Postural control is associated with fall risk. Patients with rheumatoid arthritis (RA) have a higher risk to fall than healthy subjects. The objective of this study was to identify associations between variables of postural control with prospective falls in patients with RA.For the baseline, the balance performance of 289 men and women with RA, ages 24–85 years, was evaluated by SPPB, FICSIT-4 and Romberg tests. Postural sway for Romberg, semitandem, tandem and one-leg stands were measured with the Leonardo Mechanograph®. Self-reported disability was assessed using the Health Assessment Questionnaire (HAQ) and the Activity-specific Balance Confidence Scale . Falls were reported in quarterly reports over a year. Univariate and multiple logistic regression analysis were used to explore any associations with falling. Receiver-operating characteristics were determined, and the area under the curve is reported.A total of 238 subjects completed the 1-year follow-up, 48 (20.2%) experienced at least one fall during the observational period. Age , HAQ , FICSIT-4 scoring 0–4 , and one-leg standing  showed significant associations with falls. With regard to the SPPB and ABC-scale, no statistically significant associations with falls were found. The quartiles containing the worst results of medio-lateral sway of Romberg , total sway of semitandem  and tandem , and area of sway of semitandem  stands were associated with falls.The assessment of a one-leg stand seems to be a good screening tool to discriminate between high and low risk of falls in RA patients in clinical practice. A low FICSIT-4 score and several sway parameters are important predictors of falls.DRKS00011873).The study has been registered at the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform (ICTRP) since 16 March 2017 ( The use of the one-leg stand as a screening tool allows a more precise discrimination between high and low risk of fall than SPPB in patients with RA.A low FICSIT-4 score identifies RA patients at high risk of falling.The medio-lateral sway of the Romberg and semitandem, the area of sway in semitandem, as well as the total path length and velocity of sway in semitandem and tandem stands can be used to predict falls.The utilisation of FICSIT-4 is superior to Romberg tests in research projects due to a sum score that compensates for missing values.The training of medio-lateral and anterior–posterior balance strategies should be the focus of fall prevention strategies and the therapy of fallers.Balance is a multidimensional muscle function domain that is fundamentally related to preserving independence and mobility, and is one of the most important indicators for predicting falls , 2. PostPatients with rheumatoid arthritis (RA) are at a higher risk of falling than healthy people , 7. KnowOne of the most commonly used performance measures to screen for fall risk is the Short Physical Performance Battery (SPPB). The SPPB evaluates the results of a balance assessment , the gait speed and chair rise test with the highest score indicating high functional performance . The insPostural sway measurements are usually obtained in standing or dynamic conditions with the subjects eyes opened or closed. Posturography uses force plates to measure and software to analyse the displacement of the body’s centre of pressure (CoP). The output consists of several sway parameters describing the three-dimensional extent of postural sway, thus the individual postural control and balance mechanisms , 23. In This prospective, observational study was conducted at the Centre for Muscle and Bone Research, and the Department of Rheumatology and Clinical Immunology at the Charité – Universitätsmedizin Berlin. Inclusion criteria included age ≥ 18 years, a confirmed diagnosis of rheumatoid arthritis according to the 2010 classification criteria of the American College of Rheumatology , the abin = 289 was calculated based on the sample size estimation software nQuery + nTerim 3.0.As this analysis was linked to a cross-sectional study investigating the prevalence of sarcopenia in RA (SarkoRA), the sample size calculation was based on the assumption of a prevalence of 25% in RA patients with a two-sided 95% confidence interval. A sample size of In order to address the patient’s perspective throughout the research process, as recommended by the European League Against Rheumatism (EULAR) , two patCRP) .Tab.Tab36].TFurthermore, the analysis contains dichotomous variables, which are related to whether the standing positions Romberg, semitandem, tandem and one-leg stand could be held for 10 s or not, e.g. “Romberg_Balance failed”.th and in the following month if it was conducted after the 15th. Every 3 months they had to report and specify their falls in a standardised protocol. If the subject experienced a fall, further questions about the fall situation had to be answered. The subjects had to describe in their own words the cause of the fall and any conditions that might have led to the fall. If there were any uncertainties regarding the documentation, the participants were contacted via telephone by the study centre. Falls were defined, in accordance with the consensus statement of the ProFaNE group, as ‘‘an unexpected event in which the participants come to rest on the ground, floor, or lower level’’ [After the baseline assessment, all participants were asked to complete a fall diary over a period of one year. They began fall monitoring within the same month if the baseline assessment was conducted before the 15 level’’ . Falls d2 tests.The descriptive data are presented as mean and standard deviation (SD) for continuous and normally distributed variables, and median and interquartile ranges for skewed variables. Categorical variables are reported in frequencies and percentages. The group of non-fallers and fallers were compared with t-tests for independent samples, Mann–Whitney-U-tests or ChiPostural sway variables were stratified into quartiles in order to integrate the missing data of failed balance assessments. Quartile 1 (Q1) included the subjects with the best results and was defined as the reference. Quartile 4 (Q4) contained the persons with the worst results and those who failed the assessment.In the first analysis step, univariate logistic regression was performed followed by a multiple logistic regression with an adjustment for age and sex in order to explore associations between variables of balance and performance with regard to falling. The results for this are presented along with the odds ratio (OR), the 95% confidence interval (CI) and the p-value (2-sided). For the CoP variables, the logistic regression model was used to estimate the OR for falling in each quartile (Q2-Q4) compared to the best quartile (Q1).Receiver-operating characteristics (ROC) were analysed to determine the quality of the prediction and the area under the curve (AUC) along with the associated 95% CI and p-value also reported. The ROC analyses did not provide specific cut-off values; therefore, these results are not shown.n = 187, 78.6%). There were 48 (20.2%) persons who reported a fall episode in the observation period, of which 83.3% were female. In Table Two hundred thirty-eight subjects between 24 and 85 years of age completed the one-year follow-up 82.3%). The mean age was 60.2 ± 11.6 years. The majority of the sample consisted of females (%. The mep = 0.016) and more limited in their activities of daily life  (Tables p = 0.03) and a significantly higher proportion of fallers (29.2%) were poor performers, scoring 0–4 in FICSIT-4 . The failure rate of performing one-leg stances was significantly higher in the falls group (pleft = 0.031). Fallers demonstrated lower balance confidence , but this was not significant (p = 0.321) . For the semitandem stance, the path length and the velocity of CoP in the medio-lateral direction , the area of sway (p = 0.029), the path length in total and the speed of the movement of the CoP over time (p = 0.039) were also significantly different between the groups. For the tandem stance, the path length in total and the speed of the movement of the CoP over time (both p = 0.034) as well as the path length and the velocity of CoP in the anterior–posterior direction (both p = 0.015) showed once again significant differences between the groups (Table In Table p = 0.017). There were no associations with fall risk found for sex, RA disease duration, and disease activity , low FICSIT-4 score (0–4)  and failed one-leg stand . The ABC-scale and SPPB remained non-significant.In terms of balance and performance assessments, the univariate logistic regression analysis revealed significant associations for HAQ score , thus a better predictive quality for falls than the univariate regression. Similar results were obtained for the performance of one-leg stand. The probability of falling increased significantly in the case that the subject had failed the test. The AUC of the adjusted association was higher at 0.62  and significant compared to the unadjusted association  , semitandem PLen, VmeanCoP  and StdElA  and tandem PLen and VmeanCoP . The AUCs of those unadjusted and significant models were between 0.59 and 0.61 (Table In Table p < 0.001). Although most of the models were not statistically significant, all adjusted models showed higher and significant AUCs than the crude models  and one-leg standing as a single test showed significant associations with falls, which was not the case for the SPPB. Gait speed and CRT as independent variables and components of the SPPB also showed no significant associations (shown elsewhere ). The rePosturography results of the present study showed a higher proportion of fallers in the worst quartile (Q4) of the postural sway variables compared to the reference quartile (Q1). Numerous sway variables of the Romberg, semitandem and tandem stance positions showed significant group differences between fallers and non-fallers. The medio-lateral sway of both path length and velocity showed significant associations with falls in the Romberg and semitandem stance. In a prospective study by Stel et al. involving a sample of an older population the medio-lateral sway during normal standing (Romberg) was evaluated and it was found to be strongly associated with recurrent falls . This fiNo associations were found for anterior–posterior sway in the logistic regressions. Only the unadjusted logistic regression model of anterior–posterior sway in the tandem position showed a significant and high AUC, such that it can be probably used to discriminate between falls and no falls, but the ORs were not significant. There are studies in which it has been shown that there is higher anterior–posterior sway in patients with RA compared to healthy subjects , 45, 46,The area of sway in semitandem, the total path length and velocity of sway in semitandem and tandem were associated with falls in the unadjusted models. The results of a study by Kawabata et al.  confirmeIn terms of postural control and falls, there is conflicting evidence on the role of disease activity and duration of disease. In some previous studies there has been found to be disease activity associated with increased risk of falls , whereasHowever, a longer RA disease duration is associated with higher HAQ scores . In the This study has multiple strengths, including the prospective design and the use of quarterly fall diaries, which made data collection more reliable than retrospective studies reporting on fall history. The regular telephone contacts and reminders by the study centre made it possible to record falls promptly and keep the drop-out rate low. One source of weakness in this study, which could have affected the results, was the incidence of falls in the study group. Previously reported findings on the incidence of falls in patients with RA suggest that the incidence of 20.2% of this study is a relatively low rate , 13. FurDuring the execution of the Romberg test a high failure rate was seen for the tandem stand onwards, which is problematic especially for research due to the missing values. For the statistical analysis in the current study, the issue could be solved by constructing quartile variables for the sway parameters and by integrating dichotomous variables, e.g. “One-leg _Balance (failed/done)”. In clinical practice, missing values can be ignored and, in particular, a single one-leg stand, if failed, seems to be a valid tool for predicting fall risk; in the context of research the FICSIT-4 is superior to the Romberg tests, because the composite score integrates failed positions.The results of the presented analyses support the use of the FICSIT-4 assessment, including the ability to perform a one-leg stand, to determine fall risk in rheumatoid patients. For the screening of fall risk in clinical practice a one-leg stand might be appropriate, as this can be used to differentiate between patients at high risk of falling (failed) and those at low risk of falling (held for 10 s).For the assessment of sway parameters in a population of RA patients, the semitandem stand showed the most applicable results. In order to determine fall risk in this population, path length, area of sway, velocity of sway and medio-lateral sway during a semitandem stand can be used. The semitandem stand was safe to perform, was completed by almost all subjects and was moderately challenging for the postural system. This position is particularly suitable for samples over a wide range of age as well as for the elderly or subjects with a chronic disease. For younger and active subjects, positions should be chosen that challenge the balance system to the maximum. This can be achieved by using one-leg stands, closed eyes or dynamic positions.For the development of prevention or physical therapy programmes, the training of medio-lateral and anterior–posterior balance strategies should be focused on. The mobility and perception of the foot, and the prevention of joint deformities in order to improve balance ability should be prioritised.


High-throughput metabolomics was conducted with the patients’ serum samples using mass spectrometry. After controlling for CKD severity and other clinical hypertension risk factors, we identified ten metabolites that have significant associations with blood pressure. The quantitative importance of these metabolites was verified in a fully connected neural network model. Of the ten metabolites, seven have not previously been associated with blood pressure. The metabolites that had the strongest positive association with blood pressure were aspartylglycosamine (p = 4.58 × 10−5), fructose-1,6-diphosphate (p = 1.19 × 10−4) and N-Acetylserine (p = 3.27 × 10−4). Three metabolites that were negatively associated with blood pressure  have been reported previously to have beneficial effects on hypertension. These results suggest that intake of metabolites as supplements may help to control blood pressure in CKD patients. Blood pressure is one of the most basic health screenings and it has a complex relationship with chronic kidney disease (CKD). Controlling blood pressure for CKD patients is crucial for curbing kidney function decline and reducing the risk of cardiovascular disease. Two independent CKD cohorts, including matched controls (discovery  Hypertension is the leading risk factor for many diseases, including cardiovascular disease, stroke, kidney disease, etc.  One of tMetabolites are organic compounds, produced intermediately during metabolism. They are used for chemical reactions in cells. Metabolites have been thoroughly studied in CKD. It has been suggested that metabolites have strong clinical value for CKD . StudiesMetabolites have been studied closely with CKD and blood pressure independently, but never in conjunction. In this study, using an approach combining traditional statistical methods and deep learning methods, we show that, within the confinement of CKD, certain metabolites are directly associated with blood pressure after adjusting for CKD severity. p = 0.06) and the combined dataset (p = 0.07), but not in the validation cohort (p = 0.6). Sex was not associated with blood pressure. Age, weight, BMI and eGFR were found to be significantly associated with blood pressure in the discovery, validation and combined cohorts. In the combined cohort, weight and BMI had the largest effects on blood pressure . These results indicate that increases in age, weight and BMI and decline in kidney function are associated with increase in blood pressure, which is consistent with previous findings. Based on regression results, in the combined cohort, the clinical characteristics together explained 20% variance in blood pressure (adjusted R2 = 0.20).Two cohorts with 1376 subjects  were used for this study. The basic clinical characteristics are summarized in All the subjects’ serum samples went through mass spectrometry to identify metabolites. A total of 25,107 features were identified. To remove collinearity within the features and reduce the dimensionality of the analysis, we performed feature reduction using the correlation clustering algorithm , after wThe relationships between these 1755 selected features and blood pressure were evaluated using a linear regression model while adjusting for CKD stage in the discovery cohort, then in the validation cohort. In both cohorts, 31 features were found to be significantly associated with blood pressure, and the exact metabolites for these 31 features were identified. Final regression models were carried out by combining data from both cohorts . In the 2 = 0.1342). By combining clinical characteristics, the total explainable variance of blood pressure increased to 23.29% . This model had a prediction accuracy of 46%, which was better than random chance  but far from being suitable for application in a clinical setting. By adding the additional ten metabolites, the model’s accuracy increased to 52% . Hypertension is both a cause and a consequence of CKD, making controlling blood pressure a vital strategy to slow down CKD progression [It is estimated that around 20% of the world’s adults have hypertension. Hypertension is closely intertwined with many diseases, including CKD, which has an estimated global burden of 10% . Aspartylglycosamine was firstly identified as a biomarker of hypertension under CKD and also as a biomarker of a congenital disorder of deglycosylation [p = 1.19 × 10−4). As a glycolytic intermediate, fructose 1,6-diphosphate treatment mitigated ischemic acute renal failure [We designed a study to examine the relationship between metabolites and blood pressure within the context of CKD. Two large cohorts  of 1376 subjects were recruited. Metabolites were detected in the patients’ serum samples using mass spectrometry. Through a series of statistical analyses, we identified ten metabolites associated with blood pressure after adjusting for CKD severity. The importance of these ten metabolites was further validated through statistical analysis of Rsylation ,20. Ther failure  and prev failure . Even th failure  and has  failure , which mp = 6.39 × 10−3), which had similar trends with a previous study in cardiovascular disease [p = 0.01). Although no direct association with blood pressure has been found, dodecanedioic acid was found to help maintain blood sugar levels [Phosphocreatine was negatively associated with blood pressure . A previous study showed trends of 3-methyladenine levels consistent with our study of hypertension. After treatment with 3-methyladenine, vascular smooth muscle cells were sensitive to senescence that contributed to hypertension, indicating 3-methyladenine as a potential risk factor for hypertension [N-acetylneuraminic acid was negatively associated with blood pressure. However, a previous study showed that N-acetylneuraminic acid was positively associated with hypertension in patients with cardiovascular disease, which may be a result of different pathological states [p = 0.04), which is more concordant with the second study. Additionally, in the present study, we identified that a backbone of mammalian cell membranes, sphingosine phosphate, was negatively associated with blood pressure. A number of studies have confirmed the protective effects of sphingosine phosphate in hypertension and blood pressure regulation, indicating that the modulation of sphingosine phosphate signaling is a potential therapeutic target of hypertension under CKD ,34,35,36rtension . Here, wl states . Our stul states . Howeverl states . In our Our study contained two large cohorts of CKD patients and matched controls. All participants were ethnically Chinese, and all patients provided written informed consent. The first cohort contained 824 subjects  who were recruited between February 2011 and 2013 from the Affiliated Hospital of Shaanxi Institute of Traditional Chinese Medicine. The second cohort contained 552 subjects  who were recruited between 2013 and 2016 from Xi’an No. 4 Hospital and Baoji Central Hospital. The four-variable equation of the Modification of Diet in Renal Disease (MDRD) Study was used to estimate GFR (eGFR) . SubjectBlood pressure was classified into five groups based on conventional definition: normal (systolic < 120 and diastolic < 80), elevated (systolic: 120–129 and diastolic < 80), high stage 1 (systolic: 130–139 and diastolic: 80–89), high stage 2 (systolic: 140–180 or diastolic: 90–120) and hypertensive (systolic > 180 or diastolic > 120). Blood pressure was subsequently coded numerically as 1 to 5 for further analysis. Serum samples were collected from all participants. Serum samples were obtained after overnight fasting and sera were separated and stored at −80 °C for biochemical analysis. Blood biochemistry was determined by the clinical laboratory. The metabolomic procedure included sample preparation, metabolite separation and detection. Data preprocessing and statistical analysis for metabolite identification was performed following our previously described protocol [Mass spectrometry was performed with a Waters XevoTM G2 QTof MS. The scan range was from 50 to 1200 m/z. For positive and negative ESI modes, the capillary and cone voltages were set at 2.5 kV and 45 V, respectively. The desolvation gas was set at 550 °C with a desolvation gas rate of 900 L/h. The source temperature was set at 120 °C, and the cone gas rate was set as 50 L/h. The data were obtained in centroid mode. The LockSpray frequency was set as 10 s, and the data were averaged over 10 scans. The data acquisition rate was set to 0.1 s with a 0.1 s interscan delay. During analysis, centroid data were collected with a scan time of 0.1 s and an interscan delay of 0.02 s. Leucine–enkephalin was used as the lockmass at the level of 300 ng/mL with a flow rate of 5 μL/min.To obtain a pooled quality control sample, 50 µL of all the samples were pooled, and 10 ions, including m/z 161.9852, 391.2812, 381.2846, 764.5300, 441.1958, 820.8169, 208.1360, 133.0861, 486.2534 and 429.2741, were extracted for assessment. The continuous analyses of 6 replicates of quality control samples were used to measure injection precision. RSD% of retention times and peak areas were also measured using quality control samples. The sample preparation repeatability was calculated by 6 parallel samples, and the method repeatability of RSD% of retention times and peak areas of 10 ions was measured from quality control samples. The above-mentioned procedure was performed every day.Algorithm 1 Correlation Clustering AlgorithmV, E+, E−    H ← ∅  while V ≠ ∅ do   C ← ∅   V’ ← ∅   Pick a random pivot i ∈ V   C ← {i}   for j ∈ V and j ≠ i do    if j, i ∈ E+ then     Add j to C    end if     if j, i ∈ E− then     Add j to V’    end if   end for   V ← V’   Add C to H  end while  return HRequire: Overall, 25,107 features were identified through mass spectrometry. Each feature was described by its retention time and molecular weight. Many of the features were highly correlated. We conducted feature reduction using a correlation clustering algorithm (Algorithm 1) . The algAlgorithm 2 Pearson Correlation Threshold Checki, j, t  P ← pearson  Q ← |P|  return Q > tRequire: In the discovery cohort, linear regression was carried out to evaluate the relationship between blood pressure and metabolites. To account for the potential correlation between metabolites and CKD stages, an interaction term between feature and CKD stage was added to the regression model. Statistically significant features recurrent in the model of the validation cohort were retained. A final regression model was conducted combining samples from both cohorts. The Benjamini–Hochberg method was used as the multiple test correction method.A feature importance algorithm  was usedE fragment, literature comparisons and database searches, including the Human Metabolome Database , KEGG , METLIN , MassBank  and Chemspider . Additionally, some metabolites were confirmed by comparison with available reference standards under the same UPLC–HDMS condition.The final list of blood pressure-associated metabolites was identified and annotated using exact molecular weights, m/z element composition using MassLynx i-FIT software , MS, MSThis study was approved by the Ethical Committee of Shaanxi Traditional Chinese Medicine Hospital (permit number: SXSY-235610), and written informed consent was received from all participants before inclusion in the study. The clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki.By conducting a large-scale high-throughput metabolomics study, we identified ten metabolites that were associated with blood pressure after adjusting for the severity of CKD and other hypertension risk factors. With clinical characteristics and metabolites, we explained 23.29% of the variance in blood pressure. A deep learning model that utilized both clinical characteristics and metabolites reached an accuracy of 52%. Although better than random chance, these results are not clinically meaningful and further demonstrate that hypertension is a complex disease with many potential risk factors. The identified metabolites potentially hint at alternative metabolomics-based strategies for controlling hypertension in CKD patients.


Diabetes mellitus (DM) is a common endocrine disease with serious effects on multiple organs including the kidneys. This study aimed to investigate the subtle effects of type 2 DM (T2DM) on the kidneys.This was a prospective case-control study conducted in the Radiology Department of University of Science and Technology Hospital (USTH) campus, Sana’a, Republic of Yemen, from 1 January 2020 to 31 November 2020. The renal length (RL), renal width (RW), resistive index (RI), and pulsatility index (PI) were prospectively measured in patients with T2DM and healthy controls. The results were compared using the independent samples t-test. Comparisons were likewise performed between patients with controlled DM and patients with uncontrolled DM.A total of hundred individuals, 50 diabetic patients and 50 controls, were enrolled in this study. Their mean age was 54 ± 7.88 years (range: 40–75 years). The RL, RI, and PI of both kidneys were significantly higher in T2DM than in the control group. Moreover, the RL, RI, PI and creatinine were slightly higher in patients with uncontrolled than in those with controlled DM.T2DM has significant accentuating effects on the RL, RI and PI associated with low effective renal plasma flow, even before acute kidney injury or chronic kidney disease diagnosis, which may be attenuated by careful regulation of DM. Ultrasound Doppler is a highly valuable imaging modality for evaluating the subtle effects of T2DM on kidney dimensions and blood flow. The RI can be implemented as a tool for the early diagnosis of kidney disease and contribute to slowing the disease progression and preventing renal failure. Diabetes mellitus (DM) is a common disease with serious effects on multiple organs, including the kidneys. DM leads to micro- and macrovascular kidney disease and increased susceptibility to infection. It predisposes patients to renal infection, renal or perirenal abscess, or emphysematous pyelonephritis. In long term, it can lead to diabetic nephropathy (NP), renal papillary necrosis, or renal artery stenosis (RAS).1Ultrasound (US) plays a critical role in evaluation of chronic kidney disease (CKD), and is the imaging modality of choice for determining the cause of acute kidney injury (AKI) and understanding the renal pathophysiological characteristics.3It is a non-invasive, inexpensive, widely available, and radiation-free imaging modality that can determine the morphology of the kidney by measuring the renal length (RL), renal width (RW), renal volume and parenchymal thickness. It can also determine kidney function by measuring the RL, RW, parenchymal thickness, and parenchymal echogenicity.6Duplex US can help determine renal function by identifying large renal arterial and venous abnormalities and the renal resistive index (RI), and pulsatility index (PI). The renal RI is a recently suggested method for assessing renal perfusion, detecting RAS, evaluating the risk of progression in CKD, and predicting the renal outcome in AKI. In diabetic CKD, a higher renal RI correlates with vascular and interstitial kidney damage and is a reliable predictor of disease progression.7The RI and PI are calculated from the blood flow velocity in renal arteries during the cardiac cycle and used as measurements of downstream resistance in the arteries to detect peripheral vascular diseases. They increase with higher renal vascular resistance and they are useful in the investigation and monitoring of RAS. High RI and PI are associated with low effective renal plasma flow.8Because of lack of previous studies about the subtle changes of the kidneys of DM patients before clearly diagnosing diabetic NP, this study was designed to evaluate early subtle changes of the kidneys of DM patients with no obvious kidney disease, by comparing their renal measurements to those of non-diabetic individuals.This was a prospective case-control study involving DM patients and non-DM controls conducted in the Ultrasound unit of the Radiology Department of University of Science and Technology Hospital (USTH) campus, Sana’a, Republic of Yemen, from 1 January 2020 to 31 November 2020.Type-2 diabetes mellitus (T2DM) patients referring for US imaging of the kidneys who were more than 40 years old and provided informed consent were enrolled in this study. Patients with known CKD or AKI, patients on haemodialysis, kidney transplant patients, and solitary kidney patients were excluded.Ultrasound (US) and Doppler were performed with the same Ultrasound machine (Siemens Acuson X600 Ultrasound System) using the standard gray-scale B-mode with a curved array transducer of 2–5 MHz and a standard protocol. The gain and time gain compensation of US images were adjusted manually. All participants were examined by the same radiologist with five years’ post doctorate experience in US Doppler imaging.The length of the right and left kidneys was measured in the visually estimated largest longitudinal section of each kidney. The width of both kidneys was measured in sections perpendicular to the longitudinal axis . The renThe renal PI was measured according to the following equationThe parenchymal echogenicity of both kidneys was assessed by applying low tissue harmonic. Creatinine was investigated only in DM patients. The body mass index (BMI) of the participants was measured according to the following equationData analysis was performed using IBM SPSS Statistics version 25, . Means and standard deviations were calculated for age, BMI, RL, RW, RI, PI, creatinine and duration of DM. The renal measurements in the DM patient group were compared to those in the non-DM (control) group using the independent samples t-test. Comparisons were likewise performed between patients with controlled DM and patients with uncontrolled DM according to the last measurements of haemoglobin A1c (HbA1c). A p-value of less than 0.05 was considered statistically significant.This study was approved by the Research Ethics Committee of USTH under a protocol issued on 26-4-2019. Informed consent was obtained from all participants. Anonymity was safeguarded during and after the study.A total of one hundred individuals, 50 DM patients and 50 controls, were enrolled in the study. Their mean age was 54 ± 7.88 years (range: 40–75 years). Females accounted for 74% and males accounted for 26% of the participants. The mean BMI was 29.51 ± 7.32 in the patient group and 25.65 ± 6.05 in the control group.The RL, RI, and PI of both the right and left kidneys were significantly higher in the DM than in the control group  and 4. MDM is a chronic metabolic disease associated with serious complications in various organs. Metabolic changes in DM may lead to glomerular hypertrophy and sclerosis, tubulointerstitial inflammation and fibrosis, and NP onset and progression with many structural and functional changes in the kidneys.In this study, the BMI was significantly higher in the DM than in the control group. This finding is consistent with Friedman et al., who reported a strong relationship between T2DM and obesity, which is a risk factor for kidney disease and a leading cause of CKD.14In this study, we found a significantly greater RL in the T2DM than in the control group. This result is consistent with Umanath and Lewis, who found that kidney size and weight increase by an average 15% in DM patients and remain increased even after a decrease in kidney function.17We also found that the renal RI was significantly higher in the DM than in the control group. This result is in line with Afsar and Elsurer, who found that the RI is increased in most studies on T2DM.23In this study, we found no significant difference in the RL between controlled and uncontrolled DM patients. This was explained by Umanath and Lewis, who reported that kidney size and weight increase by an average 15% in DM patients and remain increased even after a decrease in kidney function.A previous study reported that creatinine is a useful biochemical measure in approximating the GFR.A limitation of this study is that creatinine levels were not measured in the control group. Therefore, creatinine comparisons between the DM and control groups were not performed. Another limitation is that renal artery diameter measurements could not be performed in all patients and controls due to technically difficulties in measuring it. Therefore, such comparisons were not performed. Further studies with comparing creatinine and diameter of renal arteries in the DM and control groups are recommended.T2DM has a significant accentuating effects on RL, RI and PI of the kidneys even before diagnosing AKI or CKD, that may be attenuated by careful regulation of DM which can be slowing disease progression and preventing renal failure. Ultrasound Doppler is a highly valuable imaging modality for evaluating the subtle effects of T2DM on kidney dimensions and blood flow. RI can be implemented as an important tool in early diagnosis of kidney disease.AAA: Provided US Doppler and collected data.SAA: Organized and analyzed data and wrote the final draft of the article and is responsible for the integrity of the work.AAQ: Revised the manuscript.AMH: Interpreted data and revised the manuscript.


BMP-2, BMP-7, and profibrotic and calcification factors was determined in kidney and perivascular adipose tissues (PVAT). BMP-2 was higher in stage III CKD patients compared to control subjects. BMP-7 was lower at any CKD stage compared to controls, with a significant further reduction in stage III patients. A similar imbalance was observed in MWF rats together with the increase in systolic (SBP) and diastolic blood pressure (DBP), or pulse wave velocity (PWV). MWF exhibited elevated urinary albumin excretion (UAE) and renal expression of BMP-2 or kidney damage markers, Kim-1 and Ngal, whereas renal BMP-7 was significantly lower than in Wistar rats. SBP, DBP, PWV, UAE, and plasma creatinine positively correlated with the plasma BMP-2/BMP-7 ratio. Periaortic and mesenteric PVAT from MWF rats showed an increased expression of BMP-2 and profibrotic and calcification markers compared to Wistar rats, together with a reduced BMP-7 expression. BMP-2 and BMP-7 imbalance in plasma, kidney, and PVATs is associated with vascular damage, suggesting a profibrotic/pro-calcifying propensity associated with progressive CKD. Thus, their combined analysis stratified by CKD stages might be of clinical interest to provide information about the degree of renal and vascular damage in CKD.Arterial stiffness is a major vascular complication of chronic kidney disease (CKD). The development of renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD might be associated with an imbalance in bone morphogenetic proteins (BMP)-2 and BMP-7. Plasma BMP-2 and BMP-7 were determined by ELISA in CKD patients  and Munich Wistar Frömter (MWF) rats. Age-matched Wistar rats were used as a control. The expression of  Chronic kidney disease (CKD) is a progressive condition with high morbidity and mortality and is especially prevalent in the diabetic and hypertensive adult population ,2. It isIncreased arterial stiffness is a major and often overlooked vascular complication of CKD leading to increased cardiac workload, reduced coronary artery perfusion, and chronic cardiac dysfunction ,6. One cβ) superfamily which are involved in a variety of processes not only restricted to bone formation [Bone morphogenetic proteins (BMPs) are growth factors belonging to the transforming growth factor beta  of MWF rats, together with the expression of renal damage markers, Kim-1 and Ngal, as well as profibrotic and procalcifying factors Runx2, Bglap, ALP, Col1A1, and βTGF.Against this background, we hypothesize that an imbalance in BMP-2 and BMP-7 occurs at CKD stages I-III associated with the development of hypertension, vascular stiffness, and progressive kidney damage. To test this hypothesis, we analyzed plasma BMP-2 and BMP-7 levels in the Munich Wistar Frömter (MWF) rat, a genetic model with spontaneous nondiabetic albuminuria that mirrors several features observed in patients with CKD , includiPlasma BMP-2 levels were significantly higher in stage III CKD patients as compared to controls, whereas levels were similar to controls in CKD stage I or II patients A. BMP-7 p < 0.05) BMP-2 and lower  BMP-7 concentrations compared with CKD patients without atrial fibrillation . To further assess kidney damage, mRNA levels of tubular damage markers, Kim-1 and Ngal, were determined. Expression of both markers was significantly higher in the MWF compared to the Wistar group , collagen 1A1, and βTGF were significantly higher in mesenteric PVAT than in MWF  or βTGF between groups  [BMP-7 is a physiologic antagonist of TFGn of CKD ,45. Thern of CKD ,47,48,49n of CKD ,51 and tn of CKD ,53. Inte (Bglap) ,55,56,57 (Bglap) ,59. In p (Bglap) ,59. In t (Bglap) ,29,42. TSeveral limitations of this study are important to note. First, PWV was not determined in the CKD patient cohort. Although the MWF rat is a good experimental model that mirrors many features observed in patients with CKD, assessment of PWV in CKD patients at different CKD stages will be of interest. Second, the patient number in each CKD stage is too small to be able to perform homogenous subgroups, i.e., diabetic or hyperlipidemic patients, and a greater CKD patient cohort will be necessary for further studies. Third, the younger age of the control group might carry a potential bias in the data interpretation as the average age between the different CKD groups increases with the CKD stage and BMP-7 levels seem to be higher at younger ages, at least in some diabetic mice models . Fourth,In conclusion, an imbalance in BMP-2 and BMP-7 levels observed in plasma, kidney, and PVATs is associated with 25-OH-cholecalciferol deficiency, increases in blood pressure and arterial stiffness, and might indicate a profibrotic/pro-calcifying propensity associated with progressive CKD. Thus, we suggest that the BMP-2/BMP-7 ratio might be of clinical interest once validated in a higher number of patients. Strategies to reduce and/or correct this imbalance in experimental models and clinical practice are warranted.2; (ii) 90 to 60 mL/min/1.73 m2; and (iii) 59 to 30 mL/min/1.73 m2. Patients with diabetes or with eGFR < 30 mL/min/1.73 m2 on hemodialysis were excluded from the study. Control group were healthy subjects (n = 26) with normal weight and without hypertension.Plasma samples, anticoagulated with ethylenediamine tetraacetic acid (EDTA), were obtained from 121 CKD patients (>18 years old) from the Hypertension Unit of the Nephrology Department of the Hospital Universitario 12 de Octubre in Madrid. Patients were classified into three groups according to the estimated GFR (eGFR), calculated using the CKD-EPI formula : (i) >90Clinical history data were used to obtain anthropometric measurements , systolic (SBP) and diastolic blood pressure (DBP) values, glycemic parameters (plasma glucose and glycated hemoglobin), lipid profile , and renal function parameters . A diagnosis of essential hypertension was based on a previous history of hypertension or BP/DBP ≥ 140/90 mmHg measured in the clinic following the European guidelines . DeficieTwenty-two-week-old male normotensive and normoalbuminuric Wistar  and MWF rats  were housed in groups of two under controlled dark–light cycles (12 h/12 h), temperature conditions, and with access to food  and water ad libitum. Urinary albumin excretion (UAE) was determined in 24 h-old urine collected in metabolic cages after 24 h acclimation as previously described . On the After hemodynamic measurements, animals were euthanized by anesthesia overdose, blood was collected in heparinized tubes to obtain plasma, and tissues  were removed and frozen for further study (plasma determinations and PCR studies). All experimental procedures were performed in accordance with the European Union Laboratory Animal Care Rules (86/609/ECC directive) and were approved by the Animal Research Committee of Complutense University (PROEX 205/18). All efforts were made to avoid animal suffering in accordance with the ARRIVE guidelines for reporting experiments involving animals.® laboratory on a plasma sample. Determination of total plasma BMP-2 and BMP-7 concentration in both patients and rats was performed using specific ELISA kits according to the manufacturer’s specifications . Rat and human BMP-2 shares 100% homology (https://www.ncbi.nlm.nih.gov/homologene/926 (accessed on 13 September 2022)), whereas BMP-7 shares 97% homology (https://www.ncbi.nlm.nih.gov/homologene/20410 (accessed on 13 September 2022)). The ELISA for BMP-2 (DBP-200) has a sensitivity of 29 pg/mL and an intra- and interassay coefficient of variation of 2.6% and 7.3%, respectively. The ELISA for BMP-7 (NBP2-70002) has a sensitivity of 9.38 pg/mL and an intra- and inter-assay coefficient of variation of 6.77% and 6.60%, respectively. The ELISA for NGAL  has a sensitivity of 0.04 ng/mL and an intra- and inter-assay coefficient of variation of 3.6% and 7.9%, respectively.Measurements of potassium, calcium, phosphate, 25-OH-cholecalciferol and creatinine were performed by MegalabKim-1 and Ngal (kidney) or Runx2, Bglap, ALP, Col1A1, βTGF, (PVAT), BMP-2, and BMP-7 (kidney and PVAT). Both Kim-1 and Ngal are markers for kidney injury, specifically for tubular damage, and are a positive control of CKD in the MWF rat. Optimal annealing temperature and amplicon sizes were checked for each pair of primers. RT-qPCR analyses were performed in a CFX96 Instrument . A total of 10 ng of cDNA from ten samples of each group were run in duplicate. mRNA levels were determined using intron-skipping primers, GADPH and ATPF-1 as housekeeping genes for normalization, and SYBR Green Master Mix .Total RNA was isolated from the W and MWF kidney and PVAT samples (n = 5/strain for each tissue) using Qiazol Reagent . The samples were processed with 500 µL trizole using 35–45 mg of tissue. After centrifugation  and 200 µL chloroform addition, centrifugation  was repeated. The supernatant was collected, mixed with 150 µL isopropanol, and centrifuged . The pellet was resuspended in 300 µL 75% ethanol. Afterwards, the instructions of the RNA Spin illustraTM kit  were followed and the concentration and purity of RNA were assessed with NanoDropTM 2000/c . Reverse transcription was performed on 500 ng of RNA with iScript cDNA synthesis kit  using random hexamer primers  for Kim-t test or one-way ANOVA with the Newman–Keuls test, and nonparametric variables were compared by the Kruskal–Wallis test. Categorical variables were compared using Fisher’s exact test. Correlations were calculated using Pearson’s correlation coefficient. Data analysis was performed with SPSS v26 software for patient data and with GraphPad Prism 8 for animal data. Data are presented as mean ± standard error of the mean and statistical significance was set at p < 0.05.Based on previous studies, the number of animals per group was n = 5, accepting an alpha risk of 0.05 and a beta risk of 0.2 in a bilateral contrast, to detect a difference equal to or greater than 1.6 units. A standard deviation of 1.2 and a loss-to-follow-up rate of 10% were assumed. Continuous variables were compared by Student’s


Kidney transplantation (KTx) improves prognosis in children with kidney failure; still, these patients are prone to cardiovascular damage due to multiple risk factors. Our aim was to assess myocardial structure and function in pediatric KTx by conventional and speckle-tracking echocardiography (STE) in association with established cardiovascular risk factors.Forty-two KTx and 39 healthy age- and gender-matched children were evaluated. KTx recipients were further categorized according to the control of hypertension assessed by 24-h ambulatory blood pressure monitoring (ABPM). Subjects underwent pulse wave velocity (PWV) measurement, conventional echocardiography, and 2-dimensional STE. Left and right ventricular  global longitudinal strain (GLS), and LV circumferential strain (GCS) were measured. Glomerular filtration rate (eGFR) was calculated according to the Schwartz formula.KTx patients had increased blood pressure and arterial stiffness. LV ejection fraction (EF) was preserved along with elevated LV mass index (LVMi) while LVGLS was significantly lower, whereas LVGCS and RVGLS were increased in KTx. Uncontrolled hypertensives had lower LVGLS compared to those with controlled hypertension. Using multiple forward stepwise regression analysis, 24-h SBP and relative wall thickness (RWT) were independent determinants of LVMi, whereas antihypertensive therapy, eGFR, and HOMA-IR were independent determinants of LVGLS.Cardiac morphology and function show distinct changes after KTx. Along with comparable ventricular volumes, LV hypertrophy and subclinical myocardial dysfunction are present. Control of hypertension and kidney graft function are major factors of LV performance. STE may be useful to reveal early myocardial dysfunction in pediatric KTx.A higher resolution version of the Graphical abstract is available as The online version contains supplementary material available at 10.1007/s00467-022-05422-7. Children with chronic kidney disease (CKD) are at high risk of developing cardiovascular diseases . Kidney Beyond the pretransplant metabolic changes associated with uremia, children are also exposed to transplant-associated factors, such as immunosuppressive treatment with its cardiometabolic effects and a gradually decreasing graft function, as well as risk factors such as hypertension, increased arterial stiffness , post-trEarly detection of CV dysfunction in the pediatric population is of crucial importance in the prevention of later CV events. Subtle alterations in cardiac structure are already present in children with chronic kidney disease (CKD) with no or mild symptoms . Left veIn addition to alterations in cardiac geometry, systolic and diastolic function of the heart can also be impaired even if conventional functional features such as ejection fraction (EF) are preserved , 8. Two-Accordingly, the aim of the present study was to assess myocardial structure and function in pediatric KTx recipients by conventional echocardiography and STE in association with established CV risk factors.n = 39, age 13.7 ± 3.5 years, range 8.11–18.55 years).Between January 2017 and June 2018, 42 kidney transplant recipients transplanted in childhood  were enrolled in this single-center cross-sectional study. Inclusion criteria were a functioning allograft and no history of overt cardiovascular anomalies. Age- and gender-matched healthy children without any chronic diseases were enrolled as controls , fasting glucose, and serum insulin level were assessed by routine laboratory methods. eGFR was calculated according to the Schwartz formula . The homHeight and weight and BMI were expressed as Z-scores according to Hungarian pediatric growth charts . Body suOffice brachial blood pressure (OBP) and heart rate were measured by a validated automated oscillometric device  in sitting position using appropriate cuff sizes . Heart rIn KTx patients, 24-h ambulatory blood pressure monitoring (ABPM) was performed by using a validated oscillometric device . ABPM was set to record blood pressure in 20-min intervals during the day and every 30 min during the night. Mean 24-h as well as daytime and nighttime systolic blood pressure (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP), and nocturnal systolic and diastolic blood pressure fall were recorded. ABPM data were expressed as Z-score for sex and height . The diath percentile for height in patients with or without antihypertensive medication. In patients with controlled hypertension, both SBP and DBP were below the 95th percentile for height and patients were taking antihypertensive medication. The normotensive group included patients with SBP or DBP below the 95th percentile without taking antihypertensive medication. Nocturnal dipping was defined as nocturnal decrease in BP measured by ABPM. Patients with dipping below 10% were considered as non-dippers [Hypertensive children were further classified according to the control of hypertension. Uncontrolled hypertension was defined as SBP and/or DBP values exceeding the 95-dippers .Based on OBP and ABPM results, patients having normotensive OBP values but hypertension on ABPM were classified as masked hypertensives, whereas patients with white coat hypertension had elevated OBP but normotension on ABPM .th percentile at night, but with normal blood pressure during the day were categorized as having isolated nocturnal hypertension while patients with BP exceeding 95th percentile during the day, but with normal blood pressure during the night were categorized as having isolated daytime hypertension. Patients with both daytime and nocturnal hypertension considered to have sustained hypertension [Finally, based on ABPM measurements, patients with BP exceeding 95rtension , 17.Aortic pulse wave velocity (PWV) was assessed by applanation tonometry  as described previously , 19. ThrEchocardiographic examinations were performed with a Vivid E95 ultrasound system equipped with a M5SC-D phased-array transducer . All measurements were performed according to current guidelines . There wRight ventricular (RV) basal diameter was measured as the transversal diameter at the basal third of the RV cavity on the apical 4-chamber view. Tricuspid annular plane systolic excursion (TAPSE) was measured using M-mode tracing of the tricuspid annulus at the free wall on the apical 4-chamber view.Pulsed wave Doppler interrogation at the level of the mitral valve coaptation was obtained to determine early (E) and late diastolic (A) peak LV inflow velocities and their ratio (E/A). Pulsed wave Tissue Doppler Imaging (TDI) was used to measure systolic (s’), early (e’), and late diastolic (a’) velocities at the mitral lateral and medial annuli. The ratio of E-wave velocity to averaged e’ velocities of the mitral medial and lateral annuli was calculated as an estimate of LV filling pressures .STE is based on B-mode gray-scale tracking of 2D “speckles” or “kernels.” Using the end diastolic dimensions as a surrogate for the original length and reference point, these spots can be tracked as they move through the cardiac cycle to determine the degree of strain. Strain is a dimensionless parameter that represents the fractional change in the length of a myocardial segment in systole, where the longitudinal and circumferential shortening during myocardial contraction is represented by negative values and is expressed as a percentage (%). Since the myocardium contracts longitudinally and circumferentially during systole, these values are negative percentages, more negative values indicating better cardiac contractility, and accordingly if absolute values are considered, lower values of strain parameters implying dysfunction.STE was performed with a dedicated software  using ECG-gated grey-scale cine-loops of three to five consecutive cardiac cycles by one experienced operator (A.B.). The endocardial surface of the given chamber was manually contoured on the end-diastolic frame. The algorithm automatically traces the endocardium throughout the cardiac cycle and calculates strain values. LVGLS was calculated using apical 2-, 3-, and 4-chamber views while global circumferential strain (GCS) was assessed from parasternal short axis views at the level of mitral valve, papillary muscles, and the apex. RVGLS was measured from the apical 4-chamber view . SegmentIntra- and interobserver variability values of the key STE parameters showed appropriate agreement. The intra- and interobserver variability for LVGLS was 0.9481 , 2.7% , and 0.9377 (CCC), 3.2% (CV) respectively, while for RVGLS, the same parameters were 0.8894 (CCC), 4.9% (CV), and 0.8246 (CCC), 5.2% (CV) respectively.t-test or Mann–Whitney U-test was used for comparing continuous variables for two groups according to normality. One-way ANOVA or Kruskal–Wallis test was used to compare multiple groups. Correlations between variables were evaluated by Pearson’s rank correlation test or non-parametric Spearman correlation. Stepwise multiple linear regression analyses were performed to assess the independent variables affecting LVMi and LVGLS. The p values reported are two-sided and taken to be significant at < 0.05. Inter- and interobserver variability was assessed by calculation of coefficient of variation (CV) and by Lin’s concordance correlation coefficient (CCC). Ten subjects  were re-analyzed in a blinded fashion by the operator of the initial measurements (A.B.), and the same subjects were also analyzed by a second operator (A.F.).Statistical analysis was performed using STATISTICA version 13.4 . The Shapiro–Wilk test was used to detect the normality of data distribution. Variables are expressed as means ± SD, median (interquartile ranges), or percentage as appropriate. Categorical variables were analyzed using chi-square or Fisher’s exact test. Student’s General characteristics of the study groups are summarized in Table There were no significant differences with regard to age, gender, and weight Z-score between the KTx and control groups, while KTx patients were significantly shorter compared to controls.n = 13), focal segmental glomerulosclerosis (n = 10), polycystic kidney disease (n = 4), nephronophthisis (n = 4), VACTERL syndrome (n = 2), Denys–Drash syndrome (n = 2), ischemic kidney injury (n = 2), Alport syndrome (n = 1), Wegener’s granulomatosis (n = 1), tubulointersitial nephritis (n = 1), and unknown etiology (n = 2). The mean age at transplantation was 9.0 ± 3.7 years. Thirty-eight children received their first graft, while 4 had a second transplantation. Seventy-one percent of the patients received kidneys from cadaveric donors; the prevalence of living related kidney donation was 12/42 (29%); 32 patients required hemo- and/or peritoneal dialysis prior to transplantation ; 10 patients were transplanted preemptively. The mean GFR was 68.42 ml/min/1.73 m2; most patients were in CKD stage II, with only 3 in CKD stage IV.Indications for KTx were congenital anomalies of the kidney and urinary tract (n = 36); steroid was added in 10 patients. Two patients were treated with a combination of tacrolimus and steroid; 1 child was on tacrolimus monotherapy. mTOR inhibitor sirolimus was administered in 2 children in combination with mycophenolate mofetil.Transplant recipients were on standard immunosuppression with tacrolimus and mycophenolate mofetil , beta-blockers (n = 18), ACE-inhibitors (n = 6), and alpha-adrenergic blocking agents (n = 2). A majority of the patients were on monotherapy (n = 14); 11 patients received double or triple combinations of antihypertensive medications. Seven patients had new-onset hypertension according to ABPM and were not yet on antihypertensive medication.Twenty-five patients were treated for hypertension. Antihypertensive medication consisted of calcium-channel blockers (Z-scores of blood pressure as well as of PWV of the KTx group significantly exceeded those of the control group.p < 0.001). LVH was present in 13 patients (30%), ; however, conventional indicators of LV and RV systolic function  did not differ from controls. Conventional Doppler-derived transmitral E wave was similar to the healthy controls while A wave was significantly increased, and as a result, E/A ratio was significantly lower in KTx patients.RWT and mean LVMi of KTx patients were significantly higher compared to the healthy subjects , while the absolute value of LVGCS and RVGLS was significantly higher in KTx patients.To analyze the effects of hypertension on myocardial structure and function, hypertensive KTx patients were compared with normotensive KTx patients.General characteristics, blood pressure, and PWV data of both KTx groups are shown in Table Based on 24-h ABPM results, 11 patients had controlled and 21 had uncontrolled hypertension, while 10 patients were normotensive. Normotensive KTx patients were thinner and had significantly lower BMI than patients with hypertension. Thus, Z-scores were used for statistical comparison of the blood pressure groups.No differences were observed in terms of age, time on dialysis, or time since transplantation as well as for PWV values among the KTx groups.Accordingly, due to the definition of hypertension, ABPM-measured blood pressure of hypertensive KTx children was significantly higher compared to the normotensive KTx children. The 24-h SBP and DBP Z-scores of the uncontrolled hypertensive patients were significantly higher, greater than 2 and 1.5 Z-scores respectively. Controlled hypertensives had lower blood pressure, although for the 24-h SBP value, it was still significantly elevated, almost 1 SD higher than that of normotensive children. These clear-cut differences were masked when considering office BP data.Both systolic and diastolic nocturnal dipping were significantly impaired in the uncontrolled group compared to the controlled hypertensives. The prevalence of non-dipping phenomenon was 81% in uncontrolled and 45% in controlled hypertensive patients.Echocardiographic parameters according to blood pressure control are shown in Table p = NS). There were no differences in LVEF and TAPSE between hypertensive and normotensive KTx patients, while deceleration time (DT) was tendentially increased in the uncontrolled hypertensive group.LVMi was significantly higher both in controlled and uncontrolled hypertensive patients compared to the normotensive group, while RWT was not different between the groups. LVH was present in 13 patients (4 in the controlled and 9 in the uncontrolled group). In the controlled hypertensive group, 2 patients had concentric and 2 eccentric hypertrophy, while in the uncontrolled hypertensive group 7 had eccentric and 2 concentric hypertrophy  the lowest LVGLS values whereas controlled hypertensives had the highest values Table .n = 8), isolated daytime hypertension (n = 3), and patients with isolated nocturnal hypertension (n = 10). Comparing LVGLS results of the normotensive KTx patients  to the ABPM subcategories, patients with isolated daytime HT had worse values  followed by those with sustained hypertension , and those with isolated nocturnal HT .Based on OBP and ABPM results, 10 patients had masked and 4 had white coat hypertension. According to ABPM measurements, the 21 uncontrolled hypertensive patients could be further divided into sustained hypertension , while the results for the sustained and isolated nocturnal hypertension categories (LVGCS – 26.54 ± 1.80 and – 27.10 ± 5.15 respectively) did not differ from the normotensive KTx group (LVGCS – 27.14 ± 3.86). The differences in RVGLS did not reach the level of significance.Concerning the LVGCS values, patients with isolated daytime hypertension had the worst values , a well-known independent cardiovascular risk factor , 30 relaIncreased muscular mass (that is higher LVMi) may cause diastolic dysfunction preceding impairment of systolic function , 33. TheMoreover, similarly to adult patients with predominantly diastolic dysfunction and preserved LVEF,  LVGCS in the KTx group were significantly higher, suggesting, that the increased circumferential deformation compensates for the worsening of LVGLS, which together result in the preservation of the EF. These results point to the pathophysiological continuum that results in heart failure with preserved ejection fraction (HFpEF) in this population .LVGLS was also found to be a predictor of outcome in the adult general population, patients with CKD and in adult KTx as well. In the Copenhagen City Heart Study, LVGLS predicted long-term risk of cardiovascular morbidity and mortality in a low risk general population . In a prIn KTx patients, there was a significant correlation between LVMi and BMI Z-score, ABPM, and RWT. The effect of blood pressure as well as BMI on LVMi is well established , 43. KTxp = 0.07).While both the 24-h and separately assessed night and daytime SBP means were closely related with LVMi, the correlation with the dipper phenomenon showed only a trend  on cardiac structure, the category of myocardial hypertrophy and mechanics, could not be assessed in detail. Concerning calcium and phosphate metabolism and its influence on cardiac function, the Ca × P product and PTH were not associated with the results of STE; however, FGF23 — an important factor of myocardial dysfunction in CKD — was not examined. Moreover, the cross-sectional design of the study precludes establishing a causal relationship between the studied parameters.In conclusion, pediatric KTx patients show several high-risk features in terms of CV disease, and these metabolic and hemodynamic factors are associated with changes in cardiac morphology and function. While conventional measures of LV and RV performance do not effectively reflect these changes, STE-derived strain parameters may conversely serve as sensitive markers of myocardial damage. Early detection of subtle alterations and targeted treatment may prevent later CV complications. All these data suggest the use of STE in children may be promising and its predictive value should be evaluated in longitudinal studies.Graphical abstract(PPTX 63.7 kb)


As previously reported, an increased repolarization temporal imbalance induces a higher risk of total/cardiovascular mortality.The aim of this study was to assess if the electrocardiographic short period markers of repolarization temporal dispersion could be predictive of the hospital stay length and mortality in patients with acutely decompensated chronic heart failure (CHF).Mean, standard deviation (SD), and normalized variance (VN) of QT (QT) and Tpeak‐Tend (Te) were obtained on 5‐min ECG recording in 139 patients hospitalized for acutely decompensated CHF, subgrouping the patients for hospital length of stay (LoS): less or equal 1 week (≤1 W) and those with more than 1 week (>1 W).p < .05), a decrease of blood pressure (p < .05), lower ejection fraction (p < .05), and higher plasma level of biomarkers  in >1 W LoS subjects. 30‐day deceased subjects reported significantly higher levels of QTSD (p < .05), Te mean (p < .001), TeSD (p < .05), QTVN (p < .05) in comparison to the survivors. Multivariable Cox regression analysis reported that TeVN was a risk factor for longer hospital stay ; whereas, a longer Te mean was associated with higher mortality risk .We observed an increase of short‐period repolarization variables (TeSD and TeVN, A longer hospital stay is considered a clinical surrogate of CHF severity, we confirmed this finding. Therefore, these electrical and simple parameters could be used as noninvasive, transmissible, inexpensive markers of CHF severity and mortality. Patients were defined as decompensated following the European Society of Cardiology guidelines.ClinicalTrials.gov number is NCT04127162.All patients provided written informed consent for the use of their records for research purposes and the study was in accordance with good clinical practice and the principles of the Declaration of Helsinki regarding clinical research involving human patients. The study underwent the Ethical Committee of Policlinico Umberto I approbation. The 2.2Five minutes ECG (Miocardio Event™) II lead signals were acquired, digitalized at a sampling frequency of 500 Hz, and wirelessly transmitted to a cloud platform for data storage via mobile phoneWe, therefore, calculated mean, variance, and SD (QTSD and TeSD) values for each of these repolarization phase intervals and, finally, we calculated the VN for a mean of QT (QTVN) and Te (TeVN)2,QTVN = QT variance/(QTe mean)2.TeVN = Te variance/(Te mean)Software for data analysis was designed and produced by our research group with the LabView program .2.3χ2 test. Unpaired Student's t‐test was used to compare data for the normally distributed variables; on the contrary, Mann–Whitney tests were used to compare non‐normally distributed variables . Uni‐ and multivariable forward  Cox proportion‐hazard regression analysis was used to determine the association between repolarization variables (covariates) and some dichotomized variables (dependent variables). In particular, we considered separately the following dependent variables: first, 30‐day mortality, and, second the different lengths of in‐hospital stay (≤1 W or >1W). p values of less than or equal to .05 were considered statistically significant. All data were evaluated by use of the database SPSS‐PC+ (SPSS‐PC+ Inc.).All variables with normal distribution were expressed as means ± SD whereas non‐normally distributed variables were as median and interquartile range (i.r.). Categorical variables were analyzed with the 3p < .01), better left ventricular ejection fraction (p < .05), in range blood calcium concentration (p < .001) than >1 W of LoS one (Table p < .001) and lower high‐sensitivity cardiac troponin T (p < .05) (Table p < .05).Of the initially 146 eligible patients, 6 were excluded because the repolarization signals were suboptimal for the analysis, consequently, 139 patients were studied. At the time of presentation, all patients were in NYHA functional class IV. 29 patients died within 30 days from the enrollment : 19 patients died of respiratory failure, 7 from terminal heart failure, 2 from fatal acute myocardial infarction, 1 from arrhythmic sudden cardiac death (sustained ventricular tachycardia and ventricular fibrillation). The demographic and clinical characteristics of the two groups are provided in Table p < .05) and TeVN (p < .05) than the ≤1 W (Table p < .05), Te mean (p < .001), TeSD (p < .05), QTVN (p < .05) than the survivors' group (Table Subjects from the >1 W LoS group showed a higher TeSD ( W Table . In addiup Table .p < .05). The same two statistical analyses demonstrated that 30‐day mortality was related to QTSD (p < .05), Te mean (p < .05) and TeSD (p < .05) values (Table p < .05) relation : 1.02 (1.01–1.03), p: .003.Uni‐multivariable Cox regression analysis reported just one significant relationship between a longer hospital stay and TeVN , nor Te mean  at discharge showed substantial changes compared to the hospital admission. Conversely, the blood concentration of NT‐pro‐BNP was found to be lower at discharge than at admission , as expected.Finally, 65 patients among the 110 survivors were re‐evaluated before discharge (ECG markers and NT‐pro‐BNP determination). Neither QT mean  is still little studied, some authors believe that this interval represents a noninvasive marker of transmural dispersion of repolarization in the left ventricle,Thus, the morphological and structural alterations of the myocardium resulting in specific modifications of these electrocardiographic markers. This allows for the patient's telemonitoring over time, as when the clinical and morpho‐structural improvement occurs , a relative improvement of the electrocardiographic parameters should be observed.In conclusion, patients with acute decompensated CHF and ≥1 W length of in‐hospital stay showed elevated short‐term repolarization markers. In particular, these patients had higher TeVN, TeSD, and higher levels of CHF biomarkers.Finally, in the subgroup of re‐evaluated, survived patients, the substantial stability of both QT mean and Te mean from admission to discharge suggests, once again, the predictive capability of these ECG markers. As shown in Table Obviously, the present study supplies a working hypothesis, that needed to be confirmed in larger and case–control studies.Nevertheless, it could be hypothesized that these markers could be used as a noninvasive, transmissible, inexpensive, electric, surrogate marker of hospital length of stay, of CHF clinical severity, suggesting higher mortality risk.5The main limitation of this study is the small sample size. This aspect can be overcome by continuing the enrollment and the involvement of more centers. With an adequate sample size, it will be possible to verify the predictive power of the variables under examination even in subjects with less severe degrees of decompensated CHF.In addition, an actual limitation of the study is the absence of patients treated with SGLT2 inhibitors. The sample was in fact studied before the recent indications provided by the European Society of Cardiology guidelines on the use in class I evidence A of these drugs in subjects with heart failure.Furthermore, the geographic variability, already described in the past,The authors declare no conflict of interest.


The heart rate, pulse pressure variation and serum hemoglobin level significantly changed in the H3 stage (p < 0.05). Discussion: The change of second heart sound (S2) was at the H2 stage and was earlier than routine monitoring methods. Therefore, PCG change may be a new indicator for the early detection of HS severity.Introduction: Hemorrhagic shock (HS) is a severe medical emergency. Early diagnosis of HS is important for clinical treatment. In this paper, we report a flexible material-based heart sound monitoring device which can evaluate the degree of HS through a phonocardiogram (PCG) change. Methods: Progressive hemorrhage treatments  were used in swine to build animal models. The PCG sensor was mounted on the chest of the swine. Routine monitoring was used at the same time. Results: This study showed that arterial blood pressure decreased significantly from the H1 phase, while second heart sound amplitude (S2A) and energy (S2E) decreased significantly from the H2 phase. Both S2A and S2E correlated well with BP ( Hemorrhagic shock (HS) is one of the leading causes of death after trauma, which is caused by the depletion of intravascular volume through blood loss to the point of being unable to match the tissue’s demand for oxygen ,2. ThereIn recent years, the multi-physiological signal method has been used to determine the degree of blood loss. For example, the combination of Doppler and electrocardiogram (ECG) signals has been used to classify the severity of bleeding ,7. CompaHeart sounds are the noises that are generated by the beating heart and the resultant flow of blood through it. The second heart sound (S2) is a component of the heart sound. S2 has two audible components, the aortic closure sound and the pulmonic closure sound. Therefore, S2 is produced in part by hemodynamic events immediately following the closure of the aortic and pulmonic valves. The vibrations of the second heart sound occur at the end of ventricular contraction and identify the onset of ventricular diastole and the end of mechanical systole. In recent years, many studies about PCG have shown that the second heart sound spectral-frequency features can be used to estimate the mean arterial pressure (MAP) and pulmonary artery pressure ,13. As aDuring the progress of hemorrhagic shock, effective circulatory blood-volume reduction leads to significant arterial pressure decreases. Although other studies have proved that the second heart sound has a good correlation with the BP ,16, the This study was performed in eight healthy male Bama swine . All operations follow the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health. The Medical Ethics Committee of the Chinese People’s Liberation Army General Hospital approved the protocol for this experimental study .Swine were sedated with an intramuscular injection of midazolam (0.3 mg/kg) and xylazine hydrochloride (0.03 g/kg) and then intubated. Anesthesia was maintained with sevoflurane (1–1.5%). Intravenous rocuronium (1 mg/kg) was administrated for mechanical ventilation . The serum hemoglobin (Hb), glucose (Glu), and lactate (Lac) levels were detected using an ABG analyzer . All swine were laid in the supine position. After local infiltration anesthesia of lidocaine (2%), two catheters were inserted into the right carotid artery and jugular vein via the right cervical incision to allow monitoring of the blood pressure and central venous pressure (CVP), respectively. Another catheter was advanced into the right femoral artery via puncture guided by portable ultrasound for blood extraction. Nasopharynx temperature and pulse oxygen saturation (SpO2) were measured by a multifunctional monitor .The cardiopulmonary signals  and nasopharyngeal temperature of the swine were monitored continuously during the experiment, and the baseline values were recorded simultaneously. Then, a three-stage graded hemorrhage and resuscitation protocol was conducted  . The relTwo wearable synchronized PCG and ECG sensors developed by Wenxin Tech  were attached to the aortic valve second auscultation area (A spot) and the pulmonary auscultation area (P spot) on the left chest surface of the swine, respectively . The devAfter data cleansing, the heart sounds were extracted and separated into the S1 and S2. The characteristics of S1 and S2 signals, including the first sound amplitude (S1A); the first sound energy (S1E); the pre-ejection period (PEP); the second sound amplitude (S2A); the second sound power (S2E); and the left ventricular systolic time (LVST) were measured using an automatic analysis software that was developed by Bayland Scientific and Wenxin Tech . The parameters  that were marked on a combination of ECG, PCG, and frequency are shown in All continuous variables are expressed as mean ± standard deviation (mean ± SD). ANOVA was used to compare the hemodynamic and heart sound parameters variation in different hemorrhagic shock and resuscitation steps. The statistical differences between any two steps were analyzed by an LSD (least significant difference) post hoc test. A bivariate linear correlation (Pearson) was used to test the relationship between the heart sound parameters and circulatory variables. SPSS software, version 22.0  was used to perform the statistical analysis.The monitoring of systemic blood volume by PCG requires the coordination of a series of cardiac hemodynamic indicators and cardiac electrical activity. Therefore, the PCG sensor and ECG sensor need to work synchronously. PCG was used as the main indicator to evaluate systemic blood volume, and ECG was used as the synchronous processing indicator. The signal acquisition and processing of the PCG sensor and ECG sensor are shown in p = 0.003; 74.38 ± 13.16 vs. 95.0 ± 15.35, p = 0.005; 63.0 ± 13.05 vs. 83.38 ± 15.14, p = 0.009, respectively); H2 ; and H3  stage. The SI progressively increased in the H1 ; H2 ; and H3  stages. The CVP had significant decreases in the H2 and H3 stages . However, the HR, PPV and Hb significantly changed in the H3 stage . The serum Glu and Lac levels had significant elevation in the last transfusion stage . The transfusion of autologous blood resulted in partial hemodynamic variables, including HR, SBP, MAP, DBP, SI, PPV and Hb restored toward baseline values .Changes in the SBP, MAP, DBP, HR, SI, CVP, pulse pressure variation (PPV), Hb, Glu and Lac during graded hemorrhagic shock and resuscitation are shown in p = 0.013, and 3475.88 ± 2091.99 vs. 3963.13 ± 2157.06, p = 0.012, respectively); H2 ; and H3  stage. The S2Aa and S2Ea significantly decreased in the H2  and H3  stage. The S1Aa/S2Aa had significant decreases in the H3 stage . However, no significant changes in the S1Ap, S2Ap, S1Ep, S2Ep, S1/S2Ap and S1/S2Ep were observed throughout the protocol . The PEPa significantly elevated in the H1 stage , whereas the PEPp elevated in the H3 stage . The autologous blood transfusion caused a restoration in the S1Aa, S2Aa, S1Ea, S2Ea, PEPa and PEPp to baseline values .Changes in the S1A (S1Aa); S1E (S1Ea); S2A (S2Aa); S2E (S2Ea); PEP (PEPa); andLVST (LVSTa) at A spot, and S1A (S1Ap); S1E (S1Ep); S2A (S2Ap); S2E (S2Ep); PEP (PEPp); and LVST (LVSTp) at P spot during graded hemorrhagic shock and resuscitation are shown in p < 0.001; r = 0.559, p < 0.001; r = −0.550, p < 0.001; r = −0.526, p < 0.001, respectively); ΔMAP ; and ΔDBP . There were strongly negative correlations between the ΔLVSTa and ΔHR, ΔSI, and ΔPPV . On the other hand, both ΔS1Aa and ΔS1Ea did weakly positive correlate with the ΔSBP, ΔMAP and ΔDBP, respectively . A receiver operating characteristic (ROC) curve analysis showed that the sensitivity and specificity of S2Aa ≤ 251.5 mv for the diagnosis of SBP < 90 mmHg were 0.968% and 0.417%, respectively, and the sensitivity and specificity of S2Ea ≤ 243 for the diagnosis of SBP < 90 mmHg were 0.984% and 0.408%, respectively. The area under the curve (AUC) was 0.795  for S2Aa and 0.788  for S2Ea. The sensitivity and specificity of S2Aa ≤ 204.5 mv for the diagnosis of MAP < 60 mmHg were 0.930 and 0.354, respectively, and the sensitivity and specificity of S2Ea ≤ 182 for the diagnosis of MAP < 60 mmHg were 0.942 and 0.354, respectively. The AUC was 0.705  for S2Aa and 0.707  for S2Ea , stroke volume (SV), stroke volume variation (SVV), and systematic vascular resistance (SVR) because of limited conditions in the animal laboratory. The correlations between the S2A or S2E and CO, SV, SVV, and SVR are unavailable. Further research is needed to assess the accuracy of BP estimation by PCG analysis in clinical use. Second, since decreased BP leads to a decrease in amplitude and frequency of the heart sound, when there is no BP drop due to chronic or small amounts of bleeding or cardiovascular compensation in awake patients, the S1 or S2 change might be insignificant. With more detailed research on heart sound features, whether the S1 or S2 distinguish the BP drop that is caused by blood loss or other reasons needs to be further investigated. Third, it is hard to keep both PCG and ECG signals measured at their standard positions and leads simultaneously due to the curved surface of the swine body. Lastly, other factors such as heart sound detection errors may induce bias.Our study provides novel and converging cardio-physiological evidence that hemorrhage-induced BP drop can produce a heart sound decrease synchronously, which occurs earlier than HR, CVP, PPV, Hb, or metabolic variables. The S2A or S2E correlates well with the BP. It has high sensitivity in the diagnosis of SBP < 90 mmHg, implying that the S2 may serve as a potential candidate for cardio-physiological markers of HS. The S2 signal might be capable of promptly determining the degree of blood loss indirectly, which would provide a valuable means for real-time remote triage and decision making. Therefore, the S2 might be a new, earlier marker for predicting hemorrhagic shock than the other parameters that are evaluated in this study. Further, although the simpler, small patch is site-dependent, it is easy to be handled by a trained person. While the findings of our study need to be confirmed in the clinical setting, they do suggest a role for the clinical application of wearable PCG monitoring in high-risk trauma patients in the prehospital setting.


Patients with a disturbed blood pressure profile had the highest LVMI (p = 0.049), while extreme dippers had the highest augmentation index (AIx75HR) (p = 0.027). Elevated systolic and diastolic BP dipping were risk factors for positive AIx75HR (OR 1.122 95CI (1.009–1.249) and OR 1.095 95CI (1.017–1.177). We concluded that disturbed circadian BP profile was common in children with PH and should not be considered a marker of secondary hypertension. A disturbed circadian BP profile may be associated with higher body weight. In pediatric patients with PH, non-dipping is associated with increased left ventricular mass, and extreme dipping may be a risk factor for increased arterial stiffness.Our study aimed to evaluate factors affecting circadian BP profile and its association with hypertension-mediated organ damage (HMOD) in pediatric patients with primary hypertension (PH). The study included 112 children  with untreated PH. Non-dipping was defined as a nocturnal drop in systolic or diastolic BP  < 10%, and a nocturnal drop >20% was defined as extreme dipping. The nocturnal SBP drop was 10.9 ± 5.9 (%), and the DBP drop was 16.2 ± 8.5 (%). Non-dipping was found in 50 (44.6%) children and extreme dipping in 29 (25.9%) patients. The nocturnal SBP decrease correlated with BMI Z-score (r = −0.242,  Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is currently a more and more easily accessible tool to assess arterial blood pressure (BP) values. ABPM not only helps to detect white coat hypertension and is more useful to control the effectiveness of antihypertensive therapy than office measurements but also provides a valuable insight into the BP variability and fluctuations over the whole day sleep–wake cycle . MoreoveThere has been more than three decades of research on circadian BP patterns among hypertensive patients; and yet, there are still conflicting results as to whether dipping status is a valuable predictor of cardiovascular disease (CVD) morbidity and mortality and if it is associated with hypertension-mediated organ damage (HMOD). Studies in adults showed that both a lack of BP decline and excessive drop of BP at night might be indicators of CVD events ,4. For eTherefore, our study aimed to assess dipping status, its determinants, and its relationship with precisely evaluated HMOD: left ventricular mass, urinary albumin excretion, and indicators of arterial damage: common carotid artery intima-media thickness (cIMT), arterial stiffness  in a cohort of pediatric patients with untreated primary hypertension (PH).p = 0.05, and an effect size of 0.50 should be at least 64  [The sample size estimated based on the available literature with a statistical power of 0.8, ny HMOD) ,10,11. Tny HMOD)  and confBefore the initiation of the study, approval from the local bioethics committee was obtained . All procedures were performed in accordance with the Declaration of Helsinki on the treatment of human subjects and its later amendments. All legal representatives of the patients, and patients if aged 16 years and older, signed informed consent to participate in the study.2). If possible, all measurements were compared with Polish normative data and expressed as Z-score [All examinations were performed upon admission using the same protocol. The following clinical parameters were assessed: age (years), sex, duration of arterial hypertension (months), duration of pregnancy (weeks), birth weight (g), and basic anthropometric parameters such as height (cm), weight (kg), and calculated body mass index (BMI) (kg/m Z-score . Overwei Z-score .2) [Laboratory tests were conducted using standard local laboratory methods. The blood was drawn after at least 8 h of fasting in a sitting position in the morning (between 7:00 and 9:00 a.m.). The following complete biochemical tests were assessed: serum potassium (mmol/L), sodium (mmol/L), creatinine (mg/dL), uric acid (mg/dL), total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol (mg/dL), and triglycerides (mg/dL). Lipid disturbances were classified following , and hyp2) . All tesThe BP measurements were carried out according to protocols suitable for pediatric populations  and desc2.7) [Left ventricle mass index (LVMI) was calculated with parameters drawn from echocardiography (ECHO) measurements using M-mode assessment of the left ventricle with simultaneous recording of ECG in the second limb lead. The detailed methodology was described in our recently published manuscript . Measure2.7) . Left ve2.7) . Assessment of arterial damage and central properties of the arteries were also described thoroughly in manuscripts of our previous studies ,25. SphyAdditionally, left and right common carotid artery intima-media thickness (cIMT) was evaluated with a 13-MHz linear transducer , using already described methods  and expraPWV ≥ 95th percentile, cIMT ≥ 95th percentile, and a positive value of AIx75HR were assumed as indicators of arterial damage in the studied patients. p-value < 0.05 was considered of statistical significance.Collected data were archived in an anonymized form  with password-protected user-level access. Statistical analysis was conducted using Dell Statistica 13.0 PL software . First, the Shapiro–Wilk test was used to assess the normality of data distribution. Continuous variables were presented as mean ± standard deviation (SD) and interquartile range (IQ). The following tests were used during statistical analysis: student T-test, Mann-Whitney U test, ANOVA, Kruskal–Wallis ANOVA, Spearman’s rank correlation, Pearson correlation, chi-squared test, Fisher’s exact test, receiver operating characteristics (ROC) analysis, and logistic regression. In the logistic regression model, unadjusted odd ratios for the presence of HMOD and blood pressure dipping as continuous predictors were calculated. We did not include blood pressure values in the model as there were no significant correlations between 24 h blood pressure  and blood pressure dipping. Test results with a Basic clinical parameters and results of laboratory tests of all examined patients were depicted in Office peripheral and central blood pressure and ambulatory blood pressure are depicted in The parameters of hypertension-mediated organ damage were presented in The significant correlations of systolic and diastolic BP dipping with clinical and laboratory parameters in the whole group of 112 children are shown in The correlations of central systolic blood pressure and markers of HMOD with BP dipping are depicted in p = 0.083), aortic pulse wave velocity (p = 0.213 and p = 0.527), and common carotid artery intima-media thickness (p = 0.484 and p = 0.357). The left ventricular mass index was the highest in the non-dipper group, significantly higher compared to the dipper group (p = 0.049), and the augmentation index was the highest in the extreme dipper group, significantly higher compared to the non-dipper group (p = 0.027).All children were divided into three groups according to their BP dipping pattern—dippers, non-dippers, and extreme dippers. Results of differences in studied parameters between the groups are depicted in Analysis by logistic regression revealed that elevation in systolic and diastolic BP dipping increases the risk for abnormal AIx75HR (odds ratio (OR) 1.122, 95 confidence interval (95CI) (1.009–1.249), and OR 1.095, 95CI (1.017–1.177), respectively) . p = 0.034) and 15.7 , p = 0.002). 24-h mean arterial pressure Z-score and other indices of 24-h blood pressure did not predict AIx75HR with statistical significance (AIx75HR (%) vs. 24 h MAP Z-score: AUC 0.506, 95CI (0.358–0.654), p = 0.939).ROC analysis demonstrated good diagnostic profiles for the presence of abnormal AIx75HR. The cut-off value of systolic and diastolic BP dipping to predict positive AIx75HR was 7.4 , Our single-center cross-sectional study aimed to assess the dipping status in pediatric patients with untreated primary  hypertension. First, we revealed that the non-dipping phenomenon is present in as many as half of the patients, and almost a quarter of them can be classified as extreme dippers leaving only a minority of patients with normal dipping status. Secondly, body mass and body mass index were significant determinants of dipping status. As for the analysis of the relation between dipping status and HMOD, systolic blood pressure dipping correlated negatively with left ventricular mass index, and non-dippers were found to have significantly higher left ventricular mass compared to dippers. Conversely, the augmentation index correlated positively with blood pressure dipping, and extreme dippers were characterized by the highest augmentation index. The latter association was confirmed by logistic regression and ROC analysis. Interestingly, no significant associations were revealed between central blood pressure, aortic pulse wave velocity, common carotid artery intima-media thickness, and dipping status.We analyzed patients at one tertiary nephrology center with confirmed primary hypertension. We managed to collect a group of more than 100 treatment-naive patients. Our cohort can be considered representative of adolescent patients with primary hypertension. The mean age in our group was between 14.5 and 15 years, and the male gender was predominant. Additionally, more than 2/3 of the patients were overweight and obese—similar percentages are found in studies by other authors ,29,30,31Arterial hypertension is the most important independent risk factor for cardiovascular morbidity and mortality worldwide. A particularly strong relationship is found between systolic blood pressure and the risk of stroke . Hard enFor many years, the importance of assessing not only the BP value itself but also other derivatives such as pulse pressure or BP variability has been raised. Assessment of pressure variability can be done in the long-term (visit-to-visit) range but also in the shorter term. Since the introduction of the ABPM study into widespread use, circadian variability has become the most commonly assessed variability. Arbitrarily years ago, it was accepted that the normal nocturnal drop in blood pressure was 10% (dippers vs. non-dippers). In subsequent years, data emerged indicating that it was also useful to separate patients with a high >20%) nocturnal drop (extreme dippers) and those whose nighttime pressure increases (reverse dippers) 0% noctur. As for The nocturnal drop in systolic blood pressure correlated negatively with body weight and BMI . These results indicate that overweight and obesity are risk factors for impaired nocturnal pressure drop. Other studies have found similar results in adults and children ,43. ObesA sub-analysis of 26 patients showed a strong positive relationship between urinary potassium excretion and a nocturnal blood pressure drop. Evaluation of urinary excretion of the component is a simple marker of its dietary supply. Population studies have shown that increasing dietary potassium is associated with a reduction in blood pressure and cardiovascular risk. Bankir et al. found a positive association between daytime urinary potassium excretion and blood pressure dipping . ConversOur study showed that an impaired circadian blood pressure profile is a risk factor for left ventricular hypertrophy. These findings are consistent with the results of numerous adult studies . NeverthIn addition, we showed that the phenomenon of extreme dipping is associated with an increase in the augmentation index. Patients defined as extreme dippers are characterized by a significant (>20%) decrease in nighttime blood pressure. Palatini, in a study involving more than 10,000 adults, showed that extreme dipping is a risk factor for cardiovascular complications, but only in patients over the age of 70 . InteresElevated urinary albumin excretion indicates subclinical endothelial damage not only in the kidneys and is an independent risk factor for cardiovascular morbidity and mortality . EvaluatTo date, two questions remain unresolved: first, whether we can effectively influence the circadian blood pressure profile and whether restoring a normal blood pressure profile reduces cardiovascular risk. Current European guidelines recommend prescribing treatment with long-acting drugs in a single morning dose  . Most stThe strength of our study is the relatively large group of pediatric patients with untreated  hypertension and the in-depth analysis of HMOD. Limitations are certainly the cross-sectional nature of the study, and the lack of validation of the OSCAR 2 SUNTECH device in the pediatric population  is a standard parameter assessed by ABPM, its significance, especially in the pediatric population, is not clear. Our single-center, cross-sectional study showed that both a disturbed circadian blood pressure profile (non-dipping) and a large nocturnal drop (extreme dipping) are common phenomena in pediatric patients with primary hypertension. Excess body weight was associated with disturbed blood pressure dipping. Noteworthy, the impaired circadian blood pressure profile was associated with increased left ventricular mass. On the other hand, extreme dipping was related to increased arterial stiffness. Our study indicates that an impaired circadian blood pressure profile should not be considered a marker of secondary hypertension but rather a marker of risk for hypertension complications. The cross-sectional nature of our study does not answer the question of whether we have therapeutic options to influence the circadian profile of blood pressure and whether its normalization is associated with regression of HMOD. There is no doubt that further prospective studies targeting the issue of the circadian blood pressure profile in adolescent patients with primary hypertension are needed.