To compare renal sinus fat volume (RSFV) separately within the right and left kidneys between bilateral nephrolithiasis patients and healthy controls.n = 102) and healthy control (n = 130) groups. Age, sex, blood pressure [systolic blood pressure (SBP) and diastolic blood pressure (DBP)], estimated glomerular filtration rate (eGFR), body weight, and height of each participant were extracted. Volumetric renal sinus adipose tissue was measured separately for both kidneys on CT images. Urea, serum creatinine (Scr), uric acid (UA), total serum cholesterol (TCH), serum triglyceride (TG), and serum high- and low-density lipoprotein  cholesterol levels were obtained.This cross-sectional study analyzed patients who underwent unenhanced abdominal computed tomography (CT) divided into nephrolithiasis (p > 0.05). However, nephrolithiasis patients had higher age, BMI, SBP, and RSFV; higher Scr, UA, TCH, and TG serum levels; and lower HDL-cholesterol level and eGFR. Average left RSFV was significantly higher than right RSFV in healthy controls . A significant relationship between bilateral RSFV, age, BMI, SBP, and eGFR was noted in bilateral nephrolithiasis patients. Multivariate linear regression analysis showed age, BMI, and LDL-cholesterol to be independent predictors of left RSFV, and only BMI was an independent predictor of right RSFV.Overall, 232 participants  were enrolled. There were no differences in sex, DBP, urea, and LDL-cholesterol between the two groups (all Our data showed renal sinus adipose tissue accumulation and the relationship among RSFV, age, BMI, and LDL-cholesterol in bilateral nephrolithiasis patients. Nephrolithiasis is one of the most common urological conditions with a high recurrence rate. It has been thought to be related to diet and abnormal renal handling of electrolytes over the last several decades. However, recently a large number of epidemiologic studies showed a consistent link between nephrolithiasis and other systemic disorders including cardiovascular disease (CVD), metabolic syndrome (MS), and atherosclerosis (AS) –3. DespiIncreasing evidence suggests that ectopic fat deposition or fat accumulation within and around non-adipose tissues and organs plays an essential role in the development of adjacent anatomical organ dysfunction and systemic disorders . EpicardTo the best of our knowledge, to date, RS fat has not been evaluated in patients with nephrolithiasis. Thereby, the hypothesis explored in this study was that RS fat accumulation is more prevalent in nephrolithiasis. The present study aimed to determine (1) whether patients with nephrolithiasis have more RSFV than healthy controls and (2) whether RSFV is related to other possible variables in nephrolithiasis.The retrospective study sample comprised patients from the Renmin Hospital of Wuhan University, Wuhan, China who underwent unenhanced abdominal computed tomography (CT) between October 2017 and April 2019.Patients with bilateral punctiform calculi (stones with diameter < 0.5 cm) without obvious clinical symptoms were included. Patients with an underlying cause of urinary calculi, certain systemic metabolic diseases causing abnormal calcium and phosphorus metabolism, hydronephrosis or renal cyst affecting the measurements, congenital anatomical abnormalities of the kidneys, liver disease, chronic intestinal disease, and merging of the tumor were excluded from the analyses. Further, kidney transplant recipients, patients with any autoimmune disease, known coronary artery disease, previous coronary revascularization, chronic diarrhea, or inflammatory bowel disease and patients with a history of stroke were also excluded from the study. According to the inclusion and exclusion criteria, 232 participants  were analyzed. The control group consisted of healthy adults with no kidney stones and signs or symptoms of systematic diseases. All participants provided written informed consent at enrollment. All investigations were performed following institutional guidelines with approval from the institutional ethics review board.Unenhanced abdominal CT images were captured using a General Electric medical systems Lightspeed 64-slice CT spiral CT scanner. The CT scanning range covered the abdomen with 0.625-mm slices above the S1 level . All imaging analyses were performed on a dedicated Advantage Workstation . RS fat quantification was performed in a semi-automated method that required a slice-by-slice manual definition of borders on CT axial images, and the total volume of RS fat was obtained. According to Foster et al. [Repeated measurements were performed in 22 arbitrarily selected patients by another experienced radiologist to determine the inter-observer variability in RSFV measurements. Inter-observer variability was evaluated using Pearson's correlation coefficient for these measurements on identical images.2). Blood pressure [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] measurements were performed by a professional medical assistant. The estimated glomerular filtration rate (eGFR) was estimated in all subjects using the abbreviated modification of diet in renal disease study equation [Age, sex, body weight, and height of each participant were recorded after their admission. Body mass index (BMI) was calculated as the ratio of weight (kg) to height squared  were explored. Multivariate linear regressions were performed to determine significant associations between RSFV and other variables , adjusted for potential confounders. Bland–Altman plots were utilized to assess potential systematic biases within the repeated measurements. Statistical significance was set at p < 0.05.Statistical analyses were performed using the Statistical Package for Social Sciences for Windows version 23.0 . Dependent variables were analyzed to determine whether they were normally distributed using the Kolmogorov–Smirnov test. Means and standard deviations were calculated for continuous variables. Linear associations between continuous variables were assessed using the Spearman correlation test. Differences between the nephrolithiasis and control groups were tested by Student's r = 0.99 for intra-observer variability and r = 0.98 for intra-observer variability.Intra-reader and inter-reader RSFV measurements are plotted in Fig. The baseline characteristics of 102 bilateral nephrolithiasis patients and 130 healthy subjects are shown in Table 3 versus 4.56 ± 2.29 cm3, p = 0.02; right RSFV: 4.14 ± 3.12 cm3 versus 3.34 ± 1.90 cm3, p = 0.01). Moreover, the average left RSFV was significantly higher than the right RSFV in the control group    , 31, 32.The present study has several limitations. First, the results were associative and observational. Therefore, we cannot establish a causal relationship between RS fat and nephrolithiasis. Second, the results may have been affected by unrecognized potentially confounding variables. To account for this possibility, we performed multivariable regression analyses that accounted for factors known to influence RSFV. Third, our study population primarily included Chinese individuals. Larger studies are needed to determine if the results of this study are generalizable to individuals of other races and ethnicity. Finally, kidney stone composition was not analyzed in this study. The mechanism underlying kidney stone formation may differ according to the stone composition and affect biochemical indices.In conclusion, our results demonstrate the presence of RS adipose tissue accumulation in bilateral nephrolithiasis patients. Further, left RS fat was found to be correlated with age, BMI, and LDL-cholesterol in these patients. Our findings may serve as a basis for future prospective trials exploring the potential benefit of therapeutically targeting kidney stones and the cardiovascular system in nephrolithiasis patients as part of the routine management to mitigate nephrolithiasis-associated morbidity and recurrence.


Significant changes in BTP amplitude were noted during recovery from hypocapnia, but not during the hyperventilation manoeuvre itself. However, a significant increase in heart rate and pulse pressure and decrease in mean arterial pressure were also observed to accompany hypocapnia, which may have confounded our findings. Whilst further investigation is required, the results of this study provide a starting point for better understanding of the effects of carbon dioxide levels on BTPs. Further research in this area is needed to identify the major physiological drivers of BTPs and quantify their interactions with other aspects of cerebral haemodynamics.Hypocapnia is known to affect patients with acute stroke and plays a key role in governing cerebral autoregulation. However, the impact of hypocapnia on brain tissue pulsations (BTPs) is relatively unexplored. As BTPs are hypothesised to result from cerebrovascular resistance to the inflow of pulsatile arterial blood, it has also been hypothesised that cerebral autoregulation changes mediated by hypocapnia will alter BTP amplitude. This healthy volunteer study reports measurements of BTPs obtained using transcranial tissue Doppler (TCTD). Thirty participants underwent hyperventilation to induce mild hypocapnia. BTP amplitude, EtCO Cerebral autoregulation is a homeostatic mechanism, which maintains cerebral blood flow through regulation of various body systems, including the cardiovascular, respiratory, and nervous systems [2) is associated with vasodilation [2) and increased cerebral blood flow velocity [Carbon dioxide  and ultrasound methods . StudiesUnlike TCD measurement of cerebral blood flow, transcranial tissue Doppler (TCTD) aims to measure the movement of brain tissue. This could be advantageous for clinical monitoring, as TCD relies on the detection of relatively weak ultrasound backscatter generated by red blood cells moving through the major arteries . ConsequIt has been theorised that BTP generation can be described by a plethysmographic-like model, where pulsatile cerebral arterial blood supply exceeds venous drainage in systole, causing tissue expansion and relaxation over the cardiac cycle . This re2 from ~40 mmHg to ~20 mmHg resulted in BTP reductions ranging between −25% and −50% [2 by ~5 mmHg) on BTPs in a larger cohort of 30 healthy volunteers.A previous study by Kucewicz et al. investigated the relationship between hypocapnia and BTPs in four healthy subjects who were asked to hyperventilate for 20 min . Brain tand −50% . The aim2 varies considerably between individuals, and in cerebrovascular and non-cerebrovascular disease states [2 on BTPs in a larger cohort. This will facilitate physiological modelling of BTPs and will be used to assess whether there is a need to adjust BTP measurements for confounding by PaCO2. The results of this study will also be used to guide future BTP analysis in both healthy and diseased individuals.As PaCOe states , it is iHealthy participants were recruited from university staff, students, and their relatives, in line with a protocol approved by the University of Leicester Medicine and Biological Sciences Ethics Committee (Reference: 18110). Recruitment exclusion criteria included participants under 18 years old, and those with a significant past medical history of cardiovascular, respiratory, or neurological illness. Written informed consent was obtained from all participants.2 measurements from external monitoring equipment. Physiological measurements were obtained using a Nihon Kohden Lifescope Monitor to acquire three-lead electrocardiogram (ECG) and brachial blood pressure data. A Nihon Kohden OLG-3800 capnograph was used to record EtCO2 (a surrogate of PaCO2), and a Finapres Model 1 was used to obtain continuous blood pressure measurements. All signals were sampled at a frequency of 160 Hz and recorded for further analysis using ‘in house’ data analysis software and a Graphical User Interface (GUI) developed in MATLAB . Measurements were collected in a distraction-free laboratory, maintained at a target ambient temperature of 24 °C. BTPs were measured using a Brain Tissue Velocimetry (Brain TV) TCTD prototype . This system is designed for bilateral monitoring and is equipped with a pair of standard 2 MHz TCD probes, held in place on the forehead using a bespoke headset designed ‘in house’. Probes were placed symmetrically on the forehead approximately 1 cm above the orbit. As with conventional TCD measurement of blood flow, both left and right sides were monitored. TCTD data are recorded alongside additional ECG, blood pressure (BP), and CO2 levels [2 reduction of 5 mmHg. Hyperventilation was followed by a 2-min recovery period. A second hyperventilation period aiming to achieve an EtCO2 reduction of 10 mmHg (by further increasing the respiratory rate) was attempted. However, this was difficult to implement due to participant protocol adherence difficulties.The experimental protocol was adapted from a previous study involving TCD measurement of middle cerebral artery (MCA) cerebral blood flow to explore cerebral haemodynamic responses to COThe in-phase and quadrature-phase (IQ) data from each TCTD recording were down-sampled from 8 kHz to 160 Hz to reduce the size of our files, giving a temporal resolution of 6.25 ms. Tissue velocity at each depth was estimated using an autocorrelator  and inteBTP signals were displayed in MATLAB with the R-R wave intervals overlaid and traces manually inspected to allow the user to remove any cardiac cycles containing artefacts. Artefacts were defined as any noticeable perturbations not regularly repeating with the cardiac cycle. Similarly to artefacts in TCD measurements of cerebral blood flow, other artefacts result from motion of the probe or of the participant during recordings. Further analysis was based on these cleaned (artefact free) data.Inspection of the quality of the recordings showed that good quality signals were obtained through the forehead for the first 20 gates, corresponding to depths within the brain ranging from 22 to 60 mm. Signal quality weakened beyond this depth, therefore only data from the first 20 gates were analysed. A small number of additional gates (one to three of the deepest gates) were removed during analysis of recordings from 5/30 participants due to limited penetration of the ultrasound beam in specific subjects.For each recording, a Bulk BTP signal was calculated by averaging signals across all available depths. The Bulk BTP signal shows collective displacement of brain tissue in the direction of the beam over time (corresponding to the instantaneous bulk movement of tissue located at a depth of 20–60 mm from the face of the probe). A further quantity describing the magnitude of each pulsation, beat-to-beat Bulk BTP amplitude, was estimated by calculating the absolute difference between the peak and the trough of the Bulk BTP signal for each cardiac cycle.2) were analysed to provide beat-to-beat estimates of pulse pressure (PP), mean arterial pressure (MAP), heart rate (HR) and EtCO2. HR was calculated by measuring the length of the subject’s R-R interval and determining the frequency per minute, which gives an instantaneous HR for each cardiac cycle.The remaining physiological measurements  for each participant. Data were imported to Stata 12 for further statistical analysis. The distribution of Bulk BTP Amplitude features across our cohort was non-normally distributed  and is therefore summarised by a median value and IQR. All other features were normally distributed across the cohort. Comparisons between hyperventilation and baseline and recovery periods were made using a paired t-test, or non-parametric Wilcoxon signed-rank test. A Bonferroni correction was used to adjust for multiple comparisons yielding an adjusted, highly conservative, p = 0.004 threshold for significance.Time series for an entire recording are shown in 2 levels and no effect on the results was observed, therefore data from all participants were included in the analysis.Sensitivity analysis was carried out by removing data from the four participants that did not experience a significant change in CO2, PP, MAP and HR. Changes in left and right BTPs are reported as differences between median BTP amplitude values, with statistically significant changes identified using a Wilcoxon signed-rank test. Potential differences in BTP amplitude between men and women were explored using a Mann-Whitney test.Physiological measurements were compared between baseline and hyperventilation phases, and between hyperventilation and recovery phases, using a paired t-test to quantify the magnitude and direction of changes in EtCOp < 0.0001) drop in EtCO2, starting from a baseline mean (SD) EtCO2 level of 37.4 (2.6) mmHg,  signalling a partial return to baseline. However, EtCO2 values measured during the recovery phase remained 1.6 mmHg  lower than the baseline value. Closer scrutiny of individual responses to hyperventilation revealed that responses to the breathing manoeuvre varied between participants from a maximum drop in CO2 levels approaching −10 mmHg to zero response  took part in this study; ages were skewed towards younger participants, median age 25 years , range 19 to 46 years. The hyperventilation task successfully generated a significant −5.0 mmHg  with an almost complete return to baseline during the recovery. Although this p-value is not below the Bonferroni corrected value of p = 0.004, the 95% CI suggests an increase in PP of at least 0.5 mmHg. MAP decreased by −3.5 mmHg , also returning almost to baseline. HR increased by +4.4 bpm  and then decreases by −6.0 bpm  in recovery (overshooting the baseline). All incidental physiological changes, except for PP, were found to remain significant after correcting for multiple hypothesis tests. Comparison of values obtained before and after hyperventilation  confirmed no significant differences in PP, MAP, or HR, confirming the transient reversible nature of induced changes.As expected, hyperventilation also generated significant additional responses in other physiological variables. Baseline, hyperventilation and recovery changes averaged across the entire cohort are summarised in p = 0.001 was identified in the right hemisphere, and a drop of −1.3 µm (−6.3%), p = 0.02 in the left hemisphere  increase in both hemispheres during hyperventilation . Closer misphere . Note thComparing BTP amplitude estimates from the left and right sides suggested a slightly stronger impact of the manoeuvre on the right side. However, comparison of paired left and right median BTP values did not reveal any significant differences between paired left and right measurements during baseline, hyperventilation, or recovery. A Mann-Whitney test did not reveal any significant differences in BTP values between the men and women in this cohort.2, which was accompanied by an increase in HR and PP, and a decrease in MAP. Trends in our data suggest there may be a slight increase in BTP amplitude during hyperventilation, followed by a decrease in recovery. However, the magnitude of changes in BTP associated with the hyperventilation task were small (1 to 4 µm). This is of a similar level as the participant’s beat-to-beat variability and much smaller than the variability in BTPs between participants. A statistically significant decrease in BTP between hyperventilation and recovery was noted in both hemispheres.In this study, a brief 90 s period of mild hyperventilation was found to induce a significant reversible drop in EtCO2 (from ~40 mmHg to ~20 mmHg) over a period of 20 min [2. we found that BTP amplitude had potential to increase as well as decrease over the period of our experiment. Converting absolute to percentage changes, to aid direct comparison of our results with Kucewicz’s, suggested BTP changes, in individual participants can range between +71% and −31% during hyperventilation, and +77% to −42% in recovery. Monitoring over a longer hyperventilation period would be needed to confirm whether a decrease in BTP would eventually be observed during a longer hyperventilation period.Comparing these results with previous findings, Kucewicz et al.  observedf 20 min . Based on = 4) and differs from the current study by invoking a much larger EtCO2 reduction over a longer hyperventilation period, during which other physiological processes may begin to dominate. In their study, findings for the recovery period were not reported and a different Doppler measurement system was utilised, providing a global assessment of BTP amplitude in a 2D plane rather than along a single beamline. A finding of reduced BTP amplitude during hypocapnia is expected, as hypocapnia causes vasoconstriction, with reduced arterial blood supply to the brain in systole reducing tissue expansion [2 manoeuvre differ widely between individuals. The underlying reasons for these wide variations between participants are unclear, and we are therefore currently unable to confirm the relationship between CO2 and BTPs.To the best of our knowledge, Kucewicz et al.  are the Whilst our study improved on the previous literature by using a larger sample size of 30 participants and a wider range of additional physiological measurements, we were unable to confirm a clear relationship between BTP amplitude and hypocapnia. Overall, median BTP amplitude increased slightly (by ~1 µm) during the manoeuvre itself, with a pronounced decrease in BTP in recovery.2 and BTPs in isolation.A much better understanding of the relationship between BTPs and other factors, such as cerebral blood flow and brain metabolic demand, will be required to explain our findings. Future research in this area should measure cerebral blood flow using conventional TCD to assess whether changes in BTPs mirror cerebral blood flow velocity changes. Cerebral autoregulation is a dynamic process, which involves various interacting parameters, making it difficult to examine the relationship between EtCOOur findings suggest that a period of hypocapnia (even as short as 90 s) has the potential to cause a vasoconstrictive response that continues even beyond re-instatement of normocapnia, or indeed hypercapnia. This phenomenon was recently demonstrated in both healthy volunteers  and pati2 without simultaneously inducing changes in other potential confounders such as PP and HR. In a previous cross-sectional study, it was found that participants with higher pulse pressure had significantly higher BTPs; a 1% higher blood pressure was associated with a 0.8% higher Bulk BTP amplitude [2 does reduce BTP amplitude over a longer hyperventilation duration, but that the impact of CO2 was obscured in our experiment by larger increases in BTP associated with changes in other parameters, particularly PP. A more sophisticated statistical model based on information from further experiments with other variables under controlled conditions would be needed to better understand this parameter space.Further work is required to confirm our findings, and to better understand how the severity and duration of hypocapnia impacts BTP amplitude. A limitation of our study is that we were unable to alter EtCOmplitude . Visual 2 studies which found a similar association [This study found that MAP decreased with hypocapnia. This was an anticipated result and agrees with previous COociation ,16. Inteociation , it is iFinally, this study also found an increase in PP with hypocapnia. The relationship between hypocapnia and PP is rarely explored in existing literature. However, assessment of orthostatic intolerance (OI) during hyperventilatory states suggest similar increases in pulse pressure during hypocapnia . In prev2 and PP [It has been suggested that BTP measurements may be of clinical utility in conditions such as stroke or depression . However2 and PP . Therefo2 value of −1.28 mmHg compared to baseline) [For example, a recent meta-analysis found that patients with acute stroke demonstrate mild hypocapnia (a pooled EtCOaseline) . Applyin2 and BTPs. More elderly patients should be recruited, as many of the proposed clinical uses for BTP measurements (including cerebrovascular disease and stroke) occur more frequently in an elderly population.Whilst this study expands on previous BTP work and uses well-established hypocapnic intervention methods , there a2 values, including hypocapnic changes, but also hypercapnia using inhaled CO2. This would allow dose-response modelling of the impact of CO2 on BTP measurements, whilst also allowing testing of previous work by Kucewicz et al. at the extremes of induced hypocapnia [Another limitation of this study was that a small hypocapnic range was explored. Only a reduction of 5 mmHg was investigated, meaning that the expected hypocapnic range for common disease was not fully explored. Future studies could aim to explore a wider range of EtCOpocapnia .2 measurements in this study. Whilst not a limitation of the study methods, care must be taken in future work in the selection of EtCO2 measurement techniques. Previous research has highlighted discrepancies in measured EtCO2 levels between measurements made using nasal cannulae vs. a face mask [Finally, it is worth noting that a nasal cannula was used for EtCOace mask . Both thAs our TCTD measurements were obtained through the forehead  we were unable to detect blood flow through the skull. This makes it difficult to exclude the possibility of BTP estimates being locally affected by the presence of major pulsating arteries, such as the anterior cerebral artery (ACA). To check the positioning of the probe in relation to large arteries, future studies should combine TCTD with MR angiography measurements showing the positions of the major arteries relative to the ultrasound beam.2-induced BTP changes. The results of this study may assist in exploring the clinical utility of BTP measurements as they suggest that mild hypocapnic changes are unlikely to be a major cause of BTP disruption.This healthy participant study showed changes in BTP amplitude associated with recovery from mild transient hypocapnia. However, physiological responses to the manoeuvre varied considerably between participants, and since significant changes in PP, HR and MAP were also recorded, it was difficult to confidently determine the true impact and time course of CO


The activation of the sympathetic nervous system, which usually leads to a swift surge in blood pressure in the morning hours (MBPS) may be the cause of left ventricular hypertrophy (LVH) and endothelial dysfunction (ED) in early autosomal dominant polycystic kidney disease (ADPKD) patients. We studied the association between MBPS and LVH in ADPKD patients with preserved renal functions.Patients with ADPKD with preserved renal functions were enrolled. Prewaking MBPS was calculated using ambulatory blood pressure monitoring. The patients were categorized as MBPS (≥median) and non-MBPS (<median). Left ventricular mass index (LVMI), endothelial-dependent dilatation , and carotid intima-media thickness (CIMT) evaluated.p < 0.001), hs-CRP  LVMI  and mean awake SBP surge was higher  and FMD (%) was lower  in MBPS group. In the binary logistic regression analysis, the presence of MBPS in model 1 , and age in model 2  were the only independent determinant of LVH.Fifty-six patients  were enrolled. Gender distribution was similar-among-the-groups. The mean age was higher in the MBPS group (50.1 ± 13 vs 37.3 ± 10.3). Urinary albumin (49.5 vs 16 mg/g creatinine, MBPS seems to be an important and independent determinant of LVH in ADPKD patients with preserved renal functions. It may be worth assessing the effect of reduction in MBPS as a new therapeutic target to prevent LVH in-patients-with-ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by extra-renal manifestations ranging from liver disease to various cardiac abnormalities such as mitral valve prolapses . In addiInterestingly, even in the normotensive population, the isolated elevation of morning BP has been found associated with left ventricular hypertrophy . This imThis cross-sectional study took place in the nephrology clinic of Bursa Uludag University Faculty of Medicine.A total of 114 ADPKD patients from the Caucasian population who were diagnosed based on positive family history for ADPKD and renal ultrasonography findings  were conThe primary exposure was MBPS, and the primary outcome was LVH and ED. Secondary outcomes were other CV characteristics, including carotid intima-media thickness (CIMT) and left ventricular geometry. After providing detailed medical history and undergoing a physical examination, each participant was questioned for major cardiovascular risk factors such as age, sex, DM, smoking status, HT, and medications. Venous blood samples for biochemical analyses were taken after an overnight fast. Glucose, creatinine, uric acid, and lipid profiles were determined using standard methods. High-sensitivity CRP (hs-CRP) was measured using the nephelometric method . The estimated glomerular filtration rate (eGFR) was computed by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) and the creatinine equation, as defined by Levey et al. . Spot urThe 24-h BP monitoring was performed using a Contec-branded device , and the results were analyzed using the manufacturer’s computer software. Ambulatory measurements were carried out once every 30 min from 7 am until 11 pm and once every 60 min from 11 pm until 7 am. An evaluation was performed by taking the mean values of day and night blood pressures into account. HT was considered to be present if the average systolic blood pressure (SBP) was 135 mmHg and/or the average diastolic blood pressure was 85 mmHg during the entire day. MBPS can be calculated by two way with different thresholds such as sleep-trough  and prewaking MBPS (>34 ± 21 mm Hg presence of MBPS) defined by Kario et al. . We usedx + 0.6. Thereafter, the LVM index was obtained using the following formula: LVM/body surface area. Relative wall thickness (RWT) was measured at end diastole as the ratio of /left ventricular diameter (LVDd). LVH was defined as LVMI values >125 g/m2 in men and >110 g/m2 in women. Increased RWT was accepted as ≥0.45.Standard 2 D and Doppler transthoracic echocardiography were performed with a widely available transducer and equipment  by standard techniques with the subjects at rest in the left lateral decubitus position. All echocardiographic measurements were performed based on the American Society of Echocardiography Guidelines (ASE) . During Geometric patterns were based on the upper normal limits for LVMI and RWT; (I) normal geometry (NLV) , (II) concentric remodeling (CR) , (III) eccentric hypertrophy (EH) , and (IV) concentric hypertrophy (CH) (increased LVMI and increased RWT).CIMT was measured from 10 mm proximal to the right common carotid artery bifurcation segment using the same device with a 12 MHz linear-array imaging probe. CIMT was calculated as the distance between the lumen-intima and media–adventitia interfaces. Flow mediated dilatation (FMD) of the brachial artery as surrogate marker of ED was measured according to the American College of Cardiology Guidelines. Briefly, subjects were allowed to rest for 20 min in a supine position in a semi darkened room at 23 °C. The left arm was positioned on a table at heart level. The resting diameter of the right brachial artery was measured 3–5 cm above the antecubital fossa using the same device with a 12 MHz linear-array imaging probe. Then, a blood pressure cuff was inflated around the right forearm to at least 50 mmHg above the systemic blood pressure for 4–5 min. Sixty seconds after cuff release, the diameter of the brachial artery was measured. The diameter change caused by FMD was expressed as the percentage change relative to that at the initial resting scan (FMD %).t-test, Mann–Whitney U test, Pearson chi-square, and Fisher’s tests were used for intergroup comparisons. The relationship between continuous variables was determined by Pearson or Spearman correlation coefficients as needed. A value of p < 0.05 was considered statistically significant.SPSS Statistics for Windows, Version 21  was used for statistical analysis. Descriptive statistics were reported as the mean ± standard deviation for variables with normal distribution and median (min–max) for variables with skewed distribution. Categorical variables were presented with frequency and percentage. Student’s r = 0.79), eGFR was excluded from the regression model. There was also a high correlation between MBPS and dipper status (r = 0.6); thus, two separate models, one including MBPS and the other, including dipper status, were used. Age and average SBP were used in both models.Clinically relevant factors that could affect LVH were included in binary logistic regression analysis. These factors were age, GFR, average SBP, MBPS, and dipper status. Because of the multicollinearity between age and GFR , uncontrolled hypertension, or required at least two antihypertensive drugs for BP control. Seven patients with diabetes, four patients with coronary artery disease, and three patients who were pregnant were also excluded from the study . The remPatients with MBPS were older and had higher hs-CRP, ACr, RWT, and LVMI values . Among Bp = 0.18), smokers , and RAS blocker users , but these differences were not statistically significant. Patients with or without LVH had a similar frequency of dipper status . Mean age , average SBP , BMI , HDL-cholesterol  were higher, and GFR  was lower in patients with LVH compared with those without LVH. ACr  and LDL-cholesterol  tended to be higher in patients with LVH, but the difference was not statistically significant.Patients with LVH tended to be more commonly female . Normal geometry and concentric remodeling were seen in 3.6% vs. 32.1% and 14.3% vs. 46.4% of the patients in MBPS and non-MBPS groups, respectively.The patients in the MBPS group had a significantly higher frequency of concentric and eccentric LVH compared with those in the non-MBPS group . The frep = 0.044) was independent predictors of LVH. THE average SBP was not independently associated with LVH . In the second model, only age  was independently associated with LVH. The average SBP and dipper status did not have independent associations with LVH .In the first model, the presence of MBPS (OR 6.625, 95%CI 1.048–41.882, with LVH . The r2 with LVH . The r2 In the present study, we have shown, for the first time, a close relationship between prewaking MBPS and LVH in ADPKD patients with preserved renal function. There was also an independent association between higher age and LVH. Patients with MBPS had a higher mean LVMI value and also a higher rate of LVH. The presence of MBPS was also associated with worse endothelial functions, as shown by a higher RWT, a lower FMD, and a tendency toward higher CIMT.In numerous studies, these CV abnormalities have been reported in ADPKD patients, but no clear etiology has been found until now. Although the main characteristics of ADPKD are cyst development throughout the body, noncystic findings such as increased sympathetic activation, early hypertension, and ED are not rare, and the cause of these abnormalities is not clear.We hypothesize that increased sympathetic activity, especially in the early hours of awakening, may partly explain both prominent LVH and ED, which are prevalent in these patients ,15. CV aThis finding was consistent with previous studies . FurtherChronic pain is usually the result of increased cyst distension, which may activate the renal efferent sympathetic nerves. Hypertensive ADPKD patients with normal renal function have increased sympathetic activity, which partly explains HT in the early period of the disease . Here, wMBPS is multifactorial and also may be affected by environmental factors. Although high salt intake is a risk factor for HT no relation has been found between the MBPS and the rate of sodium consumption until now .Our study has certain limitations, including the small sample size and cross-sectional and observational design. Another limitation of the present study is the fact that we did not evaluate the effects of seasonal variations, sodium consumption or excretion rate, alcohol consumption, stress or pain level, or sleep apnea, all of which may influence the presence and extent of MBPS. In the regression analysis, we did not include all factors that could potentially affect left ventricular hypertrophy, such as hemoglobin and albumin. Lack of more sophisticated and accurate measurement methods for left ventricular mass, such as magnetic resonance imaging, is another limitation of this study.To our knowledge, this study is the first one to investigate the effects of MBPS in ADPKD patients with preserved renal functions. The findings of this study suggest an independent association between LVH and MBPS and also between LVH and age in ADPKD patients. MBPS also seemed to be associated with worse endothelial functions, as shown by higher RWT, lower FMD, and a tendency toward higher CIMT. However, our results are not generalizable to all ADPKD patients because of the cross-sectional nature and limited sample size. It may be worth investigating the effects of reducing MBPS on the development of LVH and ED in patients with early ADPKD patients in randomized controlled studies.


Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. Through its effect on cardiovascular risk and end-stage kidney disease, CKD directly affects the global burden of morbidity and mortality. Classical optimal management of CKD includes blood pressure control, treatment of albuminuria with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, avoidance of potential nephrotoxins and obesity, drug dosing adjustments, and cardiovascular risk reduction. Diabetes might account for more than half of CKD burden, and obesity is the most important prompted factor for this disease. New antihyperglycemic drugs, such as sodium-glucose-cotransporter 2 inhibitors have shown to slow the decline of GFR, bringing additional benefit in weight reduction, cardiovascular, and other kidney outcomes. On the other hand, a new generation of non-steroidal mineralocorticoid receptor antagonist has recently been developed to obtain a selective receptor inhibition reducing side effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. Moreover, two new potassium-lowering therapies have shown to improve tolerance, allowing for higher dosage of renin-angiotensin system inhibitors and therefore enhancing their nephroprotective effect. Regardless of its cause, CKD is characterized by reduced renal regeneration capacity, microvascular damage, oxidative stress and inflammation, resulting in fibrosis and progressive, and irreversible nephron loss. Therefore, a holistic approach should be taken targeting the diverse processes and biological contexts that are associated with CKD progression. To date, therapeutic interventions when tubulointerstitial fibrosis is already established have proved to be insufficient, thus research effort should focus on unraveling early disease mechanisms. An array of novel therapeutic approaches targeting epigenetic regulators are now undergoing phase II or phase III trials and might provide a simultaneous regulatory activity that coordinately regulate different aspects of CKD progression. Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. The global estimated prevalence of CKD is 13.4% (11.7–15.1%) . The DALIt has been well-acknowledged that when the glomerular filtration rate (GFR) decreases below a critical level, CKD continues to progress unabatingly toward end-stage kidney disease (ESKD). The loss of a critical number of nephrons causes a vicious cycle of further nephron loss, and this damage is perpetuated even when the underlying cause of the disease is treated . There aIn the last few decades some therapeutic agents have been identified as useful in retarding the progression of CKD. Several clinical trials have demonstrated that both renin-angiotensin-aldosterone (RAS) system inhibitors and more recently, agents that inhibit sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubule, reduce the loss of GFR in the long-term. The main mechanism of their action is based on the reduction of intraglomerular pressure, therefore proteinuric CKD get the most benefit from these therapies. On the other hand, and despite some positive results obtained from preclinical studies, there are no established strategies to modulate inflammation or delay progression of tubulointerstitial fibrosis. Hence, although several new therapeutic agents have been developed recently that look promising for the prevention of CKD progression, it is certainly necessary to develop agents that target different components of the fibrogenic cascade. In this article we review the therapeutic targets for preventing CKD progression, focusing in the latest developments in treatment approaches for delaying CKD progression, we reflect on potential new biomarkers and novel therapeutic targets, as well as future lines of treatment, including regenerative therapies.RAS blockade with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is the cornerstone therapy to reduce proteinuria, CKD progression, and cardiovascular risk. These benefits appear to be comparable between ACEI and ARBs when they are used in equivalent doses, and carry comparable adverse effects besides cough which is exclusive to ACEi.+ >5.5 mEq/L) led to the early withdrawal of 11 patients  despite seven weeks of treatment with dose of candesartan (16 mg/day) were randomized to receive candesartan at a dose of 16, 64, or 128 mg/day. After 30 weeks, the maximal dose of candesartan (128 mg/day) achieved an additional decrease in proteinuria of 33%. Reductions in BP were not different across the three treatment groups, although elevated serum potassium levels  and hyperkalemia. However, in neither of the two studies was dual therapy compared to an equipotential dose of either drug in monotherapy, and therefore the dual blockade effect could not be analyzed separately from the effect carried by the use of different dosage. In the PRONEDI trial, in patients with overt diabetic nephropathy, the combination therapy consisting of lisinopril 20 mg plus irbesartan 300 mg was compared with the use of lisinopril at a dose of 40 mg and irbesartan at a dose of 600 mg in monotherapy. In this study, proteinuria decreased in the three groups similarly, with no differences in CKD progression or adverse effects  after a median follow-up of 32 months, indicating that optimization of RAS blockade depends on dosage rather than the use of a single or combined RAS blocker .Our goal should be the maximum well-tolerated RAS blockade dose, regardless of whether it is achieved with ARB, ACEI in monotherapy or their combination.The development of direct renin inhibitors made it possible to inhibit the RAS at its rate-limiting step (the conversion of angiotensinogen to angiotensin I) and thereby to achieve more complete blockade. Two early randomized trials reported additional lowering of albuminuria in subjects with diabetic nephropathy receiving the combination of a direct renin inhibitor and ARB therapy vs. ARB therapy alone , 12. HowTherefore, Aliskiren may be a suitable alternative RAS blocker for those intolerant to either ACE inhibitors or ARBs.2 and negative or trace proteinuria and GFR 45–59 ml/min/1.73 m2 and no dipstick proteinuria to 16 among those with GFR 15–29 ml/min/1.73 m2 and ≥2+ dipstick proteinuria. Overall, 91% of patients included in this large series should be considered as having a “low or moderate risk for kidney disease progression” and the number of patients necessary to treat to avoid an event was >100  included in this study had advanced CKD with serum creatinine between 3.1 and 5 mg/dL. The benefit from ACE inhibitors in terms of reaching ESKD or doubling of serum creatinine was present even in those patients with advanced CKD and especially when proteinuria was above 1 g/day. Serious hyperkalemia was similar with benazepril and placebo  appears to participate in the development of tubulointerstitial fibrosis, mediated through one of the Ang II type 1 receptors that are present in the glomerulus. Ang II also contributes in cytokine and chemokine-mediated recruitment of inflammatory cells into the kidney. Overall, these effects can generate profibrotic factors such as TGF-β, connective tissue growth factor, epidermal growth factor (EGF), and other chemokines. In fact, regression of glomerulosclerosis has been observed in rodents on RAS blockade but this phenomenon has not been observed in humans.post-hoc studies, some biomarkers of inflammation and serum fibrosis, such as interleukin 6 (IL-6) or Dickkopf 3 (DKK3), were measured sequentially; treatment with RAS blockade did not modify their levels . Kidney tissue studies are likely needed to describe the local mechanisms that pass unnoticed in serologic test studies , and induced less hyperkalemia. Its tissue distribution is well-balanced between cardiac and renal tissues, contrary to spironolactone and eplerenone  . This coHyperkalemia is the main limiting factor for the use of this therapeutic group and ARB blockade. This effect could probably be mitigated with the use of the novel anti-hyperkalemia agents patiromer and sodium zirconium cyclosilicate, that have demonstrated a good tolerability and safety profile that remain consistent in the long term, in contrast with previous antihyperkalemic agents including resins that were generally poorly tolerated , 37 Tab.SGLT2 inhibitors have shown remarkable additional benefits in delaying CKD progression on top of the standard RAS blockade. SGTL2i were originally developed to lower plasma glucose in type 2 diabetic patients, but large randomized controlled trials have demonstrated both renal and cardiovascular protection in both proteinuric diabetic and non-diabetic CKD patients and this effect cannot directly be explained by improved glucose control. The SGLT2i Cardiovascular outcome trials primarily demonstrated the efficacy of this treatment class in reducing CV risk among those with type 2 diabetes. However, secondary and exploratory analyses of these data highlighted a potential role for SGLT2i therapies in reducing adverse renal outcomes, even though the study populations were not generally considered to be at significant risk of progressive DKD .The EMPA-REG OUTCOME and the CANVAS trials showed a reduced risk of new onset diabetic nephropathy and a large regression of albuminuria (return to ACR ≤ 3 mg/mmol), respectively , 40. LatThe CREDENCE trial was a double-blind, randomized study to assess renal treatment outcomes with canagliflozin (100 mg) among adults with type 2 diabetes and CKD. The relative risk of the composite of ESKD, doubling of the serum creatinine level or renal death was 34% lower in the canagliflozin group vs. the placebo. The components of ESKD were reduced by 32% and the risk of dialysis or kidney transplantation was reduced by 26% .DAPA-CKD trial was halted early because of overwhelming efficacy, demonstrating that in patients with proteinuric CKD with or without diabetes, dapagliflozin significantly reduced the risk of 50% decline in GFR, ESKD, or death by 39% compared to placebo. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes .+/K+ ATPase activity, thus lowering glomerular hyperfiltration. Another mechanism is reduced tubular workload by reducing SGLT2 cotransporter activity and therefore reducing both the energy and aerobic requirements of the system. An additional mechanistic proposal is that SGLT2i agents reduce inflammation and hypoxic injury in the kidney over time. Prolonged albuminuria and high intracellular glucose levels within proximal tubular cells trigger the expression of inflammatory cytokines, growth factors, and fibrotic mediators as well as the production of reactive oxygen species. Therefore, it is possible that the renoprotective effect of SGLTi may be partly due to a reduced local inflammatory response and fibrosis.Conclusive evidence concerning the mechanisms responsible for the renoprotective effects observed with SGLT2i is lacking, but several hypotheses have been proposed to explain the apparent slowing of DKD progression over time associated with these drugs. One of the proposed mechanisms is an improved glomerular hemodynamics due to constriction of the afferent arteriole induced by elevated adenosine levels secondary to increased membrane NaEndothelins (ETs) are a family of vasoconstricting peptides. ET-1, the main isoform in human kidneys, is an important regulator of kidney function in health and disease, and its abnormal activation promotes kidney disease progression. It has been found to be increased in CKD patients and correlates well with kidney function and albuminuria. Two receptor subtypes are activated by ET-1; receptors type A and B. ET-A receptor provokes podocyte and mesangial lesions, oxidative stress, and inflammation leading to proteinuria and glomerulosclerosis. ET-B receptor inhibition induces fluid overload and precipitates congestive heart failure , 45.Several studies in diabetic nephropathy, hypertensive kidney disease, and focal segmental glomerulosclerosis demonstrated that ET-1 inhibition can reduce proteinuria and improve kidney function . In a raMore recently, the SONAR study that included over 2,600 patients with type 2 diabetes, CKD with GFR between 25 and 75 ml/min and albuminuria between 300 and 5,000 mg/g and receiving optimum doses of RAS blockade, were randomized into receiving 0.75 mg atrasentan orally (another ET-1 receptor inhibitor that is more selective for ET-A receptor) or placebo after an enrichment period in which albuminuria decreased by more than 30% with no fluid overload. After median follow up of 2.2 years, Atrasentan reduced the risk of doubling serum creatinine or reaching end-stage kidney disease, with no significant differences with placebo in hospitalizations due to heart failure (3.5 vs. 2.6%) however there was a significant increase in fluid overload. Moreover, fluid retention was still more frequently observed in those treated with atrasentan .Sparsentan, a dual endothelin-angiotensin II antagonist, showed promising results in reducing proteinuria in patients with FSGS after 8 weeks, but 16.4% of patients with sparsentan suffered from orthostatic hypotension and 12.3% had fluid retention, although none were considered serious and no patients were withdrawn from the study . The DUPRecent data support that a component of CKD progression is mediated by mechanisms used by the kidney to increase acidification in response to an acid challenge to systemic acid-base status. An acid challenge to systemic acid-base status increases nephron acidification through increased production of endothelin, aldosterone, and angiotensin II, each of which can contribute to kidney inflammation and fibrosis that characterizes CKD . SeveralThus far, multiple clinical trials have been designed with the aim of delaying the progression of CKD. Most of these clinical trials have aimed to limit glomerular hyperfiltration, but there are other factors such as parenchymal cell loss, chronic inflammation, and fibrosis that are known to contribute to CKD progression and need to be addressed. Therefore, only a more holistic approach targeting all of these factors will likely achieve a more complete response and better kidney outcomes, aiming not only to delay kidney progression but also to reverse CKD.However, despite promising results in preclinical studies, therapeutic interventions targeting “other mechanisms” in humans such as cytokines, transcription factors, developmental and signaling pathways, and epigenetic modulators, particularly microRNAs, have been disappointing, and no additional treatments are available to date.Bardoxolone, a drug that activates nrf2, a transcription factor that controls various cytoprotective proteins, was studied to target inflammation and oxidative stress. Bardoxolone improved GFR in type 2 diabetics with CKD, an effect that persisted throughout the 52 weeks of study . NeverthNovel therapies that are currently under evaluation target renal fibrosis, including the anti-fibrotic agent pirfenidone. Although its mechanism of action is not fully understood, it interrupts the TGF-β pathway. The main clinical trial was done in patients with diabetic nephropathy, with significant improvement in GFR compared to placebo, however it failed to reduce proteinuria . AnotherPentoxifylline is being studied for its inflammatory modulation and anti-oxidative stress, and has shown in several studies a significant reduction in proteinuria when it was added to RAS blockade in CKD patients .It is still challenging to predict progression in CKD. This is mainly due to a scarcity in sensitive and specific biomarkers for predicting CKD progression early. The development of end-stage kidney disease may take several years, therefore surrogate endpoints such as albuminuria and serum creatinine have been increasingly used in trials over hard endpoints to predict CKD progression –57. AlthDickkopf-3 (DKK3) is a stress-induced, renal tubular epithelial-derived glycoprotein that induces tubulointerstitial fibrosis through its action on the canonical Wnt/β-catenin signaling pathway. Elevated urinary DKK3 levels identify patients at high risk of rapid decline in GFR during the following 12 months regardless of the etiology of CKD. Moreover, uDKK3 levels are directly associated to the degree of tubulointerstitial fibrosis in kidney biopsies . In receMoreover, several biomarkers of cardiovascular risk in CKD have been assessed, and could be classified into prognostic biomarkers, such as cardiac troponins and NT-ProBNP, Cystatin C, β2-Microglobulin, Galectin-3 and markers of inflammation or tissue remodeling such as matrix metalloproteinases (MMPs), and predictive biomarkers that predict response to treatments, such as proteinuria, insertion/deletion polymorphisms of the ACE gene, MMP levels, and renal resistive index in kidney ultrasound .Some biomarkers such as kidney injury molecule (KIM-1) , neutropThere is strong evidence from animal studies that suggests that interstitial fibrosis could be reversed and therefore could be a therapeutic target in the prevention of CKD progression –71. The Stem cell-based regenerative therapy is an alternative future treatment modality. There have been studies performed with hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells. Patients with CKD have a decreased capacity for kidney regeneration with an altered function of endothelial progenitor cells, and several studies in animal models with CKD suggest a regenerative beneficial effect of these cell-based therapies , 73.A meta-analysis of several experimental models found that stem cell-based therapy prevented progression of CKD with decreased proteinuria . MesenchProgression of CKD to ESKD carries a high burden on cardiovascular morbidity and mortality. We need to improve our understanding of early mechanisms of CKD which will consequently enable early therapeutic intervention and delay CKD progression or even reverse it. In addition to RAS blockade, SGLT2 inhibitors and bicarbonate therapy have proved to retard CKD progression, and new drugs targeting fibrosis and inflammation, as well as regenerative therapy may enhance these effects in our goal to mitigate CKD progression and consequently cardiovascular and global mortality.AS, CC-C, and GF-J have designed, written, and reviewed this paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The aim of our study was to compare the arterial function parameters (AFPs), such as PWVao; aortic augmentation index (Aixao); aortic systolic blood pressure (SBPao) and brachial systolic blood pressure (SBPbrach) measured simultaneously in O/OW patients and healthy subjects. In our study 6,816 subjects  aged 3–18 years were recruited and categorized by their body mass index (BMI) into normal weight (N), OW and O groups regarding their age and sex. AFPs were measured by a non-invasive, occlusive-oscillometric device. 19.9%  of the population were OW/O, 911 (516 boys) were OW and 445 (272 boys) were O. After accounting for the effect of covariates, PWVao did not differ significantly between N (5.9 ± 0.8 m/s) and OW patients (5.9 ± 0.8 m/s); and N (6.0 ± 0.7 m/s) and O patients (6.0 ± 0.8 m/s). Aixao was significantly lower in OW  and in O patients  compared to controls. No significant difference was found regarding SBPao values between controls and OW and O groups . According to our results we may conclude that the unchanged PWVao in O/OW subjects might be due to the compensatory decrease in Aixao, referring to enhanced vasodilatory status in the studied population.Prevalence of overweight (OW) and obesity (O) in children and adolescents has been increased in the past three decades. Increased arterial stiffness measuring by aortic pulse wave velocity (PWV Prevalence of overweight (OW) and obesity (O) in children and adolescents has increased in both genders in the past three decades . Obesityao), aortic augmentation index (Aixao) and aortic systolic blood pressure (SBPao)—is a widely accepted and recommended in CV risk stratification in adults —such as aortic pulse wave velocity  pupils, the identical age should be crucial. Obesity in children and adolescents is characterized by chronic sympathetic overdrive. Sympathetic overactivity occurs in obese patients, as evidence of increased heart rate, blood pressure and cardiac output (brach) . After a careful review of the available scientific literature, where the sex ratio of the studied population was given, the mean age and the SBPbrach of OW/O patients and control groups was identical, only the most relevant PWVao or cfPWV measurement was performed, no paper fulfilled these rigorous criteria.Numerous works (cc. 400)  were pubt humans , 16. Theth sexes , 18. In c output . Moreove (brach) , thus SBao, Aixao, SBPao, and SBPbrach measured simultaneously in OW/O patients and healthy subjects in a population of the wide age range (3–18 years), where the patients and control groups were accurately matched by age, sex and SBPbrach to eliminate their effects on AFPs. We intended to apply an easy-to-use, user-independent occlusive-oscillometric device, which enabled us to expand AFP measurements even into a very young (from 3 years) and large population.Therefore, the aim of our study was to compare the PWV6,816 subjects  aged 3–18 years were recruited from elementary, primary, and high schools in Szolnok town (Hungary) between 2012 and 2016. All the subjects were Caucasian without any chronic diseases, and they were not on any regular medications. Informed consent for the measurements was asked for from the parents of the subjects. The protocol was reviewed and approved by the local Institutional Ethics Committee of the University of Pécs, Pécs, Hungary.Anthropometric measurements (body weight and height) of each subject were carried out according to the WHO recommendation  . Subjectao and Aixao values (percentiles) in a normal, healthy population aged between 3 and 18 years  was used to the AFPs measurements, for which the operating procedure, in practice, did not differ from a standard digital blood pressure measurement. Clinical use of the Arteriograph is user-independent, painless and takes only 2 min with a one-cuff method, hence it is well tolerated by the youngest age group as well. Non-invasive and invasive validations and the detailed method of the device have been published previously , 24. The18 years . Since tp” value < 0.05 was used for significance. Bivariate correlation was used for testing correlations between the measured parameters and to generate the descriptive statistics of the original data. Statistical analysis was performed with the SPSS 23.0.0.0 statistical package  and R (version 3.4.4) MatchIt (version 3.0.2) package.Data are reported as mean and SD for continuous data. For statistical tests “brach, age and sex as variables to match on. The resulting groups contained 911 matched individuals in case of control vs. OW and 445 matched individuals in case of control vs. O cases that had an almost identical distribution of SBPbrach, age and sex. The plot of the mean of each covariate against the estimated propensity score, separately by weight status is shown in Supplemental Digital Content  were involved in this study. Among boys 516 were OW (14.1%), 272 were O (7.4%), whereas in girls 395 (12.5%) were OW and 173 (5.5%) were O. The total prevalence of OW and O was significantly higher in boys (21.5%) than in girls (18%) in girls (p < 0.001). Altogether 19.9% (n = 1 356) of the population were OW/O and 80.1% (n = 5 460) of the participants were N.Totally 6,816 subjects , mean arterial pressure (MAP), pulse pressure (PP) elevated with increasing age in both genders in every weight category, while heart rate (HR) decreased.Baseline characteristics of the investigated cohorts grouped by age and weight categories are summarized for boys  and girlbrach values showed an increment with increasing BMI categories (p < 0.0001). The mean HR values were also significantly different in OW and O groups . Mean SBPbrach was higher in OW, and higher in O patients, than in N subjects , the differences were significant between every patient groups (p < 0.0001).Mean HR and SBPtegories . HR showCharacteristics of the propensity score matched groups and clarified AFPs are summarized in p < 0.001). Sex ratio was the same in the investigated groups. The mean body height was almost the same both in OW and O groups compared to controls, the difference was 0.8 cm  and 1.6 cm , respectively. Obviously, the mean body weight was significantly higher in OW and O groups than in controls. Although the O patients were younger, their mean SBPbrach was significantly higher (131.2 ± 15.2 mmHg) than was in OW patients (125.6 ± 14.0 mmHg) (p < 0.0001).Mean age was significantly lower in O group (11.8 ± 3.6 ys) compared to OW group (12.7 ± 3.8 ys)  and OW patients (5.9 ± 0.8 m/s) and between N patients (6.0 ± 0.7 m/s) and O patients (6.0 ± 0.8 m/s). A significant difference was found between N and OW patients in Aixao, namely, in N patients Aixao was 9.3 ± 7.4% whereas it was 7.6 ± 7.0% in OW patients (p < 0.00001), and Aixao was higher in N subjects (9.7 ± 8.1%) compared to O patients (6.6 ± 7.2%), which difference proved to be statistically significant (p < 0.00001) as well. Regarding SBPao no significant difference was found between N and OW (110.7 ± 12.4 mmHg vs. 110.3 ± 11.9 mmHg) subjects. In the same way, the difference was not significant between the SBPao values of propensity score matched N and O subjects (115.6 ± 14.0 mmHg vs. 114.3 ± 12.8 mmHg).After the elimination of the alternating effects of age, sex and SBPao between N and OW, N and O patients after accounting for the effect of covariates. Furthermore, we observed a marked, significant decrease of Aixao in OW, and a markedly more significant decrease in O patients. Finally—similarly to PWVao–no differences were found regarding SBPao neither in OW, nor in O patients in a properly matched analysis.The most important finding of our study is that no difference was found regarding PWVao. This is in apparent disagreement with previous reports indicated increased PWVao in O children and adolescents  with elevated BMI, however, they measured regional  PWV, not aortic. Unfortunately, predicting the value of regional  PWV is not established in cardiovascular morbidity and mortality, so it is considered irrelevant from our aspect   . Therefobrach, the HR was increased in OW patients and it was significantly higher in O subjects than in controls. This finding could be explained by the previously mentioned chronic sympathetic overdrive; consequently, the increased metabolism will cause a remarkable increase in heart rate, stroke volume and cardiac output. Wilkinson et al. have found an inverse linear relationship between HR and Aixao  level in relation to fat accumulation  between patient and control groups, consequently, in this age period, the SBPao is mainly determined by SBPbrach, without any detectable morphological or functional deterioration of the aortic wall.In the overviewed and cited literature SBPAlthough the use of BMI is well-known and widely accepted technique to identify overweight and obesity, it might be misleading in some cases, because it does not distinguish fat tissue from muscle tissue, therefore individuals with a considerable muscular system may have increased BMI resulting in “artificial” obesity. In our study, age- and sex-based BMI was used to categories patients, still, other techniques such as skinfold measurements, waist-hip ratio, or bioelectrical impedance analysis would be necessary for more proper weight categorization.brach, stroke volume and cardiac output should have been measured by echocardiography in these subjects. In our study, there is a lack of these data, since it was not the aim of this investigation. Detailed history taking on overweight and obesity  and medical history about the closest family members could add relevant information to this study. Finally, there is a lack of lifestyle data  and detailed laboratory tests . Future studies of this working group will collect the above-mentioned data in order to elucidate the underlying causes of the observed phenomena and hypothesis.To confirm our theory according to which the sympathetic overdrive in OW/O patients resulting in increased cardiac output and elevated SBPN subjects, we found that OW/O in children and adolescents was not associated with increased aortic stiffness. Based on our results, we may conclude that the pathophysiological consequences in the circulatory system due to childhood OW/O are partially compensated hemodynamically in these patients, presumably by the opening of small arterioles, by decreasing peripheral arteriolar resistance. Therefore, considering our findings we might speculate that OW/O does not have any direct adverse effect on the arterial function in the by us investigated population. However, it must be emphasized, that in general accumulation of adipose tissue raises the blood pressure—as we also presented in this study—resulting in increased cardiovascular risk in the future. Hence, successful lifestyle intervention programs  may lead to the optimization of the CV risks in the affected subjects. Furthermore, it would be important to follow these OW/O patients by monitoring AFPs, to establish the possible period, when the “haemodynamic compensation/adaptation” of the arterial system might switch into deterioration, resulting in early arterial disease.Our study comprises anthropometric and AFPs data of a huge cohort of N/OW/O subjects. Interestingly, by comparing OW/O population data with the properly matched identical subset of The moment, when the compensatory functions in OW/O subjects become insufficient is hardly detectable. For this reason, we aim to design further studies to detect the beginning of this unfavorable vascular function changes.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Institutional Ethics Committee of the University of Pécs. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.MI shares a part in TensioMed Company , which produces Arteriograph and other medical devices. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Introduction. Emblica officinalis (EO) has some cardiovascular effects, and there are some animal studies that show its antihypertensive effect. This study was conducted to determine the effect of combination of EO with standard therapy on the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with uncontrolled hypertension. Materials and Methods. This was a randomized, triple-blind, placebo-controlled, 8-week study. Ninety-two patients with uncontrolled hypertension despite taking hypotensive drugs were randomly assigned into two groups to take EO  or placebo in combination with standard antihypertensive drugs. After 2, 4, 6, and 8 weeks of intervention, SBP and DBP and heart rate (HR) were measured. Data were analyzed by SPSS software using repeated measures ANOVA. Results. Eighty-one patients (41 in the drug group and 40 in the placebo group) completed the study for 8 weeks and were analyzed. The mean ± standard deviation of age was 53.64 ± 10.01 years. SBP decreased as 15.6 ± 8.23% in the EO group and 6.3 ± 7.49% in the placebo group (P < 0.001). DBP decreased as 12.3 ± 7.87% and 3.88 ± 7.98%, respectively (P < 0.001). Time effect was not significant, but the group effect was significant . No side effects were reported during the study. Conclusion. Eight-week combination therapy of EO with standard antihypertensive drugs significantly reduced the SBP and DBP more than placebo in patients with uncontrolled hypertension. Hypertension is one of the important public health and economic problems “worldwide”. The prevalence of hypertension is high both in developing and developed countries , 2. It hHypertension is an important predictor of premature death and disability and plays a key role in the mortality and morbidity from cardiovascular diseases and cerebrovascular accidents .In 2010, high blood pressure was one of the 5 or 6 leading risk factors for Global Burden of Disease (GBD) worldwide, as assessed by DALYs .The goal of the World Health Organization (WHO) is to reduce the prevalence of hypertension to 25% . HyperteSeveral plants are used in herbal medicine to lower blood pressure, and some plants have been studied for this purpose.Emblica officinalis Gaertn (EO) or amla (family Euphorbiaceae) is a medium-sized tree, native to India, and is cultivated in Pakistan, Uzbekistan, Sri Lanka, Southeast Asia, China, and Malaysia. Its other names are Phyllanthus emblica Linn, Emblica pectinata Ridl, emblic myrobalan, and Indian gooseberry .The sample size was calculated employing the formula for comparing two means, considering type 1 error = 0.5, power = 80%, Cohen's This triple-blind, placebo-controlled, randomized clinical trial was performed at the cardiovascular clinic of Tabriz (Iran). The registration code in the Iranian Center for Clinical Trials is IRCT20090527001957N7.After confirming the eligibility and filling the informed consent form, the patients were assigned into two groups through block randomization. Blocks of four  were randomly selected to make the randomization list. Sequentially numbered opaque sealed envelopes were used for randomization concealment. The drug and the placebo were administered to the patients in similar packages and the same dose . There were letters A, B, C, or D on the containers, where A and C were EO capsules and B and D were placebo. The patients, the researcher, and data analyzer were blinded to the content of the containers.Both groups continued their previous antihypertensive treatments. Complementary intervention in group 1 was EO capsules (500 mg) three times a day after meal  and in group 2 was the placebo capsules three times a day after meal for 8 weeks. Patients were reminded once a week through telephone to adhere to their medications.Changes of SBP and DBP were the primary outcomes which were measured with calibrated mercurial sphygmomanometer  using the appropriate cuff while observing the standards of BP measurement .Measurements were repeated 3 times with intervals of 3 minutes, and the average systolic and diastolic pressure was recorded for each patient at each visit. The setting of BP measurement remained constant at baseline and at the end of the study.Response to treatment was defined as SBP < 140 and/or DBP < 90 or a reduction of SBP by more than 10 mm Hg and/or DBP reduction of more than 5 mm Hg . Other oTo measure the heart rate after 10 minutes of rest, the heart rate was measured for 30 seconds.nd, 4th, 6th, and 8th week.SBP and DBP were measured at baseline and at the 2th week.HR, fasting blood sugar (FBS), serum cholesterol and triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), BUN, and creatinine were measured at baseline and at the 8To measure the medication adherence, patients were asked to mark the medications they have used in a checklist. Moreover, patients had to bring their remaining medications back at the next visit. Taking less than 20% of medications was considered as poor adherence .t-test.The data were analyzed by SPSS software (version 17). The mean ± standard deviation was utilized to describe the quantitative variables, and number and frequency percentage were employed for the qualitative variables. Comparison of qualitative variables between groups was done using the chi-square test. Quantitative variables were compared between groups using P values less than 0.05 were considered as statistically significant.To assess the effect of the time and treatment on the systolic and diastolic pressure, repeated measures ANOVA was used. Normal distribution of systolic and diastolic pressure was confirmed by Kolmogorov–Smirnov test. Mauchly's test was used to assess the sphericity. Of the 287 patients who were assessed for eligibility, 92 patients were enrolled in the study and randomly assigned into two groups. Eighty-one patients (41 in the drug group and 40 in the placebo group) completed the study for 8 weeks and were analyzed. The CONSORT flow diagram and causes of the attrition are presented in Age of participants ranged from 35 to 74 years. The number and median of antihypertensive drugs were 0–2 and 1 in both groups. The amounts of SBP and DBP and their changes are presented in P < 0.001). Percentage of DBP decrease was 12.3 (7.87) and 3.88 (7.98) mmHg, respectively (P < 0.001). The results of the repeated measures ANOVA adjusted for the corresponding baseline BP and age are presented in t-test for comparison between groups did not reveal any statistically significant difference between groups for HR, FBS, cholesterol and TG, ALT, AST, BUN, and creatinine at baseline and 8th week.This is the first placebo-controlled clinical trial to examine the effect of EO add-on therapy on BP. The results of this study revealed that EO in combination with standard antihypertensive drugs reduced the systolic and diastolic blood pressure more than placebo in patients with uncontrolled hypertension. The frequency of response to treatment was significantly higher in the EO group. No significant complication was reported. EO has an astringent effect, but constipation was not observed if taken after meal. As in our study, nobody suffered from this disorder. In the case of constipation, sweet almond oil can be used .Phyllanthus emblica (PE) extract on endothelial dysfunction and biomarkers of oxidative stress in patients with type 2 diabetes mellitus. Blood pressure changes were observed, and reduction of the endothelial reflection index showing the improvement of endothelial function was said to be attributed to the anti-inflammatory and antioxidant action of PE [There are some animal and a few low-quality studies that show the effect of EO on blood pressure –16, 21. Emblica officinalis), and reduction of blood pressure was also observed [Phyllanthus emblica (PE) extract on cold pressor-induced cardiovascular changes in healthy people and observed the reduction of arterial stiffness and radial and aortic BP in the PE extract group [Gopa et al. evaluated the hypolipidemic efficacy of amla  and flavonoids (quercetin and kaempferol) . PreviouNowadays, scientists believe the effect of oxidative stress on blood pressure , 29, andOne of the limitations of our study was the lack of use of Holter monitoring of BP because of the high costs, and it is suggested for the future studies. Another limitation of the study was the lack of checking the adherence to antihypertensive drugs at the beginning of the study (we just asked patients about their adherence to their antihypertensive medications). In addition, we were not able to explain the effect of EO alone on hypertension because it was an “add-on” study.Evaluation of the antihypertensive effect of EO in comparison with standard antihypertensive drugs can be mentioned in future trials. In addition, the antihypertensive effect of EO in higher stages of hypertension could be evaluated. If it is approved, EO could be applied in hypertensive patients as a safe and effective intervention.Eight-week intervention with EO plus standard antihypertensive drugs significantly reduced the systolic and diastolic blood pressure more than placebo in patients with uncontrolled hypertension.


The influence of liver disease on the pharmacokinetic profile, the risk of acute kidney injury, and excessive drug exposure in patients treated with vancomycin was examined.A retrospective cohort study was performed with patients discharged from a medical center between January 2011 and June 2018 who received vancomycin therapy. Patients were stratified according to liver dysfunction (no to mild liver dysfunction (NMLD) and moderate to severe liver dysfunction (MSLD) based on the Child–Pugh score. The risk of acute kidney injury was compared between patients who were stratified by the attainment of a target serum trough concentration (10 mg/dL to 20 mg/dL) and the vancomycin ratio formed between the area under the curve and minimum inhibitory concentration. The impact of liver dysfunction and a daily dose of vancomycin on the risk of acute kidney injury and vancomycin AUC:MIC > 600 were tested using logistic regression with and without adjusting for the study variables.A total of 408 patients empirically treated with vancomycin were included in this study (237 with NMLD and 171 with MSLD). Mean vancomycin trough concentrations  and AUC:MIC ratios  were significantly higher in the MSLD group when compared to the NMLD group, respectively. Vancomycin clearance was also lower in the MSLD group and corresponded to a longer half-life. The proportion of patients who developed acute kidney injury was greater in patients with MSLD when compared to NMLD ; however, the difference was statistically insignificant. Furthermore, supratherapeutic serum trough concentrations and AUC:MIC ratios were more common in the MSLD group versus the NMLD group .MSLD correlates with an increased risk of supratherapeutic vancomycin exposure. Although patients with MSLD had a higher risk of acute kidney injury, the difference was not significant. Staphylococcus aureus [Vancomycin (a glycopeptide antibiotic) has been used to treat serious gram-positive infections, specifically methicillin-resistant s aureus , 2. Earls aureus , 3. Vancs aureus –6.A direct relationship exists between the vancomycin trough concentration and nephrotoxicity, with a greater risk occurring in patients with trough concentrations greater than 15 μg/mL . SuprathDrug clearance is an important factor in determining AUC. Estimating clearance in patients with liver disease is often challenging because the standard approach to estimating renal function (Cockcroft-Gault) relies on serum creatinine. Because serum creatinine is dependent on muscle mass, and individuals with liver disease often have low muscle mass, renal function is often over-estimated . UltimatRenal function is often acknowledged when selecting a vancomycin dosing strategy; however, liver function is not commonly considered. Furthermore, data to support the influence of liver dysfunction on vancomycin pharmacokinetics are limited –16. One A retrospective cohort study was performed using patient records gathered from a pharmacy-managed vancomycin pharmacokinetic service in an academic community medical center with 365 beds located in Somerville, New Jersey, USA between January 2011 and June 2018. Patients who were treated with vancomycin during hospitalization were screened.Data extracted included age; gender; race; creatinine clearance (CrCl); body mass index (BMI); vancomycin dosing strength and frequency; vancomycin through level; estimates of liver function; comorbidities identified using International Classification of Diseases codes; procedures; length of hospitalization; mortality; Child–Pugh scores; and relevant laboratory values . Child–Pugh scores were used to stratify patients into groups based on liver dysfunction: no to mild liver dysfunction  or moderate to severe liver dysfunction  . This prAssuming a 10% rate of supratherapeutic vancomycin trough concentrations, a total of 42 patients in each group would provide a power of 90% in detecting a relative difference in the proportion of patients reaching supratherapeutic concentrations of 30% with a two-sided alpha level of 0.05 . PatientA total of 414 eligible patients receiving vancomycin therapy were screened for inclusion into the study; 6 were excluded because they were missing variables needed to calculate liver dysfunction severity. This study included a final total of 408 patients.The primary outcome of this study was the incidence of patients with acute kidney injury while on vancomycin therapy. Acute kidney injury was defined as a ≥ 0.5 mg/dL rise in serum creatinine or a 50% increase above baseline (whichever was greater) through the course of therapy for two or more consecutive days . SecondaTrough concentrations were drawn thirty minutes prior to the upcoming dose, with a ±  1-hour leeway. If the trough concentration was drawn outside the 1-hour window, the trough was extrapolated to 30 min prior to the next scheduled dose using standard pharmacokinetic calculations with an estimated elimination rate constant and half-life. The area under the curve was estimated with DoseMe software, which uses a Bayesian approach, as previously described . The mint test for continuous data and the Chi square test or Fishers’ exact test for categorical data. One-way analysis of variance was used to test the differences in the means of outcome values among the three groups stratified by the level of vancomycin as noted in the AUC:MIC ratio.The differences in the baseline characteristics, vancomycin dosing variables, and clinical outcomes stratified by the level of liver dysfunction (NMLD group vs. MSLD group) were tested using the Normality testing was performed using the Shapiro–Wilk test. If data were not normally distributed, the Mann–Whitney U test or Kruskal–Wallis Rank Sum test was used to compare the medians. Pearson correlation coefficients were calculated to test possible correlations between vancomycin trough concentration and key pharmacokinetic parameters including vancomycin ratio of AUC:MIC, clearance (ml/min), the volume of distribution per weight (L/kg), and half-life (hour).Logistic regression analysis was performed to determine factors which influence the occurrence of acute kidney injury, supratherapeutic vancomycin concentration, and mortality, vancomycin AUC:MIC ratio of > 600, with and without adjusting for the severity of liver dysfunction, daily dose of vancomycin used, sex, age, body mass index(kg/m ), CharlsOf the 408 patients included in the study, 237 had NMLD and 171 had MSLD. Patient demographics and dosing characteristics are summarized by the level of liver dysfunction in Table Patients’ vancomycin trough concentrations and clearance increased linearly as their AUC:MIC ratios increased Table . VancomyAfter adjusting for sex, age, and total daily dose of vancomycin, body mass index, and Charlson comorbidity index score, the incidence of acute kidney injury was 2.48 times (95% CI: 0.98–6.28) higher in patients with MSLD than those with NMLD, but the impact was statistically insignificant  had an increased mean vancomycin trough concentration as well as a higher prevalence of a supratherapeutic trough concentration when compared to those with no or less severe liver disease (i.e. NMLD). Previous studies have shown a correlation between increased trough concentration and the incidence of adverse drug reactions, particularly nephrotoxicity , 25.Acute kidney injury is a well-known, adverse drug reaction that may occur secondary to vancomycin exposure. The development of acute kidney injury includes a variety of risk factors as reported in published literature, including concomitant nephrotoxins, advanced age, total daily doses exceeding 4 grams, and hypotension , 27. TraA vancomycin ratio of AUC:MIC > 600 occurred more often in MSLD patients than NMLD patients. Regardless of the metric being used (trough or AUC:MIC), the prevalence of a supratherapeutic concentration in this patient population is of concern. Unlike previous studies that have evaluated risk factors for toxicity, this present study evaluates both liver disease as a chronic condition and drug exposures as defined by serum trough concentration and a/the AUC:MIC ratio. The secondary clinical outcomes  were significantly higher in the more severely ill patients. Acute kidney injury was more common in the MSLD group versus the NMLD group. The difference was not significant and was likely related to a type II error given the wide confidence interval and the low overall incidence of acute kidney injury in the studied cohort (5.4%). Another concern regarding vancomycin therapy and supratherapeutic trough concentration is the incidence of ototoxicity , 31. DueThe higher rate of acute kidney injury, mortality, and length of stay in the MSLD group may not be attributed solely to vancomycin therapy and subsequent trough concentration. The severity of illness (particularly liver disease) also influences the length of stay, acute kidney injury, and mortality rates. Furthermore, patients with liver dysfunction can have a concomitant occurrence of hepatorenal syndrome. Hepatorenal syndrome is a reversible renal impairment that can occur in those with advanced liver cirrhosis or fulminant hepatic failure . AlthougThere are some limitations to the study that should be considered. The influence of concomitant medications, particularly nephrotoxins, were not included in the analysis due to the lack of data availability. Diuretics are known to increase risk of acute kidney injury and are recommended by clinical practice guidelines for the management of ascites in advanced liver disease , 34. TheThis study examined the influence of pharmacokinetic parameters in patients with MSLD. While vancomycin half-life was prolonged, clearance decreased in this patient population, which led to an increase in supratherapeutic exposure. Although MSLD was associated with an increased risk of nephrotoxicity, the increased risk compared to individuals with NMLD was not statistically significant. When initiating vancomycin treatment in patients with liver dysfunction, clinicians should consider dosage and/or frequency reductions to minimize the occurrence of supratherapeutic concentrations and potential adverse consequences. Future studies are needed to determine if dosage adjustments improve patient outcomes and if patients with liver disease are at greater risk of vancomycin related toxicity.