Whereas hypertension is an established cardiovascular risk factor in the general population, the contribution of increased blood pressure (BP) to the huge burden of cardiovascular morbidity and mortality in patients receiving dialysis continues to be debated. In a large part, this controversy is attributable to particular difficulties in the accurate diagnosis of hypertension. The reverse epidemiology of hypertension in dialysis patients is based on evidence from large cohort studies showing that routine predialysis or postdialysis BP measurements exhibit a U-shaped or J-shaped association with cardiovascular or all-cause mortality. However, substantial evidence supports the notion that home or ambulatory BP measurements are superior to dialysis-unit BP recordings in diagnosing hypertension, in detecting evidence of target-organ damage and in prognosticating the all-cause death risk. In the first part of this article, we explore the accuracy of different methods of BP measurement in diagnosing hypertension among patients on dialysis. In the second part, we describe how the epidemiology of hypertension is modified when the assessment of BP is based on dialysis-unit versus home or ambulatory recordings. Hypertension among patients with end-stage kidney disease (ESKD) receiving either long-term hemodialysis or peritoneal dialysis (PD) is highly prevalent and often remains poorly controlled ,2. Two mIn the first part of this article, we explore the accuracy of various BP monitoring techniques in diagnosing hypertension among patients on dialysis. In the second part, we describe how the epidemiology of hypertension is modified when different methods are used in the assessment of BP.A literature search of the MedLine/PubMed database was performed from inception until September 2022 with the aim to identify studies that explored the diagnostic accuracy and predictive value of different BP monitoring techniques in ESKD patients on dialysis. Search terms used were “hypertension”, “hemodialysis”, “peritoneal dialysis”, “end-stage kidney disease”, “home BP monitoring” and “ambulatory BP monitoring”. Reference lists of prior reviews in this area were also searched for additional studies and information. All types of studies, such as diagnostic-test studies, cross-sectional analyses, prospective observational studies, randomized controlled trials and meta-analyses, were eligible for this article if they reported relevant data with respect to the diagnosis and epidemiology of hypertension. Studies that were conducted in the general hypertensive population or in patients with earlier stages of kidney disease were excluded.Peridialytic BP measurements are the recordings obtained by the dialysis-unit personnel at the beginning and at the end of each hemodialysis session ,2. TheseOne approach to improve the diagnostic performance of peridialytic BP measurements is the concomitant assessment of intradialytic BP. These measurements are obtained during the hemodialysis procedure, typically every 30 min, using an automatic cuff attached to the hemodialysis machine ,2. In daSince the calculation of an average is time-consuming and impractical, consideration of the median intradialytic BP from the measurements obtained during a single mid-week hemodialysis session also appears to be an appropriate method to screen for hypertension at the bedside. A mid-week median cut-off systolic BP of 140 mmHg provides 80% sensitivity and 80% specificity for the diagnosis of systolic hypertension. Similarly, a mid-week median intradialytic diastolic BP of 80 mmHg offers 75% sensitivity and 75% specificity in the detection of diastolic hypertension . FurtherHome BP monitoring (HBPM) is an established technique that is recommended by international guidelines for the assessment and management of hypertension in the general population or in patients with predialysis chronic kidney disease . HoweverThe technique of HBPM has been more widely adopted in the assessment of hypertension in patients receiving long-term PD, possibly because PD is a home-based modality for renal replacement therapy. Among 81 stable PD patients, a recent study showed that self-measured home BP for 1 week had at least similar or even better accuracy than standardized dialysis-unit BP in diagnosing hypertension, as confirmed by the reference-standard method of 24-hour ABPM . The areApart from its superior diagnostic performance, additional advantages of the technique of HBPM exist and merit attention. In DRIP, home BP was more sensitive than peridialytic BP in detecting the reduction in 44-hour ambulatory BP provoked by the probing of dry weight over 8 weeks of follow-up . ContrarSubstantial evidence also supports the notion that HBPM is a useful tool to guide therapeutic decisions and improve the management of hypertension . The feaThe chronobiology of BP should be taken into consideration in the design of a sufficient scheme for home BP measurements. Home systolic BP is characterized by a steady increase at a rate of 0.40 ± 0.25 mmHg/hour over the interdialytic interval. This rising pattern reaches a plateau after approximately 48 h . TherefoInterdialytic ABPM represents the “reference-standard” technique for diagnosing hypertension ,2. This Studies exploring the epidemiology of hypertension in patients on dialysis have used different definitions and provided considerably variable results with respect to the prevalence and control of BP ,39,40. TA more accurate description of the epidemiology of hypertension was provided by two larger studies that incorporated the reference-standard method of ABPM ,43. The Some earlier studies that were based on conventional dialysis-unit BP recordings suggested that hypertension control in patients receiving long-term PD is superior compared to those on hemodialysis. For example, among 1202 patients enrolled in the 1995 Peritoneal Dialysis Core Indicators Study, only 29% had an office systolic BP > 150 mmHg and 18% had a diastolic BP > 90 mmHg . HoweverThe risk association of BP with cardiovascular morbidity and all-cause mortality among patients on dialysis represents an area of controversy . In the Recent studies have shown that peridialytic BP should be interpreted within the context of hypervolemia and not as an isolated risk factor. In an analysis from the international Monitoring Dialysis Outcome Initiative (MONDO) database, the volume status of 8883 hemodialysis patients was assessed using bioimpedance spectroscopy . All-cauTwo separate prospective observational studies showed that the BP measurement technique is another factor that modifies the prognostic association of BP with all-cause mortality. The first study enrolled 150 hemodialysis patients who underwent a baseline assessment of BP with four different techniques: self-measured home BP for 1 week, 44 h ABPM and routine and standardized peridialytic BP measurements averaged over six consecutive hemodialysis sessions . During The second study included a larger sample size of 326 hemodialysis patients who underwent a similar assessment of BP at baseline. The duration of follow-up was longer also (median follow-up: 32 months) . In multThe notion that ambulatory BP provides superior prognostic information relative to office BP is further supported by a prospective cohort study of 108 stable PD patients . At baseThe superior prognostic significance of home or ambulatory measurements over dialysis-unit BP cannot be attributed to the higher number of BP recordings that these techniques provide. Observational studies showed that both home and ambulatory BP retain their ability to prognosticate the all-cause death risk, even when the average of a small number of randomly selected BP recordings is used as a risk predictor ,52,53,54The reverse epidemiology of hypertension demonstrated by observational data is not accordant with the results of two earlier meta-analyses of randomized controlled trials showing that deliberate lowering of BP with the use of antihypertensive therapy offers cardiovascular protection in patients on dialysis. The first meta-analysis included eight trials involving a total of 1679 dialysis patients. Relative to placebo or no therapy, the use of antihypertensive medications was associated with 29% reduced risk for cardiovascular events (risk ratio (RR): 0.71; 95% CI: 0.55–0.92), 29% lower risk for cardiovascular death  and 20% lower risk for all-cause death  . The secIn conclusion, although the present work provides mainly a qualitative evaluation of diagnostic accuracy and predictive value of different BP monitoring techniques in the dialysis population, a growing body of evidence supports that home and ambulatory BP measurements are superior to routine and standardized dialysis-unit BP recordings in diagnosing hypertension, in assessing the presence of target-organ damage and in prognosticating the risk of all-cause mortality. Undoubtedly, 44 h ABPM is the “gold-standard” technique that provides the highest accuracy and precision, but some weaknesses  limit the adoption of this method in daily clinical practice. A more feasible approach to improve the assessment and long-term management of hypertension is the broader use of HBPM. Large randomized controlled trials are now needed to demonstrate the superiority of home-BP-guided over predialysis-BP-guided antihypertensive therapy in causing regression of end-organ damage and in improving “hard” cardiovascular outcomes in this high-risk patient population.


Patients with end-stage renal disease are more likely to suffer cognitive impairment. Cognitive impairment may lead to long-term severe adverse consequences.To explore the impact of different blood purification therapy on cerebral blood flow and cognitive functions in end-stage renal disease.This prospective study evaluated patients with end-stage renal disease undergoing blood purification from January to March 2021. Matched healthy controls were also included. Participants performed neurocognitive measurements, including a mini-mental state examination, logical memory test-20-minutes delayed, verbal fluency test, digit span test, clock drawing test, and stroop color and word test C. In addition, we tested plasma amyloid-β protein levels, serum Fe and hemoglobin levels in blood samples. Cerebral blood flow was measured using pulsed pseudocontinuous arterial spin labeling. We analyzed and compared the correlation between cognitive function, biomarkers, and cerebral blood flow between patients and healthy subjects, as well as between patients with different treatments.P < 0.05). The patients showed higher plasma concentrations of amyloid-β40, amyloid-β42, Tau, and pTau181 than healthy controls (P < 0.05). The group receiving both hemodialysis and hemodiafiltration had higher cerebral blood flow signal values in the left caudate nucleus . They also exhibited better verbal fluency function than the hemodialysis-only group (P < 0.05).A total of 44 patients with end-stage renal disease  and 46 healthy controls  were recruited. Patients receive hemodialysis three times a week, and 27 of them have been replaced hemodialysis for hemodiafiltration twice a month. The cognitive function of patients was worse than healthy controls (Patients with the end-stage renal disease showed widespread cognitive declines. Cerebral blood flow generally decreased in the cerebral cortex and increased in subcortical regions. The hemodiafiltration may protect verbal function by increasing cerebral blood flow in the left caudate. End-stage renal disease (ESRD) is severe chronic kidney disease. Extracorporeal blood purification (BP) therapies such as hemodialysis (HD) and hemodiafiltration (HDF) are the most widely used treatment for patients with ESRD. Patients with ESRD undergoing BP (ESRD-BP) are more common to occur cognitive impairment (CI) . CI may The mechanism of CI in ESRD-BP is unclear. Uremic toxicity and cerebral neurovascular abnormalities are involved in the pathogenesis. Renal failure accumulates uremic toxins in the circulation, and the neurotoxicity of urinary toxins directly affects cognitive function. Protein-bound uremic toxins accumulate in plasma and systemic organs, such as indoxyl sulfate, and p-cresyl sulfate . IndoxylIn contrast, elevated uremic toxins disrupt the blood-brain barrier (BBB) . It affeThough Aβ and Tau are an essential indicator of cognitive functions during BP, it is hard to detect the exact Aβ and Tau levels in the brain with acceptable spatial resolution. Notably, BP may pull the blood along with Aβ and Tau out for circulation, and the strength of this “pull” may be reflected by its impact on the cerebral blood flow (CBF) in distinct brain regions. Cerebrovascular damage in ESRD-BP patients, as well as BP-induced rapid changes in blood pressure, osmolarity, and acid-base balance, all of which affect the brain’s CBF. The percentage decrease in mean flow velocity was related to the decline in cognitive function, including overall function, executive function, and verbal fluency . PseudocWe hypothesized that HD and HDF would affect the CBF differently in patients with ESRD, leading to changes in blood flow that pull Aβ out in specific brain regions. We measured plasma Aβ, Tau protein levels, and CBF using pCASL. We aimed to perform case-control and BP-treated subgroups analyses on changes in regional CBF.This study was approved by the hospital ethics committee  and registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2100042710). All participants were recruited from the Department of Nephrology at hospital and informed and signed the consent forms before enrollment. The study was completed in accordance with the principles of the Declaration of Helsinki.This prospective study evaluated patients and healthy controls (HCs) from January to March 2021. Patients with ESRD inclusion criteria were following: who met the ESRD diagnostic criteria and received HD three times a week for no less than 3 months, with or without HDF two times a month; were right-handed, aged 45–75 years, junior high school education or above; normal vision and hearing ability, normal limb muscle strength, no color weakness or blindness; could read and sign informed consent. Exclusion criteria included the following: patients with brain damage such as stroke or tumor; history of traumatic brain injury; with neuropsychiatric disorders; history of drug or alcohol abuse.Then we matched the HCs by age, sex, and education level of the included ESRD-BP group. We recruited HCs from the local community in Nanjing through advertisements. Inclusion criteria of the HCs: who was healthy; mini-mental state examination (MMSE) score ≥25 points; were right-handed; no history of severe heart, brain, liver, or kidney disease; no history of alcohol and drug abuse; no family history of mental illness; read and sign informed consent. The PASS 11 software was used to calculate the sampling of each group according to the incidence of CI in ESRD and HCs. The sample size was estimated by comparing the correlation coefficients of the two samples with α = 0.05 (one-sided) and β = 0.10. The result was 21 cases. Assuming a loss to follow-up of 20%, we arrived at a sample size of at least 25 cases for each group.® technology . The multiplex Neurology 3-Plex A kits (Cat. No. 101995) and pTau181-V2 assay kits (Cat. No.: 103714) were purchased from Quanterix. Calibrators and quality controls were measured in duplicate. All sample measurement was performed on a single run basis. Operators were unknown participants’ disease status.Blood samples were taken in the morning, before hemodialysis treatment. EDTA plasma was separated within 1 h after 3–5 ml blood was collected, and stored in a refrigerator at −80°. Using the fully automated SIMOA HD-X platform , the plasma Aβ40, Aβ42, Tau, and p-Tau181 concentrations were quantified using an ultra-sensitive SimoaAll participants underwent the MMSE , logicalUsing Philips MR Imaging DD 005 (Philips Ingenia II) MRI with a brain 16-channel coil to scaning in the study at the hospital. CBF was measured using pCASL. During the examination, the subjects were in a supine position, with a quiet and awake state, closed their eyes, and lay flat on the scanning bed. The subjects’ head and the coil were fixed with a foam pad to reduce head movement. We performed routine scans to exclude obvious intracranial lesions at first. Then we use pCASL technology to collect functional magnetic resonance imaging data of CBF. pCASL scan parameters: 3D-Grase sequence imaging, repetition time (TR) = 4464 ms, echo time (TE) = 12 ms, TI = 2000 ms, flip angle (FA) = 90°, acquisition matrix 64 × 60, field of view (FOV) = 240 mm × 240 mm, number of layers = 22 layers, thickness = 6 mm, layer spacing = 0 mm. Then use 3D-TFE sequence imaging technology to collect whole brain structure image data. T1-3D scan parameters: TR = 9.6 ms, TE = 3.7 ms, FA = 9°, acquisition matrix = 256 × 256, FOV = 256 mm × 256 mm, thickness = 1.1 mm, layer spacing = 0 mm.1 was used to calculate the CBF maps prior to spatial normalization , non-parametric t-test was used to compare groups. Enumeration data were reported by frequency, and comparison between groups was performed by χ2 test. After D’Agostino-Pearson test Pearson’s correlation analysis was performed on laboratory data, CBF values and neuropsychological scale data. The difference was statistically significant with P < 0.05.All data were processed using SPSS software  and GraphPad Prism Version 8.0.1 (244). Kolmogorov–Smirnov was used for normality test for measurement data. Normal distribution data were reported as mean ± SD, P < 0.05 and voxel-level P < 0.001.Multiple comparisons were corrected in normalized CBF maps comparison between groups were assessed with the Gaussian random field (GRF) at cluster-level P > 0.05). There was a statistically significant difference between the two groups in MMSE (P < 0.05).According to the inclusion criteria, we included 56 patients with ESRD-BP and 53 HCs. All participants received cognitive assessment, clinical examination, and MRI. Among them, 5 patients and 3 healthy controls were unable to complete MRI. Participants with head movements exceeding 3° and 3 mm (7 patients and 4 HCs) were excluded. Finally, participants who participated in the statistical analysis were 44 patients with ESRD-BP and 46 healthy subjects . There wESRD–HD-Xcontrol|/Scontrol). The scores of MMSE, logical memory test-20-minutes delayed, VFT, digit span test, and clock drawing test in the ESRD-BP group were lower than those in the HCs group, and the stroop color and word test C score were higher than that in the HCs group. The result indicated that the cognitive function of the patient group was worse than the HCs group. Because the scale of the neurophysiological tests varied, the standardized Z-score was calculated to examine the deviations of each neuropsychological assessment (Z score = |XP < 0.05).The plasma concentrations of Aβ40, Aβ42, Tau, and pTau181 in the peripheral blood of the ESRD-BP group were higher than those of the HCs . The difPatients with regular HD three times a week were allocated into two groups according to whether they were accompanied by HDF twice a month. We compared the age, sex, education level, eGFR, HD duration, whether with high blood pressure history, whether with diabetes history, blood pressure and blood glucose levels, peripheral blood serum Fe content and hemoglobin (Hb) content, and plasma Aβ40, Aβ42, Tau, pTau181 concentration, Aβ42/Aβ40 ratio, neurocognitive assessments such as MMSE, logical memory test-20-minutes delayed, VFT, digit span test, clock drawing test, stroop color, and word test C. Among them, the Aβ42/Aβ40, blood glucose levels, and VFT score difference between the two groups is statistically significant .Comparison in the HD + HDF and HD groups of brain regions showed that higher CBF value of the left caudate nucleus in the HD + HDF group was increased than HD group .r = 0.302; P = 0.046)    . There i= 0.804) . There i= 0.776) .We assessed cognitive functions and the cognition-related peripheral plasma proteins in patients with end-stage renal disease on long-term regular dialysis. We discovered that the cognitive function of the patients was worse than the healthy controls. The largest difference between groups was in overall cognitive function, while the verbal fluency suffered the least. The plasma concentrations of amyloid-β40, amyloid-β42, Tau, and pTau181 of the end-stage renal disease group were higher than the healthy controls.–/– knockout mice . HDF is an extracorporeal renal-replacement technique in which diffusion and convection are conveniently combined to remove “middle molecules” (0.5–5 kDa). Therefore, HDF treatment may remove more Aβ40, which accounts for 90% of the total Aβ, from human peripheral blood, resulting in a higher Aβ42/Aβ40 ratio, and is associated with better verbal fluency function. The general pros of HDF are that it improves the quality of the patient’s dialysis, makes the function of the cardiovascular system more stable, ensures the quality of the patient’s survival, and reduces cardiovascular mortality . The genAdditionally, pCASL was used to measure the CBF in patients with ESRD-BP, and we expected to use it as an indirect indicator for Aβ. HDF adds convection to the diffusion of HD, and when blood is filtered, transmembrane pressure is formed, so the effect on CBF varies. We performed a CBF-based brain map comparison between the two subgroups. The HDF group showed higher CBF of the left caudate nucleus than the HD group. Brain perfusion levels are associated with cognitive function. A prospective longitudinal study using arterial spin labeling imaging found a significant decrease in CBF after initiation of HD in older adults, suggesting that decreased cerebral perfusion may be related to the observed cognitive decline .Conversely, increased perfusion would benefit cognitive function. The caudate nucleus is located in the subcortical part of the basal ganglia, involved in executive function. The caudate nucleus is involved in phonologic and semantic verbal fluency . This stOur study had some limitations. First, the lack of associations between CBF of the left caudate nucleus and neurocognitive assessment may reflect a power issue. Second, we compared two hemodialysis modalities, HDF and HD, but did not include patients undergoing peritoneal dialysis. Finally, the exact mechanism of how HDF increases CBF was not studied. In the future, multi-center and large-sample studies are needed to explore how the mechanism of HDF affects cognition function.In summary, the hemodiafiltration group showed better verbal fluency function among patients with end-stage renal disease and a higher amyloid-β42/amyloid-β40 ratio than the hemodialysis group. The increased cerebral blood perfusion might protect the cognitive function.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by IEC for Clinical Research of Zhongda Hospital, Affiliated to Southeast University. The patients/participants provided their written informed consent to participate in this study.XW, XC, LZ, and YW: guarantors of integrity of entire study. XW, XC, YT, LZ, YW, ZH, WJ, and YY: study concepts/study design or data acquisition or data analysis/interpretation, manuscript drafting or manuscript revision for important intellectual content, approval of final version of submitted manuscript, and agrees to ensure any questions related to the work are appropriately resolved. XW and YT: literature research and statistical analysis. XW, XC, LZ, YW, and ZH: clinical studies. XW: writing—original draft. WJ and YY: writing—review and editing. All authors contributed to the article and approved the submitted version.


While an association of the intraoperative driving pressure with postoperative pulmonary complications has been described before, it is uncertain whether the intraoperative mechanical power is associated with postoperative pulmonary complications.Posthoc analysis of two international, multicentre randomised clinical trials (ISRCTN70332574 and NCT02148692) conducted between 2011–2013 and 2014–2018, in patients undergoing open abdominal surgery comparing the effect of two different positive end–expiratory pressure (PEEP) levels on postoperative pulmonary complications. Time–weighted average dynamic driving pressure and mechanical power were calculated for individual patients. A multivariable logistic regression model adjusted for confounders was used to assess the independent associations of driving pressure and mechanical power with the occurrence of a composite of postoperative pulmonary complications, the primary endpoint of this posthoc analysis.2O, and 7·6 [5·1–10·0] J/min, respectively. While driving pressure was not independently associated with postoperative pulmonary complications , the mechanical power had an independent association with the occurrence of postoperative pulmonary complications . These findings were independent of body mass index or the level of PEEP used, i.e., independent of the randomisation arm.In 1191 patients included, postoperative pulmonary complications occurrence was 35.9%. Median time–weighted average driving pressure and mechanical power were 14·0 [11·0–17·0] cmHIn this merged cohort of surgery patients, higher intraoperative mechanical power was independently associated with postoperative pulmonary complications. Mechanical power could serve as a summary ventilatory biomarker for the risk for postoperative pulmonary complications in these patients, but our findings need confirmation in other, preferably prospective studies.The two original studies were supported by unrestricted grants from the European Society of Anaesthesiology and the Amsterdam University Medical Centers, Location AMC. For this current analysis, no additional funding was requested. The funding sources had neither a role in the design, collection of data, statistical analysis, interpretation of data, writing of the report, nor in the decision to submit the paper for publication. It is uncertain whether mechanical power, a summary parameter for intensity of ventilation that has been shown to have an association with mortality in critically–ill patients, also has an association with occurrence of postoperative pulmonary complications in surgery patients. We conducted a search of MEDLINE, Embase, CINAHL, and Web of Science between 1989 – March 2022 with various search terms for mechanical power and postoperative pulmonary complications. The search identified one posthoc analysis of a randomised clinical trial in 1156 adult patients undergoing major non–cardiothoracic, non–intracranial surgery, conducted in an academic tertiary hospital in Melbourne; that study, comparing a low versus high tidal volume, found that the highest intraoperative mechanical power had an independent association with occurrence of postoperative pulmonary complications.In this current analysis, using individual intraoperative ventilation data of patients at risk for postoperative pulmonary complications and scheduled for open abdominal surgery that were included in two recent international randomised clinical trials of a low versus a high level of positive end–expiratory pressure, we found that higher time–weighted average mechanical power had an independent association with occurrence of postoperative pulmonary complications. The association was neither affected by the level of positive end–expiratory pressure nor by body mass index.Exposure to higher mechanical power has an independent association with occurrence of postoperative pulmonary complications in at risk patients undergoing open abdominal surgery. Next to being a useful digital biomarker, with prognostic capacities for outcome, mechanical power may also serve as a target, to limit the intensity of intraoperative ventilation.Alt-text: Unlabelled boxPostoperative pulmonary complications often occur in patients after major surgery and result in attributable morbidity and mortality.The mechanical power of ventilation is a recently introduced ventilation parameter that summarizes the amount of energy per unit of time transferred from the ventilator to the respiratory system, and part of this energy acts directly on lung tissue where it can cause iatrogenic harm.16The effects of the intraoperative mechanical power on the occurrence of postoperative pulmonary complications in abdominal surgery have not yet been investigated thoroughly. In theory, limiting the intraoperative mechanical power could reduce the risk for postoperative pulmonary complications and as such improve postoperative outcomes. We tested the hypothesis that the mechanical power has an association with occurrence of postoperative pulmonary complications, independent of driving pressure, using individual patient data from two prospective trials that compared postoperative pulmonary complications at different levels of positive end–expiratory pressure (PEEP) in patients at risk for postoperative pulmonary complications planned for open abdominal surgery.Individual patient data of two recent international, multicentre, randomised clinical trials–the ‘Protective ventilation using high versus low PEEP’ (PROVHILO) trial (ISRCTN70332574),,Inclusion and exclusion criteria of the two studies have been reported before;As dictated by the protocol of the two studies, several baseline parameters, like medical history and vitals, were collected preoperatively. Intraoperative ventilation parameters were manually collected at the start of invasive ventilation and hourly thereafter until the end of surgery. Besides, several non–ventilator parameters, like intraoperative fluid management and prophylactic antibiotic use, were collected.,The driving pressure and the mechanical power were calculated at the start of invasive ventilation, and hourly thereafter until the end of surgery. Since plateau pressure was not recorded in every patient, dynamic driving pressure was calculated as peak pressure – PEEPWe used the same primary endpoint of the two original studies for this posthoc analysis: postoperative pulmonary complications up to postoperative day seven, defined as a collapsed composite of mild and severe respiratory failure, acute respiratory distress syndrome, pulmonary infection, pleural effusion, atelectasis, pneumothorax, and bronchospasm. Mild and severe respiratory failure were defined as a PaO2 < 60 mmHg or SpO2 < 90% in room air during at least 10 min in need of supplemental oxygen (excluding hypoventilation), and PaO2 < 60 mmHg or SpO2 < 90% despite supplemental oxygen or in need for non–invasive or invasive mechanical ventilation (excluding hypoventilation), respectively. A description of each element of the composite is provided in the No sample size calculation was performed, as all available data from the two original trials was used. Patient demographics, ventilation variables, and parameters were presented using descriptive statistics. Continuously distributed variables were expressed as medians and their interquartile ranges. Categorical variables were expressed as n (%). Mann–Whitney U–tests and Chi–squared tests were used to compare groups where appropriate.2) as low as 0·05, with 28 or less predictors considering an alpha level of 0·05.To assess the association between the intraoperative mechanical power and postoperative pulmonary complications, a multivariate logistic regression analysis model was used. Covariates were considered for adjustment in all models described based on clinical relevance and were included in the main multivariable logistic regression model by forced entry. The following covariates were considered: age, sex, body mass index, type of surgery, ARISCAT score, American Society of Anesthesiologists (ASA) classification, history of chronic obstructive pulmonary disease, history of active cancer, history of heart failure, preoperative peripheral oxygen saturation, respiratory rate, heart rate, mean arterial blood pressure, fraction of inspired oxygen and end–tidal carbon dioxide in the first hour of intraoperative ventilation, the use of antibiotic prophylaxis, specific procedure, duration of surgery, duration of anaesthesia, use of epidural, type of anaesthesia, amount of blood loss, total amount of fluid administered, use of any transfusion, urine output, emergency procedure and trial. In all models, the participating centre was included as random effect to account for clustering. After checking for collinearity between driving pressure and mechanical power, using gender, BMI, ASA classification score and ARISCAT score as covariates, driving pressure and mechanical power were combined in the same multivariable model with all considered covariates. Missing values were imputed by the median if <5% of data was missing. The E–value was measured, to quantify the evidence strength for the association in the possible presence of unmeasured confounding.Three sensitivity analyses were performed. The primary analysis was repeated without imputation of missing data. To evaluate the effect of the allocated intervention on the association between the mechanical power and postoperative pulmonary complications, the main model was reassessed for patients in both the low and high PEEP intervention groups. The interaction between PEEP intervention group and intensity of ventilation was assessed. To investigate the effect of body mass index on the association between the mechanical power and postoperative pulmonary complications, the interaction between body mass index and intensity of ventilation was assessed.p<0·05 was considered significant.All analyses were performed with R statistics (version 3.4.3), and a The two original studies were supported by unrestricted grants from the European Society of Anaesthesiology and the Amsterdam University Medical Centers, Location AMC. For this current analysis, no additional funding was requested. The funding sources had neither a role in the design, collection of data, statistical analysis, interpretation of data, writing of the report, nor in the decision to submit the paper for publication. Schuijt and Serpa Neto had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors took the responsibility to submit the paper for publication.’2) comparing the PROVHILO and PROBESE study. Besides, the distribution of ASA classification score differed, as 32·9% of patients classified as ASA class 3 in the PROVHILO study, compared to 63·0% of patients in PROBESE study.Merging the databases of the two studies resulted in a total of 2870 patients. Of these, 1191 (41·5%) patients could be used for the current posthoc analysis . The maiPostoperative pulmonary complications occurred in 425 (35·9%) patients . The mos2O, and 7·6 [5·1–10·0] J/min, respectively. Ventilator parameters, including driving pressure and the mechanical power, during the first 5 hours of ventilation are shown in respectively 2O (p=0·997), and 7·9 [5·4–10·4] and 7·5 [4·9–9·8] J/min (p=0·026), respectively.Ventilation parameters at the first hour of ventilation are presented in eTable 5 in the Online Supplement. Median tidal volume was 7·9 (7·3–8·1) mL/kg predicted body weight and median respiratory rate was 12 (10–13) /min at the first hour of ventilation. Median time–weighted average driving pressure and mechanical power were 14·0 [11·0–17·0] cmH2O in driving pressure was not , but an increase of 1 J/min in mechanical power was associated with occurrence of postoperative pulmonary complications after adjustment for all confounders   . The comp=0·748 and p=0·960 . No interaction was found between driving pressure or mechanical power and PEEP intervention group, respectively  p=0·960 , meaningIn this posthoc analysis of two randomised controlled trials comparing intraoperative ventilation at two different levels of PEEP in patients at increased risk of postoperative pulmonary complications planned for major abdominal surgery, we found that higher mechanical power was, but higher driving pressure was not, independently associated with increased occurrence of postoperative pulmonary complications after adjustment for confounders. The association of the mechanical power with postoperative pulmonary complications was not affected by body mass index or treatment allocation, i.e., the level of PEEP used did not affect this finding.,,,,,Compared to other cohorts of abdominal surgery patients, our patient cohort had similar baseline characteristics.,,This study is the first to investigate both intraoperative driving pressure and the mechanical power in patients undergoing open abdominal surgery. In contrast to previous studies in patients undergoing intraoperative ventilation for abdominal and non–abdominal surgery, we found no significant association of intraoperative driving pressure with postoperative pulmonary complications.,Despite the absence of an association between intraoperative driving pressure and postoperative pulmonary complications, driving pressure remains a valuable digital biomarker. Driving pressure has been found to be associated with patient outcome in both intraoperative ventilation,,,,,Many equations for calculating the mechanical power in an individual patient have been suggested and used.This analysis has strengths. This is the first study to report on the association between the exposure to the mechanical power and postoperative pulmonary complications in patients undergoing open abdominal surgery using longitudinal data collected at fixed timepoints. Patients undergoing laparoscopic abdominal surgery were excluded, as pneumoperitoneum influences intraoperative ventilation due to higher intra–abdominal pressure. The combined international studies were conveniently sized, recently performed, conducted in a short period of time and included a large number of academic and non–academic centres worldwide, increasing robustness and generalizability of the results. We also followed a preplanned analysis plan. Besides, the characteristics of the two original trials were provided.This study also has limitations. The included data was the result of merging two randomised clinical trials, one could question the generalizability for regular intraoperative care. However, the sensitivity analysis showed no differences in parameters of intensity of ventilation between PEEP intervention groups. Besides, all patients had an increased risk for postoperative pulmonary complications and underwent open abdominal surgery and were mechanically ventilated following endotracheal intubation. This could decrease generalizability in patients with a lower risk for postoperative pulmonary complications, undergoing laparoscopic abdominal or non–abdominal surgery, or when using supraglottic airway devices. Also, in post–hoc analyses a form of residual confounding cannot be excluded. Unfortunately, important factors that could also have an association with the outcome of interest, like fluid balance and history of valve disease, were not collected in the original studies. Tube size was also not recorded in the two studies. Furthermore, the use of a composite endpoint could be seen as a limitation. However, the incidence of the separate postoperative pulmonary complications was reported and even minor pulmonary complications, like unplanned supplementary oxygen, are associated with clinically relevant outcomes, like duration of hospital stay.In this merged cohort of surgery patients at an increased risk for postoperative pulmonary complications that were planned for open abdominal surgery, higher mechanical power was independently associated with postoperative pulmonary complications. The mechanical power could serve as a summary ventilatory in these patients, but our findings needs confirmation in other, preferably prospective studies.Marcelo Gama de Abreu declares consultations at Ambu, ZOLL, Lungpacer and patents on variable pressure support. Serpa Neto reports lecture fees from Dräger, outside of the submitted work. Schultz reports personal fees from Hamilton  outside of the submitted work. All other authors declare no competing interests.


Circulating parathyroid hormone (PTH) concentrations increase in heart failure (HF) and are related to disease severity. The relationship between PTH and congestion is still a matter of debate. The objective of this analysis was to evaluate the role of PTH as a marker of congestion and prognosis in HF. We enrolled 228 patients with HF. Intact PTH concentrations and HYDRA score  were evaluated. The study endpoint was all-cause mortality. PTH levels were higher in acute compared with chronic HF and in patients with clinical signs of congestion . PTH concentrations significantly correlated with NYHA class and HYDRA score. At multivariate analysis of HYDRA score, estimated glomerular filtration rate (eGFR), and corrected serum calcium were independently determinants of PTH variability. Fifty patients (22%) died after a median follow-up of 408 days (interquartile range: 283–573). Using univariate Cox regression analysis, PTH concentrations were associated with mortality . Using multivariate Cox regression analysis, PTH was no longer associated with death, whereas HYDRA score, left ventricular ejection fraction, and eGFR acted as independent predictors for mortality . Our study demonstrated that intact PTH was related to clinical and subclinical markers of congestion. However, intact PTH did not act as an independent determinant of all-cause death in HF patients. The parathyroid hormone (PTH) is one of the most important regulators of bone and mineral metabolism, mainly acting on calcium, phosphorus, and vitamin D reabsorption and excretion from bones, kidney, and gut . The carThe relationship between PTH and heart failure (HF) has been pointed out according to current evidence ,6,7,8. PIntact PTH values > 65 pg/mL seemed to be associated with a 50% increased risk in incident HF in the Multi-Ethnic Study of Atherosclerosis (MESA) . Data shNevertheless, the in-depth evaluation of the possible association of PTH with congestion status in HF is still a matter of debate and there is scarce evidence in the current literature. Higher PTH plasma concentrations were related to worse New York Heart Association (NYHA) class ,17,18,19The aims of the present study were to evaluate the relationship between PTH and congestion biomarkers of HF and to consider the impact of PTH plasma concentrations on the overall prognosis of patients with both acute (AHF) and chronic (CHF) HF.We enrolled 228 consecutive HF patients who were admitted to the Cardiology Unit of Hospital of Altamura–Bari  between January 2010 and November 2013 due to acute decompensation (AHF) or because they were followed-up as outpatients (CHF).We collected clinical characteristics, blood chemistry data, BIVA, and pharmacological treatments from all patients. Left ventricular ejection fraction (LVEF) was calculated by means of echocardiography (Simpson’s method). BNP levels were assessed using a microparticle enzyme immunoassay . The intra- and inter-assay variability coefficients ranged from 0.9% to 5.6% and 1.7% to 6.7%, respectively. Serum creatinine was measured with a Beckman Coulter AU 680 chemistry analyser. Intact serum PTH was determined by Electro-ChemiLuminescence Immunoassay Kit , with a normal range of 15–65 pg/mL and an inter-assay coefficient of variation ranging from 5.7 to 6.3%. All of these measurements were performed as a routine evaluation of the patients admitted to our department.Inclusion criteria were: diagnosis of AHF or CHF, age > 18 years old, and willingness to be included in the study. Specifically, CHF was defined in case of the presence of specific signs  and symptoms ; echocardiographic features for definition of the type of CHF were adopted in relation to international guidelines . PatientWe considered as exclusion criteria all acute conditions, such as myocarditis, pericarditis, pulmonary embolism, acute coronary syndrome, and recent cardiac surgery intervention. We also excluded patients with cancer, end-stage kidney failure and/or haemodialysis, primary hyperparathyroidism, and systemic inflammatory diseases.Patients were considered as suffering from coronary artery diseases if they experienced previous myocardial infarction and/or coronary revascularization ; diabetes was defined as cases of fasting plasma glucose level ≥ 126 mg/dL or use of antidiabetics, whereas hypertension was identified by blood pressures higher than 140/90 mmHg.The primary endpoint was all-cause mortality which was ascertained from available medical records or National Death Records.The study complied with the Declaration of Helsinki and was approved by the local Institutional Review Board. Written informed consent was obtained from each patient at inclusion .To correct serum calcium concentration levels, we used the following equation: corrected calcium = total calcium (in mg/dL) + 0.8 ×  .2) as (140 − age in years) × (weight in Kg)/(72 × serum creatinine in mg/dL) × 0.85  : 12.9–17.6) . EvidencePVS (dL/g) was calculated from haematocrit and haemoglobin values at admission using the Strauss–Duarte formula: (100 − haematocrit in %)/haemoglobin (in g/dL) .BIVA was assessed on the right side of the body using tetrapolar impedance plethysmography that emitted a 50 kHz alternating sinusoidal current  ,33. The The two vector components, R and Xc, of BIVA were recorded and divided by the subject’s height. (R/Xc graph). The results were visualized as a BIVA-derived hydration percentage . This value was calculated by an equation that used two components, R and Xc . The normal values are in the range between 72.7% and 74.3%, corresponding to the 50th percentile of the R/Xc graph .We previously demonstrated the prognostic ability of four markers related to the different components of congestion in HF: BNP (“haemodynamic” congestion), ePVS (“intravascular” congestion), hydration index BIVA-derived , and BUN/Cr (“venous” congestion). A simple score was generated based on the number of different elevated parameters of congestion: BNP > 441 pg/mL, BUN/Cr > 25, Duarte-PVS > 5.3dL/g and Hydration > 73.8% that we called the HYDRA score (range from 0 to 4) [Categorical variables were presented as percentage (%), and continuous variables were expressed as the mean and standard error of mean (SEM). Comparisons between two groups were performed with Student’s t-test or the Mann–Whitney U-test where appropriate. One-way analysis of variance (ANOVA) was used when comparisons were performed among more than two groups. The Spearman’s rho correlation coefficient was used to analyse the correlation between PTH levels and other variables. Multivariate regression analysis was utilized in order to assess the determinants of PTH levels. Receiver-operating characteristic (ROC) curve analysis was performed to calculate the area under the curve (AUC) values, and the optimal cut-off values for mortality were calculated as the point of maximum sensitivity and specificity.p-Values below 0.05 were defined as statistically significant.Univariate and multivariate Cox proportional hazards regression models with estimations of hazard ratios (HR) and 95% confidence intervals (95% CI) were performed to evaluate the impact of variables on mortality. Statistical analysis was performed using STATA software, version 12 .Two hundred and twenty-eight patients  were included in this study. Patients with AHF showed significantly higher PTH plasma levels compared with uncongested patients.These results were in line with the overt expression of clinical signs of congestion: patients with peripheral oedema or orthopnoea had higher levels of PTH compared with those who did not experience such signs A,B.p < 0.01 for all). Nevertheless, PTH levels were correlated to HYDRA score , corrected serum calcium , and eGFR  in patients with AHF, whereas only HYDRA score remained significantly correlated to PTH plasma levels in patients with CHF .In addition, PTH levels significantly correlated to BNP levels (rho = 0.43), BUN/Cr (rho = 0.17), ePVS (rho = 0.23), and hydration status (rho = 0.43). At multivariate regression analysis, HYDRA score, corrected serum calcium, and eGFR remained significantly associated to PTH plasma levels . Furthermore, the decrease in the eGFR values was related to the increase in HYDRA score (p < 0.001 ANOVA)  B.p < 0.001) and eGFR .Similarly, PTH levels were inversely related to the corrected serum calcium plasma values . The cumulative mortality incidence was 22%. Using univariate Cox regression analysis, PTH plasma levels, type of HF, age, NYHA class, LVEF, eGFR, and HYDRA score were predictors of mortality .p = 0.003). Nevertheless, the multivariate Cox regression analysis revealed that PTH levels were no longer associated with mortality in HF patients, whereas HYDRA score, LVEF, and renal function still remained independent predictors for mortality —a potential marker of platelet activation—in patients with symptomatic HF , our stuTherefore, although PTH is related to congestion in HF, thus providing further advice to physicians for the comprehension of the fluid overload status of patients with HF as a congestion biomarker, its prognostic impact is questionable and related to kidney function. Indeed, LVEF, eGFR, and multiparametric score for congestion identification provide interesting prognostic insight in the evaluation of all-cause mortality in HF patients. Our group has already demonstrated the prognostic implication of creatinine clearance in patients with HF  as well Although reduced LVEF is known to be directly related to adverse events and prognosis in patients with HF , the ideThis paper has some limitations. Firstly, we did not evaluate the presence of secondary hyperparathyroidism. As the main aim of the paper was to evaluate the impact of the serum level of PTH in patients with HF, we did not concentrate on the causes for secondary hyperparathyroidism, which could be the focus of further studies in the context of HF. The lack of end-stage kidney failure/dialysis patients and the demonstration of the independent value of our results from kidney function reduce the probability for secondary causes of hyperparathyroidism. Secondly, the retrospective nature of this study is a further limitation: dedicated cohort longitudinal studies might be managed in order to reinforce the results. Finally, this was a single-centre study: the involvement of several HF centres located at different sites might promote confirmation of the results.PTH is a reliable biomarker for congestion status in patients with HF as it is related to peripheral oedema, orthopnoea, and HYDRA score, independently from renal function. PTH was not an independent predictor for all-cause mortality in HF but might contribute to the correct evaluation of the congestion status of patients with both AHF and CHF.


The incidence of chronic kidney disease (CKD) has been found to increase with age. This has resulted in an increase in the number of elderly patients undergoing renal replacement therapy. There is a significant risk of error in making treatment decisions in patients with advanced CKD based solely on biochemical parameters of renal function, if the changes in the functional status of patients' health are not taken into account.AimTo determine the interrelated dependencies between chronic kidney disease with the functional status of patients aged over 65 years and to elucidate differences in functional status between CKD patients and controls.MethodsPatient subjects were qualified according to their assessed outcomes from the study protocol, which were achieved by: geriatric interview, assessing functional status by the IADL, Barthel and Tinetti tests together with assessing kidney function by performing laboratory tests of glomerular filtration rate (GFR), creatinine and urea. Subjects were divided into two groups: method 1—according to GFR and method 2—according to GFR and functional test results. The data were statistically analysed by structural equation modelling and k-means.Resultsp < 0.01), along with the number of medications taken and age . A highly negative relationship was observed between the CKD stage and the Tinetti test results , whilst more moderate ones were found with the IADL and Barthel scores . The patient groups demonstrated differences in health status when selected by method-2 for: age, comorbidity, number of medications taken, fitness test outcomes . Those groups divided according to GFR, however only showed differences in age, comorbidity and the number of medication taken (p < 0.005).Positive relationships were found between the CKD stage and comorbidity (β = 0.55, ConclusionsThe functional status worsens in geriatric patients suffering from CKD. It may thus be important to also account for disruptions to functional status when assessing CKD advancement in the elderly in addition to the GFR. The biggest problems for the over 80 s suffering from CKD are gait and balance disorders, leading to a high risk of falls. Another common problem is polypharmacy, found in both the geriatric population and particularly in those suffering from CKD. A comprehensive assessment of health status of the elderly with CKD is not only determined by measuring markers of renal function (i.e. creatinine and GFR), but by also assessing changes in functional, emotional, cognitive and nutritional status. Such assessments require medical professionals to have the appropriate expertise and skills in order to use the appropriate scales and tests for making any geriatric assessment comprehensive, supplementing diagnoses with additional clinical information relevant for further treatment. Assessment of functional status is especially important, as undertaking renal replacement therapy in end-stage renal failure in patients with frailty syndrome may further deteriorate their functional status or shorten their survival. The poor functional state of the patient may be the reason for a decision to treat the patient with assisted peritoneal dialysis at home or to refrain from renal replacement therapy with both hemodialysis and peritoneal dialysis.The study primarily aimed to answer whether CKD and functional status are related and secondly to determine what the differences are, if any, between the functional status of CKD patients compared to controls.Incidence rates of CKD increases with age and thus becomes a social problem in the elderly. Almost 50% of people aged over 70 years are diagnosed with CKD grade 3–5 . PatientOther studies have also shown that morbidity is associated with polypharmacy and mortality in the elderly . PolyphaPhysical fitness  of elderly patients is the ability to perform daily life activities, whether independently, with the aid auxiliary devices or from people such as eating and preparing meals, maintaining personal hygiene and that of their surroundings as well as moving around, the ability to take medications independently, using the telephone and exercising personal control over finances. Progressive aging however leads to a gradual loss of both fitness and being able to independently execute daily activities. A comparative study has shown that the ability of being able to carry out complex everyday activities  had decreased to 9.9% in 90-year-olds compared to rates of 79.4% in those aged 65–69 years . The 201The presented study emphasises the role of undertaking a comprehensive geriatric assessment, particularly to detect changes in the patient's functional status when assessing CKD advancement. It also suggests a reversal from the current trend of relying only on laboratory parameters in such an assessment. This research is also highly relevant and needed because there are as yet still no guidelines for medical practitioners in geriatric nephrology on which is the most appropriate tool for assessing functional status in the elderly suffering from CKD.inter alia, age, comorbidity (number of diseases), the recorded history of medications taken.1. Geriatric interview including, 2. Geriatric physical examination, including:Assessing the patient's functional status using the Lawton IADL test, the Barthel test and the Tinetti test to assess the risk of falls.3. Additional blood tests for creatinine, urea and GFR assessment .The study subjects were assessed according to the developed protocol, which included the following procedures:Co-morbidity was evaluated by a questionnaire completed by patients during geriatric interview coupled with studying their available medical history. Questions were asked whether subjects were/had been suffering from the following medical conditions: 1) Heart attack, 2) Heart failure, 3) Hypertension, 4) Atherosclerosis, 5) CNS diseases such as stroke, TIA, 6) Hemiparesis, 7) Dementia, 8) Chronic lung disease, 9) Chronic connective tissue disease, 10) Chronic peptic ulcer disease, 11) Chronic liver disease, 12) PCHN, 13) Malignant neoplasm, 14) Chronic hematological diseases, eg. leukemia and 15) Others. One point per condition was awarded whenever confirmed by the subject.The geriatric interview established what and how many medications were taken daily by the subjects backed up by checking the patient’s medical history notes. Only prescription medication was considered; dietary supplements were excluded. One point was awarded per medication.The I-ADL scale was used instead of the ADL scale because this evaluates not only basic life functions, but also other complex functions as well as being more effective in those elderly patients without comorbidities. This I-ADL scale assesses eight daily activities: 1) Using the telephone, 2) Doing everyday shopping, 3) Preparing meals, 4) Daily house cleaning, 5) Loading laundry, 6) Using transport, 7) Taking one’s medication and 8) Managing one’s finances. One point was awarded per independently performed activity, with therefore a maximum score of 8 points possible. Zero points were given whenever subjects received help with these activities or whenever they hadn’t actually been engaged in. Thereby, the fewer the points, the less effectively a subject performs such everyday activities. A decrease in I-ADL scores over time indicates that a patient’s general condition is deteriorating.The second scale used was the Barthel scale because this contains extra and important questions which are absent in the I-ADL scale concerning personal hygiene as well as ones on crucial geriatric issues such as urinary and faecal incontinence. The Barthel scale is also more suited to disabled patients. The scale evaluates ten everyday life activities as follows: 1) Eating meals, 2) Moving (from a bed to chair and back), 3) Maintaining personal hygiene , 4) Using the toilet, 5) Washing and bathing the whole thing body, 6) Walking on flat ground, 7) Walking upstairs, 8) Getting dressed and undressed, 9) Controlling urination and 10) Controlling defecation.The following point ranges were adopted according to the scale of difficulty encountered by subjects: 5–15 points for performing activities independently, 5–10 points when assistance is given and zero points for not engaging in any given activity. The maximum possible Barthel score is thus 100 points, with 86–100 being regarded as minor, 21–85 as medium-severe and 0–20 points as a very severe patient’s condition.The Tinetti test was used to evaluate gait and balance, as this test is regarded as being the gold standard for diagnosing disorders in such areas. A subject fully passing a balance test receives a 16 point maximum while a maximum score of 12 is awarded for the gait test; giving a total maximum score of 28 points. A score of ≤ 25 indicates that there is a risk of falls, and a score of < 19 indicates that a subject's risk of falls increases five times.The scoring scales assessing functional status by the IADL, Barthel, Tinetti methods can be found in the footnotes at the end of this paper.The study group were patients aged over 65 years of age, hospitalised at the Nephrology Clinic of the Military Institute of Medicine and those patients under long-term care at the Dialysis Center, also from the Military Institute of Medicine.2 -normal or increased GFR.G1: ≥ 90 ml/min/1,73m2 -slight reduction in GFR.G2: 60–89 ml/min/1,73m2 -decrease in GFR between slight and moderate.G3a: 45–59 ml/min/1,73m2 -reduction in GFR between moderate and severe.G3b: 30–44 ml/min/1,73m2 -severe decrease in GFR.G4: 15–29 ml/min/1,73m2 -end-stage renal disease.G5: < 15 ml/min/1,73mAccording to the guidelines of KDIGO of 2012, CKD is divided according to following GFR classification:2) had similar results to patients from the control group. For the purposes of this study, the division into 3 groups were thus used.This study did not adopt this division into 5 groups (according to the KDIGO guidelines) because after initial analysis of results, it turned out that patients G1 and G2  according to GFR division and, 2) according to division by GFR and functional test results.2); n=28 (where n is number of participants of the group).- Group-1, the haemodialysis, with CKD stage V (GFR of <15 ml/min/1.73m2); n=62.- Group-2, with CKD stage III-IV .- Group-3, controls, subjects without CKD, n=23, patients with a GFR of ≥60ml /min/1.73mThe following groups were obtained when the GFR criterion was used:2), n=28, who were on haemodialysis together with n=16 subjects with CKD stage IV that had similar functional test results; giving a total of n=44.- Group i.1 with CKD stage IV-V  and similar functional test results; n= 34.- Group i.2 with CKD stage II-III  to the theoretical matrix (designed by the researcher). The stronger the fit, the more closely the data matches the researcher's reasoning as expressed in the structure of the theoretical model. The structural model itself was estimated by the IBM AMOS v.13 using the asymptotically distribution free (ADF) method . The k-mSelected multi-group comparisons of significance were performed by ANOVA  which determines whether there are any statistically significant differences between independent groups of quantitative variables. It compares intra-group variation with inter-group variation . It founp < 0.01), demonstrating that medications taken accounted for 3.8% of the variability in CKD scores (R2 = 0.03). A moderate relationship between comorbidity and CKD was found at β = 0.55, p < 0.001, showing that comorbidity is accounted for by 30% of the variability in the CKD scores (R2 = 0.30). The relationship between age and CKD turned out to be weak at β = 0.30, p < 0.001, meaning that patient age accounts for 9% of the variability in CKD scores (R2 = 0.09). The number of medications taken and comorbidity were found to be moderately related to each other at β = 0.56, p < 0.001, but there was no relationship observed between the number of medications taken and age, nor was there one between comorbidity and age; both being statistically insignificant. CKD is negatively associated on how patients cope with daily activities as measured by the I-ADL test, , which shows that CKD accounts for 24% of the variability in patient scores , meaning that the higher the CKD stage, the worse patients are able to cope with everyday activities. CKD is also negatively associated with how patients cope with daily activities as measured by the Barthel test. This relationship turned out to be moderate , with CKD accounting for 16% of the variability by this test . The higher the CKD stage, the worse the patient is able to cope with everyday activities. In addition, CKD is negatively related to the patient's gait and balance, where CKD is strongly associated with the Tinetti test values, , indicating that CKD explains 51.2% of the variability in patients' scores in this test . Thus the higher the CKD stage, the greater gait and balance are impaired. The described results are presented in Fig. The theoretical model chosen for this study was based on scientific studies that shows the relationship of CKD with patient age, comorbidity, number of medications taken and functional status. The patient's age, comorbidity and the number of medications taken are considered exogenous variables  in the model of chronic kidney disease. We assumed that when these factors rise, their increase was positively related to the CKD stage (i.e. a positive relationship). However, chronic kidney disease is also a variable in the theoretical model concerning the patient's physical condition; understood as being physical fitness. The theoretical model assumes a negative relationship between CKD and functional status, i.e. the higher the CKD stage, the worse functional status; i.e. a negative relationship. The analysis using structural equations revealed a weak relationship between CKD and the number of medications  consisted of 44 subjects who had the highest concentrations of creatinine  and urea but the lowest GFR i.e. Those with advanced CKD stage IV-V. This group had the lowest mean age among all the groups distinguished but the highest comorbidity and they took the most drugs. Outcomes from the Tinetti test were average, whilst they were high for everyday activities (according to the IADL and Barthel tests) Fig. , Table 2A second cluster was classified by algorithms into 34 people with average study levels of creatinine, urea and GFR; this being subjects with stage II-III CKD Fig. ,Table 2.The algorithms classified 35 subjects in the third cluster with the lowest creatinine and urea concentrations but the highest GFR value. These were subjects without CKD , Int = the magnitude of the effect size index, i.e.; 0.01–0.06 , 0.06–0.14 (Medium) and > 0.14 (Large), [Description of symbols used in Tables (Large), .A cluster analysis was also performed on the variables described in the theoretical model by using the k-means method where a modelled grouping of variables was introduced for those undergoing dialysis, with and without renal failure, in such a way that only subjects belonging to groups selected on the basis of GFR values were classified to the clusters.This aimed to determine whether there are significant differences between these groups and what profile is characteristic for each of these groups, in terms of the variables described in the theoretical model. The solution to the cluster analysis is presented in Fig. n = 62, Table n = 28, Table People belonging to the group with renal insufficiency  Table .2 = a measure of the proportion of total variance (related to the effect size index), Int. = the magnitude of the effect size index, i.e.; 0.01–0.06 , 0.06–0.14 (Medium) and > 0.14 (Large), [Description of symbols used in Tables (Large), .The analysis using structural equations demonstrated the different extents by which CKD is associated with all the studied variables in the elderly .As an independent factor, having CKD worsens the physical condition of elderly patients and results in a two-fold increase in the risk of impaired functional status compared to those elderly people without CKD –17.The mechanisms underlying this relationship are complex. Some studies have associated CKD with increased comorbidity, especially with cardiovascular diseases, which in turn reduces physical activity and thereby an impaired functional status . Indeed,The relationship between CKD and patient age is unclear. A multicentre meta-analysis by S. Hallan (JAMA in 2012), demonstrated that low GFR and high albuminuria are associated with mortality and ESRD  irrespective of age . NonetheThe problem of polypharmacy is common among older patients, but there are only a few scientific reports regarding any direct relationship between the number of medications taken with CKD. The presented study however showed a weak relationship between CKD and the number of medications taken, whereas an English study showed that approximately 20% of patients with CKD take more than 10 different medications daily .p < 0.005. As expected, i.3 group outcomes showed the lowest comorbidity, patients taking the least drugs, highest scoring in gait and balance tests (Tinetti test) along with the fitness tests .Our study has revealed that the patient groups i.1, i.2, i.3 significantly differed from each other in terms of: age, comorbidity, number of medications taken and fitness test outcomes ; Patients from i.1 group are however younger, have the highest comorbidity, take the most medications, and have average study results in for the fitness tests. The average study outcomes in tests of daily activities in this group can be explained by their lower age compared to the ages of the i.2 subjects (72.4 years vs 84 years). Nevertheless, the high scores from the IADL test (7.5 pt/ 8pt.) and Barthel test (97.5 pt/ 100pt) did not correlate with the low score in the Tinnetti test (22.6pt /28 pt). These results suggest there is an additional factor present that increases the risk of falls within this patient group; this might be the large number of drugs taken (average of 10 /day) or the high concentrations of creatinine (average 4.98 mg /dl) or urea (average 129.45 mg /dl).The i.2 group have the highest mean age (84 years), take less drugs than dialysis patients, and have a lower comorbidity compared to dialysis patients. Furthermore, they scored the lowest in the gait and balance test (17.3pt / 28pt in the Tinetti test) and also the lowest results in the fitness tests . Such low scoring in the functional tests are due to the presence of advanced CKD (stage III) and the age of the respondents. Similar observations have been presented by D. Weiner and S. Seliger .One can assume that the low scores obtained by patients aged over 80 years in the Tinetti test will lead to more frequent falls in these patients. Indeed, yearly falls are observed in around 30% of people aged over 75 years without CKD, in about 38% of people with CKD and about 50% of patients on haemodialysis –29. DisoBoth CKD patient groups, (i.e. stage III of CKD and the HD—stage IV-V of CKD) gave more inferior test scores for the functional test compared to controls thus providing evidence that CKD significantly worsens the functional status of patients irrespective of age.p < 0.005. Differences in daily activities were found to be insignificant as measured by the Tinetti, IADL and Barthel scales which shows that assessing of the health of patients with CKD should be made not only on the basis of GFR values, but also by assessing changes in the functional status of patients.Our results demonstrate that those subject groups with renal failure, without renal failure and those undergoing haemodialysis significantly differ from each other in terms of: age, comorbidity and number of medications taken; Finally, the amount of medications taken by the patient groups also needs commenting on. The most drugs were taken by the HD patients (~ 10), regardless of group breakdown, whilst slightly fewer were taken by CKD patients ( approx. 7), and the least by the control group (approx. 5). This means that the problem of polypharmacy concerned all subjects and therefore it is necessary to take remedial measures to reduce this unfavourable phenomenon.CKD in the geriatric population worsens their functional status. The causal relationship, , has been confirmed and proven by both the results using the theoretical model and the results of the cluster analysis. This indicates that the more CKD is advanced, then the worse the functional state is. Furthermore, subjects aged over 80 years with CKD (being at least in stage III), achieved the worst results in the gait and balance disorders test (Tinetti test). It is in fact these disorders that particularly need to monitored when assessing the functional status of such patients. Polypharmacy is also another common problem in the elderly, especially in patients with CKD.https://doi.org/10.1111/j.1532-5415.1986.tb05480.xhttps://www.leadingagemn.org/assets/docs/Tinetti-Balance-Gait--POMA.pdfhttps://doi.org/10.1093/geront/9.3_Part_1.179https://www.alz.org/careplanning/downloads/lawton-iadl.pdfhttp://www.sciepub.com/reference/163871https://stopstroke.massgeneral.org/pdfs/barthel_reprint.pdf


Liuzijue training (LZJ) is a traditional exercise integrating breathing meditation and physical exercise, which could prevent and improve hypertension symptoms.We aimed to evaluate the therapeutic effect of LZJ on hypertensive patients from the perspectives of blood pressure (BP), vascular endothelial function, immune homeostasis, and gut microbiota.We conducted a randomized, controlled, single-blind experiment to assess the effect of 12 weeks LZJ in hypertensive patients. We measured the blood pressure level, vascular endothelial function, serum inflammatory factor concentration, and fecal microbial composition of hypertension patients.Compared with aerobic training, LZJ has a more significant effect on serum inflammatory factors (IL-6 and IL-10) and gut microbiota. PCoA analysis showed that LZJ tended to transform the gut microbiota structure of hypertensive subjects into that of healthy people. This process involves significant changes in Bacteroides, Clostridium_sensu_stricto_1, Escherichia-Shigella, Haemophilus, Megamonas, and Parabacteroides. In particular, Bacteroides and Escherichia-Shigella, these bacteria were closely related to the improvement of BP in hypertensive patients.In conclusion, our results confirm that LZJ could be used as an adjuvant treatment for hypertensive patients, which could effectively reduce BP, improve the immune homeostasis and gut microbiota structure in patients, and provide a theoretical reference for the use of LZJ in the clinic.http://www.chictr.org.cn/listbycreater.aspx, identifier: ChiCTR2200066269. Hypertension is a common chronic disease caused by the interaction of genetic and environmental factors , 2. It iNumerous studies have shown that regular exercise could reduce BP levels and improve its complications . The guivia regulating the composition and structure of gut microbiota  Patients with secondary hypertension, such as increased BP or drug-induced hypertension caused by acromegaly, Cushing's syndrome, and other diseases; (ii) In the high-risk or very high-risk state in the stratification of cardiovascular risk level; (iii) Patients with heart, liver, kidney, other organ dysfunction and severe complications such as diabetes; (iv) Patients with a history of intestinal surgery, inflammatory bowel disease, abdominal disease, lactose intolerance, chronic pancreatitis, or other malabsorption diseases.Inclusion criteria for healthy subjects: (i) Age 45–80, gender unlimited, healthy; (ii) Those who have no habit of overeating and have relatively regular diet; (iii) Have no regular exercise habit at ordinary times ; (iv) In the past month, those who did not take antibiotics, steroids, microbial preparations, blood activating and blood stasis removing herbs, and had no history of diarrhea and other gastrointestinal disorders; (v) Those who have not participated in clinical trials of Taichi, Baduanjin, and other exercise therapies in the past 6 months; (vi) Understand and voluntarily participate in the experimental research, sign the informed consent form, and be able to cooperate to complete the test index detection, with good compliance. Exclusion criteria for healthy subjects: (i) patients with heart, liver, kidney and other organ dysfunction, diabetes, and other serious complications; (ii) People with chronic gastrointestinal diseases; (iii) Long term heavy smokers and drinkers; (iv) Serious trauma and operation history in recent 6 months.This trial is a randomized, controlled, single-blind trial. The sample size is estimated by taking BP as the therapeutic index. It is effective to reduce BP by 5 mmHg in anticipation of exercise intervention . The forZα = 1.96, Zβ = 1.28, δ = 5, σ = 7.79, substitution formula: n = α = 0.05, β = 0.10, 1-β = 0.90, bilateral test, check the normal distribution table n1 = n/(1–10%) ≈ 28, 28 subjects are required for each group. There are 56 patients in both groups.Assuming that the withdrawal or loss rate is 10%, according to the formula: It is estimated that 56 hypertensive subjects will be included in the study. They will be numbered according to the order in which they were included in the study. The random numbers will be obtained through SPSS 24.0 software. The random numbers will be sorted from small to large, and then the subjects will be randomly assigned to different groups (LZJ and AT) according to the random numbers. The researcher in charge of subject recruitment and data statistics did not know the grouping of test subjects, and only made statistical analysis based on the number of subjects.http://www.chictr.org.cn/listbycreater.aspx; ChiCTR2200066269).The study was planned as part of the Key Project of Science and Technology of Sichuan (Grant No. 2020YFS0302). This study followed the principles in the Declaration of Helsinki and has been approved by the Medical Ethics Committee of the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine , and was registered at the China Clinical Trials Registry  Sports field: a field with a quiet environment and flat ground for training; (ii) Exercise time: 15:00–16:00 on Mondays, Wednesdays, and Fridays; (iii) Exercise frequency: Three centralized pieces of training every week for 12 weeks, a total of 36 times.The time of concentrated exercise is 1 h, including 5 min of preparatory activities ; 50 min of exercise; LZJ and AT have a 5-min relaxation activity after exercise. One set of LZJ exercise is about 12 min and four sets of LZJ movements were performed. A 2-min interval was adopted between two sets and exercises to rest. The AT subjects completed 50 min of AT exercise on the treadmill , maintaining the heart rate between 40 and 60% of the predicted maximum rate for age. Determined by the following formula: target heart rate = [(220-Age)- rest HR]*(40–60%)+rest HR . After 2During the intervention, other factors interfering with the experimental results were excluded. All subjects were not allowed to take any antibiotics, steroids, microbial agents, or traditional Chinese medicine for activating blood circulation and removing blood stasis, as well as other drugs that affect serum inflammatory factors and gut microorganisms. Exercise training such as Taichi and Baduanjin were also prohibited.All hypertensive subjects were required to follow up once before the intervention  and after the intervention . Our main purpose was to collect data on the SBP and DBP of hypertensive subjects.Office SBP and Office DBP were defined by Korotkoff sound phase 1 and phase 5, respectively. The measurement was performed by two experienced physicians and was measured twice. The measurement was considered valid if the difference between the two measurements was <10 mmHg; otherwise, a third measurement was taken, and the average value was used for analysis .The first test of ambulatory blood pressure monitoring (ABPM) was performed before the exercise intervention and used to determine the baseline of hypertensive participants. The second test was performed immediately 48 h after the end of the last exercise intervention to analyze the effect of the exercise intervention. The BP cuff was worn on the non-dominant arm. Subjects were instructed to maintain their customary daily activities, not to exercise, and to relax and unbend the arm during the recording interval for daytime ABPM. An ABPM recording was deemed to be complete if there were at least 14 readings between 6:00 am and midnight and at least six readings between midnight and 6:00 am . As recoBlood samples were drawn at baseline and post-intervention. Blood samples were immediately placed at room temperature for 10 min and then centrifuged at 3,500 rpm for 15 min Preyson Medical Devices) and stored in a freezer at -80°C until they were ready for processing and analysis. Serum nitric oxide (NO), endothelin-1 (ET-1), Interleukins-10 (IL-10), interleukins-6 (IL-6), and matrix metalloproteinase-9 (MMP-9) levels were measured using enzyme-linked immunosorbent assay (ELISA) kits  according to the manufacturers instructions and the data were analyzed. All the samples were discarded after the analysis.Fecal samples were collected from participants at baseline and post-intervention. DNA from fecal was isolated by TGuide S96 magnetic bead method soil/feces genomic DNA extraction kit  and stored at -80°C for future use. The V3-V4 region of the 16S rDNA gene was amplified by the following primers to generate an amplicon library for each sample, 338F (5'-ACTCCTACGGGAGGCAGCA-3') and 806R (5'-GGACTACHVGGGTWTCTAAT-3'). The amplified products were purified with VAHTSTM DNA Clean Beads  and Monarch DNA Gel Extraction  and quantified by the Qubit 2.0 fluorometer (Invitrogen). The final library was determined whether it meets the requirements of operation by detecting the concentration (Qubit) and size (Agilent 2100); The PacBio Binding Kit was used to combine the library with Primer and Polymerase; The final reaction product was purified by Ampure PB beads and placed on Sequel II sequencer for sequencing.On the PacBio platform, the marker gene was sequenced using SMRT Cell to obtain Circular Consensus Sequencing (CCS) sequences. Then the CCS sequences were filtered, clustered, and denoise to make species annotation.We analyzed 16S rDNA gene diversity using the Quantitative Insights into Microbial Ecology tool. The Chao, Shannon, Chao1, and ACE diversity indices were used to determine the α-diversity on the operational taxonomic units (OUT) level. Based on the Bray–Curtis distance algorithm, we conducted permutation multiple analysis of variance (PERMANOVA) for gut microbiota data at all levels, and PCoA visualization was conducted at the genus level. The least absolute shrinkage and selection operator (LASSO) was a variable selection method based on the sample data of the penalty method . Based ot-test and expressed as mean ± standard deviation; Otherwise, they will be counted using the Mann-Whitney-U and expressed as intermediate values (25–75th percentile).The significance level was determined by appropriate statistical analysis. SPSS 24.0 software  was used for statistical analysis. The normality of all continuous parameters was first checked using the Shapiro-Wilk test. Variables with Gaussian distribution were calculated by m2, respectively. Patients of taking calcium channel blocker of the LZJ group and AT group were 20 (95%) and 17 (85%), respectively, and the remaining patients did not take antihypertensive drugs. Furthermore, indexes of BP were not significantly different between LZJ and AT groups at baseline.Considering the impact of common antihypertensive drugs on BP, we asked patients not to change the treatment plan and dose of antihypertensive drugs during the test, while controlling important demographic characteristics, such as age and body mass index (BMI). The descriptive statistics of the biodata and anthropometry of the subjects are shown in P-values of 0.25 and 0.10, respectively. For the Day SBP, there was no obvious change after the intervention  subjects' BP decreased after AT intervention, 1 (5%) subject's BP was consistent with that before the intervention, and the other 14 (70%) subjects' BP increased. After LZJ intervention, the BP of 15 (71%) subjects decreased, and those of 6 (29%) subjects increased . The proP = 0.022 and P = 0.030, respectively , while had no effect on NO level (P = 0.28). LZJ intervention had no effect the ET-1 and NO levels of BP responders, with the P-values of 0.21 and 0.58, respectively  and promoted the differentiation of IL-10 (P = 0.01), indicating that LZJ exercise could significantly improve the immune homeostasis of BP responders.High expression of MMP-9 was a typical indication of hypertensive patients, which further caused the activation of endothelial cells, vascular endothelial dysfunction, and immune homeostasis imbalance –35. BothIn conclusion, exercise intervention had little effect on the vascular endothelial function of BP responders in this experiment. Unexpectedly, exercise intervention had a great effect on the immune balance of BP responders. In particular, LZJ could significantly improve the immune homeostasis of hypertensive patients by regulating the concentrations of IL-6 and IL-10. Previous studies have shown that exercise intervention could reduce hypertension complications by regulating immune homeostasis and lowering BP , 37. TheNumerous studies have shown that gut microbiota disorders were associated with hypertension . After cFirstly, we used α-diversity indexes  to evaluate the changes in the microbial community structure of BP responders after exercise intervention. P = 0.002). The F/B ratio has been used extensively as a proxy for broad shifts in microbial community structure from mammalian feces (P = 0.017), indicating that this exercise could improve the dysbiosis of gut microbiota caused by the elevation of BP level.However, there was a significant difference in Firmicutes/Bacteroidetes (F/B) ratio between hypertension and healthy people. As seen in an feces . After eP = 0.0001, Compared to α-diversity, the β-diversity index was most sensitive to the structural difference of gut microbiota. Regarding β-diversity, the Bray-Curtis metric was in general the most sensitive to observing differences between groups . We condSubsequently, we used the LASSO model to screen the most significantly changed microbiota of hypertensive subjects after LZJ intervention at the genus level. The result showed that Bacteroides, Clostridium_sensu_stricto_1, Escherichia-Shigella, Haemophilus, Megamonas, and Parabacteroides were the main characteristic bacteria genus . Among tP = 0.042, According to our results, LZJ exercise reversed the abundance of both taxa in hypertension patient, especially Bacteroidetes  could selectively reduce the BP level of hypertensive patients, and showed a certain positive effect on hypertensive patients. Through decision tree screening, LZJ intervention has a beneficial impact on 57% of hypertensive patients, while only 25% of hypertensive patients are beneficially affected by AT. Therefore, compared with AT exercise, LZJ intervention was more suitable for hypertensive patients and has a more positive clinical effect.Immune homeostasis plays a key role in the pathogenesis of hypertension. The immune imbalance will release a large number of inflammatory mediators , stimulate vascular fibrosis, and end organ damage . Both paIn addition, the balance of gut microbiota is an important factor in BP homeostasis, although its mechanism is complex and partly unknown . There iTo explore the causes of baseline LZJ lowering BP, we used LASSO and logistic regression models to screen the baseline characteristic microbiota of BP responders at the genus level. The results showed that the baseline characteristic colonies of BP responders were: Bacteroides, Faecalibacterium, and Subdoligranulum. These characteristic microbiotas are all related to the metabolism of short-chain fatty acids –51. As aTo sum up, our experiment proves that LZJ may be more effective than conventional AT in treating hypertension. This exercise could be used as an auxiliary treatment scheme for hypertension and is suitable for extensive clinical promotion. Specifically, compared with AT, LZJ was more generally applicable to hypertensive patients and showed a higher proportion of BP responders. It has a more significant effect on the improvement of inflammation and gut microbiota, which could reduce the abundance of harmful bacteria and increase the abundance of probiotics in the gut microbiota, especially Escherichia-Shigella and Bacteroides. But, the relatively low number of patients may be regarded as a limitation, and experiments in more and larger studies are also needed in the later stage to comprehensively determine the antihypertensive effect of LZJ.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Medical Ethics Committee of the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine . The patients/participants provided their written informed consent to participate in this study.LX and LQ designed and supervised the entire study. SW, CZ, NL, TD, LX, JW, and LQ performed the experiments. SW and CZ prepared the manuscript. LQ and SW were involved in the data analysis and manuscript revision. All authors contributed to the article and approved the submitted version.