicable diseases (NCDs) are, by far, the leading cause of death worldwide. The major NCDs responsible for these deaths included cardiovascular diseases, causing about 17.9 million deaths that account for 44% of all NCD deaths and 31% of all global deaths in the year 2016 [The percentage of the population with controlled blood pressure (BP) status also varies considerably among countries, for example, in developed nations like Canada, the percentage of population with controlled BP is 65% in contrast to the 6% found in Pakistan . In a meWhile it is difficult to modify the demographic and behavioral patterns and norms and socioeconomic status of the hypertensive population, increasing their knowledge through educational interventions on treatment, however, can positively influence patients’ beliefs about medicines and help vulnerable countries like Pakistan control the burden of the disease of HTN and, through it, many of the deaths due to cardiovascular and other related causes. Earlier studies, which are very few in number, depict that hypertension-related knowledge is extremely poor in the Pakistani hypertensive population and that they were mainly focused on private tertiary care hospitals, which are mostly accessed by the middle-class and elite populations . In an eIt was a cross-sectional study conducted at a tertiary-care charity hospital in Karachi, The Indus Hospital. Patients with hypertension for one or more years and taking antihypertensive medications were selected for the study from the general medicine and cardiology outpatient departments (OPDs). The age criterion was set as more than 24 years of age and diagnosis of hypertension was confirmed via a thorough history. Patients presenting with hypertension for the first time were excluded and so were patients with secondary hypertension and females with gestational hypertension. Ethical approval was granted by the Indus research department. Interviews were conducted by medical trainees and third-year medical students. Patients were selected as per the inclusion criteria after informed consent was taken.Patients presenting to the outpatient general medicine and cardiology clinics at The Indus Hospital were considered for this study. The modified “hypertensive knowledge level scale (HK-LS)” scale was employed to assess the knowledge. Besides the 33-item-based HK-LS, further questions were introduced in the interview to assess the demographic characteristics of the patients, medical history, height, weight, substance use, information about the duration of hypertension, systolic and diastolic blood pressure readings, comorbidities, and intake of antihypertensive medications. Additional questions went on to address drug compliance, diet and lifestyle modifications, and the complications of hypertension. The questionnaire was designed after extensive review by experts in the field of hypertension and research methodologies. Each correct answer was given one point while an incorrect answer was allocated zero. The minimum score was zero and the maximum score was 33. Only the 33 questions falling under the modified HK-LS were counted toward the score; the rest of the questions were not marked. Each interview took about 15-20 min to complete. Blood pressure was recorded with the patients sitting in a relaxed position for 15 minutes; the average of three readings was noted from each arm alternatively, using the manual sphygmomanometer. The readings were recorded by the research staff in the provided space on the interview proforma. The interviewer filled in the form, noting the demographic variable, ethnicity, formal education ascertained by the total number of schooling years, occupation, history of hypertension and its management, comorbidities , substance abuse, height and weight taken, and, finally, the HK-LS answers were noted down with the last seven questions contributing to determining the basic knowledge of the patient regarding hypertension.A total of 335 patients were included in the study, of which more than half were females 192 (57.3%). The mean±SD age of patients was 52.5±11.5 years. The majority of the patients were Urdu speaking 144 (43%). It was observed that 213 (63.6%) hypertensive patients were not working for a living. The median SBP and DBP in hypertensive patients were 140 and 86 mmHg, respectively (interquartile range (IQR): 130-146 and 80-90, respectively. The median duration during which the patients were suffering from hypertension was five years (IQR: 3-9), and they were taking medications for the same for a median of four years (IQR: 2- 8), postulating that patients started medication one year after diagnosis. In 225 (67.2%) patients, there was a family history of hypertension while 139 (41.5%) patients had a family history of cardiovascular disease. A total of 111 (34%) patients were addicted to some kind of substance in the past while 104 (31.8%) patients were found to be currently addicted to paan, beetle nuts, cigarettes, and naswar ; followed by renal problems, 54 (24.3%); heart problems 46 (20.7%); and others  patients demonstrated moderate knowledge, 62 (18.5%) showed high knowledge, while 7 (2.1%) patients had low knowledge. After classifying them in two groups on 50% cut-off knowledge, 317 (94.6%) had high knowledge and 18 (5.4%) had low knowledge.The median age of males was 56 years as compared to females, whose median age was 50 (IQR: 45.8-65 vs 42 -58) years, though males are older than females and the p-value was statistically significant p<0.0001, Table , Table 1We observed female patients had a higher BMI as compared to male patients  VI criteria. Another study found controlled blood pressure in only 3% of all hypertensive patients; this could be attributed to our sample population being those visiting a tertiary hospital while their sample was of the general population -18. An oHypertensive patients' basic knowledge and awareness of risk factors of hypertension and its complications is considerably good, as 79.4% of patients had moderate knowledge of hypertension, while on the 50% cut-off, 94.6% had high knowledge. Our observation is in accordance with the findings of previous studies who found hypertensives demonstrated knowledge, positive perception, and attitude to the treatment of hypertension -21. A moPrevious studies have concluded that professional activity relates to low knowledge scores in hypertensive patients. We found there was no significant association in the median HKLS score between groups of gender, negative associations with professional activity, and blood pressure status. Although it was found in a few studies that the level of knowledge about hypertension is affected by gender, women showing a higher level of knowledge with regards to the definition and complication of HTN, in some others, it was found that men have higher knowledge -27. Our This study is a single tertiary hospital-centered study focusing on a full analysis of knowledge regarding hypertension of the hypertensive population on medications for more than one year. It found a level of knowledge of specific aspects of hypertension, by taking care of which hypertensives may improve their blood pressure control. The questionnaire used for knowledge assessment was a validated HKLS. Despite the comprehensive nature of this survey, a few limitations of this study are as follows. First, our study was confined to a single center in the urban area, therefore, results cannot be generalized to the rural population. Second, the white-coat effect was not taken into account, which could have possibly resulted in the difference in the BP levels of visiting patients. No monitoring regarding the quality assurance of BP measurements was carried out, therefore, it is not known to what degree doctors complied with the rules. Our study did not take into account compliance with drug therapy by the patient. We obtained no data on drug classes, doses used, and the dosing schedule, to carefully investigate their adherence to medical treatment. Our sample was limited to hypertensives so it cannot be generalized to the whole population, those who have it but are yet not diagnosed, and those who are likely to have it in their future. Their knowledge is also important. We did not analyze the sociodemographic and educational variables to find their association with clinical variables levels and knowledge of hypertension.It is concluded from our study results that hypertensive patients had adequate knowledge of hypertension except in the areas of lifestyle modification; however, despite their adequate knowledge, many patients did not have controlled BP status. This depicts not a lack of knowledge and awareness but rather a lack of prevention of risk factors related to hypertension. Effort on the part of physicians is needed to increase the level of knowledge about lifestyle changes, the basic concept of hypertension, and drug compliance by educating and motivating patients and public enlightenment in a conducive manner, e.g. by pamphlets or posters about their target blood pressure according to age, family history, and comorbids, and reinforce the need for patient’s compliance with antihypertensives for life, when required, in order to control the disease and decrease the associated morbidity and mortality. Alternatively, educating patient groups could be an intervention to be tested to improve knowledge of these aspects. We recommend further studies to look into the preventive strategies already employed by patients to control their BP and assess their effectiveness.


To determine if increasing variability of blood pressure influences determination of cerebral autoregulation. A prospective observational study was performed at the ICU of a university hospital in the Netherlands. 13 comatose patients after cardiac arrest underwent baseline and intervention (tilting of bed) measurements. Mean flow velocity (MFV) in the middle cerebral artery and mean arterial pressure (MAP) were measured. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, coherence, gain, and phase were calculated in the very low and low frequency bands. The CV of MAP was significantly higher during intervention compared to baseline. On individual level, coherence in the VLF band changed in 5 of 21 measurements from unreliable to reliable and in 6 of 21 measurements from reliable to unreliable. In the LF band 1 of 21 measurements changed from unreliable to reliable and 3 of 21 measurements from reliable to unreliable. Gain in the VLF and LF band was lower during intervention compared to baseline. For the ICU setting, more attention should be paid to the exact experimental protocol, since changes in experimental settings strongly influence results of estimation of cerebral autoregulation. Postanoxic encephalopathy is a common phenomenon after cardiac arrest and causes high mortality and morbidity . AdaptinCerebral autoregulation (CA) describes the process of cerebral vasodilation and vasoconstriction to maintain a stable CBF over a wide range of perfusion pressures. This adjustment of CBF to changes in cerebral perfusion pressure is directed by central regulation-mechanisms , 3 and bAfter cardiac arrest, the spontaneous variability of arterial pressure is significantly lower compared to age- and sex-matched control patients . In addihttp://www.car-net.org) with recommendations to improve the standardization and settings for TFA applications in studies of dynamic autoregulation  years. Twelve patients had ventricular fibrillation (VF) or ventricular tachycardia (VT) as initial rhythm, and 1 patient initially had a pulseless electrical activity (PEA). Four patients died in the ICU, all because of severe postanoxic brain damage. The clinical and laboratory data on admission are summarized in p < 0.0001) (p = 0.0028) (Tilting of the bed induced a significant increase in CV of MAP from 3.056 ± 1.464 at baseline to 8.238 ± 2.646 during intervention ( 0.0001) . The CV  0.0028) .p = 0.6776)  compared to baseline (0.3757 ± 0.4473) ( 0.6776) . On indip = 0.8281) (p = 0.3265) (There were no significant changes on a group level in coherence between baseline (0.4449 ± 0.2692) and intervention (0.4313 ± 0.2702) in the VLF band ( 0.8281) . There w 0.3265) . On an ip = 0.0058) (p = 0.0523) (The gain in the VLF band during intervention (0.5578 ± 0.3046) was lower compared to the gain in the VLF baseline (0.7746 ± 0.2579) ( 0.0058) . The gai 0.0523) .p = 0.4548 and 0.570, respectively)  compared to the phase in baseline position  (ctively) .Amplification of blood pressure variability changed the interpretation of CA as measured by Mx and TFA. This difference in test results is not related to physiological changes in CA, as both baseline and intervention were performed at the same time-point after cardiac arrest. This difference in test results is most likely related to bias induced by very low variability in the blood pressure and MFV signal at baseline, which renders estimation of CA with these methods unreliable.For the estimation of dynamic CA, TFA is considered the gold standard. The white paper on TFA methodology provides recommendations on the optimal cut-off values of coherence and parameter settings . No recoThe optimal recording time of signals for autoregulation to stabilize is largely unknown. Recording time for the autoregulatory index Mx significantly influences validity of the measurements. Mx calculated on intervals shorter than 6 minutes is at risk for changes due to insufficient stabilization of the signal . The Mx The white paper recommends a minimum window length for TFA analysis of at least 100 seconds . This isThe extent to which TFA outcomes are influenced by quality of the signals differs between different parameters. In our study, increased variability of signals resulted in decrease in gain in both the LF and VLF bands, whereas phase remained stable. This is most likely related to the fact that gain reflects the strength of the autoregulation, which may be changed by increased amplitude of the signal. In contrast, phase is related to velocity of dynamic changes in autoregulation. Since augmentation of the variability is unlikely to change the timing of the arterial and cerebral pulses, phase may remain unchanged during the intervention.The use of the coherence function is recommended to identify conditions where estimates of gain and phase may not be reliable. The intervention changed the level of coherence from unreliable to reliable in a substantial portion of patients, but the reverse (change from reliable to unreliable) occurred in a similar proportion of patients. Since the variability was extremely low, the input signal may have been too low for adequate determination of TFA coherence at baseline.This was supported by visual inspection of the raw data and linking this with individual outcomes of TFA. Visual inspection of the raw signals can easily identify whether oscillations in MAP and CBFV are present and whether these oscillations are temporally related. In the few patients who showed variability in both MAP and CBFV, the results of TFA appeared reliable, with higher phase values in VLF than in LF and lower gain values in VLF than in LF. In contrast, when TFA was performed in patients with low MAP variability, these normal patterns were not observed, even if coherence was above the threshold.In an earlier study we proved that the spontaneous variability of the MAP remained low during the entire study period after cardiac arrest . In the This study has a number of limitations. We performed an observational study in a relatively small population. Tilting of the bed may result in changes in quality of the recorded signal, such as loss of signal, motion artefacts, and baseline drifts. Reanalysis of the raw signals however was carefully performed by an independent expert (J.C.), using only good quality signals and verifying correct TFA settings, but this did not alter the outcome. Changes in the bed position may influence the pressure in the veins draining the cerebral venous blood. These changes in venous outflow pressure may influence cerebral perfusion and thus the validity of the autoregulation measurements.The white paper on TFA methodology currently provides no recommendations about minimal necessary blood pressure variation to perform a reliable TFA. Given the results of this study, addition of minimal necessary variation of input signals to the white paper on TFA methodology may improve the validity of TFA measurements. For the ICU setting, more attention should be paid to the exact experimental protocol, since changes in experimental settings strongly influence results of estimation of CA. The optimal level of variation of the signals will be difficult to establish because of the lack of golden standards of autoregulation for comparison of the results. Computer modelling may be helpful to establish the effects of changes in different parameters on the measurements of autoregulation.


A single center, prospective cohort study recruiting 107 burn patients and 62 control patients was conducted to characterize the early phase of acute hyperglycemia in patients with burns. A total of 1643 blood samples were collected, and blood glucose and serum proinflammatory cytokines were detected and analyzed. A mouse severe burn model was used to study the underlying mechanisms of acute hyperglycemia postburn. An expression profile of IL-1 receptor, serum IL-1β and pancreatic islet function were detected in both control mice and burned mice. The data in this article is associated with the research article published in Biochim Biophys Acta “Acute pancreatic beta cell apoptosis by IL-1β is responsible for postburn hyperglycemia: evidence from humans and mice”  Specifications tableValue of the data•The data furnishes the scientific body with information on random blood glucose and its regulation in control and burn patients.•The data describes changes in serum levels of major proinflammatory cytokines and their association with blood glucose postburn.•The data on mice offers extra evidence on that serum IL-1β specifically induces pancreatic beta cell dysfunction.•The data will foster further examination of the potential of IL-1β neutralization in glycemic control in patients with burns.1A total of 1643 blood samples were collected, of which 1358 blood samples were from burn patients and 285 blood samples were from control patients 22.1www.chictr.org.cn (ChiCTR-OOB-15006420) as described previously Human study was approved by the institutional review board of Fourth Military Medical University and registered at 2.2Animal experiments were performed according to the National Institutes of Health Guidelines for the Use of Laboratory Animals and were approved by the Fourth Military Medical University Committee on Animal Care. After being anesthetized, 30% total body surface area (TBSA) and full-thickness burn model was conducted as described previously 2.3Continuous variables were compared by Mann–Whitney U or Student׳s t-test as appropriate. Linear relationships between variables were tested by Pearson׳s correlation coefficient. Multiple linear regression analysis was performed to evaluate independent contributions of the studied variables to blood glucose. The results are expressed as means ± SEM unless noted otherwise. A p value of less than 0.05 was considered statistically significant.


P = 0.004), female gender , eGFR  and myocardial infarction history  were identified as the main clinical predictors for intimal hyperplasia. Preatherosclerotic lesions in ITA samples from patients undergoing coronary revascularization were associated not only with classical cardiovascular risk factors such as age and gender, but also with other clinical variables, namely kidney function and myocardial infarction history.In this study, we aimed at performing a histomorphometric analysis of human left internal thoracic artery (ITA) samples as well as at correlating the histomorphometric findings with the clinical profile, including risk factors and medication. Distal segments of ITA were obtained from 54 patients undergoing coronary artery bypass grafting. Histological observation was performed in paraffin-embedded transverse sections of ITA through four staining protocols: hematoxylin-eosin, van Gieson, Masson’s trichrome and von Kossa. Morphometric analysis included the intimal width (IW), medial width (MW) and intima/media ratio (IMR). No overt atherosclerotic lesions were observed. Mild calcifications were observed across the vascular wall layers in almost all samples. Multivariable linear regression analysis showed associations between IW and IMR and the following clinical variables: age, gender, kidney function expressed as eGFR and myocardial infarction history. Age (odds ratio = 1.16,  Vascular structural changes have been associated with cardiovascular diseases . In partA wide array of techniques is available to study the vascular histomorphology. Despite the growing use of non-invasive methods, the histomorphologic study of isolated vessels remains as a useful tool to understand the structural properties of vessels. Moreover, the quantitative assessment of the vascular structure provides valuable information that complements the qualitative microscopical observation . SeveralThe human internal thoracic artery or ITA  has long been recognized as atherosclerosis-resistant vessel –11. SeveIn this context, we aimed at performing a histomorphometric analysis of ITA samples and at correlating the histomorphometric findings with the clinical profile, including risk factors and medication.Experiments were performed on left ITA distal samples harvested from patients undergoing coronary revascularization. Written informed consent was obtained from each patient and the experiments were performed with the approval from the research ethics committees of the Faculty of Medicine of University of Coimbra and the University Hospital of Coimbra , with the following references CE-107/2014 and PC-388/08, respectively. The study was conducted in accordance with the Declaration of Helsinki and was not registered in any research database.Smoking history was defined as history of consumption of any form of tobacco . Arterial hypertension was defined as systolic and diastolic blood pressure exceeding 140 mmHg and 90 mmHg, respectively, or history of high blood pressure or need of antihypertensive drugs. Diabetes mellitus was defined as history of diabetes and current treatment with either insulin or oral drugs. Dyslipidemia was defined as the presence or absence of history of dyslipidemia diagnosed and/or treated by a physician. Peripheral vascular disease (PVD) was defined as claudication either with exertion or at rest; amputation for arterial insufficiency; aorto-iliac occlusive disease reconstruction; peripheral vascular bypass surgery, angioplasty or stent; documented abdominal aorta aneurysm, repair or stent; or non-invasive carotid test with > 75% occlusion. Cerebrovascular disease was defined as unresponsive coma for longer than 24h, cerebrovascular accident or transient ischemic attack. Kidney function was evaluated by the value of estimated glomerular filtration rate (eGFR), from Modification of Diet in Renal Disease formula . The hig2.2H2O, 0.9 KH2PO4, 0.6 MgSO4.7H2O, 25 NaHCO3 and 11.1 Glucose), previously aerated with 95% O2 / 5% CO2 and adjusted to pH 7.4, and then isolated to remove most of the perivascular tissue.Vessel samples from 54 patients were harvested and prepared as described previously . BrieflyLeft ITA samples were fixated in 10% buffered formaldehyde. Histomorphology was observed with a light microscope (Leica DM1000 LED). Samples were studied with the following stainings: (a) Hematoxylin-Eosin, (b) Verhoeff-Van Gieson , (c) Masson’s Trichrome  and (d) von Kossa . Staining protocols from the manufacturer were followed and performed in the Laboratory of Experimental Pathology, Faculty of Medicine, University of Coimbra.Histomorphologic analysis included both histopathologic and histomorphometric analysis. For the purposes of histomorphometric analysis, the Java-based image processing software ImageJ was used. Calibration of the scale in ImageJ was performed considering the distance per pixel indicated for each image by the Leica Application Suite V4.8.0 (Leica Microsystems). Maximal IW and MW were measured and mean values of 2 measurements per location were determined. Furthermore, IMR was calculated as the ratio between IW and MW. These results were then stratified according to the classification previously proposed by Kaufer et al. : grade 0Data is generally presented as mean ± standard error of mean (SEM) for continuous variables and as frequencies and percentages for categorical variables. N corresponds to the Number of patients.Multivariable linear and logistic regression analysis were performed to identify clinical predictors for continuous and dichotomous dependent variables, respectively. Clinical variables with a significant individual association in analysis of variance (P < 0.200) were retained for regression analysis by the backward stepwise method.2 is presented as a measure of percentage of explanation of the models (e.g. an adjusted R2 of 0.200 means that 20.0% of the variation may be explained by the variables included in the model). Constructed model presented higher predictive power than no model as assessed by analysis of variance with P < 0.050. Multicollinearity was assessed by the variance inflation factor (VIF).For the linear regression models, the adjusted Rp value (P > 0.050) indicates a good calibration of the model [For the logistic regression model, the model performance was evaluated considering two properties, (a) the calibration and (b) the discriminatory power. Calibration was assessed by the Hosmer-Lemeshow test which analyses the differences between the observed and the predicted results. The obtainment of a non-significant he model .2 is also presented as a measure of percentage of explanation of the model.The discriminatory power was evaluated considering the area under the receiver operating characteristic (ROC) curve or AUC , which wStatistical analysis was performed with IBM SPSS Statistics version 25.0.0  and JMP Pro 13.1.0  and graphs were prepared with GraphPad Prism 7 .Verhoeff’s Elastic Van Gieson Stain Kit (RRSK40), Masson Trichrome Stain Kit (RRSK20) and Von Kossa Stain Kit (RRSK39) were purchased from Atom Scientific. All other chemicals were purchased from Sigma-Aldrich  and correspond to the highest grade commercially available.A total of 54 patients were included in this study . The aveAll ITA samples presented characteristics of an elastic artery composed of three main layers: (a) tunica intima, (b) tunica media and (c) tunica adventitia, as presented in As shown in According to the classification proposed by Kaufer et al. , 34 63.. Also, 1As presented in Next, we aimed at identifying clinical variables associated with the histomorphologic parameters, i.e. IW, MW and IMR. Hence, we constructed multivariable linear regression models that showed several significant relationships as presented in In regard to IW, a measure of intimal thickness, there was a positive association with (a) age  and (b) kidney function measured as eGFR  despite no significant correlations were seen. Although gender was also identified as predictor in the construction of the model, the association was not significant. Moreover, myocardial infarction history was associated with significantly increased IW .Concerning medial thickness, multivariable analysis showed a positive association with eGFR and nitrate medication and a negative association with smoking history. However, univariate analysis showed no significant difference or correlation between MW and these clinical variables.Considering IMR, age  was positively and significantly associated with this histomorphometric parameter, whereas the correlation with eGFR was not significant . The associations with gender, recent smoking history, arterial hypertension and myocardial infarction where not confirmed by univariate analysis.2 increase, non-significant) and myocardial infarction history (odds ratio = 4.81). As can be seen in Next, we aimed at identifying clinical predictors for intimal hyperplasia defined as IMR > 0.25 as proposed by Kaufer et al. . Using m2 = 0.410) and it accurately predicts the probability of intimal hyperplasia . The Hosmer-Lemeshow test for the model  did not show significant differences between the observed and the predicted results and the ROC curve retrieved an AUC of 0.809 , which is higher than the threshold of 0.700 proposed by Omar et al. [Relatively to the predictive performance of the model, 41.0% of the variability may be explained by the model . As shown in Next, we used the IMR grade classification proposed by Kaufer et al.  and modiAging has long been considered a major non-modifiable cardiovascular risk factor that influences the vascular structure and function . PreviouIn regard to female gender, no study has yet reported a significant association with intimal hyperplasia or other structural changes in ITAs , 30, 32.Myocardial infarction has been previously associated with endothelial dysfunction in rat thoracic aortas . To our Kidney function expressed as eGFR also emerged as clinical predictor of intimal hyperplasia (odds ratio = 1.03). Although such association must be carefully interpreted due to the non-significant result (P = 0.059), this result is not in accordance with recent reports by Kinoshita et al. who showed that chronic kidney disease defined by a decreased eGFR at the time of surgery is associated both with intimal hyperplasia  and endoSome limitations should be attributed to our study, namely the low sample size, the heterogeneity of risk factors and other clinical variables and the lack of ultrastructural assessment.In conclusion, our study showed preatherosclerotic lesions in ITA samples from patients undergoing coronary revascularization and that intimal hyperplasia is associated not only with classical cardiovascular risk factors such as age and gender, but also with other clinical variables, namely kidney function and myocardial infarction history.


The current study aimed to investigate the relationship between the severity of gastroesophageal reflux disease (GERD) according to the Los Angeles (LA) classification and esophageal motility using high-resolution manometry (HRM) and 24-hour esophageal pH monitoring.We examined 124 patients with GERD from January 2016 to June 2018. The LA classification of each patient was determined by endoscopy. HRM was performed by the intraluminal water infusion method. HRM and 24-hour esophageal pH monitoring parameters of the patients were studied and statistically compared.On HRM examination, GERD symptoms were found to be associated with worsened distal contractile integral (DCI), ineffective esophageal motility (IEM), peristalsis break (PB), lower esophageal sphincter (LES) pressure, and the 4-second integrated relaxation pressure (IRP4s) of LES pressure along with the grade of LA classification, especially in patients having grade C and D GERD who had transverse mucosal breaks. The 24-hour pH monitoring study revealed that patients classified as having grade C or D GERD had an esophageal pH < 4.0 for a longer time than those with grade O, A, or B GERD. Similar results were found regarding the duration of the longest reflux event, the number of reflux episodes longer than 5 minutes, and the number of reflux episodes. Patients with higher grade esophagitis had higher De Meester scores, which suggested greater esophageal acid exposure. Hiatal hernia (HH) was more closely related to LES pressure, IRP4s, and acid exposure, whereas DCI, IEM, and PB were not statistically different between patients with GERD with and without HH.Patients with severe esophagitis may have motor dysfunction not only in the LES but also in the esophageal body, with resulting increased esophageal acid exposure, which causes esophagitis. Low LES pressure might be the main reason that patients with HH develop esophagitis. GERD without HH may be due to a variety of motor dysfunctions. Hiatal hernia (HH) is a frequent finding in patients with GERD. A previous study has shown that HH significantly increases the incidence of GERD.Gastroesophageal reflux disease (GERD) is one of the most prevalent gastrointestinal diseases and is defined as a condition that develops when reflux of the stomach contents causes troublesome symptoms and/or complications. In this classification, the term “mucosal break” was introduced to describe mucosal lesions of the esophagus. It replaces traditional terms such as erythema, erosion, edema, and ulcer. A mucosal break was defined as an area of sloughing or erythema clearly demarcated from the adjacent normal-appearing mucosa. According to the LA classification, GERD is divided into 4 grades designated A through D.The Los Angeles (LA) classification of GERD was presented during the World Congress of Gastroenterology in Los Angeles in 1994. HRM has become increasingly important and is now the new worldwide standard for the clinical evaluation of esophageal motility disorders. Twenty four hour esophageal pH (24-hour pH) monitoring, an advanced technique used to study esophageal acid exposure for the previous 24-hour period, was used for the current study of patients with GERD.High-resolution manometry (HRM), capable of monitoring pressure from the pharynx to the stomach together with pressure topography plotting, has been used for clinical diagnosis of functional esophageal disorders and clinical research.To the best of our knowledge, the association of pathophysiological changes in patients with GERD, such as acid exposure, esophagus body motility disorder, and low LES pressure, with the severity of mucosal break according to LA classification, during endoscopy has not been established. We hypothesized that there is a relationship between the severity of GERD and the degree of esophageal disruption of motor function. To prove this hypothesis, we designed this study to analyze the severity of GERD in relation to the degree of esophageal motor function. In this study, HRM was combined with 24-hour pH monitoring analysis and a set of data was obtained to examine the relationship between the LA classification and esophageal motility vs acid exposure to investigate the possible mechanisms of mucosal injury in patients with GERD.22.1 the diagnosis of GERD is made using a combination of symptom presentation, objective testing with endoscopy, ambulatory reflux monitoring, and response to antisecretory therapy. Heartburn and regurgitation are the most reliable symptoms for making a presumptive diagnosis based on history alone. We retrospectively analyzed the data of patients with GERD who underwent endoscopic examination, ambulatory 24-hour pH monitoring, and esophageal HRM from January 2016 to June 2018 in the Second Hospital of Shandong University, China. The inclusion criteria were a previous diagnosis of typical reflux symptoms such as heartburn and reflux; response to a proton pump inhibitor; evidence of reflux esophagitis on endoscopic examination; and age 18 to 80 years. The exclusion criteria were previous gastrointestinal surgery, pregnancy, or current medications known to affect gastrointestinal motor function or acid secretion. If patients were taking acid suppression medical therapy daily, we performed all examinations after they had discontinued this medication for at least 72 hour; otherwise, they were excluded from the study. A total of 124 patients with GERD were enrolled in our retrospective study. This study was approved by our Institutional Review Board.According to the “Guidelines for the Diagnosis and Management of Gastroesophageal Reflux Disease (2013),”2.2Gastroscopy  was carried out to identify the mucosa status of the gastroesophageal junction and to exclude other organic diseases. Two expert endoscopists performed and investigated every endoscopic evaluation. We defined endoscopic GERD by the LA classification. According to the LA classification, GERD was divided into 4 grades designated A through D. These grades are defined as follows: Grade A: 1 or more mucosal breaks confined to the mucosal folds, each no longer than 5 mm; Grade B: at least 1 mucosal break more than 5 mm long confined to the mucosal folds and not continuous between the tops of 2 folds; Grade C: at least 1 continuous mucosal break between the tops of 2 or more mucosal folds but not circumferential and Grade D: 1 or more circumferential mucosal breaks. If there was no obvious mucosal injury, it was called non-erosive reflux disease, or Grade O.2.3,10 Subsequent research has improved the diagnostic accuracy and utility of classification, resulting in the Chicago Classification v3.0 (CC v3.0) update.,12 HRM was performed in the standard fashion with the patient in the supine position after at least a 6-hour fast, using the MMS HRM system . After transnasal placement of the manometry assembly, it was positioned to record pressure from the hypopharynx to the stomach. Our manometric protocol also included a 5-minute period to assess the basal sphincter pressure and 10 swallows of 5 ml normal saline.The classification scheme for HRM, termed the Chicago Classification (CC), has evolved from conventional criteria and has improved clinicians’ ability to make manometric diagnoses.2.4,13,14; in the CC v3.0 update, only large breaks were scored.,12 The distal contractile integral (DCI), which integrates the length of the smooth muscle esophagus (cm), contractile pressure (mm Hg), and contraction duration, is used to measure the robustness of the peristaltic contractions in the smooth muscle esophagus. Ineffective esophageal motility (IEM) has been re-defined in the CC v3.0 as a swallowing DCI of <450 mm Hg/s/cm.Analysis of manometric data describes the resting characteristics of the esophageal sphincters and esophageal motor functions initiated by swallowing. The upper esophageal sphincter (UES) and lower esophageal sphincter (LES) are easily identified as zones of higher pressure. The 4-second integrated relaxation pressure (IRP4s) algorithm averages the lowest of these pressures, the nadir pressure, over 4 continuous or discontinuous seconds. Peristaltic integrity is assessed by measuring gaps in the 20-mm Hg contour along the length of the esophagus, between the UES and LES. According to the Chicago classification, a small break measures 2 to 5 cm and a large break measures >5 cm2.5During the study, the patients consumed an unrestricted diet and took no medications that could interfere with the results. The 24-hour esophageal pH monitoring was conducted using an antimony pH catheter . The sensor was positioned 5 cm above the LES. Continuous pH recording was performed for 24 hours. was used to calculate the following distal pH variables: percentage of total time when pH was <4, longest reflux event, number of reflux events longer than 5 minutes, and number of reflux episodes in 24 hours. A De Meester score of >14.72 was considered to indicate significant esophageal acid exposure.The De Meester score2.6P value < .05 was considered to indicate significance.Data analysis was performed using SPSS version 16 software. We used analysis of variance for univariate analysis of single variables. A 33.1A total of 124 patients with GERD were enrolled in this study, and they were divided into 4 groups according to LA classification: grade A, 29 cases; grade B, 17 cases; grade C, 14 cases; and grade D, 7 cases. The 57 patients with no obvious mucosal injury were classified to have grade O. The age of patients in the different groups had no significant association with the grade of esophagitis. The incidence of HH significantly increased with a higher LA grade in patients with GERD , which suggested greater and longer esophageal acid exposure , suggesting greater esophageal acid exposure.Lundell found a significant relationship between the LA classification grade and the 24-hour esophageal acid exposure values. Our findings indicated that the decrease in resting LES pressure in patients with grades C and D can reasonably explain the occurrence of the continuous mucosal break between the tops of 2 or more mucosal folds.Severe esophagitis (LA grades C and D) with transverse mucosal breaks may cause motor dysfunction not only in the lower esophageal sphincter but also in the esophageal body, which results in longer esophageal exposure to acidic gastric contents, as a recent study demonstrated. The current study confirmed this finding. Low LES pressure was an important etiology of acid reflux, and esophageal motor dysfunction aggravated the acid reflux. Acid reflux and motor dysfunction induced and aggravated esophagitis.Impaired esophageal function has been shown to be the cause of esophageal mucosal damage.The current study found that HH was closely related to LES pressure, IRP4s, and acid exposure but had no obvious correlation with esophageal body motility. These results verified that low LES pressure might be the main reason that patients with HH experience esophagitis, whereas GERD without HH may be due to a variety of reasons including esophageal body dysmotility, low LES pressure, and acid exposure.There were also some limitations of this study. First, it was a retrospective study, and we will confirm the results in a prospective study. Second, some patients did not undergo all tests , which prevented them from being included in this study and reduced the sample size.In summary, we retrospectively reviewed the data for esophageal HRM and 24-hour pH monitoring of patients with suspected GERD to observe the possible influence of mechanisms of mucosal injury. We found that patients with severe esophagitis with transverse mucosal breaks may have motor dysfunction not only in the lower esophageal sphincter but also in the esophageal body, with resulting longer and greater esophageal exposure to acidic gastric contents. In patients with GERD and HH, low LES pressure might be the main cause, whereas GERD without HH may be due to a variety of motor dysfunctions.Conceptualization: Kongxi Zhu.Data curation: Lan Liu, Shuai Li, Kongxi Zhu.Formal analysis: Hongjuan Wang.Funding acquisition: Lan Liu.Investigation: Lan Liu.Methodology: Shuai Li, Kongxi Zhu, Weihua Yu.Project administration: Hongjuan Wang, Jianqiang Guo, Hongwei Gao.Software: Hongwei Gao.Validation: Jianqiang Guo.Writing – original draft: Lan Liu, Shuai Li.Writing – review & editing: Weihua Yu, Hongjuan Wang, Jianqiang Guo, Hongwei Gao.


Arterial hypertension (HTN) is commonly encountered by clinicians treating children with steroid sensitive (SSNS) and steroid resistant nephrotic syndrome (SRNS). Although the prevalence of HTN in SSNS is less documented than in SRNS, recent studies reported high prevalence in both. Studies have estimated the prevalence of HTN in different patient populations with NS to range from 8 to 59.1%. Ambulatory HTN, abnormalities in BP circadian rhythm, and measures of BP variability are prevalent in patients with NS. Multiple mechanisms and co-morbidities contribute to the pathophysiology of HTN in children with NS. Some contributing factors are known to cause acute and episodic elevations in blood pressure such as fluid shifts, sodium retention, and medication side effects . Others are associated with chronic and more sustained HTN such as renal fibrosis, decreased GFR, and progression of chronic kidney disease. Children with NS are more likely to suffer from other cardiovascular disease risk factors, such as obesity, increased measures of arterial stiffness , impaired glucose metabolism, dyslipidemia, left ventricular hypertrophy (LVH), left ventricular dysfunction, and atherosclerosis. Those risk factors have been associated with premature death in adults. In this review on HTN in patients with NS, we will discuss the epidemiology and pathophysiology of hypertension in patients with NS, as well as management aspects of HTN in children with NS. Nephrotic syndrome (NS) is one of the most common childhood kidney diseases worldwide, with a reported incidence of 2–16.9/100,000 children . MinimalNS in children is classified by The American Heart Association as a Tier II (moderate) cardiovascular risk factor . The etiIn this review, we examine the prevalence and pathophysiological factors that contribute to the development of HTN in children with NS. We focus our review on primary NS due to MCD and focal segmental glomerulosclerosis (FSGS). We discuss BP variability, circadian rhythms, and ambulatory blood pressure monitoring (ABPM) in this patient population, and highlight management considerations of HTN in children with NS.The reported prevalence of HTN in childhood NS varies widely. Studies have used different HTN definitions, included patients at different states of NS disease activity, and recruited heterogeneous NS populations with varying glomerular filtration rates (GFRs) receiving different anti-proteinuric and antihypertensive medications, which has made it hard to discern an accurate prevalence of HTN in children with NS.The International Study of Kidney Disease in Children (ISKDC) reported diastolic blood pressure > 98th %tile in 25/195 (12.8%) of children with Nil disease (MCD), and in 11/82 (13.4%) children with focal glomerular obsolescence (FSGS) , 7. UtilIn a study examining the prevalence of hypertension in MCD and other types of NS, Küster et al. reported the pre-steroid treatment (edematous phase) prevalence of HTN (defined as BP > 95% of age) in 57 children to be 95%. After complete remission, the prevalence of HTN in this cohort decreased to 19% . Kontcho2 drop from baseline eGFR) compared to the normotensive children. It is important to point out that this cohort was composed of children with impaired kidney function and only 13.8% of the cohort had glomerulonephritis/FSGS  in a cohort of 3,834 children registered in NAPRTCS to be 48%. In a subgroup of 546 children with glomerulonephritis/FSGS, the prevalence was 17.5%. Children with HTN were more likely to reach the study endpoints , consisting of 69 (46.9%) children with Minimal Change Disease (MCD), 49 (33.3%) with FSGS, 8 (5.4%) with IgA, 2 (0.04%) with Membranous Nephropathy, and 19 (12.9%) other glomerulopathy, showed that 69 (46.9%) had prior history of HTN or blood pressure ≥95th% at baseline visit. Authors reported no statistical difference in prevalence of hypertensive status between MCD (41%), FSGS (46.9%), and IgA (62.5%) subjects . This isGabban et al. prospectively examined a cohort of 71 children 1–18 years old: 33 (46.5%) with steroid sensitive NS, 28 (39.4%) with steroid dependent NS, and 10 (14.1%) with steroid-resistant NS. HTN was present at diagnosis in 5 patients (7%) with steroid sensitive NS, 9 patients (12.6%) with steroid resistant NS and 14 patients (19.7%) with steroid dependent NS. Family history of HTN was reported in 4 cases (5.6%). In over 7 months of follow-up, the overall prevalence of HTN increased to 39.4% .Inaba et al. followed 69 children 1–5 years of age with idiopathic steroid resistant NS for ≥4 years and found that HTN, defined as the need for anti-hypertensive therapy except when given for renoprotective purpose, affected 31.9% of patients .Sarkar et al. examined in-clinic and ABPM in 99 children with frequently relapsing NS. Clinic blood pressure was >95th percentile in 63 (63.6%) patients. Ambulatory HTN was present in 33.3, 16.1% had masked HTN, and 30.3 % had white coat HTN. Nocturnal non-dipping was seen in 72 and 55 patients had a high nocturnal systolic BP load. Twenty-one patients had increased left ventricular mass index (LVMI), of which 42.9% had ambulatory HTN, 14.3% had masked HTN and 28.6% patients had white coat HTN . These cP < 0.01). In children, greater BPV was an independent predictor of composite endpoint  and complete remission ; all P < 0.05 (Data from the NEPTUNE study showed BP variability (BPV) to be associated with the study pre-determined endpoints (complete remission and composite endpoint of ESRD or loss of ≥40% GFR). Greater systolic and diastolic standard deviation (SD) and average real variability were associated with greater hazard of reaching the composite end point in adults , increased measures of arterial stiffness , impaired glucose metabolism, and hyperlipidemia.Several studies have reported on the high prevalence of obesity and overweight in children with NS. In a 10 years follow-up study, Ishikura et al. reported 8% of children with frequently relapsing/steroid dependent NS to be obese . In a loHyperlipidemia, prevalent while children are having significant proteinuria, generally improves once NS is in remission. In a subset of NS patients with steroid resistance and/or frequent relapses, hyperlipidemia becomes a chronic condition. The disorders of lipid and lipoprotein metabolism in NS contribute to the development and progression of cardiovascular and kidney disease, and has been nicely reviewed elsewhere . StudiesPatients with NS have increased arterial stiffness; Cungor et al. found significantly higher carotid-femoral pulse wave velocity (PWV) in adults with NS compared to healthy controls. Mean arterial pressure was predictive of arterial stiffness . Rahul eCandan et al. demonstrated subclinical cardiovascular disease in 37 pediatric patients with steroid resistant NS. Compared with the controls, those patients had significantly higher mean aortic PWV, mean cIMT, and LVMI. Increased aortic PWV was noted in 5% of patients, increased carotid IMT in 22%, and increased LVM index in 19% while nocturnal dipping was absent in 67.6% .In summary, the prevalence of HTN in children with NS is highly variable. This is largely due to the dynamic nature of NS disease process. Patients may be in relapses or remission, some patients require treatment with IV albumin infusion and diuretics, patents can be on different and changing doses of medications known to affect BP, and occasionally patients may develop acute kidney injury (AKI) as a complication of NS. Furthermore, studies did not use the same HTN definition, included patients at different states of the NS disease process, included heterogeneous NS populations with varying GFRs and receiving different anti-proteinuric and antihypertensive medications. Although studies examining arterial stiffness in this patient population have reported conflicting results, the majority have signaled an increased arterial stiffness  and highlighted the need for larger prospective controlled studies to further understand the prevalence and the pathophysiology of arterial stiffness in children with NS.The pathophysiology of HTN in NS is complex, with multiple renal and extra-renal contributing factors. Renal factors include sodium retention, fibrosis/loss of GFR and progression of kidney disease, and recently, a feed-forward loop between albuminuria and blood pressure has been described . On the Sodium handling in NS not only has a central role in the development of edema but also plays an important role in blood pressure regulation. Two main hypotheses have been posited to explain the development of sodium retention in NS: the underfill and the overfill hypotheses . In the In response to volume expansion, atrial natriuretic peptide (ANP) facilitates diuresis by increasing the GFR while reducing sodium reabsorption in the renal tubules. Investigators have demonstrated a blunted response to elevated serum ANP levels in NS –35. ThisInvestigators have also examined the role of nitric oxide (NO) in sodium retention and the pathogenesis of HTN in animal models of NS. Ni et al.  demonstrMany of the commonly used medications in the treatment of NS are known to affect BP and contribute to the development of HTN. Calcineurin inhibitors induce nephrotoxicity and arterial HTN . VasoconSynthetic steroids  are central in the treatment regimens of patients with NS. These steroids have slightly different glucocorticoid and mineralocorticoid activities with predominantly glucocorticoid ; traditionally, it is their salt-retaining via mineralocorticoid-receptor properties that have been blamed for the effects on BP. The exact mechanism by which the glucocorticoid effect induces HTN is unclear. The high prevalence of HTN in steroid—treated patients has been reported even in therapy with predominantly glucocorticoid activity. Synthetic steroids may play a role in BP regulation via other mechanisms, such as fluid shifts from interstitial to the intravascular compartment, elevated plasma renin activity, increased sympathetic nerve activity, altered prostaglandin biosynthesis, enhanced vascular smooth muscle responsiveness to catecholamines and angiotensinogen II, impaired vasodilation, and nitric oxide synthase activity –47.The effect of steroid therapy on BP in children with NS is variable. Some NS patients may develop HTN or worsening of HTN with steroid therapy, while others have improved BP after achieving remission despite being on high dose steroid therapy. Klepikov at al. described 7/27 NS patients who developed HTN with steroid therapy. They were more likely to be hypervolemic with severe sodium retention and suppressed renin and aldosterone levels. On the other hand, normo- and hypo-volemic patients had a robust diuresis and natriuresis with steroid therapy . KontchoRecently, a study by Haas at al. supported the existence of a feed-forward loop between albuminuria and blood pressure and implied that albuminuria could increase the risk of cardiovascular disease through blood pressure. In their study, the authors first performed a genome-wide association study for albuminuria in a large cohort and identified 32 new albuminuria loci. Then they constructed an albuminuria genetic risk scores and tested the score for association with cardiometabolic diseases. Genetically elevated albuminuria was strongly associated with increased risk of HTN. The authors also found that the relationship between BP and albuminuria was bidirectional; genetically elevated albuminuria led to higher BP and higher systolic BP predicted an increase in albuminuria. These findings suggest that pathways leading to albuminuria such as endothelial dysfunction, impaired kidney function and decreased ability to excrete sodium may contribute to the pathogenesis of HTN. Although the study was not conducted in a NS cohort, it does represent an additional significant step toward our understanding of the effects of albuminuria (the primary protein lost in patients with NS) on BP and highlights the need for further studies to better understand this complex interplay between albuminuria and HTN .Uncontrolled HTN is a well-known cardiovascular disease risk factor; in adults it is associated with cardiovascular morbidity and mortality , 50. In Salt restriction and RAAS inhibition are considered integral parts of the management of children with proteinuria and both are known to have a blood pressure reducing effect. RAAS blockade is known to have a reno-protective effect in patients with glomerular disease; some studies have demonstrated a greater reduction of proteinuria with combination ACEi/ARB therapy. This reno-protective effect has been attributed to both BP reduction and BP independent mechanisms , 52. BotStudies examining the effects of blood pressure control in children with idiopathic NS are lacking. On the other hand, the benefit of strict BP control has been demonstrated in children with CKD. The ESCAPE trial (13.5% of study cohort had glomerulopathies) showed intensified blood-pressure control to confer a substantial benefit with respect to renal function .Aldosterone is a known contributor to the sodium retention in patients with NS . RecentlSparsentan, which combines endothelin receptor type A blockade with angiotensin II inhibition, has been shown to reduce proteinuria in patients with FSGS. It also had a greater effect on lowering BP compared with irbesartan .Diuretics play an important role in the management of children with NS . DiffereIn addition, while salt restriction and RAAS inhibition represent the key pillars in the management of the hypertensive child with proteinuria, other classes of antihypertensive medications have been used. While the use of beta blockers carries the theoretical benefit of lowering BP and indirectly inhibiting the RAAS without impairing the GFR, there are several reports suggesting worsened glycemic control with this class. Vasodilators, when used alone, may result in greater sodium retention. Unlike other vasodilating drugs, calcium channel blockers do not cause renal sodium and water retention, and do not cause hyperkalemia. One perceived advantage of CCBs may be their lack of nephrotoxicity, which makes this drug class an appealing choice for monotherapy or combination therapy in patients with kidney disease. However, the safety of some CCBs (dihydropyridine vs. non-DHP) in patients with proteinuric renal diseases (mostly adults patients with diabetic nephropathy) and renal insufficiency may be questioned because of reported untoward effects on urinary protein excretion , 63. FinGiven the heterogeneity in intravascular volume status of patients with NS (volume expansion and low renin in a subset of patients while others have intravascular depletion and elevated renin levels), the management of the hypertensive child with NS should aim at addressing possible contributing factors, taking into consideration the child's clinical examination, laboratory findings and current medications.HTN is prevalent in childhood NS. The increased risk of HTN lasts many years after stopping therapy and remission of the disease. Clinicians should continue to monitor blood pressure in children with a history of NS. Multiple factors are known to affect BP and contribute to the development of HTN in NS. Treatment of HTN should address the underlying disease pathophysiology and include lifestyle modifications. HTN and the cardiovascular disease risk in children with NS may be under recognized. 24-h ABPM can identify abnormalities in blood pressure measurements and patterns in this at-risk population. The majority of existing studies that examined the prevalence of HTN in patients with NS were observational and included heterogeneous NS patient populations, which makes it challenging to draw clear conclusions about the true prevalence and explains the substantial variability in the reported prevalence . HTN in Children with HTN and NS are at increased risk for dyslipidemia, LVH, left ventricular dysfunction, atherosclerosis, and aortic stiffness, all factors that have been associated with premature death in adults . Future All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


HDBR), fluid loading is often used with the intent of increasing plasma volume and maintaining mean arterial pressure during orthostatic stress. Nine men (aged 18–32 years) underwent three randomized trials with lower body negative pressure (LBNP) before and after: (1) 4‐h of sitting with fluid loading (1 g sodium chloride/125 mL of water starting 2.5‐h before LBNP), (2) 28‐h of 6‐degree HDBR without fluid loading, and (3) 28‐h of 6‐degree HDBR with fluid loading. LBNP was progressive from 0 to −40 mmHg. After 28‐h HDBR, fluid loading did not protect against the loss of plasma volume  nor did it protect against a drop of mean arterial pressure (P = 0.017) during LBNP . However, fluid loading did protect against the loss of stroke volume index and central venous pressure observed after 28‐h HDBR. Fluid loading also attenuated the increase of angiotensin II seen after 28‐h HDBR and throughout the LBNP protocol . Our results indicate that fluid loading did not protect against plasma volume loss due to HDBR or change blood pressure responses to LBNP. However, changes in central venous pressure, stroke volume and fluid regulatory hormones could potentially influence longer duration studies and those with more severe orthostatic stress.After exposure to microgravity, or head‐down bed rest ( After exposure to microgravity, astronauts experience many physiological changes such as reductions in skeletal muscle mass  28‐h of HDBR would result in a loss of plasma volume and therefore decreased stroke volume and central venous pressure with increased heart rate in response to an orthostatic challenge, and (2) the NASA fluid loading protocol would be ineffective against plasma volume loss and these hemodynamic changes during HDBR due to compensatory natriuretic/diuretic mechanisms and resetting of the central venous pressure operating point.Nine healthy men  between the ages of 18 and 32 years participated in this study that was approved by the Office of Research Ethics at the University of Waterloo. Informed consent and general health questionnaires were obtained prior to the first testing day. All participants were free from previously diagnosed cardiovascular disease and refrained from caffeine, alcohol, heavy exercise, and medication use for 24 h prior to testing.am and posttrial LBNP was performed at ~1:00 pm. The HDBR and seated trials were completed in random order with a minimum of 48 h between test dates. All nine men completed every trial.All trials began with measurements of plasma volume and a lower body negative pressure (LBNP) test (described below) followed by one of three randomized trials: (1) 4 h sitting with fluid loading (FL‐SEAT) to account for circadian and/or inactivity effects, (2) two different 28 h HDBR trials (6°) were conducted with (FL‐HDBR) or without fluid loading (NFL‐HDBR). Pretrial LBNP testing (“Control”) was performed at ~9:00 am, 1 h after eating a light breakfast which was kept consistent between testing days. During the 28‐h trials, participants also drank 5 mL/kg of water before sleep at 11:00 pm and after waking up at 6:30 am. Water intake was ad libitum from hour 0–1.5 for all trials, and from hour 24–25.5 for the HDBR trials. Other than the aforementioned fluid loads, no water was consumed from hour 1.5–4  or from hour 25.5–28 . Diet was kept consistent between HDBR trials , and the lunch provided was the same for all trials. Water intake was also ad libitum from hour 4–24 on the HDBR testing days, and the second HDBR trial was matched to the first HDBR trial to within 25%.Subjects consumed 5 mL/kg of water the night prior to testing and the morning before each trial to maintain hydration. Testing for all trials began at 7:00 Participants underwent lower body negative pressure (LBNP) as a model for orthostatic stress before and after sitting or bed rest. The participant lay supine in the LBNP chamber to the level of the iliac crest and the chamber was sealed using a neoprene kayak skirt and a belt. The LBNP protocol consisted of a 5‐min baseline period followed by 3 min of −10 mmHg, 5 min of −20 mmHg, 3 min of −30 mmHg, and 5 min of −40 mmHg. The LBNP was stopped if systolic pressure dropped to <70 mmHg, heart rate dropped by >25 bpm, or if the participant experienced nausea, dizziness, or light‐headedness. Blood samples were taken from 3.5 to 5 min of 0 mmHg, −20 mmHg, and −40 mmHg, thus necessitating the longer times at these levels of LBNP.The NASA fluid loading (FL) protocol was followed  was inserted into the antecubital vein of the right arm. Blood volume was determined in the seated position using the previously described carbon monoxide rebreathing technique . Beat‐to‐beat blood pressure was obtained using finger‐cuff plethysmography  and was calibrated to a manual measurement for each LBNP session. Heart rate was determined from the R‐R interval of a single lead electrocardiogram . Blood flow velocity from the aortic root and the brachial artery were measured using 2 and 4 MHz Doppler ultrasound probes, respectively . Stroke volume was determined by multiplying the cross‐sectional area and the blood flow velocity of the aorta. Stroke volume was normalized to body surface area to calculate stroke volume index. Cardiac output index was determined as stroke volume index multiplied by heart rate. Total peripheral resistance index was calculated as mean arterial pressure divided by cardiac output index. Brachial flow was determined from the cross‐sectional area and the blood flow velocity of the brachial artery. One minute averages were obtained for presentation.2O using the laser level and was converted to mmHg using 1cmH2O=0.7355 mmHg.Central venous pressure was measured throughout the LBNP test using the dependent arm technique  and a P17 transducer (1–5 MHz), respectively . All images were captured to video tape  and subsequently digitized . Diameters were measured using pixel coordinates of the proximal and distal vessel walls .g for 10 min at room temperature to obtain plasma . Plasma renin was measured by radioimmunoassay , vasopressin was measured by radioimmunoassay , angiotensin II was measured by enzyme immunoassay , atrial natriuretic peptide was measured by radioimmunoassay , and norepinephrine was measured by high performance liquid chromatography. Aldosterone was measured in serum by radioimmunoassay .Blood was obtained as previously described , and osmolality was measured by vapor pressure osmometry .P < 0.03). The three pretrial tests were averaged together for presentation in tables and figures as “Control”.The current study was designed to examine the effects of a fluid loading protocol on the consequences of 28‐h of head‐down bed rest (HDBR). There were three pretrial LBNP tests performed. All pretrial tests were compared using one or two‐way repeated measures ANOVAs as appropriate. The only variable showing a difference after comparing pretrial responses was stroke volume index where FL‐SEAT was significantly greater than NFL‐HDBR at −30 and −40 LBNP  followed by Tukey post hoc tests as appropriate. For hemodynamic analysis, we compared protocols using two‐way repeated measures ANOVAs (subject and protocol as repeated measures) followed by Tukey post hoc tests as appropriate. Analysis was completed using Sigmaplot 13.0 analysis software . P ≤ 0.005); however, the reduction of plasma volume due to 28 h HDBR was not different with fluid loading (P = 0.472). There was no difference between all trials for change in serum osmolality (P = 0.366) or change in serum sodium concentration . In both HDBR trials, participants had higher heart rate than the FL‐SEAT trial at −40 mmHg (P ≤ 0.01), and the NFL‐HDBR trial had higher heart rate than Control at −40 mmHg  with no differences between trials . The NFL‐HDBR trial had lower stroke volume index at all time points compared to Control (P = 0.037) and FL‐SEAT trials  nor were there any differences between trials . At 0 and −10 mmHg of LBNP, the NFL‐HDBR trial had lower central venous pressure compared to the Control and FL‐SEAT trials . At −10 mmHg, the NFL‐HDBR trial had higher total peripheral resistance index than the FL‐SEAT trial  nor were there any differences between trials  and compared to the Control, FL‐SEAT, and FL‐HDBR trials at −40 mmHg LBNP . There was an increase of renin due to −40 mmHg of LBNP in the Control (P = 0.044), NFL‐HDBR (P < 0.001), and FL‐HDBR (P = 0.030) trials; however, there was no increase in the FL‐SEAT trial , FL‐HDBR (P < 0.001), and FL‐SEAT (P < 0.001). Angiotensin II was higher at −40 mmHg compared to −20 mmHg of LBNP  and decreased at ‐40 mmHg in the Control trial (P = 0.028). Aldosterone was higher in the Control trial at 0 mmHg compared to the FL‐HDBR trial (P = 0.007) and higher in the NFL‐HDBR trial at −40 mmHg compared to the FL‐HDBR trial  nor were there any differences between trials , yet there were no differences between trials  nor were there any differences between trials , this was not great enough to have a significant effect on cardiac output index or mean arterial pressure. This increase of central venous pressure and stroke volume without a concurrent increase of plasma volume could be due to changes in venous tone and/or cardiac contractility. Importantly, Vernikos and Convertino  found thCowings et al.  recentlyOur research group previously found that 4‐h of sitting without fluid loading did not change blood volume, resting hemodynamics , or the hemodynamic response to LBNP in men  are well‐known to occur with HDBR and microgravity. After 4‐h of HDBR renin is significantly reduced  for lower resting aldosterone after seated fluid loading compared to Control. Norsk et al. . While our results could indeed indicate that fluid loading (in either posture) decreases aldosterone, the decrease could also be an effect of circadian rhythm since aldosterone is at its highest in the morning (Chiang et al. Oral fluid loading after 28‐h HDBR was found to suppress resting angiotensin II and aldosterone, which would effectively inhibit the expected water and sodium retention, further supporting Convertino's hypothesis of a lower central volume set‐point after exposure to microgravity (Convertino et al. k et al.  found a The increase of RAAS in response to LBNP was augmented after 28‐h of HDBR, and fluid loading attenuated the RAAS response in both the seated and HDBR positions. In contrast, Waters et al.  observedOur findings suggest that while fluid loading increased stroke volume and central venous pressure after HDBR, consistent with an increase in venous return, fluid loading did not increase resting plasma volume or mean arterial pressure. Further, fluid loading after HDBR did not prevent falls in mean arterial pressure during simulated orthostatic stress, possibly due to reduced activation of the renin‐angiotensin‐aldosterone pathway.The authors have no disclosures.


Introduction. The possible risk factors for chronic kidney disease in transplant recipients have not been thoroughly investigated after living-donor liver transplantation. Material and Methods. A retrospective cohort study of consecutive adults who underwent living-donor liver transplantation between May 2004 and October 2016, in a single center, was conducted. Kidney function was investigated successively for all the patients throughout the study period, with 12 months being the shortest follow-up. Postoperative renal dysfunction was defined in accordance with the Chronic Kidney Disease Epidemiology Collaboration criteria. The patients' demographic data, preoperative and intraoperative parameters, and outcomes were recorded. A calcineurin inhibitor-based immunosuppressive regimen, either tacrolimus or cyclosporine, was used in all the patients. Results. Of the 413 patients included in the study, 33 (8%) who survived for ≥1 year experienced chronic kidney disease 1 year after living-donor liver transplantation. Twenty-seven variables were studied to compare between the patients with normal kidney functions and those who developed chronic kidney disease 1 year after living-donor liver transplantation. Univariate regression analysis for predicting the likelihood of chronic kidney disease at 1 year revealed that the following 4 variables were significant: operative time, P < 0.0005; intraoperative blood loss, P < 0.0005; preoperative renal impairment, P = 0.001; and graft-to-recipient weight ratio (as a negative predictor), P < 0.0005. In the multivariate regression analysis, only 2 variables remained as independent predictors of chronic kidney disease at 1 year, namely, operative time with a cutoff value of ≥714 minutes and graft-to-recipient weight ratio as a negative predictor with a cutoff value of <0.91. Conclusion. In this study, prolonged operative time and small graft-to-recipient weight ratio were independent predictors of chronic kidney disease at 1 year after living-donor liver transplantation. Liver transplantation (LT) was approved as a definitive therapy for end-stage liver disease outside the experimental realm by the United States National Institute of Health (USNIH) in 1983. Since then, LT has altered the natural history of end-stage liver disease and is now considered the accepted therapy for a wide spectrum of previously fatal liver diseases [Serum bilirubin level, the international normalized ratio of prothrombin time, and serum creatinine level are the 3 components of the model for end-stage liver disease (MELD), which has served as the basis for liver allocation since February 2002. This has led to the expansion of the role of renal function assessment during the pretransplant evaluation and throughout the follow-up period [In the literature, kidney function abnormalities before transplantation are mostly associated with a higher possibility of intraoperative complications, infection, prolonged postoperative hospital stay, need for dialysis, and overall financial burden . MoreoveThe aim of this study was to assess the incidence and determine the possible risk factors of chronic kidney disease (CKD) in recipients 1 year after LDLT.This was a single-center retrospective cohort study. The research protocol was reviewed and approved by the Institutional Research Board and Ethical Committee of the Faculty of Medicine, Mansoura University (Protocol No. R/16.12.82). All data were collected and analyzed to ensure data integrity and patient privacy. The study was conducted in the Gastroenterology Center, Mansoura University, Egypt.Data of all the patients who underwent LDLT in Mansoura University Gastroenterology Center between May 2004 and October 2016 were collected from a prospectively maintained database. Data were analyzed to detect risk factors of kidney dysfunction after LDLT and its impact on 1-year graft and patient survival. The exclusion criteria were age of <18 years at the time of surgery, the need for preoperative renal replacement therapy (RRT), and/or death within the first 12 months of transplantation.Patient selection, preoperative assessment, and perioperative management were performed by the same transplant team, including experienced hepatologists, surgeons, anesthetists, and radiologists. The preoperative data included the patients' demographics, MELD score, basal serum creatinine level, preoperative GFR, liver function tests, Child-Pugh classification, presence of ascites, serum electrolyte levels, and urine analysis. Routine renal function assessment before surgery included serum creatinine level, blood urea nitrogen level, serum uric acid level, urinalysis, and renal ultrasonography. A nephrological consultation was requested for cases with elevated serum creatinine levels of ≥1.5 mg/dl, proteinuria, evidence of acute kidney injury (AKI), or abnormal renal ultrasonographic findings. Intraoperative records were screened for blood loss, hypotensive events, urine output, graft-to-recipient weight ratio (GRWR), warm ischemia time, cold ischemia time, duration of surgery, and vascular complications.The postoperative data included daily serum creatinine levels and examination for detection of possible postoperative events in form of sepsis, bleeding, bile leak, primary graft failure, delayed graft function, rejection, or ischemia-reperfusion injury. Kidney functions were assessed at the following time points: days 1, 2, 3, 7, and 14 after surgery, 1 month, 3 months, and 1 year after surgery. In case of diagnosed renal impairment, patients were subjected for further assessment.2) for at least 3 months or >60 mL/(min·1.73 m2), with parameters denoting kidney damage for at least 3 months. Postoperative renal dysfunction was defined according to the Chronic Kidney Disease Epidemiology Collaboration criteria [We did not care much about the transient early postoperative fluctuations of renal function parameters which were corrected by manipulations of immunosuppressive drugs, antibiotics, and fluid balance. CKD was defined as an estimated GFR (eGFR) of <60 mL/, divided twice daily, was administered. The trough level was kept between 150 and 200 μg/L in the first 6 months and then at 100-150 μg/L. Mycophenolate mofetil was used as a part of the initial therapy or as a maintenance immunosuppressive agent. It was given orally starting from the first postoperative day at a dosage of 2 × 15 mg/(kg·day).Most of the recipients had hepatitis C virus (HCV) infection; thus, our program adopted a steroid-free protocol apart from an initial dose of methylprednisolone administrated intravenously (IV) at a dose of 10 mg/kg of the recipient's weight, immediately after reperfusion of the graft. In addition, IV infusion of 20 mg basiliximab was given on reperfusion and on the fourth postoperative day. A calcineurin inhibitor- (CNI-) based immunosuppressive regimen, either tacrolimus or cyclosporine, was used in all the patients. Tacrolimus therapy was started within the first 12 hours after reperfusion at an oral dosage of 2 × 0.05 mg/(kg·day). The tacrolimus dose was adjusted to a target range of 10-15 μg/L) [In cases with preoperative renal insufficiency (RI) or perioperative AKI, administration of CNIs was delayed for 72 hours after surgery and then a lower target level was adopted  or the Mann-Whitney U test if not normally distributed. The receiver-operating characteristic (ROC) curve was plotted between the “sensitivity” (true positive rate) and “1- specificity”  across a series of cutoff points. The area under the ROC curve is considered as an effective measure of inherent validity of a diagnostic test. This curve is useful in finding the optimal cutoff point to minimize misclassification of diseased and nondiseased subjects. Predicting the likelihood of a dichotomous variable was performed using a logistic regression analysis.Data were entered and analyzed using the IBM-SPSS version 21 software. Categorical data were expressed as number (percentage) and compared using the chi-square test (or Fisher exact test). Quantitative data were initially tested for normality by using the Kolmogorov-Smirnov test, where data were considered normally distributed if theDuring the study period, 500 patients underwent LDLT at the Liver Transplantation Unit, Gastroenterology Center, Mansoura University, Egypt. Their mean age was 51 years . Most of the recipients were men . Their median MELD score was 15 . Most of our patients had chronic HCV infection , which was the main indication for LDLT in our study . The patients' demographics are shown in We excluded 87 patients because they were aged ≤18 years (n = 4), were subjected to renal replacement therapy before surgery (n = 2), had no complete follow-up after transplantation or had been referred to another hospital (n = 12), or died during the first 12 months after surgery (n = 69). Of the 413 patients, 33 (8%) developed CKD at 1 year after LDLT .The comparison between group I patients with normal kidney functions and group II patients who developed CKD 1 year after LT is shown in Cutoff values of ≥ 714 minutes for the operative time, ≥ 7750 ml for the blood loss and ≥ 0.91 for graft-to-recipient weight ratio as a negative predictor were calculated by the receiver-operating characteristic (ROC) curve analysis  to be usMultivariate Regression Analysis for Predicting the Likelihood of CKD at 1 Year. A binomial logistic regression was performed to ascertain the effects of preoperative RI, operative time (≥714 minutes), blood loss (≥7750 ml), and GRWR  on the likelihood that participants would have CKD at 1 year. One studentized residual had a value of 2.649 standard deviations, and two studentized residuals had a value of −2.749 standard deviations, which were kept in the analysis. χ2(4) = 119.599, P < 0.0005. The model explained that 58.9% (Nagelkerke R2) of the variance in RI at 1 year and correctly classified 95.4% of cases. The sensitivity was 97.6%; specificity, 69.7%; positive predictive value, 71.9%; and negative predictive value, 97.4%.The logistic regression model was statistically significant,Of the 4 predictive variables, operative time (≥714 minutes) and GRWR  were statistically significant  was 0.805 (0.8–0.9) in our group of patients who experienced renal dysfunction at 1 year as compared with 1.008 (0.9–1.2) in the other group, reaching a statistical significance (P < 0.0005). This finding is in accordance with a Korean study that included 284 cases of LDLT . This maWe observed that the operative time was more prolonged in the renal impairment group than in the healthy group, with a statistically significant difference. A logical explanation would be the relationship between surgical duration and clamping with frequent hypotensive episodes and the need for more norepinephrine and the use of fluids rich in chloride. This finding is in agreement with those reported by relatively recent studies –30. We aIn our study, the median (IQR 25–75) intraoperative blood loss volume was 8500 cc (7000–9750) in our group of patients who experienced renal dysfunction at 1 year as compared with 5400 cc (3700–7600 cc) in the other group, reaching statistical significance (P < 0.0005) . This fiIn addition, we did not observe a significant difference between the 2 groups in relation to the immunosuppression protocol, in contrast to other studies , 17. In In conclusion, our study demonstrated that preliminary data revealed that 4 factors predicted the occurrence of CKD 1 year after LDLT. These factors are preoperative renal impairment, GRWR, intraoperative blood loss, and operative time. In the multivariate regression analysis, only 2 factors remained as independent predictors of CKD at 1 year, namely, GRWR as a negative predictor with a cutoff value of <0.91 and prolonged operative time with a cutoff value of ≥714 minutes. The retrospective design of this study is an important limitation because of the possibility of missing data. Further larger studies are recommended to better understand the tolerability and safety of different immunosuppression protocols on the pathophysiology of graft-associated renal dysfunction with the possible factors related to poor outcome.