Cardiac surgery-associated acute kidney injury (CSA-AKI) is a serious postoperative complication of cardiac surgery, an episode of which impacts on patient morbidity and mortality. Pulse wave velocity  has been shown to predict kidney disease progression, and cardiovascular and all-cause mortality in patients with chronic kidney disease. We hypothesised that PWV would also predict acute kidney injury in subjects who have undergone non-valve repair elective coronary artery bypass graft (CABG) surgery .This was a prospective, observational, exploratory study. PWV was determined with a Vicorder device, together with standard clinical and biochemical parameters. AKI staging was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines.p = 0.006. A 1 unit increase in estimated glomerular filtration rate resulted in an estimated 85% decrease in the odds of developing AKI, each year, men have an odds reduction of 15% of developing AKI compared with females and each 1 year increase in age lowered the odds of developing AKI by 87%.137 patients were included in the study. 85% were male, and mean age was 66.3 years (SD = 9.7 years). There were 40 episodes (29%) of CSA-AKI. Each 1 unit increase in PWV score was associated with a 1.5 fold greater odds of a CSA-AKI event (This pilot exploratory study revealed that PWV, assessed prior to non-valve repair elective CABG surgery, independently predicts CSA-AKI events. PWV is a simple, non-invasive technique that could potentially be used to risk stratify for CSA- AKI following elective cardiac surgery.NCT02364427. Registered 18 February 2015.ClinTrial.Gov  Acute Kidney Injury (AKI) affects around 20% of all hospitalised patients  and has Currently there is no specific therapy for AKI and the management of patients is completely supportive. Furthermore, in the absence of more sensitive biomarkers, it would appear that even a non-severe episode of AKI already confers a worse prognosis with regards to the risk of development of CKD and long term survival in patients. Thus perhaps focus should be on prevention, and early detection of risk, of AKI as opposed to cure. This is even more pertinent when one considers that the National Confidential Enquiry into Patient Outcomes and Death (NCEPOD) report in 2009  identifiAlthough factors such as diabetes, older age and low eGFR are all associated with increased risk of AKI, there is no standardized scoring method for risk . In addiThe aim of this exploratory study was to investigate whether arterial stiffness, as defined by measuring Pulse Wave Velocity, a simple non-invasive measurement score, could be identified as an independent risk factor for development of post-coronary artery bypass graft acute kidney injury.Participants were approached during routine surgical pre-assessment clinic at King’s College Hospital (KCH) in London. They were included if they were aged > 18 years, due to have CABG surgery alone with no concomitant valve surgery, and were able to give written consent. Patients were excluded if they had aortic grafts or renal stents, had renal function reflecting CKD stage 4 or 5, were receiving dialysis treatment, or had a significant psychiatric illness .Patients were assessed in a quiet treatment room in the pre-assessment clinic in the early afternoon. Data collection included blood and urine samples, patient demographics and anthropometrics , followed by blood pressure (BP), heart rate (HR), and PWV. All outcome assessments were performed at the same study visit.Pulse Wave Velocity (PWV), a measurement of arterial stiffness, was assessed at the systemic region , which is the gold standard method , using tThe development of AKI was determined according to the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury criteria . In brieVenous blood was collected at the study visit. Serum creatinine  was analysed in the biochemistry department at King’s College Hospital.After sitting quietly for 5 min, resting BP and HR were recorded in triplicate, with a 1-min interval between measurements, using an automated sphygmomanometer . The average of 3 readings was recorded.Parameters are expressed as means ± SD  and median and interquartile range for non-parametric data. Differences between groups were assessed by the independent samples median test, t-test, or chi-squared test as appropriate to the data type. Correlations were assessed by the Pearsons correlation coefficient. Linear and logistic regression analyses were used to generate regression beta coefficients (B) and odds ratios for a range of baseline variables  to determine factors that independently predicted the risk of a post-operative AKI event.n = 116) with a mean age of 66.3 years (SD = 9.7 years), and the majority of the participants were of white ethnicity . None of the participants had a history of pre-operative renal disease or were in an unstable state pre-operatively. Forty patients (29%) developed AKI according to the KDIGO criteria [H0 < 0.05 throughout. Figure A total of 137 participants were recruited to this study over a 24 month period; demographic data and baseline measurements are shown in Table criteria . Table 1p < 0.001), a higher probability of having diabetes, (p = 0.007), and a greater Pulse Wave Velocity (p = 0.049) compared to those in the no AKI group. A higher percentage of women had AKI than men.Patients who suffered an AKI event had lower values of eGFR at baseline :eGFRpulse wave velocityagegenderIt is recommended that the number of predictor variables for logistic regression modelling is limited to one predictor for every 10 events, where an event is defined as the outcome of interest  . This haThis is in agreement with the exploratory backwards stepwise model. A final, forced entry model was constructed with these predictor variables. This final model has sufficient numbers of events for stability with four predictors. eGFR, age, gender, PWV and participants receiving diabetic management were all statistically significant predictors of post-operative AKI and. as shown in Table This is the first study to investigate the relationship between PWV and development of AKI post elective CABG surgery; there is, however, previously published data that supports an association between increased levels of AS and reduced kidney function . The resThe mechanism of injury in CKD from increased AS is thought to be related to barotrauma inflicted on glomeruli in a “stiff” vascular system . PreventSeveral limitations need to be acknowledged. Firstly, our study consists of a predominantly caucasian population undergoing elective non-valve repair CABG surgery so there is a need be cautious when extrapolating these results to other patient populations. Secondly, the small number of post-operative AKI episodes meant that we had to restrict the number of dependent variables in the multivariate model. Measurement of PWV as a predictor of CSA-AKI in a larger patient population would be of interest.The results from this exploratory study indicate that PWV, assessed prior to elective non-valve repair CABG surgery, independently predicts post-operative AKI events. PWV is a simple, non-invasive technique that could potentially be used to help in stratifying the risk of post-operative AKI following cardiac surgery. Importantly, unlike other risk factors such as eGFR, there is potential to modify AS pre-cardiac surgery and reduce the risk of CSA-AKI. Further research to evaluate potential therapeutic strategies to reduce AS is warrented.


The objective of this study was to describe systemic arterial properties including characteristic impedance (ZMethods: Eighty-one JIA patients (median age 38.6) with at least 15 years of active disease were reexamined after median 29 years of disease duration and compared to 41 healthy controls. With use of echocardiography and calibrated right common carotid artery tonometric pulse traces, noninvasive estimates of pressure and blood flow from the aortic root were obtained and used to estimate the systemic arterial parameters Z0, C and R.Results: The patients had higher Z0 as assessed by Windkessel model , lower C as assessed by either Windkessel model or ratio of stroke volume and pulse pressure , and similar R compared to the controls. Years on daily prednisolone and insulin resistance were the most important correlates of Z0. Metotrexat use, polyarticular disease course and erythrocyte sedimentation rate were also associated with a higher Z0.Our results indicate that JIA patients had altered arterial properties as compared to controls. Years on daily prednisolone and insulin resistance were the most important correlates of altered arterial properties. Juvenile idiopathic arthritis (JIA) is a chronic inflammatory rheumatic disease with symptom onset in childhood and persists into adulthood in about 50% of the patients , 2.Arterial stiffness is an established independent predictor of cardiovascular disease (CVD) . Whereas0), arterial compliance (C) and vascular resistance (R) [Pulse wave velocity (PWV) is the most frequently used method for the measurement of arterial stiffness reflecting large arterial stiffness . Howeverance (R) .0, C and R have hitherto not been described in this patient group. The present study was therefore designed to characterize systemic arterial properties in detail in JIA patients as compared to matched controls. We also wanted to assess the associations between JIA disease variables, cardiovascular risk factors and arterial properties.We have previously reported an increased prevalence of hypertension and arterial stiffness as measured by PWV in adults with long-lasting active JIA . Howevern = 3), recordings of suboptimal quality (n = 5), or severe heart disease without presumed relation to JIA (n = 1). The 81 participants were not different from the 53 eligible but not participating patients regarding gender, disease duration and age (data not shown).Totally 134 JIA patients with clinically active disease for at least 15 years of disease duration were invited to a combined rheumatologic and cardiologic follow-up study after median 29 years. The patients were initially referred to the Oslo University hospital between 1980 and 85, and re-examined after median 15 and 23 years before the present study [Forty-six healthy, age- and gender-matched controls were selected randomly from the Norwegian population register. Responders with a history of diabetes mellitus, hypertension, or inflammatory arthritis were not included. Five were excluded after inclusion due to suboptimal recordings.The 81 patients underwent a clinical examination performed by a specialist in rheumatology, the controls were clinically examined by a physician.JIA was classified according to the International League of Associations for Rheumatology criteria . Active Family history of CVD was defined as a first degree having CVD before the age of 65 (women) and 55 (men). Information about smoking habits and physical activity was obtained through a questionnaire. Insulin resistance was derived from the assessments of insulin and glucose .Three measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with a difference of < 5 mmHg were averaged and taken in all participants after 5 min rest in a supine position. Arterial hypertension was defined as SBP > 140 mmHg and/or DBP > 90 mmHg, and/or use of antihypertensive medication.Blood samples were drawn after an overnight fast and analysed for high sensitive C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), insulin, glucose and cholesterol.We recorded the arterial pulse waveform from the right common carotid artery with the patient in a supine position, using a high-fidelity external applanation tonometric device . Recordings were obtained semi-simultaneously with echocardiographic doppler recordings  of blood flow from the left ventricular outflow tract and the parasternal short axis midventricular cineloops. The tonometric signal was amplified and transferred to a personal computer for processing in Matlab 7 application . We sele0, R and C [0 in the frequency domain as the average of the high frequency harmonics of the input impedance modulus [A 3-element electrical analogue Windkessel model of the systemic circulation was used to assess Z R and C . In orde modulus . C was at-test for the continuous normally distributed variables, the Mann-Whitney U-test for the continuous not normally distributed values, and the χ2 test for the categorical variables. For the continuous normally distributed variables, central tendencies were given as the mean ± SD and for the continuous not normally distributed values, median inter-quartile range. A p value < 0.05 (2 tailed) were regarded as statistically significant for all the analyses. Pearson’s Correlation coefficients and multivariate linear regression analysis were used to investigate associations between disease variables, cardiovascular risk factors and arterial properties. SPSS Version 20  was used for the statistical analyses.The JIA patients and controls, and the patient subgroups were compared using a 2-sided independent sample p = 0.028).The characteristics of patients and controls are summarized in Table 0 estimated by Windkessel model was significantly higher . Heart rate was slightly higher in the patients (p = 0.026), however R was similar in patients and controls.Z0 by Windkessel model was significantly higher in the patients with present or previous use of metotrexat, using prednisolone, and/or had polyarticular disease course as compared to the other patients .Znts Fig. , and wasnts Fig. . When in0 by Windkessel and a lower C when compared to controls. Years on daily prednisolone and insulin resistance were the most important correlates of Z0. Furthermore, the use of metotrexat, polyarticular disease course and ESR AUC correlated with higher Z0.The present long-term follow-up study indicates that JIA patients with long-term active disease have altered systemic arterial properties as demonstrated by a higher Z0 reflects the combined effect of size and stiffness  of predominantly the ascending aorta, C reflects the volume compliance of the entire systemic arterial tree. R is mainly determined by the small muscular arterioles [0 by Windkessel, our findings suggest that the central conduit arteries are altered more than peripheral arteries in adult JIA patients. Previous reports have emphasized the importance of large arterial stiffness rather than alterations of microvascular resistance in the prediction of cardiovascular risk in patients with hypertension [0 are associated with increased cardiovascular risk in the adult general population [Whereas Zterioles . Considertension , 13. Imppulation , 15.Our data support a previous study from the same patient cohort, showing higher PWV in adult JIA patients compared to controls . Thus, iIn the patient group, 8 had hypertension while controls with hypertension were excluded in order to maintain a healthy control group. However, when compared to controls, the differences in SBP and DBP were only marginal numerically, and not of statistical significance. Thus, we do not think that the difference in arterial properties between the JIA patients and controls can be fully explained by blood pressure variations. On the other hand, increased vascular stiffness predicts incident hypertension  underscoWe found an association between use of antirheumatic medication, polyarticular disease course and higher ESR AUC and insulin resistance and altered arterial properties. Larger prospective controlled studies are needed to identify determinants of altered arterial properties in JIA patients. Our findings add to the previously reported association between prednisolone use and increased arterial stiffness in JIA patients from our cohort .The strengths of this study are the inclusion of a well-defined cohort of JIA patients followed for 29 years and the fact that detailed information of arterial properties has not been presented in JIA patients before. However, the number of included participants was relatively small, and because of a cross sectional study design the prognostic value of our findings is unknown.In conclusion, our results suggest that adult patients with long-lasting active JIA had stiffer proximal aorta, and lower total arterial compliance but similar systemic resistance compared to matched controls from the general population. Years on daily prednisolone and insulin resistance were the most important correlates of altered arterial properties. Whether our findings indicate that JIA patients should enter a regular BP monitoring program needs to be determined in future longitudinal follow-up studies.


Background and Objectives: Epicardial adipose tissue (EAT) is shown to be an important factor in the development of coronary artery disease, but numerous pathophysiological mechanisms of its action are still only partially understood. There is a lack of studies on its association with different grades of essential hypertension (EH). Therefore, we aimed to evaluate the association between size of EAT depots and the risk of EH taking into account its grade. Materials and Methods: Non-obese adult patients with various cardiovascular diseases were investigated: 157 of them had essential hypertension and 101 did not. Hypertensive patients were assigned to three groups according to the grade of hypertension. EAT volume and thickness on ventricular free walls (6 locations) and grooves (5 locations) were measured using cardiac magnetic resonance imaging and compared between groups. A regression model for the prediction of EH was constructed. Results: In general, thickness  and volume of EAT depots was greater among hypertensive patients than in normotensive (NORM) group. Mean EAT thickness in all 11 locations and EAT volume were lower in NORM than in grade 1 hypertension group; similarly, EAT volume was lower in grade 1 than in grade 2 hypertension group. EAT accumulation did not differ between grade 2 and severe hypertension groups. EAT volume, dyslipidaemia status, body mass index, and age were independent predictors for EH in regression model. Conclusions: EAT accumulation is larger among hypertensive than normotensive individuals. Measurement of EAT depots could be beneficial for identification of hypertensive patients and prediction of hypertension severity. Essential hypertension (EH) is one of the most important modifiable risk factors for coronary heart disease, stroke, congestive heart failure, end-stage renal disease, and peripheral vascular disease. Uncontrolled EH may lead to the detriment of the cardiovascular system, brain, and kidneys ,2,3. EH Obesity is one of those hypertension risk factors that can be modified. Reduction of adipose tissue depots is one way of alleviating hypertension and lowering the likelihood of subsequent major adverse cardiac events . HoweverBesides abdominal depots of visceral adipose tissue, present studies take into account epicardial adipose tissue (EAT) as a new modifiable cardiometabolic risk factor, which might interact with the heart in a more direct way. EAT is identified as visceral brown adipose tissue located between the myocardium and visceral pericardium and covers more than three quarters of the surface of the heart . StudiesThe objective of this study was to evaluate the association between the size of epicardial adipose tissue depots and the risk of essential hypertension with respect to its grade.The study involved adults between the ages of 30 and 75. According to their health records, they were assigned to normotensive (NORM) and hypertensive groups. Diagnoses of essential hypertension and its grade were made by health care professionals according to Guidelines for the Management of Arterial Hypertension . People 2) individuals were excluded from this study. To exclude any confounding effect on the study results, all obese . All participants of this study gave their informed consent prior to their inclusion in the study.To assess lifestyle factors that might be associated with EH, a questionnaire was used. Hypertension risk factors such as low physical activity, frequent emotional stress, hard smoking, high salt intake, and a frequent consumption of butter and animal fats were investigated. Physical activity assessment included physical activity at work and leisure time physical activity. Low physical activity group consisted of individuals with low physical activity at work and during leisure time. Sedentary work as well as work including only walking or standing was assigned to low physical activity. Similarly, leisure time physical activity including only sitting, standing or walking was defined as low. Frequent emotional stress group was formed of individuals who subjectively indicated at least one of the following: frequent feeling of tension and anxiety, frequent feeling of suppression and slowness, frequent torment of troubled thoughts and concerns, rare ability to sit calmly and relax. At least 10 pack-years current or ex-smokers were identified as hard smokers. Excessive salt consumption group was formed of individuals who indicated additional salting of prepared meals. Participants who indicated animal fats or butter as the most frequently consumed dietary fats were assigned to another risk group.The size of EAT depots was measured using cardiac magnetic resonance tomography images. Cardiac magnetic resonance imaging was performed for each participant. Volume and thickness of EAT was measured .Volume of EAT was calculated by using modified Simpson rule . End-diaThickness of EAT depots was measured in 11 locations. End-diastolic long-axis (4-chamber) images were used for measurements of EAT thickness in right and left atrioventricular grooves and the anterior interventricular groove. End-diastolic short-axis images were used to measure thickness of EAT depots on the free walls of left and right ventricles as well as in superior and inferior interventricular grooves.On admission to our hospital, blood pressure (BP) of every patient was measured. As recommended , measureAlso, use of statins and antihypertensive drugs within the period of one year was recorded. Drugs were assigned to groups as follows: beta-blockers, diuretics, angiotensin-receptor blockers, calcium channel blockers, ACE inhibitors, and other antihypertensives.In addition, within one year to magnetic resonance tomography measurements of total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) were made.In statistical analysis, mean values of EAT thickness were used as follows: mean of all thicknesses (measurements in 11 locations), mean thickness of groove measurements (5 locations), mean thickness of atrioventricular groove measurements (2 locations), mean thickness of interventricular groove measurements (3 locations), mean thickness of measurements on ventricular free walls (6 locations), mean thickness of measurements on the free wall of the right ventricle (3 locations), and mean thickness of measurements on the free wall of the left ventricle (3 locations).T-test was used for the comparison of means with normal distribution of variables. The Mann–Whitney U test was applied for the comparison of variables that did not comply with the assumptions of normality. Frequencies between the groups were compared using the χ2 criterion. Receiver operating characteristic (ROC) curve analysis was performed in order to identify optimal cut-values for continuous variables. A binary logistic regression model was constructed for the prediction of EAT volume. Only statistically significant variables were used for the final model. Odds ratios and confidence intervals were calculated for each variable of the model. Hosmer–Lemeshow goodness of fit test was applied. Next, differences of EAT volume between grades of hypertension were assessed by analysis of covariance (ANCOVA) with body mass index (BMI), pack-years and sex as covariates. Because of the small sample size, patients with grade 3 hypertension were excluded from ANCOVA analysis. Significance level α = 0.05 was chosen for statistical analysis. Measures of central tendency are presented as follows: mean ± standard deviation, for variables with normal distribution, or median (first quartile–third quartile) for variables with other distribution. Normality of the variables’ distribution was tested using the Shapiro–Wilk test. A Despite our efforts to create groups of patients as similar as possible in terms of essential hypertension risk factors, they did have some differences. Hypertensive patients were older and had slightly higher BMI than the NORM group; a larger part of hypertensive group were also male and hard smokers. On admission, NORM group had lower BP and TG levels, and less of them used antihypertensives. On the other hand, there was no significant difference in emotional stress experiences, physical activity, and consumption of salt and dietary fats . On admi3 (100.3–153.4 cm3) and 5.4 mm (4.5–6.2 mm) respectively. Analysis showed that the size of EAT depots  were statistically significantly higher among hypertensive patients than in NORM group . Respectively, median EAT volume was 137.5 cm3 (113.1–159.5 cm3) and 108 cm3 (89–137 cm3), median EAT thickness was 5.7 mm (4.8–6.4 mm) and 4.9 mm (4.3–5.8 mm). Differences in size of EAT depots between NORM and EH1 groups were observed only when comparing volume, average values of all thicknesses and average values of all thicknesses in grooves. Differences between EH1 and EH2 were also observed when comparing volume, as well as average values of all thickness measurements. In addition to this, the size of EAT depots between EH1 and EH2 groups differed when comparing the average values of EAT thickness on the free ventricular walls . There was no difference in size of EAT depots between EH2 and EH3 groups. Detailed analysis of the size of EAT depots in different groups of patients is presented in Overall, median EAT volume and thickness were 125.5 cmThe ROC analysis showed that volume, among all EAT measurements, provides the most accurate results for identification of hypertensive patients (area under the curve was 0.687). EAT volume is also applicable for identification of EH1 patients in a mixed EH1 and NORM group. The mean EAT thickness in all measurement locations accounted for 0.669 area under the curve for identification of hypertensive patients in the whole sample.3. Optimal EAT thickness cut-points for average of all thicknesses, average of measurements in grooves, on both ventricular free walls, and on the right ventricular free wall were 4.8 mm, 6.9 mm, 2.8 mm, and 4.2 mm, respectively. We used these values in order to conduct logistic regression analysis and to construct a model which showed that EAT volume is an independent determinant of EH and along with age, BMI, and dyslipidaemia status, can be used to identify hypertensive patients. Furthermore, logistic regression analysis showed no significance for any EAT thickness measurements, whether analysing with or without the EAT volume variable. The model of the independent determinants of EH prediction is provided in According to the ROC analysis, optimal EAT volume cut-point (Youden’s Index) to indicate EH patients was 111.6 cmp = 0.039 and p = 0.003). No difference in EAT volume was found between NORM and EH1 groups. Age and dislipidaemia status were not significant covariates for EAT volume.After adjusting for sex, BMI, hard smoking, statins, and antihypertensives in ANCOVA, it was found that grade of hypertension was a significant determinant for EAT volume. According to this analysis, EAT volume differed significantly between EH2 and EH1, also between EH2 and NORM groups (respectively, Results of this study show that the size of EAT depots tend to be higher among the patients with EH compared to normotensive patients. Also, this study shows that EAT depots tend to increase up to the second grade of hypertension while patients with severe hypertension tend to have similar EAT depots to that of patients with grade 2 hypertension. Furthermore, logistic regression analysis shows that EAT volume is an independent determinant of EH and can be used for its risk prediction in conjunction with such variables as age, body mass index and dyslipidaemia status, improving the prediction accuracy. According to ANCOVA, after adjustment for sex, BMI and hard smoking, the grade of hypertension remains significant determinant for EAT volume.Some previous studies conducted by other authors confirm the increase in size of EAT depots among the patients with EH ,33,34,35Contrary to our findings, some studies have shown no association between EAT and hypertension ,24,27,28Along with EH occurrence disparities, diverging results regarding the correlation between the size of EAT depots and blood pressure are presented in the literature ,26. We hIn the literature we have found two theories of the association between EAT and EH. One of these theories states that EAT might be the cause of hypertension. Due to the oxygen deficiency, which occurs when EAT depots become larger, epicardial fat is invaded by increased numbers of macrophages and T lymphocytes, resulting in a shift of its metabolic profile. Increase in EAT depots results in increased secretion of numerous proinflammatory cytokines and vasoactive peptides, including interleukin-6, TNF-α, MCP-1, and angiotensin II ,37,38. TAnother of the theories of the association between EAT and hypertension states that depots of EAT increase because of the adaptation to higher myocardial energy demands. Researchers hypothesize that hypertension might determine the accumulation of EAT. Long-term effect of high blood pressure causes myocyte cellular hyperplasia and capillary proliferation, which subsequently increases thickness of the ventricular wall. This results in increased energy demands for contraction and might stimulate EAT accumulation to provide more free fatty acid to the myocardium ,25. StudThere were several limitations in our study. Although the sample of our study seems to be sufficiently large compared to other studies on this topic, it was difficult to determine any causal relationship, because predictive factors and outcome variables observed simultaneously without follow-up data. Also, the design of our study did not allow us to assess the significance of hypertension duration to changes in EAT depots; longitudinal studies in the future should address this option.Accumulation of EAT among hypertensive patients is larger than among normotensive individuals. Measurement of EAT depots might be beneficial for identification of hypertensive patients and prediction of hypertension severity.


Adverse cardiovascular effects, including hypertension, were described in patients with different cancers treated with tyrosine kinase inhibitors (TKI). The mechanism of TKI-related hypertension is still debated. The aim of this work was to study the effects of TKI on blood pressure (BP), searching for a relationship with possible causative factors in patients with metastatic renal cell carcinoma. We included 29 patients in a prospective, observational study; 22 were treated with a first-line drug (sunitinib), while seven participated in the second-line treatment (axitinib or cabozantinib). Patients were investigated at the beginning of antiangiogenic therapy (T0) and at one (T1), three (T2), and six months (T3) after treatment. Patients were evaluated by office blood pressure (BP) and ultrasonography to measure flow-mediated dilatation (FMD), and carotid artery distensibility (cDC) by echocardiography and nailfold capillaroscopy. Plasma endothelin-1 (p-ET-1), urine nitrates, and proteins were also measured. At T1, systolic BP, along with U proteins and p-ET-1, increased significantly. In patients with a clinically significant increase in BP (defined as either the need for an antihypertensive drug or systolic blood pressure (SBP) T1–T0 ≥10 and/or SBP ≥140 mmHg and/or diastolic blood pressure (DBP) T1–T0 ≥5 and/or DBP ≥90 mmHg), the urine nitrate concentration was lower at T0, whereas there were no differences in the p-ET-1 and U proteins. Seventeen participants showed changes in the capillaroscopic pattern at T1 with no association with BP increases. There were no differences in the FMD, cDC, and echocardiographic parameters. Our findings are consistent with those of previous studies about BP increases by TKI, and suggest a role of nitric oxide in BP maintenance in this population. VEGF and VEGFR, age, body mass index (BMI), and pre-existing hypertension [In the last several years, antiangiogenetic therapy was included in the therapeutic schemes of many oncological diseases, including renal cancer . In partrtension . The incrtension ,6, and artension . The pathogenetic mechanisms of antiangiogenic tyrosine kinase inhibitor (TKI)-related hypertension are not completely understood, and there are probably multiple mechanisms of action ,7,8. TheThis study was approved by the Ethical Committee of Verona (CESC n. 281). All of the subjects signed written informed consent.The patients that were involved in this single-center, prospective, observational study were selected from the Oncology Department of the Azienda Ospedaliera Universitaria Integrata (AOUI) in Verona. The inclusion criteria were as follows: a diagnosis of metastatic renal cell carcinoma  with indication to start TKIs , an age of 18–90 years, and a normotensive or hypertensive classification with a well-controlled BP (<140/90 mmHg). We excluded subjects with hepatic disease or severe hypertransaminasemia, chronic renal failure (plasma-creatinine >1.5 mg/dL), pregnancy, a history of abuse of alcohol or drugs in the last six months, or an inability to cooperate or undergo outpatient examinations. After verifying the inclusion/exclusion criteria, the patients were sent to the outpatient clinic of the General Internal Medicine and Hypertension for vascular exams (see below). The patients were evaluated before the start of the antiangiogenetic therapy (T0) and at one month (T1), three months (T2), and six months (T3), after the initiation of TKIs. Antihypertensive therapy was modified by our team at each study point according to the clinical need.g for 10 min. Plasma and/or serum were frozen at −80 °C until analysis.On the visit day, after a brief interview, subjects underwent BP measurement, endothelial function assessment by ultrasounds, capillaroscopy, echocardiography, and the collection of venous blood and extemporary urine samples. Blood was collected in tubes anticoagulated with EDTA (ethylendiaminetetracetic acid) and in vacuum tubes containing no additives . Urine was stored at −20 ° C until use, and then thawed at 4 °C and centrifuged at 2400 Tumor assessments  were performed every 12 weeks from the start of treatment. BP was measured with an oscillometric device  in a clinostatic position at rest; for all of the patients, we averaged three BP measurements performed five min apart. The patients were also invited to check their BP regularly at home. Since these home blood pressure measurements were not taken using the same device, but each patient used its own, these data were intended for clinical use, and are not presented. g for 10 min at room temperature, the serum was separated, stored in aliquots, and kept frozen at −80 °C until measurement.Urinary nitrates were measured using an immunoenzymatic colorimetric method through a specific laboratory kit . The assay was performed according to a procedure recommended by the manufacturer. The intra–interassay coefficients of variation were 2.7% and 3.4%, respectively. The results are expressed as a nitrate/creatinine ratio (µM/µmol). After centrifugation at 1500 Serum ET-1 levels were measured using the Endothelin-1 Quantikine ELISA Kit , according to manufacturer’s instructions. All of the samples were analyzed in duplicate. The limit of detection of this method is 0.207 pg/mL, as stated by the manufacturer. The reported intra-assay and interassay precision were <4% and <8%, respectively. A standard curve was generated by plotting the absorbance versus the log concentration using a four-parameter logistic curve fit. The urinary protein–creatinine ratio (mg/mmol creatinine) was measured in spot urine samples. Analysis was performed by an immunoturbidimetric assay on a Roche Diagnostics Cobas 8000 analyzer .The detection of flow-mediated dilatation (FMD)  was performed in a fasting state according to international guidelines : brieflyThe main morpho-functional cardiac parameters were measured in patients by echocardiography. In particular, we recorded the thickness of the interventricular septum (considering a limit of 10 mm as a cut-off for the diagnosis of cardiac hypertrophy), the main left/right diameters and volumes, the ejection fraction, and the E/A ratio (a diastolic dysfunction index when greater than 1).A periungual capillaroscopic evaluation was performed on all of the patients at each of the four study points  by a single independent expert rheumatologist blinded for information about the patients’ history or previous capillaroscopies. An OPVC  with polarized light and variable magnification was used. The instrumentation consisted of a PAL  color camera with magnification from 100× to 1000×, a source of incident, cold, and monochromatic light on the field, and a personal computer (PC) and monitor on which to view and save images, even comparing them with subsequent assessments. The modifications of the capillary pattern were classified using a semi-quantitative method in three categories  because of a change in capillary density that was not clearly detectable.CT images were evaluated jointly by oncologists and radiologists, according to the RECIST  criteria v. 4 . The appearance of new focal lesions or the enlargement of pre-existing lesions were considered signs of disease progression (with an increase of at least 20% of the transverse diameters); stable lesions were defined as having dimensional changes of up to ± 20%, while a partial response was defined as a reduction greater than or equal to 30%, which was also classified as regression. p < 0.05. SPSS Statistics 22  and GraphPad Prism 7  were used for all of the data analysis.Continuous variables are expressed as the mean ± standard deviation (SD). The comparison between continuous variables measured at different study points in each participant was performed using the Student’s T-test for paired data and/or the Wilcoxon rank test, depending on the normal distribution of the analyzed variables. Comparison between the continuous variables among the patients was performed with the Student’s T-test for unpaired data and/or the Mann–Whitney U test. To compare dichotomous variables, Fisher’s exact test was used, while the correlations were completed with the Pearson test or Spearman test. The Kaplan–Meier estimator was used to obtain progression-free survival (PFS) and overall survival (OS); a two-sided 95% CIs Cox proportional hazards model was performed for the medians and hazard ratios (HRs) for each end point. In all of the cases, a statistically significant value was considered with at n = 27) was clear cell renal cell carcinoma (ccRCC), and only a few tumors (n = 6) were non-clear cell RCC (nccRCC). Based on the international metastatic RCC database consortium (IMDC) prognostic classification [Twenty-nine patients participated in this study. Twenty-two patients were treated with sunitinib, whereas three and four participants were treated with axitinib and cabozantinib (second-line or third-line therapy), respectively. Since the mechanisms of TKIs are similar, their effect on BP is strictly linked to the assumption of the drugs, and is due to substantial pharmacological wash-out (at least two months between the first and successive lines). For this reason, we pooled all of the patients’ data, regardless of the line of therapy in the main analysis. Nevertheless, all of the analyses were repeated in the subgroup of 22 sunitinib-receiving patients (first-line therapy). The sample included five females and 24 males, aged between 45–76 years (64.7 ± 9.0 y) whose average BMI was 25.7 ± 4.5; 65% and 58.6% of them were prior smokers or hyperlipidemic, respectively. All of the subjects were previously treated locally by surgical intervention  or systemically (surgery of oligometastatic disease) and had indication of medical therapy with antiangiogenic drugs. The most common histology . The causes of drop-out were either a severe worsening of performance status or death. At baseline, 14 subjects (48.3%) underwent antihypertensive therapy . At T1, the introduction of antihypertensive drugs was needed in four patients ; a second antihypertensive drug was added for seven of the 14 subjects who were previously under treatment. At T2, three patients started calcium-channel blocker monotherapy, while a third drug was added for two subjects with prior dual medical therapy. In summary, 18 of 29 (62.1%) and 17 of 25 (86.2%) participants were treated with antihypertensive drugs at T2 and T3, respectively. After one month of TKIs and without any changes in the antihypertensive therapy, the average office systolic BP, but not the diastolic BP, increased significantly compared to that at baseline see . At T2 aTKI-sensitive and TKI-insensitive participants did not show any significant difference regarding their anthropometric and anamnestic characteristics . Both syp = 0.032). Furthermore, basal urinary nitrates were significantly lower in subjects who were already taking antihypertensive therapy at baseline , was noticed in 17 of 29 subjects (58.6%) at T1 . At T2 aNo significant changes in FMD, carotid distensibility, cIMT, and the tested ultrasound cardiac parameters, which were compared at different study points, were detectable in the whole sample or in the sunitinib subgroup . Even whAntiangiogenic therapy was shown to be significantly effective in shrinking peripheral metastasis in more than half of the participants  or stop In this study, we confirmed that a high percentage of patients treated with TKI have a significant increase in BP. We also showed that BP trajectories can be markedly different in different patients. In particular, some subjects showed a marked increase of BP values within the first month of TKI therapy, whereas others showed stable values. We considered a BP increase to be clinically significant if there was both the need to introduce an antihypertensive drug and if the final BP was above 140/90 mmHg, or when an increase greater than 10 mmHg in SBP or five mmHg in DBP occurred.Our definition is somewhat arbitrary, but it allowed us to divide our sample not only according to hypertension status, but also into groups of patients who were sensitive or non-sensitive to TKIs. Since our main focus was pathophysiological rather than clinical, we chose this definition to allow a better distinction between factors associated with the increase in BP in some, but not all, the patients. Moreover, we wanted to show that the application of even more stringent cut-offs (BP increase: >20 mmHg in SBP and/or >10 mmHg in DBP) did not shift any patients from the subgroup that was initially identified to the opposite subgroup. It has been previously shown that an increase in BP appears quickly when TKI therapy is started, and returns to its previous values quite rapidly in most patients after the discontinuation of TKI . PreviouIn our sample, we found a significant difference only in the basal urinary nitrates (a surrogate marker of both endogenous and dietary nitrate exposure)  between Furthermore, a significant increase of plasma ET-1 was detected in our sample after four weeks of therapy, but no clear correlation with BP was found. These results seem to argue against a pivotal role of ET-1 in the observed increase of BP in TKI-sensitive patients, but could be better interpreted in light of the above-mentioned reduced functional “reserve” of NO. That is, even if ET-1 increases in all of the patients, the effects on BP occurs preferentially in patients with an impaired reserve of NO. ET-1 is a potent vasoconstrictor that is produced by the endothelium in response to various stimuli, which is also associated with renal damage and cardiovascular remodeling. The ET-1 system was found to be activated in sunitinib-treated rats ; its cauRenal injury and proteinuria induced by antiangiogenic TKI has also been proposed as a potential explanation for the onset of hypertension . In a stHypertension itself has also been associated with proteinuria; however, proteinuria in hypertension usually develops slowly, and it is difficult to postulate that the rapid increase in BP after the antiangiogenic drugs could be the cause of proteinuria. In light of these considerations, although a direct role cannot be excluded, we hypothesized that proteinuria could be an epiphenomenon of TKI-induced endothelial dysfunction, which is a process that could explain both situations.Regarding the effects on microcirculatory patterns induced by anti-VEGF TKI, an increasing number of participants developed a clinical and demonstrable change in microvessels at periungual capillaroscopy, especially in terms of tortuosity, reduction in vascular diameter, and architectural disorder, but without a clear decrease in capillary density. In fact, capillary rarefaction has been demonstrated in the oral mucosa of sunitinib and telatinib-treated patients ,30; its Despite differences in the basal nitrates between hypertensive and stable subjects, our data about endothelial function when measured non-invasively by the FMD technique were not different according to the BP rise both at baseline and at different study time points. It is not clear why endothelial function was apparently not modified in line with urinary nitrates, but it should be emphasized that FMD depends 30–50% on the release of NO by the endothelium ,32, and Finally, we did not find a significant difference in the local distensibility of the carotid artery by ultrasound measurement between the different time points and the two subgroups. Thus, the hypothesis of a role of anti-VEGF drugs serving as co-factors in determining hypertension through an increase of arterial stiffness , at leasOur study has several limitations, including the small sample size and the difficulty in interpreting functional data following the use of antihypertensive medications. Furthermore, different anti-VEGF drugs were used in different lines of therapy and in various histological types of renal cancers, and this could have affected some measurement. However, it still provides important insights into the possible interpretation and the mechanisms involved in the BP rise that occur after the initiation of TKI therapy, indicating a pivotal role for NO in the endothelin system.In conclusion, in a group of patients with renal cell carcinoma, we have shown that the effects of antiangiogenic TKI on BP are detectable in nearly 50% of cases, and that urinary proteins and p-ET-1 rise in almost all patients in less than one month. The TKI-sensitive patients had lower urine nitrates than TKI-insensitive patients at baseline, but no specific correlation was detectable between BP values and u-nitrates or all of the other tested factors. We observed changes in some endothelial-related factors, such as u-nitrates, p-ET-1, and proteinuria along with BP. This result suggests that the endothelium is the main culprit of these conditions, further indicating that factors or drugs that restore NO and other factors could be potentially useful to treat or prevent increases in BP. Further studies are needed to produce a better understanding of the relationships between all these factors, and determine whether some endothelial markers, such as u-nitrates, can be potentially useful for screening, as well as which can provide the best antihypertensive therapy for this condition.


Hypertension is a highly prevalent disease and the leading cause of chronic kidney disease (CKD). Metabolic syndrome could also be the risk factor for CKD. We sought to study the association between metabolic syndrome components and the prevalence of CKD in patients with hypertension.We carried out a multi-center cross-sectional study from Apr. 2017- Apr. 2018 in 15 cities in China.p < 0.01), elevated fasting blood glucose (FBG)  and hypertension grades  were associated with the prevalence of CKD. In sub-group analysis, elevated TG remained strongly associated with CKD in both diabetes  and non-diabetes . In sub-group analysis of hypertension grades, there was also a graded trend between elevated TG and CKD from controlled blood pressure (BP) to hypertension grade 2 .A total of 2484 patients with hypertension were enrolled. Among them, 56% were male and the average age was 65.12 ± 12.71 years. The systolic BP/diastolic BP was 142 ± 18/83 ± 12 mmHg. Metabolic syndrome components turned out to be highly prevalent in patients with hypertension, ranging from 40 to 58%. The prevalence of chronic kidney disease reached 22.0%. Multi-variate logistic analysis revealed that elevated triglyceride (TG) (OR = 1.81, 95% CI 1.28–2.57, Elevated TG, elevated FBG and hypertension grades were significantly associated with the prevalence of CKD in patients with hypertension. Particularly, elevated TG was strongly associated with CKD, independent of diabetes and hypertension grades. Hypertension is highly prevalent worldwide. It has been reported that 31.1% (95%CI 30.0–32.2%) of the world’s adults have hypertension. However, the awareness, treatment and control rate are far from satisfying. Data from different countries showed that the awareness of hypertension ranged from 37.9–67%, treatment rate ranged from 29.0–55.6% and the control rate ranged only from 7.7–28.4% [We carried out a multi-center cross-sectional study from Apr. 2017-Apr. 2018 in the main 15 cities in China. Participants were enrolled from hypertension clinic using convenience sampling. Inclusion criteria were patients with primary hypertension, aged over 18 years, who could provide informed consents. Patients were excluded if they had secondary hypertension, genetic renal diseases, active cancer or recognition disorder. Each patient completed a questionnaire collecting information on demographic characteristics, medical history, lifestyle features, current medical treatment, physical examination and lab tests.According to American Heart Association, the diagnosis of metabolic syndrome includes any 3 of the 5 criteria: 1) Elevated waist circumference > =90 cm in men and > =80 cm in women (for Asian); 2) Elevated triglycerides (TG) > =1.7 mmol/L; 3) Reduced HDL-C < 1.03 mmol/L in men or < 1.3 mmol/L in women; 4) Elevated blood pressure > =130/85 mmHg or on antihypertensive drug treatment with a history of hypertension; 5) Elevated fasting blood glucose (FBG) > =5.6 mmol/L or on drug treatment for elevated glucose [As is listed above, in our study, elevated waist circumference was defined as waist circumference > =90 cm in men and > =80 cm in women; elevated TG was defined as TG > =1.7 mmol/L; reduced HDL-C was defined as HDL-C < 1.03 mmol/L in men or < 1.3 mmol/L in women; elevated FBG was defined as FBG > =5.6 mmol/L or on drug treatment for elevated glucose.Hypertension grades was defined according to 2013 ESC/ESH Guidelines for the management of arterial hypertension  . Contro2, while eGFR was calculated using Modification of Diet in Renal Disease Study equation [CKD was defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73mBaseline characteristics were analyzed and compared in patients with and without CKD. Either two-side Student’s t-test or Wilcoxon rank sum test were used for continuous variables. Chi-square test was used for categorical variables. A forward stepwise method was used to reach the logistic regression model. Odds Ratios (OR) and 95% confidence intervals from logistic regression were used to estimate the association between metabolic syndrome components and CKD. Sub-group analysis was conducted according to concomitant diabetes and hypertension grades. P < =0.05 was considered statistically significant. STATA 13.0 was used for statistical analysis.In the 2484 patients with hypertension, the average age was 65.12 ± 12.71 years. Male accounted for 55.9% of the total participants. The average BP was 142.30 ± 17.68 / 83.01 ± 11.93 mmHg. The distribution of hypertension grade was 41.6, 36.9, 14.9 and 6.7% separately. Totally 90.7% of them were taking antihypertensive therapy.Metabolic syndrome turned out to be highly prevalent. Patients with elevated TG, reduced HDL-C, elevated FBG and elevated waist circumference were 46.9, 40.1, 58.3 and 47.5% separately. Besides, 24.7% of them had diabetes and 24.2% of them were taking antidiabetic therapy. Additionally, 60.3% were using statins and 0.8% were using fibrates.The prevalence of chronic kidney disease was also high, reaching 22.0% of the total participants Table .Table 1p < 0.01). Among them, 57.9% were male in non-CKD group and 49.0% were male in CKD group (p < 0.01). No difference was found in the distribution of hypertension grades (p = 0.16) and antihypertensive therapy (p = 0.99) between the two groups. The ratio of elevated TG, reduced HDL and elevated FBG were 45.2,39.5 and 56.6% in non-CKD group compared to 54.1% (p = 0.01), 42.5% (p = 0.35) and 66.1% (p = 0.01) in CKD group. The elevated waist circumference was 45.7% in the non-CKD group compared to 54.0% in the CKD group (p < 0.01). The prevalence of DM was 23.7% in non-CKD group compared to 28.3% in CKD group (p = 0.03). Totally 22.8% of the patients in non-CKD group were taking antidiabetic therapy compared to 29.2% in CKD group (p < 0.01). Additionally, 58.2% patients were using statins in non-CKD group compared to 67.1% in CKD group (p < 0.01) (Table We compared the characteristics of patients with and without CKD. The average age was 64.3 ± 12.5 years in non-CKD group and 68.09 ± 12.94 years in CKD group (p = 0.05), elevated TG  and elevated FBG .The association between metabolic syndrome components and prevalence of CKD were explored Table . UnadjusAs diabetes plays a key role in the development of CKD, we also carried out sub-group analysis investigating whether metabolic syndrome components would still be associated with CKD in patients either with or without diabetes.p = 0.03). However, such association was not found in non-diabetes patients .The association between hypertension grades and CKD remained strongly significant in both unadjusted and multivariate adjusted models in diabetes patients , but also in patients without diabetes .Elevated TG was always independently associated with CKD, not only in patients with diabetes  or without diabetes .Reduced HDL-C was not associated with CKD in patients either with diabetes   or without diabetes , grade 1  to grade 2 . While only in hypertension grade 3, elevated TG was not associated with CKD   in the US, participants with metabolic syndrome had increased odds for chronic kidney disease compared to those without metabolic syndrome [ated FBG . In a reated FBG .Except that hypertension and diabetes have long been documented to be the major risks for the progression of CKD, elevated TG was found in our study to be associated with CKD, particularly independent of diabetes and hypertension grades. The mechanism of how the lipid level affect the injury of renal function was still incompletely understood. There are several mechanic pathways involved, including atherosclerosis, oxidative stress, chronic inflammation, hemodynamic change and endothelial dysfunction. For patients with dyslipidemia, specifically high TG, direct stimulation of glomerulosclerosis may be the key mechanism . In factTG has been strongly debated to be a causal factor driving atherosclerosis . There aThe main weakness of our study was the relatively small sample size with convenience sampling, by which the possibility of bias might exist. In addition, since it was a cross-sectional study rather than a causal design, it was difficult to tell the causal relationship between metabolic syndrome components and CKD. We could only conclude that there was a strong independent association between them.However, the strength of the study was that it was a multicenter cross-sectional study collecting data from all over the country, which made it possible for the conclusion to be generalized to all the patients with hypertension in China. Second, to our knowledge, this was the first study to evaluate the risk of CKD in patients with hypertension and other metabolic syndrome components. The importance of metabolic syndrome management in patients with hypertension should be further emphasized. Last, more attention should be focused on TG during risk management in order to prevent CKD and further research into the mechanism behind is needed.In our cross-sectional study of patients with hypertension, elevated TG, elevated FBG and hypertension grades were independently associated with the prevalence of CKD. Particularly, elevated TG was strongly associated with CKD, independent of diabetes and hypertension grades. Thus, among all the metabolic syndrome components, TG should also be concerned during the risk management of hypertension.Additional file 1. The ethics approval.Additional file 2. The patients' consent.


To compare the value of functional future liver remnant (functFLR) to established clinical and imaging variables in prediction of post-hepatectomy liver failure (PHLF) after major liver resection.This retrospective, cross-sectional study included 62 patients, who underwent gadoxetic acid enhanced MRI and MDCT within 10 weeks prior to resection of ≥ 4 liver segments. Future liver remnant (FLR) was measured in MDCT using semi-automatic software. Relative liver enhancement for each FLR segment was calculated as the ratio of signal intensity of parenchyma before and 20 min after i.v. administration of gadoxetic acid and given as mean (remnantRLE). Established variables included indocyanine green clearance, FLR, proportion of FLR, weight-adapted FLR and remnantRLE. functFLR was calculated as FLR multiplied by remnantRLE and divided by patient’s weight. The association of measured variables and PHLF was tested with univariate and multivariate logistic regression analysis and receiver operator characteristics (ROC) curves compared with the DeLong method.p = 0.015), proportion of FLR (p = 0.004), weight-adapted FLR (p = 0.003), remnantRLE (p = 0.002) and functFLR (p = 0.002) to be significantly related to the probability of PHLF. In multivariate logistic regression analysis, a decreased functFLR was independently associated with the probability of PHLF . Comparing ROC curves, functFLR showed a significantly higher area under the curve  than established variables.Sixteen patients (25.8%) experienced PHLF. Univariate logistic regression identified FLR (functFLR seems to be superior to established variables in prediction of PHLF after major liver resection.• functFLR is a parameter combining volumetric and functional imaging information, derived from MDCT and gadoxetic acid enhanced MRI.• In comparison to other established methods, functFLR is superior in prediction of post-hepatectomy liver failure.• functFLR could help to improve patient selection prior major hepatic surgery. The vailable . From a vailable –9. Previvailable –14.On the basis of these observations, we hypothesised that the combination of FLR volume and RLE on gadoxetic acid enhanced MRI , adapted to a patient’s weight, might provide a more specific estimation of the FLR’s functional reserve. The aim of the present study was to benchmark this imaging biomarker against established clinical and imaging variables for the prediction of PHLF in a population that was undergoing major liver resection.This was a single-centre, retrospective, cross-sectional study that was approved by the local institutional review board (No.1136/2017), which waived the need to obtain written, informed consent for data analysis. All patients who underwent pretreatment with gadoxetic acid  enhanced 3-Tesla MRI and MDCT within 10 weeks prior to major liver surgery (i.e. at least four Couinaud liver segments), between January 2007 and December 2016, were eligible for analysis.n = 5) and portal vein embolisation (n = 39)); (2) signs of post-hepatic biliary obstruction (n = 19); (3) atypical resections or intraoperative ablation in the FLR (n = 17); (4) previous liver resections or hepaticojejunostomies (n = 5) and (5) MR imaging artefacts (n = 2). In addition, we had to exclude one patient who suffered from an iatrogenic portal vein injury with subsequent occlusion and liver failure  treatment between imaging and liver resection  or 5 mm/4 mm (n = 7).All MDCT examinations were performed within our hospital. The minimum requirements for the imaging protocol included the following: (1) MDCT scanner with a patient size-adapted tube voltage 80–120 kVp); (2) active tube current modulation and (3) i.v. injection of 70–120 ml (depending on the body weight) of iodinated contrast agents (300–400 mg/ml iodine concentration) at a flow rate of 4–5 ml/s, followed by a saline flush of 20 ml using a power injector. Liver volumetry . All preoperative assessed liver volume measurements were blinded to the reader.The syngo.CT liver analysis software  was used in a semi-automatic workflow for the following steps: loading and assignment of the unenhanced, arterial and venous phases ; automatic liver border segmentation with the option of manual correction was performed by the software for the venous phase only; automatic exclusion of the main portal vein, the hepatic venous confluence and the retrohepatic inferior vena cava from volume calculation. Focal liver lesions were marked by the reader, semi-automatically segmented and consecutively excluded from further volume analysis. The liver resection plane was determined on the basis of postoperative imaging studies or, if not available, on surgical reports of the particular patient  equipped with a phased-array coil  and a spine coil . Among others, the MR imaging protocol included unenhanced and enhanced fat-saturated T1-weighted sequences. These were conventional, three-dimensional, T1-weighted, spoiled gradient-echo volumetric interpolated breath-hold sequences with spectrally adiabatic inversion recovery fat saturation  in the transversal plane . Parallel imaging with an acceleration factor of 2 was used. The field of view was 350–400 × 350 mm for all transverse sequences, with individual adjustments depending on patient size. The enhanced T1-weighted sequences were performed after intravenous administration of 0.025 mmol/kg gadoxetic acid, using a power injector at a rate of 1.0 ml/s, and followed by a 20-ml saline flush with a bolus-tracking system. The hepatobiliary phase was performed 20 min after contrast injection .2) in the middle of each Couinaud liver segment of the FLR, avoiding vessels, focal liver lesions and artefacts on the unenhanced and the hepatobiliary phase images  was generated and used for further analysis.MRI scans were retrospectively evaluated by a board-certified radiologist with 9 years of experience in abdominal imaging (R.N.), who was blinded to all clinical data. Images were reviewed on an IMPAX EE workstation . The signal intensity of the liver parenchyma was measured by manually placing a circular region of interest area 2.0 cm.0 cm2 inEstablished clinical parameters  were derived from indocyanine green (ICG) clearance testing, as described previously . ImagingLiver resection was performed or assisted by visceral surgeons with more than 10 years of experience in hepatobiliary surgery (K.K. and others), as described previously , using ex2 test, and the Fisher exact test as appropriate. Continuous variables were described as medians and interquartile ranges (IQRs). Possible differences in continuous variables between groups were tested by the Wilcoxon test, the t test or the Kruskal–Wallis test, as appropriate. The association between established clinical and imaging variables and functFLR with outcome (presence of liver failure), defined as the reference variable, was tested by using logistic regression analysis with the calculation of odds ratios with 95% confidence intervals. Multivariate logistic regression analysis was conducted by using a stepwise selection of parameters, with a limit of p = 0.1 to enter and to stay in the model. The association of continuous variables was tested in a general linear model. In addition, the diagnostic ability of measured variables was described by using areas under the receiver operator characteristic (ROC) curves. The areas under the dependent ROC curves were compared according to the DeLong method [P values are given as calculated and should be interpreted with care, considering alpha error accumulation. Cut-off values were defined with the Youden J statistics. Odds ratios were calculated to assess the association between the defined cut-off value and the presence of PHLF. Results were regarded as statistically significant if the probability of a type 1 error was less than 5% (p < 0.05). Statistical analyses were performed using SPSS for Windows  and MedCalc 12 .Discrete variables were described with absolute and relative numbers and by using contingency tables; possible differences in discrete variables between groups were tested with the g method . No formA total of 62 patients  with a median age of 59.8 (IQR 53.3–67.9) years were analysed. The median time from MRI and MDCT to liver resection was 0.4 (IQR 0.1–3.1) weeks and 3.6 (IQR 0.3–8.3) weeks, respectively. Detailed demographic and clinical data about the study population are given in Tables The median values of variables that predict PHLF are given in Table p = 0.002). PDR, MDCT variables and remnantRLE also entered the model, but were rejected during stepwise selection. Comparing ROC curves, functFLR demonstrated a significantly higher area under the curve of 0.904  than all other established variables . The only patient with grade C liver failure showed a preoperative functFLR of 6.59 ml/kg.Median functFLR of patients without evidence of liver failure was 12.93 (IQR 8.69–22.2) ml/kg compared to 6.29 (IQR 5.20–7.50) ml/kg in patients with grade A liver failure and 6.34 (IQR 3.78–8.28) ml/kg in patients with grade B liver failure  patients with a functFLR below the applied threshold and only one (2.8%) patient over the applied threshold, resulting in a sensitivity and specificity of 94% and 76%, respectively. The odds ratio for developing a PHLF was 47.7 (95% CI 5.7–403.5) higher in patients with a functFLR less than 8.73 ml/kg compared to a functFLR greater than 8.73 ml/kg.By means of functFLR and weight-adapted FLR, Youden’s During a median hospital stay of 11 (IQR 8–13.5) days, there were no deaths in our collective, resulting in an in-hospital mortality rate of 0%. Postoperative complications occurred in 24 (38.7%) patients. Using the Clavien–Dindo classification , we rateThe present study demonstrated that the functFLR may provide a more accurate prediction of PHLF in comparison to ICG clearance, different established volumetric analyses, as well as the RLE in a population undergoing major hepatic resection. In multivariate analysis the functFLR was independently associated with a higher probability of PHLF and its area under the ROC curve was significantly higher than for the other established clinical and imaging parameters.Currently, FLR volumetry is the method of choice for risk stratification in postoperative liver failure. Some authors have attempted to specify the demand of the FLR by calculating body surface area or body weight –25. In tVarious studies have shown that gadoxetic acid uptake reflects liver function , 31, 32.Itoh et al. assessed the functional liver remnant by MDCT volumetry—normalised to the body surface area—and the liver enhancement in gadoxetic acid enhanced MRI . CompareThe favoured cut-off value for the FLR is given with a weight-adapted FLR (i.e. FLR to body weight ratio) of at most 0.5% (i.e. 5 ml/kg), with a sensitivity and specificity of 100% and 84.1% for the prediction of death from PHLF . In our In contrast to the common definition of major hepatectomy (at least three Couinaud liver segments), we included only patients with resection of at least four liver segments, since these patients present a higher risk of PHLF. The incidence of PHLF, at about 26%, is higher than the described 0.7–9.1% in the literature , as mostThe major limitation of our study was its retrospective design. Second, compared to other studies , our colA decreased functFLR is independently associated with a higher risk of liver failure after major liver resection. Compared to established preoperative methods, the functFLR seems to be more accurate in the prediction of PHLF. This combination of volumetric and functional information could help to optimise preoperative patient selection.


Renal denervation (RDN) is a catheter-based ablation procedure designed to treat resistant hypertension (RH). The objective of our study is to determine the effect of RDN on blood pressure and renal function in patients with RH in comparison to medical therapy alone. We performed an extensive literature search for randomized control trials (RCT) reporting office and 24 hr. blood pressure changes and estimated glomerular filtration rate (eGFR) at baseline and 6 months. We calculated a weighted standardized mean difference of blood pressure and renal outcomes between RDN and control groups using random effects models. Our search yielded 608 studies of which we included 15 studies for the final analysis. A total of 857 patients were treated with RDN and 616 patients treated with medical therapy ± sham procedure. Only 5 studies were double-blinded RCT with sham control. The adjusted standardized mean difference in the change in office based systolic and diastolic pressures ; 24 hr. systolic and diastolic pressures ; and eGFR (p = 0.20) from baseline to 6 months is statistically insignificant with significant heterogeneity. Subgroup analysis showed that among sham controlled trials, 24 hr. systolic blood pressure showed a modest but statistically significant benefit favoring renal denervation in patients with RH. Our meta-analysis of 15 RCTs showed no significant benefit of RDN on blood pressure control in patients with resistant hypertension. Subgroup analysis of sham control studies showed a modest benefit in 24 hr. systolic blood pressure at 6 months with RDN. The prevalence of RH based on recent studies is ranging from as low as 12.8%2, while others have shown RH to be up to 25–30% in the general hypertensive population3. A 2012 study by Dougherty et al. showed the incidence of resistant hypertension to be 1.9% within 1.5 years of newly diagnosed hypertensive patients undergoing treatment4.Resistant hypertension (RH) is defined as blood pressure that remains above guideline-directed goal despite the concurrent use of at least three antihypertensive agents of different classes, one of which is a diuretic5. Since then, there have been numerous studies and randomized control trials to evaluate the effectiveness of this procedure in treating RH with variable results.When hypertension remains uncontrolled with lifestyle changes and antihypertensive medications, renal denervation has been a proposed intervention to aid in the treatment of RH since it was first used a decade agoet al. did not show any significant effect on blood pressure in patients with RH following renal denervation6. Over the past year, multiple randomized control trials evaluating the effect of renal denervation on RH showed promising results including: WAVE-IV7, SPYRAL HTN-ON MED8, INSPiRED9, and a Polish study by Warchol-Celinska et al.10 We, therefore, conducted a systematic review and meta-analysis based on randomized control trials to assess the efficacy of renal denervation in patients with RH at 6 months in comparison to medical therapy alone ± sham procedure.One of the most recent meta-analysis w by Fadl Elmula 13, while the remaining 10 trials were open-label clinical trials with a control group treated with optimal medical therapy21. Radiofrequency (RF) ablation was performed in all trials except the WAVE-IV7, where ultrasound energy based (US) ablation was performed. Only 13 studies reported a mean change in office based systolic and diastolic blood pressures, and 14 studies reported a mean change in 24 hr. systolic and diastolic blood pressure between baseline and 6 months post-randomization. Only 11 studies reported a change in estimated glomerular filtration rate (eGFR) between baseline and 6 months post-randomization in the treatment and control groups. The baseline characteristics of the included studies are included in Table et al.10 which was a low-quality study  at 6 months in the RDN group was −1.7 ± 11.75 vs −2.39 ± 11.67 in the control group.The change in blood pressure (24 hr. and office) at 6 months and renal function in patients in the renal denervation (RDN) and the control group for each study is listed in Supplementary Table 2 = 87.5%). The results are summarized in Fig. The adjusted standardized mean difference in the change in systolic blood pressure (office) at 6 months between RDN and control groups was −0.24  −0.60–0.11, p = 0.18) which is statistically insignificant. Subgroup analysis showed no statistical significance in both the sham controlled (p = 0.81) and non-sham controlled studies (p = 0.20). There was a high degree of heterogeneity noted among the studies (I2 = 85.8%). The results are summarized in Fig. The adjusted standardized mean difference in the change in systolic blood pressure (24 hr.) at 6 months between RDN and control groups was −0.22 , which was statistically insignificant. However, subgroup analysis among sham control studies showed statistical significance favoring renal denervation (p = 0.02). A high degree of heterogeneity was noted among the studies included in the main analysis (I2 = 92.3%), which likely accounted for the lack of difference noted between both groups. The results are summarized in Fig. The adjusted standardized mean difference in the change in diastolic blood pressure (office) at 6 months between RDN and control groups was −0.34  which was not statistically significant. Subgroup analysis showed no difference in both the sham controlled (p = 0.52) and non-sham controlled studies (p = 0.16). There was a high degree of heterogeneity noted among the studies (I2 = 79.6%). The sham control studies showed no heterogeneity (I2 = 0%), however, the result remained unchanged. The results are summarized in Fig. The adjusted standardized mean difference in the change in diastolic blood pressure (24 hr.) at 6 months between RDN and control groups was −0.19  which was not statistically significant. Subgroup analysis showed no statistical significance in both the sham controlled (p = 0.10) and non-sham controlled studies (p = 0.18). There was a high degree of heterogeneity noted among the studies (I2 = 32.9%). The results are summarized in Fig. The adjusted standardized mean difference in the change in eGFR at 6 months between RDN and control groups was 0.11  which was statistically insignificant. Subgroup analysis showed no statistical significance in both the sham controlled (p = 0.69) and non-sham controlled studies (p = 0.07). There was a low degree of heterogeneity noted among the studies  was performed in 2010, operators have become more proficient with the procedure leading to better outcomes. This also explains the heterogeneity of the results among the trials. With the exception of the change in 24 hr. systolic blood pressure, subgroup analysis (Sham vs No sham) and meta-regression analysis did not change the significance of blood pressure and renal function outcomes between RDN and control groups. The discrepancies observed between changes in 24 hr. blood pressure and office blood pressure between the two groups could be explained by “regression to the mean” effect, which occurs as a result of using specified office blood pressure thresholds while enrolling patients in these trials25. Sham control studies allow accounting for potential confounding factors including “regression to the mean effect”, the placebo effect of the procedure and improved medication adherence after renal denervation.Significant heterogeneity was observed when all the included studies were analyzed together. The differences in blood pressure changes could in part be explained by differences in study design, type of control group and type of RDN procedure performed. It is widely believed that the experience of an operator plays a major role in the success of the procedure. In the initial trials, patients were enrolled from centers with very low operator volume which probably affected the success of the procedure. However over a period of time, since the first trial  Placebo effect in patients who underwent sham controlled procedures. (2) Improvement in adherence to medications as all the patients in the trials was monitored using medication adherence tools such as witnessed medication intake, maintenance of diary, assessment of plasma drug concentration, etc. and (3) Recruiting patients who weren’t maximized on medical therapy.8 trials showed a significant reduction in blood pressure with RDN. The use of multiple catheter systems could potentially contribute to the heterogeneity noted in our analysis.The Symplicity Catheter system  is commonly used in contemporary practice. However it has several limitations including (1) presence of single electrode leading to longer ablation time, (2) presence of unipolar electrode makes a selection of ablation site challenging and (3) inability to ablate deep renal sympathetic nerve due to low radiofrequency power of the catheter limiting the penetration depth. To overcome these limitations, Symplicity Spyral catheter system  and EnligHTN catheter system  were introduced. They are multi-electrode catheters containing 4 electrodes and can simultaneously ablate 4 locations at the same time. Results from SPYRAL HTN-OFF MED and SPYRAL HTN-ON MED26. The significance was predominantly driven by SPYRAL-HTN-ON MED trial8. The renal denervation procedure (using RF ablation) performed in this trial targeted branch vessels beyond the proximal main renal artery which was unique. Animal studies have shown a greater reduction in renal norepinephrine levels with RF ablation if the distal extra-renal artery branches were targeted27. This hypothesis was further tested by Petrov et al. in a non-randomized study (N = 119) which compared the efficacy of blood pressure reduction comparing conventional renal artery denervation strategy to a novel renal denervation strategy that targets the distal branches of the renal artery in addition to the proximal renal artery. They showed a greater decrease in office and 24 hr. systolic and diastolic blood pressure among the patients who underwent the novel procedure compared to the conventional procedure. This technique of radiofrequency RDN may explain the predominantly greater reduction in blood pressure noted in the RDN group in the SPYRAL-HTN-ON MED trial.The adjusted pooled analysis of the 5 sham controlled studies showed a modest but significant benefit in the mean difference in 24 hr. systolic blood pressure change at 6 months which is contrary to the prior meta-analysis published28 was performed to test head to head comparison between US ablation, conventional RF ablation of main renal arteries and RF ablation of main + side branches of renal arteries. The study showed that significantly higher reduction in ambulatory blood pressure with US ablation compared to conventional RF ablation of main renal arteries. However, no difference in blood pressure reduction was noted between patients who underwent US ablation compared to patients who underwent RF ablation of main and side branches of renal arteries. This further explains the degree of heterogeneity noted in our analysis.RADIOSOUND-HTN trial17 or plasma drug concentration20 for a total of 344 patients . The remaining 11 studies assessed medication adherence using compliance diary or validated questionnaires. Medication non-adherence is noted among 50% of hypertensive patients and its prevalence increases especially in patients with RH. Accurate assessment of medication non-adherence is difficult given the invasive nature of the tests and incorporation into routine practice remains a challenge given the tests are cost-intensive.A predominant confounder in randomized control trials evaluating the efficacy of a novel therapy is the medication adherence among study participants. In this instance, if the medication adherence significantly improves after the patient undergoes renal denervation; the true effect of the procedure would be difficult to estimate. Among the 15 included studies, only four studies used robust methods to assess medication adherence using witnessed medication intake29. The positive results noted in the newer trials did not affect the overall result of the meta-analysis.We have also shown that patients who underwent RDN had no significant changes in renal function (eGFR) compared to the medical therapy group at 6 months post-renal denervation, supporting the safety profile of the procedure. Our findings are consistent with prior published studiesThe meta-analysis reported here combines data across studies in order to estimate treatment effects with more precision than is possible in a single study. Limitations include incorporating studies with different control arms and designs to increase the study population and maximizing the likelihood of estimating a treatment effect. However, the results of the subgroup analyses would be considered more meaningful given the lower heterogeneity. This specifically applies to the pooled analysis of 5 studies which showed a modest improvement in 24 systolic blood pressures with renal denervation. Publication bias might account for some of the effects we observed. Smaller trials are, in general, analyzed with less methodological rigor than larger studies, and an asymmetrical funnel plot suggests that selective reporting may have led to an overestimation of effect sizes in small trials. The lack of individual participant level data for meta-analysis and subgroup analysis is a limitation of our study. Given the nature of meta-analysis, the inherent weakness of the individual studies will be inherited in our study. The variability of expertise among all the physicians performing renal denervation could potentially affect the outcome of the procedure, thereby the overall outcome of the individual trials.An extensive electronic search of Embase, Scopus, Web of Science, PubMed, and manual review of the literature was performed for relevant articles using the following search terms: “renal denervation”, “renal sympathetic denervation”, and “resistant hypertension”. The search was restricted to publications in English and the final search was performed till from Jan 2008 to June 2018 (Supplementary data).30.Studies were included if they satisfied the following criteria: (1) Age of the study population >18 yrs.; (2) Original randomized control trials comparing renal denervation with medical therapy ± sham procedure, (3) Published a detailed study protocol, (4) Follow-up duration of ≥6months, (5) Patient population diagnosed with resistant hypertension on ≥3 blood pressure medications, (6) Reported estimated glomerular filtration rate (eGFR), average office or ambulatory systolic and diastolic blood pressure at baseline and 6 months following intervention, and (7) Reported characteristics of the overall study population. Studies were excluded in case of partial/complete overlap of the study population with a study already included in the analysis and also in cases of incomplete or incorrect reporting of data. All eligible studies complied with Consolidated Standards of Reporting Trials (CONSORT) quality criteria31. When both intention to treat and per protocol outcomes were reported by the authors, we only considered intention to treat values for our analysis. We directly contacted the authors when additional information was missing from the initial studies.The initial search was performed by two reviewers , and studies were selected for inclusion by mutual consensus. In case of disagreement, a third reviewer (RA) resolved disagreements through discussion to achieve a consensus. Once the studies were selected for inclusion, the data were screened to meet the inclusion criteria and thereafter the following data points were extracted: number of anti-hypertensive medications, class of anti-hypertensive medications used, eGFR, average office or ambulatory systolic and diastolic blood pressure at baseline and 6 months following the intervention. Additionally, cumulative demographic and baseline characteristics of the patient population included in the study were also extracted. The quality of included studies was assessed using the Jadad scale for randomized control trials2 statistic value greater than 50%. Publication bias was visually assessed using Deek’s funnel plot followed by a trim-and-fill procedure. The Deek’s funnel plot utilizes regression of diagnostic log odd’s ratio against 1/square root (effective sample size) and further weighting by effective sample size. A p-value of the slope coefficient of <0.10 indicated asymmetry and thereby publication bias. The significance of asymmetry in the funnel plot will be assessed using Eggers test and a trim-and-fill test will be performed if applicable to correct asymmetry33. We performed a sensitivity analysis by type of control arm (sham vs no sham controlled).Continuous variables are presented as mean and standard deviation and categorical data as percentages. The aim of our analysis was to assess the change in blood pressure (24 hr. and office measured) and renal function in patients who underwent renal denervation in comparison to patients on optimal medical therapy. We calculated an unadjusted pooled change in eGFR, office and 24 hr. blood pressure in both renal denervation and control groups. We calculated a weighted standardized mean difference among outcomes between the renal denervation group and control group with random effects models (DerSimonian and Laird). Statistical heterogeneity was defined as I34. All the above analyses were performed in R, version 3.4.3, using “mada” package.Meta-regression analysis was performed to identify potential sources of heterogeneity. We performed meta-regression for covariates including sample size (less or more than 100), region of study, year of publication, quality of study, sham vs no sham controlled, age, gender, body mass index, proportion of patients with hypertension, coronary artery disease and diabetes mellitus to identify potential sources of heterogeneity. This meta-analysis was performed in compliance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelinesOur meta-analysis of 15 randomized control trials showed no significant benefit of renal denervation on blood pressure control in patients with resistant hypertension. Subgroup analysis of sham control studies showed a modest benefit in 24 hr. systolic blood pressure at 6 months with renal denervation. Our analysis substantiates the safety profile of the procedure o based on renal function at 6 months post procedure. Given the evidence of procedure-related factors, objective assessment of drug adherence, novel renal denervation techniques, and sham control study design affects the overall study outcomes; future clinical trials must account for these variances in order to better assess the effectiveness of renal denervation in patients with RH. Furthermore, the type of ablation therapy used and target sites for ablation  must be explored in future trials. Based on the current evidence, patients with resistant hypertension and no identifiable secondary cause , maximized on lifestyle interventions and medical therapy by a hypertension specialist may benefit from renal denervation with an experienced operator.Supplementary Data