Machine learning methods may have better or comparable predictive ability than traditional analysis. We explore machine learning methods to predict the likelihood of acute kidney injury after liver cancer resection.This is a secondary analysis cohort study. We reviewed data from patients who had undergone resection of primary hepatocellular carcinoma between January 2008 and October 2015.The analysis included 1,173 hepatectomy patients, 77 (6.6%) of whom had AKI and 1,096 (93.4%) who did not. The importance matrix for the Gbdt algorithm model shows that age, cholesterol, tumor size, surgery duration and PLT were the five most important parameters. Machine learning technology can predict acute kidney injury after hepatectomy. Age, cholesterol, tumor size, surgery duration and PLT influence the likelihood and development of postoperative acute kidney injury. Acute kidney injury (AKI) is a common postoperative complication among surgical patients. The incidence of postoperative AKI accounts for 18%–47% of total hospitalized AKI patients . PostopeHepatectomy is the most common aggressive treatment for primary liver cancer. In order to control hemorrhaging during surgery, it is often necessary to block the hepatic portal. This can disturb liver microcirculation. Hepatic ischemia-reperfusion injury occurs after the hepatic portal is opened, releasing a large amount of inflammatory media and oxygen free radicals, thus inhibiting liver function. At the same time, due to surgical trauma, decreased circulation in the liver and kidneys, the release of granulocyte elastase and other factors, postoperative renal damage is also common . TherefoMany studies have used classical regression methods to identify risk factors and construct risk prediction models. However, a non-linear relationship between explanatory variables and outcome variables cannot be ruled out . Howevern = 11). As serum creatinine level examination was part of the routine preoperative assessment, we referred patients with serum creatinine >1.5 mg/dL or patients with a history of CKD, to a consulting nephrologist for preoperative risk stratification. The final cohort included 1,173 patients.This is a secondary analysis cohort study. After this retrospective observational study was approved by the ethics committee of the Asan Medical Center, data for patients who had undergone primary hepatocellular carcinoma resection between January 2008 and October 2015 were reviewed. Since this research was retrospective, informed consent was waived. All surgical procedures were performed continuously by the same surgeon. Among the 1,184 identified patients, those with stage 3 or later serious chronic kidney disease (CKD) were excluded by a consulting nephrologist  Guidelines. Postoperative AKI was defined as an increase in serum creatinine ≥0.3 mg/dL within 2 days after surgery, or an increase ≥1.5-fold in serum creatinine within 7 days after surgery .Patients’ baseline characteristics, laboratory variables and perioperative variables were collected. The baseline characteristics included age, sex, body mass index (BMI) and diabetes. Variables associated with tumor characteristics included, for example, alpha-fetoprotein. Laboratory data included hemoglobin, platelets, creatinine, white blood cell (WBC) count, glucose and total cholesterol. Intraoperative data included crysta and operative time.https://github.com/scikit-learn/scikit-learn))  was used for our analysis. The Scikit-learn package (Scikit Learning (-learn))  was usedThe sample was randomly divided into a training set and a test set, at a ratio of 7:3. The coefficients for the machine learning technique were trained with the training set and tested with the test set. Evaluation and comparison were completed with the prediction accuracy of a model constructed by machine learning and the area under the receiver operating characteristic curve. We also compared MSE, accuracy and recall rate. Missing data were estimated through multiple imputations.R is the recall and P is the precision.F1-Measure evaluation indicators are often used in information retrieval and natural language processing. They constitute a comprehensive evaluation index based on precision rate and recall rate, and their specific definitions are as follows: Precision rate indicates the proportion of correctly classified cases among the sample.Accuracy rate indicates the number of paired cases divided by the total number of cases.Recall rate indicates how many positive cases in the sample were predicted correctly.In machine learning, a random forest (forest) is a classifier that includes multiple decision trees. The categories of its output are determined by the modes of categories output by individual trees.The LightGBM (gbm) algorithm is a lifting machine learning algorithm. It is a fast, distributed and high-performing gradient lifting framework based on a decision tree algorithm. It can sort, classify, run regressions, and perform many other machine learning tasks.The construction of a decision tree model has two steps: induction and pruning. Induction is the step of constructing a decision tree (tr) by setting all hierarchical decision boundaries based on data at hand. However, the tree model is subject to severe over-fitting due to the nature of the training decision tree, and this is when pruning is required. Pruning is the process of removing unnecessary branch structures from the decision tree, simplifying the process of overcoming over-fitting and making it easier to interpret.Elevation is a machine learning technique that can be used for regression and classification problems. It produces a weak prediction model (like a decision tree) at each step and weights it into the total model. If the weak prediction model of each step generates consistent loss function gradient direction, then it is called gradient boosting (Gbdt).P < 0.040). Neither age nor tumor size showed statistically significant difference between the two groups (see The pandas_profiling package was applied to data exploration (see attachment oups see .In In Hepatectomy is an effective therapy for primary liver cancer. To block interoperative bleeding, it is often necessary to block the hepatic hilum. This can induce hepatic ischemia-reperfusion injury. It can cause not only liver dysfunction, but also kidney injury . At the Studies  have shoOngoing studies  also shoThe goal of logistic regression in statistics is different from that of logistic regression in machine learning. By default, there is a potential law in statistics. There are various restrictions in adjusting the model to meet the assumption conditions to find the potential law. However, machine learning is different; it is only concerned with the deviation between predicted and real values. Moreover, the integration algorithm adopted in this study considers more information gain when calculating. Thus, it naturally eliminates linear correlation, and also prevents non-linear correlation.In addition, variables are often screened with principal component analysis . HoweverThis study has several limitations. Firstly, not all confounding factors could be controlled, as this was a retrospective study. Secondly, caution should be exercised in interpreting the study’s results since it was a single-center study in which all surgeries were performed by an experienced surgeon. Thirdly, the machine learning techniques’ performance may vary when applied to larger samples with different covariate distributions. This study only performed internal, and not external, verification. In addition, different parameters in machine learning can result in different AUC values. Corresponding models are needed for different occasions according to needs, and should not excessively prioritize AUC values. Furthermore, an exorbitant AUC value may be unsuitable, as the accuracy, precision and recall rates may fall to unacceptable levels. This would make models unreliable in real world applications when the AUC value is high. Although most of the important reported variables are not clinically modifiable, appropriate measures could be taken to personalize prevention based on AKI risk.This study shows that all four machine learning techniques can predict AKI likelihood, among which GradientBoosting performs the best. At the same time, the Gbdt algorithm suggests that age, cholesterol, tumor size, surgery duration and PLT are the five most important weights for the likelihood of acute kidney injury after liver cancer resection.10.7717/peerj.8583/supp-1Appendix S1Click here for additional data file.10.7717/peerj.8583/supp-2Data S1Click here for additional data file.


Chronic kidney disease is a systemic disease affecting not only renal function, but also endocrine, cardiovascular, and skeletal muscle systems, with broad impact on functionality. Therefore, the assessment of body composition, peripheral muscle function, and exercise tolerance is also of great importance in this population. In addition, the development of reliable strategies that use feasible tools in clinical practice is of great importance in the functional diagnosis, clinical management and prescription of physical activity.To assess the relationship between phase angle and peak torque of knee extensors with the performance in six-minute step test of patients with chronic kidney disease undergoing haemodialysis.Observational and cross-sectional study at Haemodialysis Centre of Sírio-Libanês Hospital. The evaluations took place 3 days before the haemodialysis sessions. On the first day, patients underwent anthropometric evaluation and biochemical tests . On the second day, performed electrical bioimpedance and exercise tolerance assessed using the six-minute step test. On the last day, the evaluation of knee extensor muscles strength using isokinetic dynamometry was performed.Eighteen subjects were included, with a mean age of 62.3 ± 17.6 years. A positive linear correlation was observed between the phase angle, derived from the electrical bioimpedance, and the performance in six-minute step test in these patients. It was also possible to observe a linear correlation between phase angle and IGF1, handgrip strength, peak torque of knee extensors and quality of life questionnaire. The peak torque of knee extensors also presented a linear correlation with IGF1, the performance in six-minute step test and mal-nutrition and inflammation score.Phase angle and peak torque of knee extensors were correlated with the performance in six-minute step test. Therefore, the phase angle seems to be an important marker of reduced peripheral muscle function and exercise tolerance in haemodialysis patients.The online version contains supplementary material available at 10.1186/s12882-021-02256-7. Chronic kidney disease (CKD) is a multi-factorial syndrome that affects not only renal function, but also cardiovascular, respiratory, endocrine and musculoskeletal functions . In advaEvaluation of body composition in this population using electrical bioimpedance (BIA) is effective, the phase angle (PA) derived from BIA, which is commonly reduced in this population, appears to be a strong marker of reduction of peripheral muscle function, exercise capacity and mortality , 9. OtheMost of the available studies, correlated PA with mobility tests, however, mobility tests are not able to assess exercise tolerance, so their use and interpretation of results is limited . AnotherTherefore, studies that encourage the use of viable instruments for assessing exercise tolerance of HD patients and also that find new instrument options for simple assessments that can predict the exercise tolerance of these individuals are necessary. So far, we do not know of any study that has used the 6MST to assess exercise tolerance in this population and correlated its performance with the PA and peak torque of knee extensors. Therefore, the aim of this study was to evaluate the correlation between PA and peak torque of knee extensors with the performance in 6MST of CKD patients undergoing HD.This is a cross-sectional study that aims to assess the relationship of PA and peak torque of knee extensors with the performance in 6MST of patients with CKD undergoing HD. The sample was obtained consecutively at the HD Centre of the Hospital Sírio-Libanês, located in the city of São Paulo-SP-Brazil. The following inclusion criteria were considered: 1) patients with CKD undergoing diurnal HD; 2) patients older than 18 years old; 3) without pacemaker; 4) without cognitive or motor deficits that make evaluations unfeasible; and 5) practice regular physical activity less than twice a week. Exclusion criteria were as follow: 1) inability to perform assessments within technical acceptability criteria; and 2) cardiorespiratory instability during the tests. The study was previously approved by the Research Ethics Committee of the Sírio-Libanês Hospital , and written informed consent was provided by all participants. This study also complies with the standards of the Helsinki Declaration [All participants in the current study underwent an alternately three-day evaluation protocol, before the HD session. At the beginning of the assessments, personal and health information was collected from all participating individuals. The structure form and other questionnaires are available in the section of Collection of venous blood carried out by the sector’s nursing team, for further laboratory analysis of: urea, creatinine, IGF1, lactate, ferritin and albumin. The blood sample was taken from the HD catheter or fistula, therefore, there was no need for a new puncture for blood collection. The HD efficiency coefficient was calculated for all the patients according to Kidney Disease: Improving Global Outcomes (KDIGO)  recommenElectrical bioimpedance  was performed to evaluate body composition. Two self-adhesive patches were applied to the back of the hand and the foot, on the same sides, after cleaning the area with an alcoholic solution. To measure the cellular integrity we used PA values. After the measurement, with 50 Hz frequency, we assess the data using Fresenius Medical Care software , to calcTo measure the body nutrition and inflammation the Malnutrition and Inflammation Score (MIS) was applied. The score consists of ten items regarding clinical history, functional capacity, biochemical parameters and anamnesis. This instrument is a quantitative tool, with good reproducibility, capable of providing data, even in the face of slight changes , 23.Peripheral muscle function was assessed using three tools, as follows. The first one was the Medical Research Council (MRC) score, which consists of the assessment of six specific bilateral movements of upper and lower limbs . Then, hExercise tolerance was measured using the six-minute step test (6MST), which is an applicable and reliable field test . The steQuality of life was assessed with the Kidney Disease Quality of Life Short form (KDQOL-SF), this questionnaire is valid, adapted and reliable for the Brazilian population . It is ap < 0.05 was considered statistically significant.For statistical analysis, the Prism 8  was used. Data are presented as mean ± SD. The Shapiro–Wilk test was used to evaluate the normality of the data. To assess the relationship between variables, a linear regression was performed. According to the COSMIN guidelines, it is possible to perform the sample size calculations for expected correlations among measures . Sample A total of 40 patients were screened, but only 20 met the inclusion criteria. Of these 20 subjects, one refused and one dropped out during the evaluations Fig. . The maiBody mass index was normal in 44.5% of the patients and only 16.6% were obese. Comorbidities were collected from the patients during anamnesis. Most common comorbidities in these individuals were arterial systemic hypertension and diabetes mellitus.The baseline characteristics are described in Table Regarding PA, we observed an average value of 72.9% of the predicted. Peak torque of knee extensors had a predict average of 46.3 Nm. Average perfomance in 6MST was 71.2% of the predicted value for the studied sample. Individuals presented an average of 6.6 points in the MIS. For the HGS measurement, only three patients had venous artery fistula in the dominant limb, and thus the contralateral limb was evaluated. The results of body composition, peripheral muscle function and exercise tolerance are shown in Table p < .001).The linear regression curve between PA and the performance in 6MST is shown in Fig. p < .001)     x IGF1     x IGF1  in one of them. However, the prevalence of men is high in the HD Centre of the Sírio-Libanês Hospital, where the data were collected, as well as in the Brazilian Dialysis Census, which could explain this distribution.Another limitation is that it was not possible to control factors such as fasting before electrical bioimpedance, but we believe that this population has a rigorous routine including food intake schedules, reducing the chances of impact on evaluations. Likewise, individuals were not subdivided into sub categories for statistical analysis, wich may represent a limitation.The findings of this study reinforce the importance of continuous assessment of body composition, peripheral muscle function and exercise tolerance in HD patients. The 6MST is a feasible tool for assessing exercise tolerance in this population, especially in settings such as HD centers and hospitals.Moreover, the PA appears to be a strong marker of exercise tolerance in this population. Our results show that the use of PA could be an option for initial screening in environments where there is no physical therapist available, to refer these individuals early to a rehabilitation program.We conclude that the PA and peak torque of knee extensors have a correlation with the performance in 6MST in patients with CKD undergoing HD. Therefore, PA and peak torque of knee extensors can be used for indirect evaluation of the 6MST in clinical practice. We suggest that future studies assess the cutoff point of PA to determine the reduced exercise tolerance.Additional file 1.


In short-term studies, poor adherence to inhaled corticosteroids (ICS) has been associated with worse asthma control, but the association of long-term adherence and disease control remains unclear.To assess the relationship between 12-year adherence to ICS and asthma control in patients with adult-onset asthma.As part of the Seinäjoki Adult Asthma Study, 181 patients with clinically confirmed new-onset adult asthma and regular ICS medication were followed-up for 12 years. Adherence (%) to ICS was assessed individually ((µg dispensed/µg prescribed)×100) during the follow-up. Asthma control was evaluated after 12 years of treatment according to the Global Initiative for Asthma 2010 guideline.sd 12-year adherence to ICS was 63±38% in patients with controlled asthma and 76±40% in patients with not-controlled disease (p=0.042). Among patients with not-controlled asthma, those with lower 12-year adherence (<80%) had more rapid decline in forced expiratory volume in 1 s (−47 mL·year−1) compared to patients with better adherence (≥80%) (−40 mL·year−1) (p=0.024). In contrast, this relationship was not seen in patients with controlled asthma.Asthma was controlled in 31% and not controlled (partly controlled or uncontrolled) in 69% of the patients. Patients with not-controlled asthma were more often male, older, nonatopic and used higher doses of ICS than those with controlled disease. The mean±In adult-onset asthma, patients with not-controlled disease showed better 12-year adherence to ICS treatment than those with controlled asthma. In not-controlled disease, adherence <80% was associated with more rapid lung function decline, underscoring the importance of early recognition of such patients in routine clinical practice. 1 decline. Special emphasis should be placed on ICS adherence in subjects who do not have controlled asthma, as they seem to be at higher risk of developing fixed airway obstruction.Patients with not-controlled asthma and poor adherence show increased FEVhttps://bit.ly/2LOXL4f Successful asthma treatment plays a pivotal role in preventing exacerbations, enhancing patients’ quality of life and decreasing healthcare costs . Asthma To gain optimal benefits from pharmacotherapy, patients should be adherent to treatment, which has been shown to be often suboptimal , 8. Only1). In our recent study, poorer 12-year adherence was related to lung function decline in the long-term, but patients with good adherence used more add-on drugs, oral corticosteroid courses, had more hospital days and used more healthcare services, i.e. had features suggesting not-controlled asthma [Inadequate use of preventer medication is suggested to be related to decline in lung function, but there are no data on the association between long-term adherence and lung function decline stratified by asthma control. An Australian study  found acd asthma . Thus, wd asthma , 24.supplementary eTable 1). Patients with comorbidities or smoking history were not excluded. Study participants gave written informed consent to the study protocol approved by the ethics committee of Tampere University Hospital .The current study is part of SAAS, which is a prospective 12-year follow-up study of patients with diagnosis of new-onset adult asthma. All new adult (age ≥15 years) patients in Seinäjoki Central Hospital were included during the period 1999–2002. Diagnostic criteria, inclusion and exclusion criteria have been reported previously  . All asthma-related visits and medication information were collected for the whole 12-year follow-up period from medical records [The study was divided into two parts: baseline visit and 12-year follow-up visit . At the  records . To ensusupplementary material). Lung function measurement points were 1) baseline (diagnosis), 2) the maximum lung function (max0–2.5) during the first 2.5 years after diagnosis (after start of therapy) and 3) 12-year follow-up visit . Decline in lung function during the 12-year follow-up period was defined as change in pre-bronchodilator FEV1 from max0–2.5 to the 12-year time point.Asthma control was defined according to GINA 2010  and “note.g. one or two puffs twice daily), we interpreted that patients were adherent when the minimum ICS doses were dispensed. Adherence to ICS was determined as described recently [supplementary material). The 12-year adherence was calculated by comparing cumulative dispensed doses of ICS (µg) to cumulative prescribed doses of ICS (µg) and annual adherence by comparing yearly dispensed doses of ICS (µg) to yearly prescribed doses of ICS (µg). This adherence calculation combines elements from both MPR and PCD formulas  [The prescribed ICS dose in each patient for the 12-year period was calculated based on medication records, as described previously . Brieflyrecently , consistaterial) , 28 and aterial) .sd or median (interquartile range), but annual adherence is represented as mean±sem for clarity. Comparison of groups with ≥80% or <80% adherence to ICS were analysed by using independent samples t-test and Mann–Whitney U-test for normally and non-normally distributed continuous variables, respectively, and Pearson's Chi-squared or Fisher's exact test for categorical variables. To analyse differences in annual adherence over the 12-year period between controlled and not-controlled patients, annual adherence was plotted against time for individual patients, and mean area under curve values were compared using an independent samples t-test. A multivariable binary logistic regression analysis was performed to analyse factors associated with not-controlled asthma. A multiple linear regression analysis was performed to analyse factors associated with FEV1 decline, as described previously [FeNO) >20 ppb, ≥10 pack-years at follow-up, change (Δ) in FEV1 (baseline−max0–2.5) and average 12-year adherence (<80%) to ICS) were included in the analysis and outliers were removed to ensure homoscedasticity . A p-value <0.05 was regarded as statistically significant. Statistical analyses were performed using SPSS statistics software  and GraphPad Prism .The results are shown as mean±eviously . The corsupplementary eTable 2). At the follow-up visit patients had higher BMI, better lung function, lower blood eosinophil counts and fewer symptoms (Asthma Questionnaire 20) compared to the baseline visit (supplementary eTable 2).The majority of the study patients were female (60%), the average age was 59±13 years at the follow-up visit and half of the patients were current or ex-smokers  and not controlled (n=125). Group characteristics are shown in d asthma . Patientsd 12-year adherence to ICS was 63±38% in patients with controlled asthma and 76±40% in patients with not-controlled disease (p=0.042) .The mean±p=0.042) . Patientp=0.042) . Furtherp=0.042) . The asssupplementary eTable3). The patients having not-controlled asthma and ≥80% adherence had a higher number of asthma-related contacts with healthcare, higher blood neutrophil count and used more often long-acting β2-agonists (LABA) or leukotriene receptor antagonists  those having not-controlled asthma due to low adherence to ICS; and 2) those having not-controlled asthma despite good adherence to ICS. To see whether clinical differences exist between these groups, we evaluated asthma-related parameters in patients having not-controlled asthma and ≥80% or <80% 12-year adherence (agonists .1 reversibility (mL) than patients with <80% adherence and controlled asthma (supplementary eTable 4). In addition, patients with controlled asthma and ≥80% adherence reported using oral corticosteroids more often and had tendency to increased asthma-related visits to healthcare compared to <80% adherent patients.Assessment of patients with good asthma control revealed that patients with ≥80% adherence had lower BMI, higher total immunoglobulin E and peripheral blood neutrophil counts and lower FEV1) compared to patients with ≥80% adherence (p=0.024)  (1 (mL) decline.Next we evaluated the change in lung function in patients with controlled and not-controlled asthma and in groups of ≥80% and <80% 12-year adherence. The patients with not-controlled asthma and <80% 12-year adherence had more rapid decrease in lung function (FEVp=0.024) . Howeverp=0.024) . We carrax0–2.5) . After aversus 63%). Considering patients with not-controlled asthma, good 12-year adherence (≥80%) was associated with daily use of LABA and higher number of peripheral blood neutrophils and asthma-related contacts to healthcare. Importantly, in patients with not-controlled asthma, <80% adherence predicted more rapid lung function decline in adjusted analyses.In this study we evaluated both annual and 12-year adherence to ICS from diagnosis to 12-year follow-up visit in patients with adult-onset asthma and different categories of asthma control. The mean adherence to ICS was better in patients with not-controlled than controlled asthma . This difference was not seen in patients with controlled asthma. In addition, the observed difference may be clinically meaningful since the patients with adult-onset asthma rarely remit and a level of 7 mL·year−1 would correspond to 140 mL in 20 years and 210 mL in 30 years. Smoking and exacerbations are also important factors associated with the decline in lung function [1 decline in patients with not-controlled asthma. The finding underscores the importance of determining patients’ asthma control by GINA guidelines and to assess treatment adherence. Early recognition of patients with not-controlled  asthma and suboptimal (<80%) adherence should allow us to detect those patients who may be at risk of steeper lung function decline in the long term. Moreover, it may allow the opportunity to motivate them towards better adherence and thereby avoid undesirable outcomes in lung function. Conversely, this may help to identify patients whose asthma is not controlled despite high adherence to treatment. These patients may show non-type 2 inflammation, since they have higher blood neutrophil counts and current medications may not be effective enough to control their disease. These results further suggest that patients with late-onset asthma and insufficient therapeutic response need new treatment strategies and possibly other interventions such as support in smoking cessation and weight loss.When assessing lung function decline during 12-year follow-up in patients with not-controlled asthma, those with lower (<80%) 12-year adherence had more rapid decline in FEVIn the current study, medical records and pharmacy dispensation data were used in adherence calculations, and therefore some limitations must be addressed. The dispensed medication is not a guarantee of inhaler use, and therefore patient´s adherence to treatment may be overestimated. Although patients had guidance to correct inhaler use when medication was initiated, the correct inhaler technique could not be ensured. Furthermore, asthma control was measured at follow-up visit and not regularly during the follow-up. However, the current study with an exceptionally long follow-up period is based on objectively calculated adherence data, and assessment of asthma control includes lung function according to GINA guidelines , 8. It h1 during 12-year follow-up compared to patients with higher adherence (≥80%), which must be recognised to avoid negative consequences. In clinical practice, careful evaluation of patient´s asthma control and adherence to treatment enhances the recognition of those patients at risk of rapid lung function decline in the long-term.In conclusion, we combined, for the first time, long-term adherence to ICS with asthma control determined according to GINA guideline . The mea10.1183/23120541.00715-2020.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.00715-2020.SUPPLEMENTSupplementary material


Controversy remains whether white coat hypertension (WCH) is associated with renal prognosis in patients with chronic kidney disease (CKD).In the present multicenter, prospective study, we analyzed data of participants with CKD stage 1–4 from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE). WCH was defined according to two criteria as follows: A, clinical blood pressure (BP) ≥ 140/90 mm Hg and average 24-h ambulatory BP < 130/80 mm Hg; B, clinical BP ≥ 130/80 mm Hg and daytime ambulatory BP < 130/80 mm Hg. Renal outcome was defined as initiation of renal replacement therapy. The association of WCH with renal events was evaluated by Cox regression model.2 and urinary protein was 1.0  g/day. The overall prevalence of WCH was 4.7% and 16.6% according to criteria A and B, respectively. Incidence rates of renal events were 49.58 and 26.51 according to criteria A and B, respectively, per 1000 person-years during a median follow-up of 4.8 years. After full adjustment, WCH was associated with an increased risk of renal event  compared with patients with normal BP.A total of 1714 patients with CKD were included in the present analysis. The mean age of the population was 48.9 ± 13.8 years and 56.8% were men. The mean baseline estimated glomerular filtration rate (eGFR) was 52.2 ± 30.1 ml/min/1.73 mWCH is associated with a greater risk for renal events in non-dialysis dependent Chinese patients with CKD. Chronic kidney disease (CKD) is a leading public health challenges with a high prevalence of hypertension. Elevated blood pressure (BP) is one of the major contributors to progressive loss of renal function and development of cardiovascular disease (CVD) in patients with CKD . AccuratFour different BP patterns have been identified by a combination of arbitrary CBP and ABP cut-off values as normal BP (NT), white coat hypertension (WCH), masked hypertension (MH), and sustained hypertension (SH). In contrast to the definite prognostic value of MH and SH, the prognostic value of WCH is still controversial in primary hypertension and hypertensive patients with CKD. WCH is defined as the condition in which CBP, but not out-of-office BP, is elevated. In some studies, WCH was associated with a greater prevalence of target organ damage –6 and woThis study aimed to assess whether WCH is associated with the risk of ESRD in individuals with CKD.The Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) is a large, nationwide, multicenter, prospective cohort study of patients with CKD in which BP was evaluated on the basis of office and out-of-office measurements in a subgroup of patients at enrollment. The C-STRIDE included 39 hospitals located in 22 provinces of China. The design and method of C-STRIDE have been described in detail elsewhere –12. The CBP was measured with a mercury sphygmomanometer for three times after the participants had sat quietly for 5 to 10 min. Measurements were performed by an experienced nurse, who was unaware of the results of ABP readings. The mean of three consecutive readings was recorded as CBP for analysis. Twenty-four-hour ABP monitoring was performed via calibrated devices in each clinic center, with BP readings set at 15-minute intervals from 7:00 am to 10:00 pm and 30-min intervals from 10:00 pm to 7 am. Twenty-four-hour BP, daytime BP, and nighttime BP were defined as the mean value of BP readings during a 24-h cycle, daytime, and nighttime, respectively. Valid measurement was regarded as successful documentation of at least 70% of BP readings taken during a 24-h period. CBP and ABP measurements were taken from the non-dominant arm with an appropriate cuff size.We grouped the patients according to two criteria as follows. (1) In criterion A, conventional criteria based on CBP and 24-h ABP were used as follows: NT, with CBP < 140/90 mm Hg and 24-h ABP < 130/80 mm Hg; WCH, with CBP ≥ 140/90 mm Hg and 24-h ABP < 130/80 mm Hg; MH, with CBP < 140/90 mm Hg and 24-h ABP ≥ 130/80 mm Hg; and SH, with CBP ≥ 140/90 mm Hg and 24-h ABP ≥ 130/80 mm Hg . (2) In Renal events were defined as initiation of renal replacement therapy, including dialysis and transplantation. The end-point events were assessed every 3 months, either by phone interviews or routine clinical visits, until 31 December, 2017 in the current analysis. Suspected end-point events were ascertained by an independent end-point assessment committee. The follow-up protocol has been described in detail elsewhere .2), CKD stage 2 (60–89 ml/min/1.73 m2), CKD stage 3 (30–59 ml/min/1.73 m2), and CKD stage 4 (15–29 ml/min/1.73 m2) [A smoker was defined as a patient who was currently smoking or had ever smoked. Diabetes mellitus was defined as fasting plasma glucose levels ≥ 7.0 mmol/L or a self-reported history of diabetes or current use of anti-diabetes drugs. A history of CVD was defined as past occurrence of myocardial infarction, admittance to a hospital for congestive heart failure, or severe cardiac arrhythmia incidents . Dyslipidemia was defined by the presence of at least one of the following: serum total cholesterol level ≥ 200 mg/dL (5.2 mM/L), triglycerides ≥ 150 mg/dL (1.7 mM/L), low-density lipoprotein cholesterol ≥ 130 mg/dL (3.4 mM/L), and high-density lipoprotein cholesterol < 40 mg/dL (1.0 mM/L), or current use of lipid-lowering drugs. Anemia was defined as hemoglobin levels < 100 g/L. The glomerular filtration rate (GFR) was estimated from serum creatinine measurements and demographic characteristics by the Chronic Kidney Disease Epidemiology Collaboration equation . Patient1.73 m2) .T test, Mann–Whitney U test, and Chi square test for continuous variables and categorical variables.Continuous variables are presented as means ± standard deviations, while non-parametric variables are expressed as the median and interquartile ranges (IQR). Frequency and proportions were used for categorical variables. We used one-way ANOVA or the Kruskal–Wallis test to compare continuous variables and the Chi square test to compare categorical variables. Comparison between two groups was performed using the independent sample The incidence rate of renal events was calculated as the number of events per 1000 patient-years. The cumulative hazard ratio for four BP patterns was calculated by Kaplan–Meier (KM) curves. Log-rank tests were used to compare event rates among groups.A multivariable Cox proportional hazards regression model was used to investigate the associations between BP patterns and outcomes. Model 1 was adjusted for age (continuous) and sex , body mass index (continuous), smoking (yes vs. no), previous history of CVD (yes vs. no), diabetes (yes vs. no), antihypertension therapy (yes vs. no), albumin (continuous), dyslipidemia (yes vs no), anemia (yes vs no), causes of CKD , logarithm-transformed urinary protein (continuous), and eGFR (continuous). Further adjustment was performed with clinic systolic BP and 24‐h systolic BP (continuous) in model 2, with clinic systolic BP and daytime systolic BP (continuous) in model 3, and with clinic systolic BP and nighttime systolic BP (continuous) in model 4. Results of all regression models are reported as hazards ratios (HRs) and 95% confidence intervals (CIs). Missing data were filled with means for continuous variables with a normal distribution and with medians for continuous variables with a non-normal distribution, while categorical variables were filled with a separate category. The proportional hazards assumption was assessed by log-minus-log plots. Sensitivity analyses were performed by a competing risk model to decrease the competing risk of death before ESRD. The interactions of diabetes and glomerulonephritis (GN) with WCH on renal outcome were assessed. Additionally, stratified analysis (patients with diabetes vs. patients without diabetes) was performed.P < 0.05 was considered statistically significant.Data were analyzed using SPSS software  and SAS System version 9.4 . A two-sided A total of 1714 patients with CKD were included in the present analysis. The mean age of the study population was 48.9 ± 13.8 years and 56.8% were men. Notably, 24.7% of patients had diabetes and 9.0% had a prior history of CVD. A total of 76.7% of patients were taking at least one antihypertensive medication. According to criterion A, there were 672 (39.2%), 81 (4.7%), 529 (30.9%), and 432 (25.2%) patients in the NT, WCH, MH, and SH groups, respectively. The corresponding prevalence changed to 21.4%, 16.6%, 13.4%, and 48.6% according to criterion B in the NT, WCH, MH, and SH groups, respectively  for renal events. During this period, 286 participants experienced renal event, corresponding to an incidence rate of 37.68 per 1000 person-years. The incidence rate for each BP pattern is shown in Table P for criterion A: 0.73 and P for criterion B: 0.15, respectively). Stratified analysis of the effect of WCH on renal event in patients with diabetes compared with those without diabetes was shown in Additional file Patients in the WCH, MH, and SH groups had a higher incidence rates of renal events compared with those in the NT group Fig. . Cox anaIn the present prospective cohort study, patients with CKD stages 1–4 were enrolled and followed for a median duration of 4.8 years to investigate the role of the BP pattern for renal prognosis in patients with CKD. We found that WCH, in addition to MH and SH, were associated with an increased risk for renal events in non-dialysis dependent Chinese patients with CKD. This finding suggests that WCH should not be regarded as irrelevant in clinical practice.With the introduction of ABP monitoring to clinical practice, four BP patterns have been defined according to the combination of both CBP and ABP readings. The prevalence of WCH in patients with CKD varied in different studies, ranging from 2.3% in the African American Study of Kidney Disease and Hypertension (AASK) study , 11% in Unlike MH and SH, which have been proven to have adverse effects on prognosis in patients with CKD, the effect of WCH on long-term prognosis of patients with CKD is still controversial , 24. A sPatients with WCH had significantly higher clinical and out-of-office BP values compared with normotensive patients in the present study. The relationship between BP and outcomes shows a continuous relationship, even in the normotensive range. Comparatively small increases in mean BP are associated with substantial differences in risk. Cha et al. showed that 24-h ABP progressively increased with the categories of NT to WCH to MH to SH in 1317 patients with CKD , which aIn addition to the different criteria of the definition of WCH, some intrinsic factors of each study , might also contribute to the inconsistency in WCH values on prognosis.  For instThis study has some limitations. First, ABP monitoring was only performed once at enrollment. The BP pattern might have changed during follow-up as found in the ELSA study.  FurthermIn conclusion, our study provides evidence that WCH is associated with a greater risk for renal events in non-dialysis dependent Chinese patients with CKD. Future prospective, randomized clinical trials are required to clarify whether treating WCH can delay progression of renal disease in patients with CKD.Additional file 1: Table S1. The inclusion and exclusion criteria of C-STRIDE study. Table S2. Comparison of baseline characteristics between included and excluded participants in the current study. Table S3. Baseline characteristic of participants according to different BP patterns diagnosed by criterion B. Table S4. Hazard ratio for renal events by different BP patterns in competing risk model. Figure S1. Stratified analysis of the effect of WCH on renal event in patients with diabetes compared with those without diabetes.


Children with Fontan circulation are at risk of developing hepatic fibrosis/cirrhosis. Reliable noninvasive monitoring techniques are lacking or under development.To investigate surrogate indicators of hepatic fibrosis in adolescents with Fontan circulation by evaluating hepatic magnetic resonance (MR) T1 mapping and extracellular volume fraction measurements compared to US shear-wave elastography.We analyzed hepatic native T1 times and extracellular volume fractions with modified Look-Locker inversion recovery. Liver stiffness was analyzed with shear-wave elastography. We compared results between 45 pediatric patients ages 16.7±0.6 years with Fontan circulation and 15 healthy controls ages 19.2±1.2 years. Measurements were correlated to clinical and hemodynamic data from cardiac catheterization.P<0.001) and higher extracellular volume fractions (47.4±5.0%) than in controls . Liver stiffness was 1.91±0.13 m/s in patients vs. 1.20±0.10 m/s in controls (P<0.001). Native T1 times correlated with central venous pressures . Native T1 was not correlated with elastography in patients  or controls . Extracellular volume fraction was correlated with elastography in patients  but not in controls .MR mapping was successful in 35/45 patients, revealing higher hepatic T1 times (774±44 ms) than in controls  contains supplementary material, which is available to authorized users. The Fontan operation was introduced more than 40 years ago as a lifesaving treatment for univentricular-type heart defects. This procedure creates an artificial circulation with two serial capillary beds by connecting the caval veins to the pulmonary artery . In the Noninvasive methods for monitoring liver fibrosis are lacking or under development. Liver biopsy is considered the gold standard method for assessing other structural liver diseases. However, the heterogeneous distribution of fibrosis in Fontan liver disease often results in non-representative biopsy samples , 6–9; heA promising new technique, MR T1 mapping with calculation of extracellular volume fraction, is routinely used in the detection of myocardial fibrosis –12. ReceClinicalTrials.gov (NCT02378857). Written informed consent was obtained from all patients, control individuals, or their caretakers.This prospective study was approved by the regional institutional ethics board and was compliant with Health Insurance Portability and Accountability Act. It was registered at Adolescents with Fontan circulation, ages 15–17 years, were recruited from a follow-up program conducted at Oslo University Hospital that consisted of a comprehensive diagnostic workup prior to transition to adult care. These patients were consecutively included from March 2015 through December 2018. During a 4-day hospitalization, patients underwent a structured diagnostic workup, including MR of the liver/spleen and US elastography, performed on two consecutive days. Hepatic serological markers were sampled on Day 2, and cardiac catheterization was performed under general anesthesia/deep sedation on Day 3. Demographic, clinical and catheterization data were recorded. Catheterization data included central venous pressure measured in the conduit/inferior caval vein, liver vein wedge pressure, and peak systolic and end-diastolic ventricular pressures..For the control group, we recruited healthy individuals with a hospital-wide and internet-based announcement, by communications among hospital employee families and via social networks. For ethical reasons, the controls had to be ≥18 years to consent to contrast agent exposure; thus, the age range was different between study groupsChildren with contraindications for MR or non-diagnostic T1 mapping were excluded from this examination and further analyses. The presence of ascites was recorded. After a 3-h fast, patients and controls underwent identical scanning protocols with a 1.5-tesla (T) system . A coronal T2 half-Fourier single-shot turbo spin-echo and axial 3-D T1-W volumetric interpolated breath-hold examination were performed over the liver. An axial modified Look-Locker inversion recovery, with inline motion correction, was performed in the liver mid-section. Both exams were performed before and 15 min after intravenously administering 0.2 mmol/kg gadoterate meglumine . Before contrast injection, an axial T2* gradient multi-echo sequence was performed. Scan parameters and MR protocol details are shown in Online Supplementary Material 1.2) were placed in the periphery of both liver lobes and one was placed in the spleen (2.5–3.0 cm2) . The analysis was repeated 4 weeks later. To evaluate interobserver variation, a second radiologist with 15 years of experience performed an assessment (C.dL.).Ultrasound 2-D shear-wave elastography was performed with a LogiqE9  with a curved 1- to 6-MHz probe and fixed parameters. All subjects fasted for 3–4 h and rested for 10 min prior to elastography, and we recorded alcohol consumption in the previous week. This was to avoid falsely increased stiffness measurements from increased hepatic blood flow. Elastography was performed by two radiologists . With the subject in a supine position, we achieved velocity sampling in the right liver lobe with an intercostal approach. Measurements were collected from a circular region of interest, 1 cm in diameter, at a depth of 3–4 cm from the liver surface. The median of five measurements (m/s) was recorded, with an interquartile range/median <30% . Metabolic liver dysfunction was indicated by values outside the normal range for a given age for unconjugated bilirubin, bile acids, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and lactate dehydrogenase.t-test or Wilcoxon rank sum test, as appropriate for continuous variables, and with Fisher exact tests for categorical variables.Continuous variables are presented as means ± standard deviation (SD), for normally distributed data, or as medians and ranges for skewed data. Categorical variables are expressed as counts and percentages of the total. Groups were compared with the Student’s P-values <0.05 were considered statistically significant. Intra- and interobserver agreement were assessed with Bland–Altman analyses [We assessed correlations between continuous and categorical parameters with univariate regression analyses. Two-sided analyses ; resultsn=8) or claustrophobia (n=2).This study included 45 adolescent patients  and 15 healthy young adults . In 10 patients, MR could not be performed because of incompatible pacemaker devices or leads .Nineteen adolescents had a dominant morphological single right ventricle, and 24 had a dominant morphological single left ventricle. Two had two functionally connected ventricles; these patients were excluded from the comparison of liver analyses between patients with different ventricular morphologies. Thirty-five participants underwent successful MR examinations without complications.Native T1 times and hepatic extracellular volume fractions were significantly increased in the Fontan group compared to controls Table ; Fig. 3.P<0.001; Table Forty-five patients and 15 controls with no recent history of alcohol consumption underwent elastography. One patient could not hold the breath and was excluded because of unreliable measurements. Liver stiffness was elevated in all patients; the median velocity was 1.91±0.13 m/s in patients and 1.20±0.10 in controls ; the interobserver bias was 2.2% (coefficient of variation: 1.6). Controls had an intraobserver bias of 0.3% (and coefficient of variation: 0.6) and interobserver bias of 1.4% (coefficient of variation: 1.2) , hepatic T1 times  and spleen extracellular volume fraction  or hepatic T1 times . The hepatic native T1 time was significantly correlated with central venous pressure  and liver vein wedge pressure . The hepatic extracellular volume fraction and elastography were not correlated with central venous pressure  or liver vein wedge pressure .In adolescents with Fontan circulation, the hepatic extracellular volume fraction was correlated with elastography  and liver vein wedge pressure .For patients, the native splenic T1 and extracellular volume fraction were positively correlated with central venous pressure  Because of ethical considerations regarding informed consent, control individuals were slightly older than the patients, which might have influenced the normal values. (2) Only 35/45 patients could undergo MRI; thus, we could only compare the two techniques in 35 patients. (3) Elastography of the spleen was not accessible because artifacts made the measurements unreliable. (4) Liver biopsy was not performed because of the invasiveness and the high probability that samples would not be representative of the heterogeneous liver tissue in the adolescents with Fontan circulation. (5) The dual blood supply to the liver  provided predominantly venous oxygenation . BecauseWe compared hepatic MR relaxometry and US shear-wave elastography in adolescents with Fontan circulation. Both methods showed elevated markers suggestive of diffuse hepatic fibrosis or congestion. However, the detected changes differed between the methods; hence, they cannot be considered interchangeable. MRI appeared to be superior to US elastography because it provides a more global liver assessment, and, in addition, T1 mapping was closely related to central venous pressure. However, longitudinal, standardized studies with specific techniques for distinguishing congestion/fibrosis might reveal objective MR evidence of the development of Fontan-associated liver disease.ESM 1(DOCX 26423 kb)


We found orthostatic hypotension occurred within each level and AIS classification (n = 36). Moreover, 45 individuals with chronic SCI experienced a drop in blood pressure that did not meet the criteria for orthostatic hypotension, but was accompanied by dramatic increases in heart rate, reflecting orthostatic intolerance. A cluster analysis of hemodynamic response to a seated position identified eight distinct patterns of interaction between blood pressure and heart rate during orthostatic stress indicating varied autonomic responses. Algorithmic cluster analysis of heart rate and blood pressure is more sensitive to diagnosing orthostatic cardiovascular dysregulation. This indicates blood pressure instability cannot be predicted by level and completeness of SCI, and the consensus statement definition of orthostatic hypotension is insufficient to characterize the variability of blood pressure and heart rate responses during orthostatic stress. Both blood pressure and heart rate responses are needed to characterize autonomic function after SCI.Unstable blood pressure after spinal cord injury (SCI) is not routinely examined but rather predicted by level and completeness of injury . Our aim was to investigate hemodynamic response to a sit‐up test in a large cohort of individuals with chronic SCI to better understand cardiovascular function in this population. Continuous blood pressure and ECG were recorded from individuals with SCI ( The definition of orthostatic hypotension, based solely on an absolute decrease in blood pressure, is insufficient to characterize the adverse blood pressure and heart rate responses during orthostatic stress. Algorithmic cluster analysis of heart rate and blood pressure interaction is more sensitive to diagnosing orthostatic cardiovascular dysregulation. These results demonstrate that cardiovascular instability cannot be predicted by level and completeness of SCI, and both blood pressure and heart rate responses are needed to characterize autonomic dysfunction after SCI.  Unstable blood pressure after spinal cord injury (SCI) is not routinely examined but rather predicted by the neurological classification of SCI: individuals with high level and complete injury are anticipated to experience more frequent and severe blood pressure instability compared with lower level and incomplete SCI.Orthostatic hypotension, that is, a drop of at least 20 mmHg systolic blood pressure or 10 mmHg diastolic blood pressure when assuming an upright position, is a manifestation of this impairment.An unexpected finding was that completeness of injury did not predict the incidence of orthostatic hypotension.Additionally, the definition of orthostatic hypotension based solely on an absolute decrease in blood pressure is insufficient to characterize the adverse blood pressure and heart rate responses during orthostatic stress.Algorithmic cluster analysis of heart rate and blood pressure is more sensitive to diagnosing orthostatic cardiovascular dysregulation.These results demonstrate that cardiovascular instability cannot be predicted by level and completeness of SCI, and both blood pressure and heart rate responses are needed to characterize autonomic dysfunction after SCI.1Severe spinal cord injury (SCI) causes cardiovascular dysregulation resulting in blood pressure instability, which persists throughout life. Persistently low resting blood pressure and heart rate, autonomic dysreflexia, and orthostatic hypotension, among other manifestations  to an orthostatic provocation  in a large cohort of individuals with SCI. The sit‐up test was developed for use in populations that are unable to stand  in Bronx, NY, the Kessler Foundation (KF) in West Orange, NJ, and the Kentucky Spinal Cord Injury Research Center at the University of Louisville (UofL), Louisville, KY. A total of 207 individuals were recruited for assessments including 159 individuals with SCI and 48 age‐matched non‐injured controls. Participants provided a self‐reported medical history and physical examination or received a medical examination onsite. Inclusion criteria for all individuals were: (a) stable medical condition without current illness or infection, (b) greater than 18 years of age, (c) no history of cardiovascular or pulmonary disease unrelated to SCI, Parkinson's disease, or diabetic autonomic neuropathy. Additional inclusion criteria for participants with SCI were: (a) sub‐acute and chronic duration of injury (>6 months), (b) non‐ventilator dependent, and (c) non‐ambulatory. The SCI cohort included 85 individuals with cervical injuries (C2–C8), 21 individuals with high thoracic injuries (T1–T5), and 53 individuals with low cord injuries (T6–L3), with severity classified by the American Spinal Injury Association Impairment Scale (AIS), grade A‐D. Institutional Review Boards at each site reviewed the study protocol and consent documentation for human subject protection and granted annual approval from 2010 to 2018. All participants signed informed consent prior to enrollment in study procedures.2.2To limit the variability from the effects of medication on blood pressure and heart rate response to the sit‐up test, medications were stopped for the timespan calculated to approximate five half‐lives, whenever possible , allowing them to be adequately removed from the body. Medications that were requested to be stopped included (a) anticholinergics ; (b) sympathomimetics (α‐ and β‐agonists); (c) parasympathomimetic agents; (d) short‐acting α‐ and β‐antagonists; and (e) analgesics including opioids ; respiratory bands or electrodes placed in the 5th intercostal right and left mid‐axillary lines to monitor respiration ; photoplethysmography to monitor continuous blood pressure from the index finger, middle finger, or thumb ; and brachial blood pressure .n = 83, NI: n = 28) and for 15 min at UofL ; data collection was on‐going at JJP and KF when UofL was added as a study site and the test duration was lengthened in order to observe the prevalence of delayed orthostatic hypotension. If any research participant had symptoms of pre‐syncope while seated the individual was immediately returned to the supine position and the assessment was terminated. Blood pressure and heart rate signals were sampled at 500 Hz (JJP/KF) or 1,000 Hz (UofL) and stored for offline analysis . Discrepancies in the sample rate and acquisition software are due to timeline differences between institutions that changed software availability upon data collection.Individuals lay in the supine position and, once acclimated, 5 min of resting data were recorded. Individuals were then passively moved into the seated position with the hips and knees at a 90° angle and the back, shoulders, and legs supported with feet placed on a footplate. Beat‐to‐beat blood pressure and heart rate were recorded continuously during the transition and throughout the seated position lasting for 4 min at JJP and KF  and compared with the non‐parametric Sign Rank Sum test (2 groups) or Kruskal‐Wallis test (3 or more groups). Categorical variables are summarized as frequency count with percentage and compared using Chi‐square tests or Fisher's exact test. All tests were 2‐tailed with a significance level of 0.05. Statistical analyses were performed in SAS . When the site was added as a covariate to the statistical models, it did not affect the prevalence of orthostatic hypotension nor change the cluster analyses as the identified patterns presented in all centers, indicating the differences between protocols did not affect cardiovascular response to the sit‐up test.Demographics  and medication use are compared between SCI and non‐injured groups and within SCI subgroups (with and without orthostatic hypotension and across clusters); while age at injury, duration of injury, level of injury and severity of injury (AIS Grade A‐D) are only compared within SCI subgroups (by the incidence of orthostatic hypotension and by cluster). Continuous variables are presented as mean ± standard deviation  and AIS C  and high thoracic  SCI as compared with low cord injury  and AIS C  that did not meet the criteria for orthostatic hypotension as defined by consensus statement still had a drop in systolic blood pressure between 10 and 20 mmHg and/or a drop in diastolic blood pressure between 5 and 10 mmHg still experienced a robust increase in heart rate (>10 BPM). Those individuals with SCI that did meet the criteria for having orthostatic hypotension also experienced profound increases in heart rate. These adverse blood pressure and heart rate responses occur within all AIS classifications and injury levels except for individuals with AIS D low cord injury.Dramatic increases in heart rate that accompanied decreases in systolic and diastolic blood pressure after the assumption of an upright position were evident within each level and severity of injury Figure . Individ3.4, Table The hierarchical cluster analysis  who are non‐ambulatory is low (23%) and not related to the severity of their sensory‐motor deficits, although higher in those with cervical and high thoracic injuries compared with low cord injuries. To date, this is the largest cohort of individuals with chronic SCI who are non‐ambulatory to assess cardiovascular orthostatic regulation in response to a sit‐up test. Additionally, factors known to affect cardiovascular dysregulation in the general population were not significantly associated with orthostatic hypotension in individuals with SCI. Dramatic increases in heart rate accompanied decreases in systolic and diastolic blood pressure upon the assumption of an upright position within each level and severity of the injury group, indicating a much more profound cardiovascular deficit than discovered solely by the restrictive definition of orthostatic hypotension as defined by the consensus statement. When considering the interrelationship between systolic blood pressure, diastolic blood pressure, and heart rate upon the assumption of an upright position with hierarchical cluster analysis, we found delineated hemodynamic responses that more effectively identify the prevalence of cardiovascular dysregulation in the chronic SCI population. Further, characterization of cardiovascular orthostatic dysregulation based solely on the threshold of systolic blood pressure and/or diastolic blood pressure falls, as in the consensus statement on the definition of orthostatic hypotension, does not fully represent the degree of hemodynamic instability that occurs in chronic SCI. The diverse patterns of blood pressure and heart rate response to orthostasis in individuals with chronic injury suggests that the interaction between blood pressure and heart rate should be considered in understanding autonomic dysfunction after SCI and its consequences on morbidity and quality of life.The prevalence of orthostatic hypotension as defined by the consensus statement  in individuals with cervical SCI compared with thoracic SCI  were identified and mitigated before and throughout each assessment. Given the orthostatic provocation and the fact that the increases in blood pressure were largely in participants with lesions below T6, these responses may reflect an emerging phenomenon, orthostatic hypertension, which may have adverse effects on cardiovascular health (Fessel & Robertson, The understanding of cardiovascular dysfunction by the diagnosis of orthostatic hypotension defined by the consensus statement is not sufficient to fully characterize the prevalence or the presentation of hemodynamic responses. Moreover, including heart rate in these interactions lends insight into autonomic control of the entire cardiovascular system after SCI, not just blood pressure regulation. Patterns of blood pressure and heart rate response have been reported in non‐injured individuals with idiopathic orthostatic hypotension (Streeten et al., 4.3Factors that are predictive of orthostatic hypotension in the general population, including age at test, sex, body mass index, and the number of prescribed medications, did not significantly predict the cardiovascular hemodynamic responses to orthostatic stress in our individuals with SCI. While the level of injury did discriminate between cluster groups describing heart rate and blood pressure responses to the sit‐up test, AIS classification, and time since injury did not. A previous report examined blood pressure change in response to the sit‐up test in 52 Paralympic athletes found a significant univariate relationship with the level of neurological injury (West et al., 4.4There are multiple redundant mechanisms of blood pressure regulation during orthostatic stress Rowell, . The pat4.5There are a few study limitations that should be considered when interpreting the results presented. First, 1‐min averages of seated blood pressure and heart rate are reported, but we did not consider beat‐to‐beat blood pressure or heart rate variability which might lend insight into the contribution of autonomic neural control to these cardiovascular orthostatic responses. Second, the prevalence of delayed orthostatic hypotension was evaluated in a subset of participants who were tested beyond 3‐min and was present in 25% of those who experienced orthostatic hypotension; therefore, more attention should be paid to the prevalence and clinical significance of delayed orthostatic hypotension in the SCI population. Third, although this was a relatively large, heterogeneous group of participants with SCI, future study should be designed to determine the influence of modifiable factors such as exercise, diet, medical conditions, and use of drugs and alcohol on cardiovascular hemodynamic responses to orthostasis. Fourth, we did not evaluate the degree of the autonomic function using the ISAFSCI, which would have provided a subjective correlate of baseline cardiovascular hemodynamic compromise. Finally, although the sit‐up test is a clinically relevant orthostatic stressor, the sensitivity and repeatability of this assessment to evaluate cardiovascular autonomic integrity following SCI warrants further study.4.6Evaluation of sensorimotor function using the ISNCSCI exam does not provide enough information to describe the remaining autonomic nervous system function following SCI. Furthermore, the occurrence of orthostatic hypotension, by the definition in the consensus statement, cannot be used exclusively to ascertain the degree of cardiovascular autonomic impairment in individuals with SCI. Cluster analysis of blood pressure and heart rate responses to orthostatic stress identified eight distinct patterns that could not be fully explained by the level and severity of injury or contributing factors known to affect orthostatic cardiovascular responses in non‐injured population. Cardiovascular orthostatic dysregulation in persons with chronic SCI is highly heterogeneous and variations among individual patients should be assessed in the clinical setting independent of—but concomitant with—neurological classification of SCI.The authors have no conflict of interest to declare.SJH and JMW designed the study and provided oversight for data acquisition and data analyses. SW, JMW, BLD, SCA, MTM, ATL, AVO, BB, JTHG, and SJH performed data acquisition and data analysis. BU created the statistical design and performed statistical analyses. SW, SJH, BLD, and JMW collaborated on the interpretation of the data. All authors were involved in manuscript preparation and approved the final manuscript for submission.


With advances in care, neonates undergoing cardiac repairs are surviving more frequently. Our objectives were to 1) estimate the prevalence of chronic kidney disease (CKD) and hypertension 6 years after neonatal congenital heart surgery and 2) determine if cardiac surgery-associated acute kidney injury (CS-AKI) is associated with these outcomes.2 or albumin/creatinine ≥3 mg/mmol) and hypertension  prevalence 6 years after surgery was estimated. The association of CS-AKI  with CKD and hypertension was determined using multiple regression.Two-center prospective, longitudinal single-visit cohort study including children with congenital heart disease surgery as neonates between January 2005 and December 2012. CKD (estimated glomerular filtration rate < 90 mL/min/1.73mFifty-eight children with median follow-up of 6 years were evaluated. CS-AKI occurred in 58%. CKD and hypertension prevalence were 17% and 30%, respectively; an additional 15% were classified as having elevated blood pressure. CS-AKI was not associated with CKD or hypertension. Classification as cyanotic postoperatively was the only independent predictor of CKD. Postoperative days in hospital predicted hypertension at follow-up.The prevalence of CKD and hypertension is high in children having neonatal congenital heart surgery. This is important; early identification of CKD and hypertension can improve outcomes. These children should be systematically followed for the evolution of these negative outcomes. CS-AKI defined by current standards may not be a useful clinical tool to decide who needs follow-up and who does not. Epidemiological studies have shown the prevalence of cardiac surgery-associated acute kidney injury (CS-AKI) to be as high as 50–60% in neonates , 2. WhilWith advances in care, neonates undergoing complex cardiac repairs are surviving more frequently, resulting in a markedly increasing number of adults with congenital heart disease , 8. GiveWe hypothesized that CKD and hypertension are common in children who undergo neonatal congenital heart surgery and that CS-AKI increases long-term risk for CKD and hypertension. Our objectives were to 1) estimate the prevalence of CKD and hypertension 5–7 years after neonatal cardiac surgery and 2) determine if CS-AKI is a risk factor for later CKD and hypertension.This is a two-center, longitudinal, cohort study of neonates who underwent neonatal congenital heart surgery at the Montreal Children’s Hospital, Montreal, Canada, and the Stollery Children’s Hospital, Edmonton, Canada, between January 2005 and December 2012. Exclusion criteria were preoperative known kidney disease, already recruited into a longitudinal study, unwillingness to return to the study center for assessments, or lived too far away (> 3.5-h drive) from the center for home study visits. Institutional Research Ethics Board approval was obtained before initiating this study. Written informed consent was provided by parents/legal guardians prior to initiating study activities with participants.Patients were identified , reviewed for eligibility, and mailed invitations to contact us for study information. Responders were contacted, re-reviewed for eligibility, and invited to participate. In addition, children attending cardiology clinics in both Edmonton and Montreal fitting eligibility criteria were invited to participate, and children previously consenting to future contact during prior studies were contacted by telephone.A single standardized study visit was performed 5 to 7 years post-cardiac surgery at the clinic research center or the patient’s home. Study staff were blind to past AKI status. Blood (minimum 1.5 mL) and urine (minimum 5 mL) samples were collected. Three measures of height  and weight  were taken, and the average was calculated. Height and weight, age and gender-specific percentiles, and z-scores were calculated using Centers for Disease Control and Prevention growth charts . Three aRelevant clinical data from the index cardiac surgery admission were collected retrospectively by chart review. Preoperative variables collected included sex, gestational age (weeks), age (days), weight (kg) and length (cm) at surgery, baseline serum creatinine , ventilated at the time of surgery, and use of preoperative extracorporeal membrane oxygenation (ECMO). Complexity of cardiac surgery was categorized using the risk adjustment for congenital heart surgery-1 (RACHS-1) , the conSpecimens were kept on ice, centrifuged at 2000 RPM for 15 min at 21 °C, separated into aliquots, and stored at − 80 °C until analysis at the Montreal Children’s Hospital laboratory . Blood was measured for SCr . Urine was measured for albumin  and creatinine (modified Jaffe assay).Our primary exposure was CS-AKI, defined based on the creatinine criteria of Kidney Disease: Improving Global Outcomes (KDIGO) definition (≥ 50% rise or ≥ 26.5-μmol/L increase in postoperative SCr from baseline). SCr within the first 7 days postoperatively was used to define CS-AKI. Baseline SCr value was defined as the last SCr value collected before index cardiac surgery. We also evaluated moderate/severe CS-AKI .2 or urine albumin/creatinine (ACR) ≥ 3 mg/mmol (stage 2 CKD) [Our primary outcomes were CKD and hypertension. Hypertension was defined as a systolic or diastolic blood pressure ≥ 95th percentile for age, sex, and height , or a hie 2 CKD) . Estimate 2 CKD) .p value ≤ 0.05. Descriptive analyses are reported as frequency and proportion for categorical variables, median with interquartile range (IQR) for continuous variables with non-normal distribution, and mean with standard deviation (SD) for continuous variables with normal distribution. Associations of CS-AKI and other variables with the outcomes were evaluated using linear regression or the Mann-Whitney U tests (for continuous variables and depending on distribution), and χ2 or Fisher’s exact test . Purposeful selection was the regression strategy planned, with the following variables considered for the prediction model: sex, gestational age (term vs not), age at surgery, weight at surgery, baseline eGFR, ventilated at surgery, cyanotic postoperatively, duration of postoperative invasive mechanical ventilation, duration of postoperative ICU and hospital stays, and postoperative nephrotoxic medication use. We planned to evaluate RACHS-1 score for univariable relationship with outcomes; however, we planned to exclude it from multivariable modeling as it is a consensus-based scoring system used to categorize surgical complexity and predict outcome in the setting of limited primary data collection; it encompasses data likely to be included in other variables. In addition, for evaluation of hypertension outcome, we built 2 separate models, one including those with arch abnormalities or coarctation and one without. Variables with p < 0.2 in univariate analysis were to be included as potential predictive variables in multiple regression modeling. Given the small sample size, we predicted the ability to use multiple logistic regression to evaluate independent association of CS-AKI, and the outcomes may be limited. We estimated that we may only be able to control for the effects of up to three other variables (approximately 5 to 10 outcomes per variable). A priori, we decided that if greater than 3 variables (other than CS-AKI) were associated with the outcome, we would use stepwise, backward elimination logistic regression analysis , retaining the CS-AKI variable. Separate logistic regression models were evaluated for each of the outcomes. Assumptions of regression were tested.Statistical analysis was performed using the STATA (14.0) statistical software . Statistical significance was set at t tests or the Mann-Whitney U tests, as appropriate.Given the challenges of using creatinine-based definitions of AKI in neonates and the potential for misclassification of our primary exposure measure, we assessed the relationship between preoperative SCr, eGFR, age at surgery, and age at baseline SCr measurement (each separately), and a diagnosis of CS-AKI. Associations were evaluated using Student’s Fifty-eight neonates were enrolled in the study Fig. . Responsp = 0.006) and a higher baseline eGFR  compared with those who were classified as not having CS-AKI. Age at cardiac surgery and age at baseline SCr measurement were not associated with a diagnosis of CS-AKI.AKI status was available in all patients. Fifty-seven percent (33/58) of the cohort had a history of CS-AKI; 33% of those had stage 1 AKI, 15% had stage 2, and 9% had stage 3. Only 2 required postoperative dialysis. Ten of the 33 neonates (30%) who were classified as having CS-AKI did not recover their baseline SCr before discharge. Eighty-three percent of neonates (47/58) had a baseline preoperative creatinine drawn within 48 h of cardiac surgery, with almost all of these being drawn within 24 h. Creatinine used to determine CS-AKI status was drawn more than 7 days preoperatively in 4 children; 3 were classified as having AKI and 1 was not. Another 6 neonates had the SCr drawn more than 48 h before surgery but less than 7 days. Of those, 4 were classified as having CS-AKI and 2 were not. In these, 2 classified as non-AKI; the SCr was drawn the first and second days of life. Mean (SD) of age at baseline SCr measurement was 9.3 (7.2) days. Neonates who were classified as having CS-AKI had a lower baseline SCr . At the follow-up study visit, weight for age percentile and height for age percentile distributions in the study population were not different than the general pediatric population (p = 0.70 and 0.23 for weight and height respectively). Mean (SD) weight for age percentile was 50 (28). Only 4 children had a weight for age less than the 10th percentile and none had a weight < 5th percentile. Mean (SD) height for age percentile was 55 (29). Only 2 children had a height for age less than the 10th percentile, with both being less than the 5th percentile and both also having a weight for age less than the 10th percentile. There was no statistically significant difference in height, weight, or age in patients who had CS-AKI compared with those that did not.The mean (SD) number of years between index cardiac surgery and follow-up visit was 6.3 (0.9), which did not differ between CS-AKI groups (2. No patient had an eGFR by SCr < 60 mL/min/1.73m2. Mean (SD) follow-up time for those with CKD and those without CKD was 6.6 (0.9) years and 6.2 (0.9) years, respectively (p = 0.11). Overall, the point prevalence of microalbuminuria in our study sample was 12% (7/58), and the median (IQR) albumin to creatinine ratio was 1.43 (1.3) mg/mmol. Of the seven patients who had microalbuminuria, only one had an ACR greater than 20 mg/mmol. Thirty percent (17/57) were classified as hypertensive, with an additional 16% (9/57) being classified as having elevated blood pressure. If those with arch abnormalities or coarctation were excluded, 27% (13/48) were classified as hypertensive.Out of fifty-eight patients, 53 had blood samples to estimate glomerular filtration rate, 58 had urine samples collected, and 57 had blood pressure measurements performed during the follow-up visit. The prevalence of CKD in our study cohort was 17% (9/53). Mean (SD) eGFR was 123 (20.5) mL/min/1.73mp = 0.001). CS-AKI was not statistically significantly associated with CKD, even in moderate and severe episodes of CS-AKI. Multiple-variable analysis demonstrated that postoperative days in hospital were the only independent predictor of hypertension (HTN) at follow-up . CS-AKI was also not statistically significantly associated with hypertension even in moderate and severe episodes of CS-AKI. Given the potential association between coarctation or arch abnormalities with longer-term hypertension, we repeated the analysis for predictors of hypertension excluding these children (n = 9), and when these patients were removed from the analysis of predictors of HTN, postoperative hospital days remained the only significant predictor.Patient and surgical characteristics of children with and without CKD are shown in Table p = 0.04). The distribution of children with CKD by RACHS-1 category is shown in Fig. p = 0.025), with the highest prevalence in STAT category 5 (66%). No children in STAT 1 were classified as CKD, and 14% of both STAT 2 and STAT 4 had CKD. There was no association identified between either RACHS-1 category or STAT category and hypertension at follow-up.RACHS-1 category for type of surgical repair was associated with CKD (This is the first multicenter study evaluating both the childhood prevalence of and potential risk factors for CKD and hypertension long term after neonatal congenital heart repair. The prevalence of both CKD and HTN was higher in our study cohort compared with the general pediatric population. In Canadian children, the reported CKD prevalence is 2.1% compared with 17% in our study . AlarminA significant relationship between these long-term outcomes and the development of CS-AKI was not found in our study, even after moderate and severe episodes of CS-AKI. Higher prevalence of CKD and hypertension may represent a consequence of renal damage occurring in the context of cardiac surgery, critical illness, and immature kidneys that are not detected by the current standard definition of AKI. Non-creatinine-based renal injury biomarkers may be a useful tool in further evaluating this. It is also possible that we misclassified some of the neonates regarding their AKI status, leading to non-significant results between CS-AKI and long-term renal outcomes. Neonates who were classified as having CS-AKI had a significantly higher baseline eGFR and lower baseline SCr compared with those who were classified as not having CS-AKI. Baseline Scr may have reflected maternal SCr, and the SCr peak after surgery may have not been enough to classify them as having CS-AKI, even if true injury occurred. We did however observe that age of the neonate at surgery and age at baseline SCr measurement were not associated with a diagnosis of CS-AKI. AKI, defined by the current standard of using serum creatinine, may not be a useful indicator for dictating follow-up in neonates, given the complexities of this biomarker in this population. In this study, we did not assess for multiple AKI events over early childhood as a risk factor for CKD. It may be that cumulative kidney injury is more important than a single isolated event; children with congenital heart disease often have multiple hospitalizations as well as repeat surgical intervention, particularly those with cyanotic heart disease.Classification as cyanotic postoperatively was associated with higher prevalence of CKD. In cyanotic congenital heart disease, chronic hypoxemia leads to increase blood viscosity, which has been shown experimentally to influence endothelial shear stress, glomerular arteriolar resistance, hydraulic pressure within the glomerulus, and filtration fraction , which cHypertension was significantly associated with total length of stay in hospital after cardiac surgery. Total length of stay is likely a surrogate marker of overall illness condition, with sicker children staying longer. Children who stay longer may be at higher risk of multiple interventions, with the potential to impact the kidney as well as recurrent exposure to nephrotoxins, which could lead to elevated blood pressure in the long term.This study has a number of limitations. The sample size was small. Although it was large enough to identify meaningful differences in outcomes between the study cohort and the reference populations, it was likely not large enough to detect small differences in subgroups of patients. The small sample size also limited confounder adjustment. Albuminuria was diagnosed on a single spot urine, with 44% of the cohort with CKD being diagnosed as such by albuminuria alone. Although current guidelines recommend a spot urine for definition of albuminuria, a first morning urine in the study setting may give a more accurate assessment of this outcome, given the potential postural effects on protein excretion. There are very few studies on the prevalence of albuminuria from random spot urines in the child population, particularly in the ages included in our study. However, given the age at follow-up of the current cohort, the incidence of orthostatic proteinuria is likely low . There aThe prevalence of CKD and hypertension is high in children having had congenital heart repair as neonates. Although high prevalence of CKD has been shown in adults with congenital heart disease, this study demonstrates that there is evidence of negative renal consequences long before adulthood. This is important as hypertension and albuminuria may be modifiable contributing factors in CKD progression. This study provides evidence for healthcare providers to systematically follow these children over time for the evolution of these negative outcomes. Although the current study has limitations, CS-AKI defined by current standards did not predict CKD in this cohort. This needs further evaluation in a larger study to determine if CS-AKI can be a useful clinical tool in deciding who needs follow-up and who does not. The advent of new biomarkers may further elucidate this problem, allowing for a better understanding of the pathophysiology and possible prevention of hypertension and CKD in this vulnerable population.


Objectives: The head-up tilt test (HUTT) is a useful tool to assess autonomic function and to reproduce neurally mediated reflex. In this study, we evaluated the use of HUTT in pediatric patients aged 3–5 years with orthostatic intolerance.Materials and Methods: The medical history and HUTT records of 345  cases of patients who complained of symptoms of orthostatic intolerance and who visited the Syncope Ward, Children's Medical Center, The Second Xiangya Hospital, Central South University from January 2003 to December 2019, were reviewed retrospectively.Results: Seventy-nine (22.9%) cases had positive responses to complete HUTT , while 29 (8.4%) cases had positive responses if only basic HUTT was performed. Sublingual nitroglycerin provocation significantly increased the positive rate of the test . The most frequent hemodynamic response to HUTT was vasoinhibitory type vasovagal syncope (12.2%), Syncope (28.7%), and dizziness (22.6%) were the most common symptoms. Eight cases discontinued the test due to intolerable symptoms without severe adverse events occurring.Conclusions: HUTT was safe and well-tolerated and could be used to diagnose the hemodynamic type of orthostatic intolerance in children aged 3–5 years. Orthostatic intolerance is common in children and adolescents, and is defined as individuals who have difficulty in tolerating an upright posture and who present signs and symptoms of transient loss of consciousness, fatigue, headaches, lightheadedness, visual disturbances, sweating, vomiting, nausea, abdominal pains, and so on when standing . These sThe head-up tilt test (HUTT) is an important tool to assess autonomic function and is used for differential diagnosis of transient loss of consciousness and orthostatic intolerance in adults and children , 4. HUTTWe retrospectively reviewed 345  cases of patients who complained of orthostatic intolerant symptoms of syncope, headaches, dizziness, visual disturbances, sweating, vomiting, nausea, abdominal pains, and so on when standing upright, and who visited the Syncope Ward, Children's Medical Center, The Second Xiangya Hospital, from January 2003 to December 2019. The demographic and clinical data including HUTT records were reviewed. Heart, pulmonary, cerebral, and other system diseases were excluded after an initial evaluation consisting of history, physical examination, baseline laboratory testing, ECG, Holter ECG, echocardiography, chest X-ray, electroencephalogram, and cranial CT or MRI. According to the age range, patients were divided into three groups: group 3–4 referred to those aged above or equal to 3 and <4 years, group 4–5 referred to those aged above or equal to 4 and <5 years, group 5–6 referred to those aged above or equal to 5 and <6 years.The HUTT consisted of two stages: basic HUTT and sublingual nitroglycerin HUTT. The protocol had been carried out according to a previous study , 7. HUTTPositive responses to HUTT included vasovagal syncope (VVS), postural tachycardia syndrome (POTS), orthostatic hypotension (OH), and orthostatic hypertension (OHT) . VVS was25, P75) for non-normally distributed continuous variables, and percent prevalence for dichotomized variables. One-way analysis of variance (ANOVA) was used to analyze three or more normally distributed continuous variables. Manne-Whitney test was used to compare non-normally distributed continuous variables among groups. χ2 test, or Fisher exact test was used to compare dichotomized variables. P < 0.05 were considered statistically significant.Statistical analysis was performed by SPSS 17.0. Data were described as mean ± SD for normally distributed continuous variables, median  (There were 38 subjects [22 (57.9%) males] aged between 3 and 4 years, 114 individuals [65 (57.0%) males] aged between 4 and 5 years, and 193 subjects [93 (48.2%) males] aged between 5 and 6 years. There were no significant differences in gender ratio, history duration, basic systolic, and diastolic blood pressure among the three groups, except for the fact that HR decreased, and body mass index increased with increasing age (ctively) .x2= 8.929, P = 0.012), whereas the incidence of dizziness increased with increasing age  (The most common symptoms were syncope (28.7%) and dizziness (22.6%), followed by sighing (11.9%), chest pain (8.4%), palpitation (6.4%), headaches (5.5%), and fatigue (1.2%). Other symptoms included visual disturbances, sweating, vomiting, nausea, and abdominal pains. The incidence of syncope decreased with increasing age (= 0.032) .x2= 27.565, P < 0.001). As shown in As shown in In case of positive responses, the patients were rapidly placed in the supine position. Strategies including keeping the airways open, oxygen therapy, and intravenous glucose infusion were taken when necessary. All the patients could recover completely within 5 min of rest in the supine position.The medical history of 345 subjects aged between 3 and 5 years with orthostatic intolerance was reviewed in the present study. It was found that the most common symptoms were syncope and dizziness. Sublingual nitroglycerin provocation significantly increased the positive rate of the test compared with only basic HUTT. Vasoinhibitory type VVS was the most frequent positive response to HUTT. Eight patients did not complete the test due to intolerable symptoms, but none of these patients had severe adverse events during the HUTT process.While upright, 70% of the blood volume was below the heart . HealthyHUTT has been used to reproduce neurally mediated reflex for years to investigate the heart rate and blood pressure adaptation to position change . A studyIn our study, 79 (22.9%) cases had positive responses to complete HUTT , while 29 (8.4%) cases had positive responses if only basic HUTT was performed, demonstrating that drug-free HUTT had a low positive rate. It is necessary to perform pharmacological provocation using isoproterenol intravenous infusion or sublingual nitroglycerin . A previIt is critical to identify the tilt angle to maximize the number of true positive responses and to minimize the number of subjects who are falsely assessed as positive responses. In a previous study, it is reported that the positive response appearance time was 15.1 ± 14.0 min, and the tilt angle was 60° in children . A meta-HUTT is safe and well-tolerated. The previous study reported that the most common adverse events were the development of hypertension or tachycardia and intolerable flushing or nausea . In a prPatients with orthostatic intolerance have difficulty in tolerating the upright posture and present symptoms and signs when standing, recovering when returning to the supine position. Our 345 patients were diagnosed with orthostatic intolerance according to the clinical manifestation. We further used HUTT to define the hemodynamic responses. For general patients with orthostatic intolerance, non-pharmacologic interventions including health education of avoiding prolonged standing, tilt training, and intake of water and salt were utilized to alleviate the orthostatic intolerant symptom. For patients with positive responses to HUTT, pharmacologic interventions such as midodrine hydrochloride or metoprolol should be used when appropriate . HUTT caThere were some limitations. In our study, 16.5% of cases presented VVS response with 12.2% of cases being of the vasoinhibitory type and 6.4% of cases presented a POTS response to HUTT. However, our study was a retrospective study. Data for healthy individuals aged between 3 and 5 years were not included. The specificity of HUTT for VVS and POTS could not be concluded. Otherwise, the standards for positive responses in children below 6 years of age were controversial.In conclusion, the positive rate of the HUTT was 22.9% in pediatric patients aged between 3 and 5 years with orthostatic intolerance. The most common symptoms were syncope and dizziness. The most frequent hemodynamic response to HUTT was vasoinhibitory type VVS. Pharmacological provocation could improve the sensitivity of HUTT. HUTT was safe and well-tolerated for children aged below 6 years.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and HUTT was approved by the Ethics Committee of The Second Xiangya Hospital, Central South University. The informed consent was obtained from all the subjects directly or their guardians. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.RZ was primarily responsible for the protocol development, patient enrollment, data collecting, preliminary data analysis, and for writing the manuscript. SW assisted with data analysis and critical revision for important content and edited the draft. FL, PL, JZ, and YW were responsible for completing the head-up tilt test. YX and CW supervised the design and execution of the study, checked the data analysis, contributed to the writing of the manuscript and provided final approval of the submitted manuscript. All authors have read and approved the final manuscript and assume full responsibility for its contents.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.