Acute respiratory distress syndrome (ARDS), a complex response to various insults, has a high mortality rate. As pulmonary edema resulting from increased vascular permeability is a hallmark of ARDS, management of the fluid status, including the urine output (UO) and fluid intake (FI), is essential. However, the relationships between UO, FI, and mortality in ARDS remain unclear. This retrospective study aimed to investigate the interactive associations among UO, FI, and mortality in ARDS.This was a secondary analysis of a prospective randomized controlled trial performed at 10 centers within the ARDS Network of the National Heart, Lung, and Blood Institute research network. The total UO and FI volumes within the 24-h period preceding the trial, the UO to FI ratio (UO/FI), demographic data, biochemical measurements, and other variables from 835 patients with ARDS, 539 survivors, and 296 non-survivors, were analyzed. The associations among UO, FI, the UO/FI, and mortality were assessed using a multivariable logistic regression.P = 0.002) and as a quartile variable . To explore the interaction between UO and FI, the UO/FI was calculated, and a cut-off value of 0.5 was detected for the association with mortality. For patients with a UO/FI ≤0.5, an increased UO/FI was significantly associated with decreased mortality ; this association was not significant for patients with UO/FI ratios > 0.5 . A significant interaction was observed between UO and the UO/FI. The association between UO and mortality was significant in the subgroup with a UO/FI ≤0.5 , but not in the subgroup with a UO/FI > 0.5.In all 835 patients, an increased UO was significantly associated with decreased mortality when used as a continuous variable (odds ratio [OR]: 0.98, 95% confidence interval [CI]: 0.98–0.99, The association between UO and mortality was mediated by the UO/FI status, as only patients with low UO/FI ratios benefitted from a higher UO. Acute respiratory distress syndrome (ARDS) is a complex response to pulmonary and non-pulmonary insults. This condition, which presents as severe hypoxemia and bilateral pulmonary infiltration, is associated with mortality rates of 30–40% , 2. As pAggressive fluid resuscitation plays an important role in avoiding additional hemodynamic insults and maintaining adequate organ perfusion. However, considerable evidence indicates that a positive fluid balance (FB) may cause the extravasation of protein-rich fluids into the interstitial space and is strongly associated with poor outcomes in patients with ARDS –6. HowevTwo intervenable parameters in fluid management, the fluid intake (FI)  and urinFurthermore, the UO volume may be easily affected by the FI volume. Therefore, a simple evaluation of the association between UO and mortality that does not adjust for FI may be inappropriate. Here, we created a new index (UO/FI ratio) to reflect the dynamic fluid status and performed this secondary analysis to investigate the interactive associations among UO, FI, and mortality in patients with ARDS.https://biolincc.nhlbi.nih.gov) by the ARDS Network. The re-use of these data for a retrospective study was approved by the institutional review board at each center and by BioLINCC, and the need for consent was waived.This was a secondary analysis of a prospective RCT that was performed in 10 centers within the ARDS Network of the National Heart, Lung, and Blood Institute research network . The oriIn the original study, patients under invasive mechanical ventilation support were screened if they met the following Berlin inclusion criteria : an acutThe total UO and FI volumes within the 24-h period preceding the trial were recorded. Demographic data, including age, weight, height, sex, and ethnicity, and information regarding comorbidities such as diabetes, immunosuppression, and leukemia were collected. Biochemical measurements, including the white blood cell and platelet counts; serum creatinine, albumin, sodium, and bilirubin concentrations; and the plasma glucose concentration were also extracted. Other variables, such as the radiographic acute lung injury score, pneumothorax, and ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, were recorded.In the original study, patients were divided into three categories based on the following endpoints: (1) discharge with unassisted breathing, (2) death before discharge with unassisted breathing or before achieving unassisted breathing for 48 h, and (3) neither of these conditions. The patients’ statuses were checked at intervals of ≤30 days until either condition 1 or 2 was met, with a maximum duration of 180 days. Patients who met condition 2 were reported as non-survivors, whereas those who met condition 1 or 3 were reported as survivors.The UO/FI ratio was calculated to assess the ability to excrete excessive administered fluid. The association between the UO/FI ratio and mortality was evaluated.For most of the extracted variables, the proportion of missing values was < 5%, and these values were replaced by their means or medians. For albumin, the proportion of missing values was > 10%; therefore, this variable was excluded from the analysis. For dichotomous variables (diagnosis such as diabetes), missing values were replaced by default value (zero).Continuous variables are expressed as means ± standard deviations or medians (interquartile ranges) as appropriate. Student’s t-test and the Wilcoxon rank-sum test were used as appropriate. Categorical data are expressed as proportions and were compared using the chi-squared test or Fisher’s exact test.P-values of < 0.10 in the univariate analyses were included in the multivariable analysis. Twelve covariables were identified in this step: UO, low tidal volume intervention, leukemia, solid tumor, immune suppression, body temperature, mean blood pressure, respiratory rate, hematocrit, platelet count, serum bicarbonate, radiographic acute lung injury score, and the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen on day 0. Subsequently, a stepwise backward elimination method was used to remove variables with P-values > 0.05 (serum bicarbonate and immune suppression). Multicollinearity was assessed using the variance inflation factor method, and body temperature, hematocrit, and mean blood pressure were removed as significant variance inflation factors (≥5).A multivariable logistic regression was used for covariate adjustment. The logistic models were built using the stepwise backward method. First, variables with P-value < 0.05 was considered to reflect statistical significance. All statistical analyses were performed using Stata 11.2 .The Lowess smoothing technique was used to explore the crude relationship between the UO/FI ratio and mortality, and a cut-off value was detected. A spline linear logistic regression analysis was performed to evaluate the association between the UO/FI ratio and mortality, using the UO/FI ratio cut-off value. The interaction between UO and the UO/FI ratio was evaluated by adding the interactive item in the logistic model, and a subgroup analysis was conducted. The predictive marginal effects of the UO were estimated for different UO/FI ratios. A two-tailed test was performed, and a P = 0.003) and significantly lower FI volume . The maximum serum creatinine concentration was similar between survivors and non-survivors . The detailed baseline characteristics and comparisons are listed in Table The data of 902 patients were available in the dataset downloaded from BioLINCC. Sixty-seven patients were excluded because of a lack of relevant records. Thus, 539 survivors and 296 non-survivors  were included in the final analysis. The overall mortality rate was 35.4%. Compared to non-survivors, survivors had a significantly higher UO volume within the 24-h period preceding the trial . For interpretation, UO was used as a quartile variable in model 2 (Table P = 0.072) to quartile four  relative to quartile one. The trend of the curve in Fig. A multivariable logistic analysis was used to explore the adjusted association between UO and mortality Table . For maxP <  0.001); however, this association was not significant for UO/FI ratios > 0.5 .The crude relationship between the UO/FI ratio and mortality was explored using the Lowess smoothing technique, as shown in in Fig. P-value for the interaction = 0.044; see table in Additional file P = 0.006), but was not significant in the subgroup with UO/FI ratios > 0.5 . The predictive marginal effects of different UO values  on mortality were also estimated at different UO/FI values (≤0.5 or > 0.5) as shown in Fig. The interaction between UO and the UO/FI ratio was significant when the UO/FI ratio was used as a dummy variable , the association between UO and mortality would not be significant. Further studies are needed to validate our hypothesis and re-evaluate the heterogeneous effects of fluid strategies, such as fluid restriction and diuretic use, in patients with different UO/FI ratios.Our study had several advantages. First, all data were extracted from a rigorously designed multicenter trial, which guaranteed the accuracy of the data. Second, in contrast to previous studies, both UO and FI were used as continuous variables in our study , which maximized the statistical power. Third, to the best of our knowledge, this is the first study to report the UO/FI ratio, which may provide a better reflection of the fluid status than the UO alone. Further studies are needed to validate our findings.Several limitations of our study should also be mentioned. First, we included as many potential confounders as possible, but could not exclude residual confounding bias. For instance, the interactive effects between diuretics and the UO/FI ratio could not be evaluated in this study because the dataset did not include diuretic records. Second, we only analyzed fluid records obtained within the 24-h period preceding the original trials. Therefore, it remains unclear whether the observed association would remain consistent across different time intervals. Third, the original study included only patients under invasive mechanical ventilation support, which restricts the applicability of our findings. Finally, the retrospective nature of the study limited our ability to determine a causal relationship between the UO volume and mortality. For instance, a higher UO volume may be an indicator of better kidney function, rather than a determinant of mortality. Thus, additional investigation is needed to determine whether strategies designed to increase the UO could improve the clinical outcomes of patients with ARDS.In conclusion, in patients with ARDS, an increased UO was associated with decreased mortality. However, this association was influenced by the UO/FI ratio, and was only significant in the subgroup with UO/FI ratios of ≤0.5. Further studies are needed to validate and expand our findings.Additional file 1: Table S1. describing the interaction between UO and UO/FI.


The aim of this study was to assess the prevalence of chronic kidney disease and to identify associated factors of chronic kidney disease among hypertensive patients. A cross-sectional study was conducted among selected 578 hypertensive patients. Data were collected using face to face interviewing questionnaires and from medical chart review. Binary logistic regression analyses were performed and analyzed using SPSS version 23.0.Of the total 578 hypertensive patients the prevalence of chronic kidney disease was found to be 128 (22.1%). Of these hypertensive patients, patients with uncontrolled blood pressure, overweight/obesity, dyslipidemia and diabetic mellitus, 43.3%, 33.7%, 27.3% and 28.2 respectively. After adjustment, the independent variables the significant associated factors of chronic kidney disease among hypertensive patients were age [AOR (95% CI 1.43 (1.07–1.81)], uncontrolled hypertension 4.434 [AOR ], overweight/obese [AOR ], dyslipidemia [AOR (95% CI) 13.749 ], diabetic mellitus [AOR (95% CI) 2.137 ]. In conclusion, the prevalence of chronic kidney disease was considerably high. The major associated factors of chronic kidney disease were age, uncontrolled hypertension, overweight/obese, diabetic mellitus and dyslipidemia. World Health Organization (WHO) report that more than one third 39%) of annual death of Ethiopia population was due to non-communicable disease (NCDs) . High bl9% of annIn Sub Saharan Africa the big alarming is about 32.3% among hypertensive patients have CKD .Investigating the associated factors of CKD among hypertension is very important for prevention and control of CKD. Ethiopia was signed to achieve sustainable development goal (SDG) from 2016 to 2030 and to reduce by one third premature death from non-communicable diseases . HoweverA cross-sectional study was conducted in Tigray teaching hospitals from February to April, 2018. The data were collected using face to face interviewing questionnaire and from patients’ medical charts that was recorded from January 1, 2013 to December 30, 2018.All adult hypertensive patients who had hypertension on follow-up care at Tigray teaching hospitals, who met the inclusion criteria were included in the study. The inclusion criteria were hypertensive patients aged 18 years and above, who had regular follow-up in the cardiac clinic. Five hundred seventy eight patients met the inclusion criteria and were included in this study. A questionnaire and checklist was used to collect the data.2 in January 2013 (this is a baseline assessment) were identified and selected for this study.All adult hypertensive patients who had treatment follow-up of hypertension at teaching hospitals. Adults aged 18 years or older with hypertension and with e-GFR ≥ 60 mL/min/1.73 m2 were excluded.Hypertensive clients who were pregnant women during the study period and client who had develop the outcome of interest before or at the beginning of follow-up start. Patients with e-GFR < 60 mL/min/1.73 mA consecutive sampling technique was employed, and every patient was included in the study.Data was collected using a semi-structured face to face interviewing questionnaire and patients chart review. The questionnaire had two subparts, namely socio-demographic and clinical characteristic. Te questionnaire was initially prepared in English then translated into the local language (Tigrigna) by an individual who has good ability of the two languages then translated back to English by different person to ensure consistency. A week prior to the actual data collection period, the questionnaire was pre-tested on 5% of the total sample size patients identified from Mekelle Hospital. Data was collected by four trained B.Sc. nurses and two supervisors (B.Sc. nurses).Urine dipstick test Patient was asked to submit random midstream urine sample prior to admission in a 50 mL urine container for laboratory analysis for random urine dipstick test, protein, and creatinine. The dipstick analysis was done using the uriplus 900 urinalysis stip. The following are the grades of proteinuria as provided by the manufacturers:0: absentTraces: 15 to 30 mg/dL1+: 30 to 100 mg/dL2+: 100 to 300 mg/dL3+: 300 to 1000 mg/dL4+: greater than 1000 mg/dL.Estimated GFR is a test that is used to assess how well kidneys are working. The test estimates the volume of blood that is filtered by kidneys over a given period of time. It can be measured by using readily available equations and formulas like Cockcroft–Gault. CockcroftGault formula : (140 − Age [years]) × weight (kg) ×  × 1.73/72 × serum creatinine (mg/dL) × BSA (m2). In this case BSA will be calculated by using Mosteller formula that is BSA is equal to Data was coded, entered, edited, and cleaned by Epi-data manager version 4.2 and then exported into SPSS version 23 for analysis. Chronic kidney disease was confirmed by reviewing medical chart in the hospitals. Baseline demographic, clinical, laboratory and social characteristics were used as independent variables in the analysis.Binary logistic regression model was use to infer the association between the outcome and independent variables. In the bi-variates analysis variables with P-value < 0.25 was included in the multivariable binary logistic regression. Odds ratio with 95% confidence level was computed and P-value < 0.05 was described as having a significant association.Chronic kidney disease.Socio-demographic factors Age, sex, religion, educational, occupational, income and marital status.Clinical characteristic Blood pressure status, baseline diastolic blood pressure, baseline systolic blood pressure and baseline, stage of hypertension, type of hypertension, number of drugs, duration on drug, types of drugs, diabetes mellitus, dyslipidemia and obese.Chronic kidney disease for this study we consider patient having CKD if the physician was diagnosed as having CKD and documented in the patient’s medical chart. Chronic Kidney disease is defined as e-GFR < 60 mL/min/1.73 m by Cockcroft Gault equations.Controlled blood pressure BP < 140/90 mmHg using digital sphygmomanometer for adult hypertensive clients without diabetes mellitus and chronic kidney disease for at least three consecutive follow-up measurement and blood pressure < 130/80 mmHg using digital sphygmomanometer for adult hypertensive clients with diabetes mellitus and chronic kidney disease for at least three consecutive follow-up measurement.BMI (body mass index) A measure of the person’s weight in kilogram divided by his height in meter square. Based on this calculation body weight classified as underweight for patient with less than 18.5 kg/m2, normal weight 18.5–24.9 kg/m2, overweight 25–29.9 kg/m2 and obese for patients with BMI ≥ 30 kg/m2 , which is in line with study conducted in Malaysia, Cameroon, China, Ghana, Democratic Republic of Congo and Nigeria [1], whichIn this study the prevalence of chronic kidney disease among hypertensive patients were considerably high. Age, overweight, uncontrolled hypertension and dyslipidemia were found to be associated factors of CKD. In response to this finding, tailored future intervention that targets in prevalence and resolution of associated factors is required.Limitation of our study were excluding of incomplete medical chart and this study, we did not consider the renal biopsy for the diagnosis of CKD.


Chronic kidney disease has become an increasingly significant clinical and public health issue, accounting for 1.1 million deaths worldwide. Information on the epidemiology of chronic kidney disease and associated risk factors is limited in the United Arab Emirates. Therefore, this study aimed to evaluate the incidence and causes of chronic kidney disease stages 3–5 in adult United Arab Emirates nationals with or at high risk of cardiovascular disease. This retrospective study included 491 adults with or at high risk of cardiovascular disease  who attended outpatient clinics at a tertiary care hospital in Al-Ain, United Arab Emirates. Estimated glomerular filtration rate was assessed every 3 months from baseline to June 30, 2017. Chronic kidney disease stages 3–5 were defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 for ≥ 3 months. Multivariable Cox's proportional hazards analysis was used to determine the independent risk factors associated with developing chronic kidney disease stages 3–5. The cumulative incidence of chronic kidney disease stages 3–5 over a 9-year period was 11.4% . The incidence rate of these disease stages was 164.8  per 10,000 person-years. The independent risk factors for developing chronic kidney disease stages 3–5 were older age, history of coronary heart disease, history of diabetes mellitus, and history of smoking. These data may be useful to develop effective strategies to prevent chronic kidney disease development in high-risk United Arab Emirates nationals. During recent decades, the United Arab Emirates (UAE) has undergone rapid economic growth and modern infrastructure development, following the discovery of oil. The shift from a semi-nomadic lifestyle to an urbanized civilization has resulted in a substantial rise of chronic diseases .The prevalence of chronic kidney disease (CKD) has increased dramatically over the past two decades, with 13.4% of the population affected worldwide; the majority of the cases are CKD stages 3–5 . In a reWhile the incidence of CKD in the UAE and other Arab countries is not known , establiThis study involved a retrospective, ambulatory electronic medical record (EMR) review of patients who presented to Tawam Hospital outpatient clinics in Al Ain, between January 1, 2008, and December 31, 2008. Al-Ain is a city in the UAE, with an estimated population of 650,000, of which 30% are UAE nationals . HealthcCerner EMR management system was implemented at Tawam Hospital in January 2008, following which all patient medical records are available electronically. Ethical approval for this study was obtained from Tawam Hospital, and the United Arab Emirates University research and ethics board (IRR536/17). Informed consent was waived because patient records and information were anonymized and de-identified prior to analysis.The study population comprised of 544 consecutive patients who had either CVD or a high CVD risk, seen at primary care and specialty outpatient clinics at Tawam Hospital. The specialty clinics included obstetrics and gynecology, internal medicine and surgery, and their respective subspecialty clinics. Inclusion criteria for this study were UAE nationals ≥ 20 years of age and diagnosed with either of the following conditions: HTN or pre-hypertension, coronary heart disease (CHD), vascular disease, DM or prediabetes, smoking, dyslipidemia, being overweight or obese.2, 2 patients were renal transplant recipients and 3 had serum creatinine levels missing) . Among the 491 eligible subjects, the data for serum triglyceride (TG) and serum glycosylated Hemoglobin, Type A1C (HbA1c) at baseline were missing in 1.2% and 3.1% of subjects, respectively.Of the 544 patients who met the inclusion criteria, 53 patients were excluded (48 patients had an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 mmissing) . A total2). Overweight and obesity were defined as BMI 25–29.9 kg/m2 and ≥ 30 kg/m2 respectively. Prehypertension was classified as having a systolic blood pressure between 120 and 139 mm Hg or diastolic blood pressure between 80 and 89 mm Hg and not receiving antihypertensive medications. HTN was defined as the occurrence of any of the following: systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg or use of antihypertensive medications [Body mass index (BMI) was calculated as weight (kg) divided by height . Lipid profile and serum creatinine were measured using standard methods with Synchron Clinical System . Reference ranges for creatinine as suggested by the manufacturer were 53–115 mol/l and 58–96 μmol/l for males and females respectively.IBM SPSS version 25 was used to analyze the data. Distributions and categories were examined and categories with small sample size and skewed distributions were noted. Categories were meaningfully combined when indicated.Baseline variables stratified by gender were tested for association between subjects who did and did not develop CKD stages 3–5 using independent-samples t-test for continuous variables and Fisher's exact test (two-tailed) for categorical variables.Patient-years at risk for developing CKD stages 3–5 was calculated for each subject from the baseline visit in 2008 to the diagnosis of CKD stages 3–5 or last outpatient visit, whichever occurred first. The incidence rate was calculated as the number of new cases of CKD stage 3–5 divided by patient-years at risk.Univariable analysis was performed on each predictor variable, age , gender , CHD (categorized as no and yes), DM (categorized as no and yes), vascular disease (categorized as no and yes), HTN (categorized as no and yes), dyslipidemia (categorized as no and yes), smoking (categorized as no and yes), and obesity (categorized as no and yes). The first category in the parenthesis in the above definition was defined as the reference group. Variables with a p-value <0.1 in the univariable analysis were included in the multivariable Cox's proportional hazards analysis. A backward stepwise method based on likelihood ratios was then used with entry and removal probabilities set at 0.05 and 0.10 respectively. Proportional hazards assumption was tested using log-log plot and was not significant. A p-value < 0.05 was considered significant.2. Male subjects had higher history of CHD (13.2% vs 5.0%), vascular disease (8.8% vs 2.9%), and smoking (29.2% vs 0.8%), but had lower prevalence of obesity (40.4% vs 61.0%) than female subjects.Demographical, clinical, and biochemical data of the 491 subjects are presented in A total of 56 new cases  of CKD stages 3–5 were identified after a mean follow-up of 8.6 years . The cumulative incidence of CKD stages 3–5 over this period was 11.4% . The incidence rate of CKD stages 3–5 was 164.8  cases per 10,000 person-years.The characteristics of subjects stratified by gender that developed CKD stages 3–5 compared with those who did not develop the disease are shown in The results from our study showed that the incidence of CKD stages 3–5, in high-risk UAE nationals was more than 1% per year, during a 9-year period. The incidence rate of CKD stages 3–5 was 164.8 per 10,000 person-years. Surprisingly, the incidence rate of these CKD stages in our study was lower than expected. A Spanish prospective cohort study of 3,443 people with type 2 DM found that the incidence rate of CKD stages 3–5 is 207 per 10,000 person-years . In a USIn our study population, age, history of CHD, history of DM, and history of smoking were significant risk factors for developing CKD stages 3–5. In several studies, CHD has been found to be an independent risk factor for developing CKD ,32,33. HDiabetes is an important and established risk factor for the development of CKD ,31,34–36Smoking is a known independent risk factor for the development of CKD ,38,39, aHTN is a recognized risk factor for CKD. Numerous studies have identified a strong association between high blood pressure and CKD ,29,41. HBlood pressure control is the single most important intervention to reduce the development of CKD in high-risk patients , while tThis study has several limitations. First, the data quality and standardization of laboratory and anthropometric measurements in a retrospective study may not be as good as in a prospective study. Second, patient mortality in this study was unaccounted for, therefore, the incidence of CKD may be underestimated. Third, eGFR was calculated using the CKD-EPI equation, which has been validated in Caucasian and African American populations; there are limited available data for people of Arab descent . Finally2, taken more than or equal to three months apart. By doing so, this study accounts for the intra-individual variability in eGFR. Both these measures in our study lead to a more accurate representation of kidney function. Moreover, this study used documented anthropometric measurements and laboratory data for risk factor classification rather than self-reported information. Finally, we used the CKD-EPI equation to define CKD stages 3–5; CKD-EPI equation estimates measured GFR more accurately than the modification of diet in renal disease study equation in most studies [As for strengths, our case definition of CKD does not account for albuminuria. It is not uncommon for people to regress from moderate to normoalbuminuria naturally or as a result of treatment . Strictl studies ,48,49.The cumulative incidence of CKD stages 3–5 among high-risk UAE nationals was 11.4% over a 9-year period. The major risk factors identified were older age, history of CHD, DM, and history of smoking. Evidence-based strategies for prevention of CHD and diabetes and smoking cessation programs could lower the risk of developing CKD stages 3–5 among the UAE national population with or at high-risk of CVD.S1 TableCKD; Chronic kidney disease, CHD; Coronary heart disease, DM; diabetes mellitus, HTN; hypertension, ACEI; Angiotensin-converting enzyme inhibitors, ARB; Angiotensin II receptor blockers, BMI; Body mass index, eGFR; estimated glomerular filtration rate, SBP; Systolic blood pressure. DBP; Diastolic blood pressure, Cr; Creatinine, TC; Total cholesterol, TG; Triglycerides, SD; standard deviation, HbA1c; glycosylated Hemoglobin, Type A1C.(DOCX)Click here for additional data file.S1 DatasetID; identification, CHD; Coronary heart disease, HTN; hypertension, DLD; dyslipidemia, DM; diabetes mellitus, Angiotensin-converting enzyme inhibitors, ARB; Angiotensin II receptor blockers, HbA1c; glycosylated Hemoglobin, estimated glomerular filtration rate, SBP; Systolic blood pressure. DBP; Diastolic blood pressure, BMI; Body mass index, CKD; Chronic kidney disease.(XLSX)Click here for additional data file.


The burst suppression ratio was significantly different at 6, 7, 8, and 10 min after remifentanil infusion (p < 0.05). In female patients with propofol-induced unconsciousness, remifentanil alleviated the burst suppression ratio without affecting the bispectral value.The bispectral index is affected by various factors, such as noxious stimuli and other drugs, such as muscle relaxants. The burst suppression ratio from bispectral index monitoring is correlated with electroencephalographic burst suppression, which is associated with deep anesthesia, metabolic disorders, and brain injury. We assessed patients undergoing total intravenous anesthesia and examined the effects of remifentanil on the bispectral index, burst suppression ratio, and hemodynamic changes immediately after loss of consciousness with propofol. Seventy American Society of Anesthesiologists physical status class I and II Korean female patients scheduled for general anesthesia were administered propofol with an effect-site concentration of 5 μg/mL, using a target-controlled infusion (TCI). After losing consciousness, patients received either saline or remifentanil at an effect-site concentration of 5 ng/mL for 10 min. During this period, we recorded the bispectral index values, including burst suppression ratio, blood pressure, and heart rate. With remifentanil infusion, burst suppression ratios were lower ( The bispectral index (BIS) analyzes electroencephalographic waves and represents a numeric value to objectively evaluate the level of consciousness. It is used widely during sedation and general anesthesia . These vTotal intravenous anesthesia, usually consisting of propofol and remifentanil without a muscle relaxant, is the current gold standard during intraoperative neurophysiological monitoring, especially for brain or spinal surgeries . In thesRemifentanil has been found to decrease the BIS value during tracheal intubation and skin incision, even in the absence of other stimuli ,8,9. HowThe burst suppression describes an electroencephalographic pattern consisting of a continuous alteration between high-voltage slow-wave and depressed electrographic activity . Also, tPropofol and remifentanil both lower blood pressure and heart rate, and concomitant administration further reduces blood pressure, affecting pulse rate ,8.The primary objective of the current study was to examine the effects of remifentanil on the BIS in the absence of muscle relaxants and noxious stimuli in patients with propofol-induced unconsciousness. Next, we observed the change in the burst suppression ratio with or without remifentanil infusion. Finally, we examined the effect of remifentanil on the mean blood pressure and heart ratehttp://cris.nih.go.kr (KCT0000880) and was approved by the Institutional Review Board of Changwon Fatima Hospital (IRB No.14-03). After obtaining written permission, 70 female patients over 20 and below 55 years of age of American Society of Anesthesiology (ASA) physical status class I or II who were scheduled for total intravenous general anesthesia in gynecological surgery were included in this prospective, placebo-controlled study. This study was conducted between 2014 and 2015. The exclusion criteria were patients with cardiovascular disease, diabetes mellitus, or neurologic disease; those who were taking medications that affect the central nervous system; anticipated difficulty in airway management; body mass index over 30; or refusal to participate in the study.This study was registered on 15 October 2013 at n = 35 for each group), by a person who was not involved with the recruitment and selection of patients.Premedication was omitted, and standard monitoring, including electrocardiography, non-invasive blood pressure, and pulsoximeter, was initiated on arrival to the operating room. A BIS Quatro sensor was attached to the patient’s forehead according to the manufacturer’s guidelines and connected to a BIS-Vista monitor . Patients were randomized into either the remifentanil or control group based on computer-generated random numbers with a 1:1 allocation ratio  with the Schnider pharmacokinetic model. When the target concentration reached 5 μg/mL, the patient’s loss of consciousness was assessed via verbal responses and eyelid reflexes. If the patient did not lose consciousness at the target concentration of 5 μg/mL within 5 min, the patient was excluded from the study.After administration of glycopyrrolate 0.2 mg and 1% lidocaine 20 mg, propofol was infused to the target effect-site concentration of 5 μg/mL using an infusion device  of BIS values, the primary outcome, with mean difference of 8.26, and standard deviation (SD) of 15.23, respectively. Considering alpha = 0.05, power = 80%, and drop-out rate for 10%, the estimated sample size was 70.Sample size was calculated based on a pilot study  and p-values below 0.05 were considered statistically significant.Continuous variables were expressed as mean ± SD, and categorical variables were expressed as numbers, including percentages. To assess the effects of remifentanil, repeated measure ANOVA tests were used, including post-hoc analysis (Friedman test). To compare the variables at each time point, an independent Three patients in the control group and two patients in the remifentanil group did not lose consciousness at the propofol effect-site concentration of 5 μg/mL during 5 min of observation. Therefore, a total of 65 patients participated in the study . The twop < 0.05), but there was no difference between the two groups. Also, the BIS values did not show any difference at any time point between the two groups during the study period (p < 0.01). In addition, the ratios in the remifentanil group were significantly lower than in the control group at 6, 7, 8, and 10 min (p < 0.05) (p < 0.01). The numbers of patients with burst suppression was significantly different at 7, 8, and 10 min (p < 0.05)  . The num < 0.05) . The medp < 0.05), but there was no difference between the groups at any time point (p < 0.05)  .In this study, we found no effect of remifentanil on the BIS in patients with propofol-induced unconsciousness, even in the absence of noxious stimuli and muscle relaxants. Also, the mean blood pressure and heart rate were not affected, although ephedrine was more likely to be required following remifentanil infusion. By contrast, burst suppression ratios were lower following remifentanil infusion and more prominent at the later time points.Considering the gender difference in opioid sensitivity ,22, we iAt light anesthetic depths, like sedation, controversies exist, whether remifentanil decreased BIS ,12 or noAlthough this study was conducted with unstimulated, unparalyzed, and unconscious patients, the common patients in the operating room usually receive lots of stimuli, such as intubation or surgical stress. Usually, catecholamine is released more and in turn, this increases the BIS values . Then, lThe observation of intraoperative burst suppression can predict postoperative delirium  and SoehAlthough we found a lower suppression ratio when remifentanil was infused, no difference could be found in the BIS. However, when considering a suppression ratio of 40% or more is invariably and linearly correlated ,27, it iIn cardiac surgical patients, Soehle et al.  found thIn this study, the burst suppression ratio of the propofol-infused patients was lower when remifentanil was infused simultaneously. The changes remifentanil produces in the electroencephalography(EEG) are typical of μ-receptor agonists. Also, the EEG shifted from low-amplitude, high-frequency activity during baseline to high-amplitude, low-frequency activity during opioid infusion, culminating eventually in delta activity at maximal drug effect . HoweverIn this study, seven patients required ephedrine to maintain blood pressure following remifentanil infusion. Therefore, we further analyzed whether ephedrine affected the BIS and burst suppression ratio values by excluding the patients who were administered ephedrine. The results did not differ, suggesting the ephedrine might not affect the BIS and burst suppression.Opioids typically decrease heart rate and mean arterial pressure. Propofol is also known to lower blood pressure and heart rate. In this study, there was no significant difference in mean arterial blood pressure, whether remifentanil was infused or not. However, seven patients required ephedrine to maintain blood pressure following remifentanil infusion, indicating that ephedrine may affect these results. We observed a further decrease in heart rate later, when remifentanil was administered.The current study was not without limitations. First, we used fixed doses of propofol and remifentanil, so varying the dosage may alter the results. Second, we infused remifentanil for only 10 min, so the effects of a longer period of remifentanil infusion are unknown. Additionally, the low values of the burst suppression ratio preclude any definitive conclusion about subtle BIS value modification. Finally, the results cannot be generalized to male patients and other types of surgery.In conclusion, remifentanil infusion at a 5 ng/mL effect-site concentration does not affect the BIS value in the absence of muscle relaxants and noxious stimuli in unconscious female patients with a propofol effect-site concentration of 5 μg/mL. Suppression ratios were lower when remifentanil was infused. Although the mean blood pressure and heart rate were not affected, heart rate decreased more following the infusion of remifentanil later in this study.


Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for >3 months, with implications for, among others, bone health. Advanced stages of CKD have an increased risk of fragility fractures. Trabecular bone score (TBS) is a relatively new gray-level textural parameter, which provides information on bone microarchitecture and has been shown to be a good predictor of fragility fractures independently of bone density and clinical risk factors. We aimed to review the scientific literature on TBS and its utility along the CKD spectrum and in kidney transplant recipients. In total, eight articles had investigated this topic: one article in patients with reduced kidney function, two in patients on hemodialysis, and five in kidney transplant recipients. In general, all the studies had shown an association between lower values of TBS and reduced kidney function; or lower TBS values among the hemodialysis or kidney transplant patients compared to healthy controls. Moreover, TBS was shown to be a good and independent predictor of fragility fractures in patients with CKD or who underwent kidney transplantation. TBS postulates itself as a valuable marker to be used in clinical practice as an assessor of bone microarchitecture and fracture risk predictor in these specific populations. However, evidence is to some extent limited and larger follow-up case-control studies would help to further investigate the TBS utility in the management of bone health damage and increased fracture risk in patients with CKD or kidney transplant. The presence of a higher albuminuria in each stage of GFR carries a poorer prognosis for the progression of CKD  defines chronic kidney disease (CKD) as abnormalities of kidney structure or function, present for >3 months, with implications for health . CKD is Among other health consequences, the declines in kidney function cause changes in bone mineral metabolism which weaken the skeletal system , 3. The Therefore, the evaluation of the risk of fracture in these specific stages is very important. It is a silent agreement among the bone health community that in the earlier stages of CKD stage 1–3), the fracture risk assessment is made as in the general population; whereas by the time a patient progresses the advanced stages (stages 4–5), bone metabolism derangements become so dominant and the fracture risk increases so much that the general population's criteria may not be relevant anymore , 16. Bon, the fraTrabecular bone score (TBS) is a relatively new gray-level textural parameter, which provides information on bone microarchitecture . A homogThe aim of our study was to review the current scientific literature on TBS and chronic kidney disease. We identified studies that have investigated the ability of TBS to assess bone health and to predict fracture risk along the CKD spectrum or kidney transplantation.Using both free text and MESH terms , a systematic search of the literature was performed in PubMed database with no time and study type limit, until January 2018. Abstracts were selected. References of the retrieved articles were checked manually for further studies.2 and normal kidney function as GFR ≥ 60 ml/min per 1.73 m2 (n = 199) had a significantly lower mean TBS than those with normal kidney function . The 5-years probability of having a fragility fracture was higher among individuals with reduced kidney function with TBS values below the median  than those with TBS values above the median . Moreover, TBS showed to predict fracture independently of age, sex, FRAX score, and BMD in both groups. These results suggest that as in the general population, TBS may be a useful parameter to predict fracture risk in patients with reduced kidney function.KDIGO defines the reduced kidney function as GFR < 60 ml/min per 1.73 m 1.73 m2 . Adults 2  and this difference remained significant even after adjusting for age and serum levels of parathyroid hormone, phosphate, alkaline phosphatase, and 25-OH-vitamin D3. Furthermore, TBS was significantly lower among patients on dialysis without osteoporosis than controls without osteoporosis, and this was independent of BMD or other covariates .Yavropoulou et al. studied the possible association of TBS with other factors that reflect bone health in a cross-sectional case-control study of 50 patients with ESRD undergoing chronic hemodialysis . ParticiIn the second study, Brunerova et al. aimed to contribute further to the study of the utility of TBS in the ESRD patients on dialysis . They asKidney transplantation has the best prognosis for patients with severe end-stage renal failure . Improvip < 0.001) and a higher fracture probability as assessed by FRAX. During the mean follow-up period of 6.6 years, 31 (9%) kidney transplant recipients sustained one or more incident fragility fractures. The recipients who sustained a fracture had a significantly lower TBS than those who did not . TBS was able to discriminate between recipients with and without a fracture . Furthermore, the kidney transplant recipients with a lower TBS were less likely to remain fracture-free (p = 0.017). Finally, lower TBS was associated with fracture independent of FRAX .Naylor et al. investigated TBS in 327 adults kidney transplant recipients (mean age = 45.3 ± 12.4 years) who received their transplant in Manitoba, Canada; and compared it with 981 matched healthy individuals (mean age = 45.4 ± 12.3 years) . Kidney p < 0.001). The duration of dialysis before the transplant showed to have no effect on TBS post-transplant.Peres-Saez et al. performed a cross-sectional study to analyze bone health outcomes in 53 ESRD patients (mean age = 55.8 ± 12.1 years) at the time of undergoing kidney transplant surgery . The conp = 0.072). Interestingly, no differences in TBS or BMD between patients on glucocorticoids and those glucocorticoids-free were found; neither a correlation between TBS or BMD with the cumulative glucocorticoid dose.Moreover, Perez-Saez et al. investigated TBS also in long-term (mean follow-up time = 10 years) kidney transplant patients in the same population with the previous study . The 40 Luckman et al. followed 47 kidney transplant recipients (mean age = 50.5 ± 13.7 years) for 12 months after their kidney transplant . All patn = 114 patients) or simultaneous pancreas kidney transplantation (n = 33 patients) (p = 0.023). Low TBS values (≤1.31) were a good predictor of non-vertebral fractures, but not of combined vertebral and non-vertebral fractures. Even after adjusting for the relevant covariates, TBS remained significantly associated with prevalent non-vertebral fractures independently of femoral neck BMD and FRAX .Most recently, Aleksova et al. investigated TBS in 146 patients (mean age = 48 ± 13 years) with progressed CKD  who had undergone a kidney (atients) . The meaTo the best of our knowledge, this is the first literature review of the utility of TBS in bone health assessment and fracture risk prediction in patients with chronic kidney disease undergoing dialysis or kidney transplantation. In general, these studies are in line with each other in associating lower TBS values with an impaired kidney function along the CKD spectrum and among the kidney transplant recipients; and concluding that TBS can predict fracture risk independently of bone density in this population.The lack of a well-established strategy to assess bone health and fracture risk in patients with end-stage renal disease is an important matter of bone community. The presence of bone health deterioration in these patients could have possible therapeutic implications which could decrease the risk of having a fragility fracture and furthermore, improve their prognosis. The current gold standard method to assess bone deterioration, bone biopsy, is an invasive technique with a limited availability . Thus, rIn patients with ESRD on hemodialysis, TBS suggests that a significant deterioration of bone quality might be present, independent of bone mass and other biochemical changes in ESRD, postulating itself as a valuable marker in assessing bone quality in these patients , 37. NevThe majority of studies on TBS and CKD are on kidney transplant recipients, as an exposed group to ESRD and other causes of osteoporosis, such as glucocorticoids use. They have robustly shown that patients who had undergone a kidney transplant had a lower TBS than matched controls, suggesting of a remained bone microarchitecture alteration after the kidney transplant , 42, 43.The wide range of TBS values in patients with reduced kidney function , on hemoIn overall, current evidence suggests that the management of bone health alterations and fracture risk assessment among patients with CKD and those after kidney transplantation, might be similar to that of the non-CKD population. The studies robustly show a damage of bone microarchitecture as measured by TBS , and confirm the ability of TBS to predict the risk of fragility fractures in this population. Based on these insights, TBS assessment is reasonable in the fracture risk prediction in this population. Additional investigation on the TBS thresholds in this population will eventually contribute to the improvement of their clinical management.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.DH is co-owner of the TBS patient and has corresponding ownership and position at medimaps group. 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.


Furthermore, baseline uncontrolled blood pressure, left ventricular hypertrophy, and pulse wave velocity ≥ 9 m/s were able to identify patients at higher risk of developing CVAEs during FU. These preliminary findings indicate that blood pressure control, left ventricular mass, and pulse wave velocity may predict CVAEs in MM patients treated with carfilzomib. Carfilzomib is a second-generation proteasome inhibitor approved for the treatment of multiple myeloma (MM). It seems to determine cardiovascular toxicity, primarily arterial hypertension. No predictive factors for cardiovascular adverse events (CVAEs) are known in patients affected by multiple myeloma treated with carfilzomib. We evaluated the role of cardiovascular organ damage parameters to predict CVAEs in MM patients taking carfilzomib. Seventy patients affected by MM were prospectively enrolled. A comprehensive cardiovascular evaluation was performed before carfilzomib therapy; they underwent a transthoracic echocardiogram and the assessment of carotid-femoral pulse wave velocity. All the patients were followed up (FU) to determine the incidence of CVAEs. The mean age was 60.3 ± 8.2, and 51% were male. The median FU was 9.3  months. A proportion of 33% experienced CVAEs, 91% of them had uncontrolled hypertension, 4.5% acute coronary syndrome, and 4.5% cardiac arrhythmias. Subjects with CVAEs after carfilzomib treatment had significantly higher blood pressure values, left ventricular mass (98 ± 23 vs. 85 ± 17 g/m Carfilzomib is a second-generation proteasome inhibitor approved for the treatment of multiple myeloma (MM) that is demonstrated to improve the overall rate response and progression-free survival in MM patients compared to other chemotherapeutic strategies ,2,3. HowLeft ventricular mass is a morphological parameter that describes cardiac remodeling and the presence of left ventricular hypertrophy is a sign of cardiac organ damage . LikewisThe aim of our study was to determine if parameters commonly used to assess cardiovascular organ damage are able to predict the incidence of CVAEs in MM patients undergoing treatment with carfilzomib.From April 2017 to April 2018, 70 MM patients, followed by the Myeloma Unit , were prospectively enrolled. The inclusion criteria were the history of new diagnosed/refractory/relapsed MM in patients with clinical indication to carfilzomib treatment, and age ≥ 18 years. Patients were excluded if they had cardiac amyloidosis, were aged < 18 years, and denied informed consent.The study protocol was approved by the ethic committee of our hospital “A.O.U. Città della Salute e della Scienza” of Turin (Protocol Number 0038655) and each patient signed a written consent form.The enrolled patients underwent a comprehensive cardiovascular evaluation c/o our Echo Lab  before the beginning of carfilzomib infusions. We collected anamnestic information and performed a complete examination, including measurement of office blood pressure values, ambulatory blood pressure monitoring, electrocardiogram, transthoracic echocardiogram, and evaluation of carotid-femoral pulse wave velocity. Antihypertensive treatment was optimized in patients with uncontrolled blood pressure values, since office blood pressure < 140/90 mmHg was required to start every carfilzomib infusion.Office blood pressure (BP) measurements were performed according to the current guidelines ,17. An aEvery patient underwent an ambulatory blood pressure monitoring (ABPM) according to the current recommendations . A valid2 (≥49 g/m2.7) and ≥95 g/m2 (≥47 g/m2.7) respectively in men and women. LV volumes were assessed through the Simpson’s Biplane technique from apical 4- and 2-chamber views and indexed to body surface area, then used to evaluate LV systolic function as LV ejection fraction (EF). LV diastolic function was defined through the evaluation of early diastolic Tissue Doppler (TDI) velocities (e’ waves) of septal and lateral mitral annulus, mitral valve inflow (E and A wave velocity), tricuspid regurgitation peak velocity, left atrial volume (indexed to body surface area) and E/e’ ratio, according to the current recommendations  months from carfizomib treatment start : of thes.4 monthsp = 0.01; LVH 52.2% vs. 21.7%, p = 0.01); furthermore, cf-PWV was higher in patients with CVAEs . However, no differences in baseline GLS values were seen between groups. Blood pressure control and cardiovascular organ damage were similar in patients who had grade 1–2 and grade ≥ 3 CVAEs.We divided our population into 2 groups based on the incidence of CVAEs during follow up . No signp = 0.003, and 53% vs. 25%, p = 0.02, respectively). Cf-PWV = 9 m/s was chosen as the most sensitive cut-off by creating a ROC curve. Similarly, CVAEs rate was significantly higher when baseline BP was uncontrolled .Likewise, we observed that patients with baseline LVH and cfPWV ≥ 9 m/s had an increased incidence of CVAEs compared to those who had normal LVMi and cf-PWV < 9 m/s at first visit  was sensitive in recognizing who would experience CVAEs : we assiBP control represented the most sensitive parameter in recognizing patients at risk of developing CVAEs (BP sensitivity 70%), while LVH and cf-PWV allowed us to reach a higher specificity and to be more accurate. Furthermore, the score ≥ 1 was even more sensitive than BP control alone and enabled us to identify patients that could develop adverse events after carfilzomib treatment with a sensitivity of 87% and the same accuracy (63%) as BP control alone .Finally, 48 patients underwent a follow up clinical evaluation that was performed after a mean period of 6 ± 2.6 months at our Echo Lab. The examination was primarily based on checking office blood pressure values and optimizing the antihypertensive treatment if necessary.p = 0.001; DBP 72 ± 9 mmHg versus 78 ± 11 mmHg, p = 0.002) and the prevalence of patients with office blood pressure < 140/90 raised from 43% to 68% (p = 0.02). Patients treated with antihypertensive drugs were 66% (versus 46% at baseline visit), with a greater number of medications per person.Anthropometric variables did not change from the first visit. We observed an improvement in blood pressure control: systolic and diastolic office blood pressure values were significantly lower compared to the first evaluation . However, in our population, baseline left ventricular mass and cf-PWV were significantly higher in patients who experienced CVEAs during carfilzomib therapy. Furthermore, we recognized left ventricular hypertrophy, cf-PWV ≥ 9 m/s, and baseline uncontrolled office blood pressure as parameters able to distinguish subjects with increased risk of developing CVAEs over time.Left ventricular hypertrophy is known to be a direct consequence of an elevated afterload; several studies have demonstrated its independent predictive value on incidence of CVAEs over time . CarfilzThe ubiquitine-proteasome system plays an important role in endothelial cells, too: the inhibition of proteasome activity is associated with increased intracellular oxidative stress, reduced eNOS activity , and accA recent animal study  has alsoLeft ventricular hypertrophy and cf-PWV are known predictors of CVAEs incidence in different populations ,27,28. THowever, the results obtained in our 70-patient cohort are preliminary and need to be confirmed by further investigation on a larger population of MM patients, in order to state with stronger evidence the potential predictive value of such parameters.As regards cardiovascular adverse events, in our population the incidence was 32.9%, but only 7.2% of patients had a grade ≥ 3 CVAE. In the overall cohort, 30% had arterial hypertension, and only 5.7% required a temporary interruption of chemotherapy. These data overlap with what has been previously demonstrated in literature ,2,3.The incidences of myocardial infarction and arrhythmias 1.4%) were similar to the ones described in the literature [% were siFinally, patients who underwent a follow up evaluation better blood pressure control then during their first visit: this is probably related to the optimization of the antihypertensive treatment.Our intervention is likely to have determined a reduced incidence of major events in our cohort: CVAEs after carfilzomib treatment in carefully followed patients from a cardiovascular health standpoint can be limited to a mild–moderate worsening in blood pressure, allowing patients to continue the oncological therapy.The main limitation of this study is represented by the small cohort. However, it is important to underline that this is the first study with the aim of systematically evaluating the cardiovascular profile of MM patients undergoing carfilzomib treatment, in order to find predictors of adverse events following chemotherapy. The second important limitation of the study is the short-term follow up. Further evaluations are needed to determine the incidence of long-term CVAEs.Our study demonstrated that a comprehensive cardiovascular evaluation and management in patients undergoing carfilzomib treatment may help identify subjects at higher risk of experiencing CVAEs during follow up and determine a low incidence of major CVAEs, which are mainly represented by worsening in blood pressure control, necessitating the interruption of chemotherapy.The results we obtained indicate that the presence of at least one among LVH, high cf-PWV, and uncontrolled hypertension, before carfilzomib infusions, may have a predictive role in identifying patients who are likely to experience CVAEs during treatment. Although BP control has proved to be more sensitive than LVH and cf-PWV, performing a TTE and measuring cf-PWV can improve our ability to correctly identify patients at risk of CVAEs compared to blood pressure control alone.These findings are preliminary. If additional investigation on a larger cohort confirms the primary results, these parameters may be included in the baseline evaluation of MM patients undergoing carfilzomib treatment, helping differentiate subjects who need a more aggressive antihypertensive treatment and a stricter follow up from the beginning.


Chronic kidney disease (CKD) is associated with excess cardiovascular mortality, resulting from both traditional and nontraditional, CKD-specific, cardiovascular risk factors. Nontraditional risk factors include the entity Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) which is characterised by disorders of bone and mineral metabolism, including biochemical abnormalities of hyperphosphatemia and hyperparathyroidism, renal osteodystrophy, and vascular calcification. Increased arterial stiffness in the CKD population can be attributed amongst other influences to progression of vascular calcification, with significant resultant contribution to the cardiovascular disease burden. Pulse wave velocity (PWV) measured over the carotid-femoral arterial segments is the noninvasive gold-standard technique for measurement of aortic stiffness and has been suggested as a surrogate cardiovascular end-point. A PWV value of 10 m/s or greater has been recommended as a suitable cut-off for an increased risk of cardiovascular mortality. CKD is a risk factor for an excessive rate of increase in aortic stiffness, reflected by increases in PWV, and increased aortic PWV in CKD shows faster progression than for individuals with normal kidney function. Patients with varying stages of CKD, as well as those on dialysis or with a kidney transplant, have different biological milieu which influence aortic stiffness and associated changes in PWV. This review discusses the pathophysiology of arterial stiffness with CKD and outlines the literature on PWV across the spectrum of CKD, highlighting that determination of arterial stiffness using aortic PWV can be a useful diagnostic and prognostic tool for assessing cardiovascular disease in the CKD population. Chronic kidney disease (CKD) is increasingly recognised globally as a major public health problem. CKD is defined as abnormalities of kidney structure and/or function, present for at least 3 months, the prevalence of which is estimated to be between 8 and 16% worldwide . ConsideCardiovascular disease is the leading cause of death in CKD and a predominant driver for this is increased conduit artery stiffness, in particular of the elastic thoracic aorta. Increased carotid-femoral aortic stiffness, as measured by segmental pulse wave velocity (PWV), is a strong, independent predictor of cardiovascular mortality in this population , 6. AlthCarotid-femoral PWV is utilised as the noninvasive gold standard measure of arterial stiffness, with assessment of changes in vascular stiffness having been advocated as a suitable surrogate cardiovascular end-point in clinical trials. Development of vascular calcification and arterial stiffness observed with progression of CKD results in a different age-related pattern of PWV change than in the disease-free normal population. In addition, PWV has been demonstrated to characterise the progression of arterial disease in a CKD population , 9. ThisFunctional aortic stiffness is a result of both normal nonlinear pressure dependent changes in aortic wall properties and  intrinsic structural changes. Increased aortic stiffness and its relatively easily measured manifestation, inappropriately increased PWV, result in the pathophysiological consequences of an increase in the magnitude of the aortic pressure waveform as well as other changes in the morphology of this wave including more rapid decay of diastolic blood pressure magnitude resulting in increased pulse pressure measured either centrally or at the brachial artery. These alterations in pressure wave morphology are associated with increased pulsatility exposure in feeding arteries to low impedance vascular beds, such as the kidneys and brain, with organ parenchyma exposed to high levels of mean blood pressure and increased mechanical strain, as well as being atherogenic in coronary arteries and associated with a decreased ability to augment coronary blood flow in hyperemic states.There remain controversy and uncertainty regarding the predominant cause of these deleterious central blood pressure changes with conflicting hypotheses put forward. The traditional model of central pressure augmentation due to increased pressure wave reflection and from a predominant distal reflection site has been challenged by a more contemporary suggestion. This proposes that increased central blood pressure is predominantly due to increased proximal aortic stiffness and in fact decreased impedance mismatch distally which is caused by increased pulse pressure due to increased central pressure propagating distally .Whatever the predominant underlying mechanism for the effect of increased central blood pressure and other changes in the pressure waveform associated with increased aortic stiffness, the clinical sequelae include increased cardiovascular and cerebrovascular events and deleterious effects on kidney function. Any primary renal effects that increase blood pressure will exacerbate the “vicious cycle” relationship between operating blood pressure and intrinsic aortic wall stiffness. Increased blood pressure causes increased functional stiffness due to the nonlinear volume pressure relationship of the aortic wall. Similarly, CKD or degenerative processes that primarily increase aortic stiffness will increase blood pressure.Arteries demonstrate a gradual, age-related impairment in vascular function likely related to reduction in endothelium-derived nitric oxide bioavailability and increased production of vasoconstrictors , 12. Inc arteriosclerosis, in contrast to atherosclerosis. Atherosclerosis is the underlying pathology of cardiovascular disease and is characterised by abnormalities in lipid metabolism leading to lipid-filled macrophage deposition in the subendothelial layers of the arterial wall, which results in chronic inflammation .–49.47–49One randomized controlled trial involving patients with CKD Stages 3b to 5 assessed the effect of vitamin D supplementation on arterial stiffness measured by PWV . PatientIn an attempt to improve cardiovascular disease, the use of phosphate binders in nondialysis CKD patients has also been studied in randomised trials with assessment of changes in PWV as a surrogate end-point. These studies however, which have varied from 38 to 120 patients with CKD Stages 3 and 4 and involved varying phosphate binder treatment  over 9- to 12-month periods, have not shown any change in PWV with this intervention , 62.Long-term cardiovascular outcomes of patients undertaking either peritoneal dialysis or conventional satellite hemodialysis are similar, but overall they are significantly worse compared to age- and gender-matched individuals in the general population . Longer Conflicting reports exist in observational studies regarding the impact of dialysis modality on arterial stiffness as measured by PWV , 67. StuHemodialysis causes significant changes in volume loading and blood pressure as a function of ultrafiltration. In observational studies, PWV is relatively stable during nondialysis days , althougFrom a cardiac perspective, inappropriately increased PWV is associated with increased left ventricular mass in patients on hemodialysis, highlighting the mechanistic contribution of increased arterial stiffness to the development of left ventricular hypertrophy in this cohort . HemodiaVascular calcification in patients on dialysis is common, often extensive and progressive, and the causes are multifactorial. Contributing factors include the use of calcium-containing phosphate binders as well as higher calcium dialysate. Exogenous calcium loading has been associated with an increase in arterial stiffness in dialysis patients, independent of age, blood pressure, and dialysis vintage . Higher Several small studies have also assessed the impact of exercise programs in patients undertaking dialysis. Exercise is hypothesised to improve overall cardiovascular risk and potentially mitigates the impact of hypertension upon arterial stiffness. One cross-over study of 19 patients showed a trend towards improvement in PWV in patients who undertook interdialytic exercise, with subsequent deterioration in PWV after cessation of exercise . Other tKidney transplantation improves cardiovascular prognosis, but its impact on arterial stiffness is still controversial. Kidney transplantation may potentially mitigate the development of further worsening of arterial stiffness , and donThe prognostic significance and change in PWV in the CKD population need further investigation. The influence of dialysis modality upon PWV requires further evaluation, including the assessment of progression of arterial stiffness with different dialysis modalities. The contribution of residual kidney function, arterial turbulence, and fluctuations in volume state to changes in PWV also warrant further investigation. It has been hypothesised that peritoneal dialysis causes less hemodynamic and cardiovascular stress than hemodialysis; however, differences in mortality and cardiovascular outcomes have not been shown. Changes in PWV measured in carefully conducted trials would be helpful to determine the contribution of arterial stiffness in patients with ESKD.Additionally, improvement in arterial stiffness in kidney transplantation should be investigated further. Kidney transplantation is the gold standard therapy for ESKD and is associated with reduced mortality, in part by mitigating the rate of vascular calcification due to restored calcium phosphate homeostasis. However, kidney transplant recipients have multiple cardiometabolic risk factors which still contribute to development of cardiovascular disease. PWV could potentially be utilised as a study end-point to assess the effect of interventions in improving overall cardiovascular outcomes in the context of graft dysfunction and posttransplant diabetes in this cohort. Of interest would be to study the use of newer hypoglycaemic agents, such as SGLT-2 inhibitors, in posttransplant diabetes with measurement of PWV as a surrogate cardiovascular end-point, although these medications would be used with caution in kidney transplant recipients with impaired kidney function.Recently, new oscillometric methodologies using simple brachial cuffs, such as Mobil-O-Graph, have been introduced in patients with CKD to measure parameters of 24-hour arterial stiffness including PWV. This enables study of the 24-hour variability of these parameters, which will hopefully lead to better cardiovascular risk stratification and improved cardiovascular outcomes of CKD patients .In conclusion, PWV is increased in CKD compared to healthy age-matched populations. It provides a unique, noninvasive clinical tool for determining arterial stiffness and hypertensive end-organ damage. Multiple studies have reported the predictive value of heightened PWV in the development of any major vascular disease. In the CKD cohort, studies utilising PWV have demonstrated greater progression of arterial stiffness, in contrast to the general population with normal kidney function, corresponding to an increase in cardiovascular mortality. Factors such as CKD stage, exogenous calcium load, dialysate calcium, volume status, and dialysis modality may all contribute to progression of PWV. Further interventions to reduce the burden of cardiovascular disease in the CKD population are essential and could be studied initially using PWV measurement as a surrogate marker.


The cumulative evidence in the past three decades situates ambulatory blood pressure monitoring (ABPM) as a central element in diagnosing and predicting the prognosis of subjects with hypertension. However, for various reasons, this diagnostic and prognostic importance has not been translated in equal measure into making decisions or guiding antihypertensive treatment. Mean 24-h, daytime, and night-time blood pressure estimates, the occurrence of divergent phenotypes between clinic measurements, and ABPM, as well as the main elements that determine blood pressure variability over 24 h, especially night-time dipping, are all elements that in addition to providing evidence for patient prognosis, can be used to guide antihypertensive treatment follow-up enabling greater precision in defining the effect of the drugs. In recent years, specific indices have been developed using 24-h monitoring, evaluate the duration of treatment action, the homogeneity of the effect over the monitoring period, and its possible effects on variability. In future controlled clinical trials on antihypertensive therapies it is necessary to evaluate the effects of those treatments on hard endpoints based on therapy guided by ABPM.The online version of this article (doi:10.1007/s40119-015-0043-1) contains supplementary material, which is available to authorized users. Non-invasive clinic blood pressure (BP) measurement dates back to the early twentieth century and corresponds to the invention of the mercury sphygmomanometer by the Italian physicist Scipione Riva-Rocci, and the description of arterial sounds by the Russian physician Nikolai Korotkoff. Since then, changes in the procedure for clinic measurement have been few and have mostly been based on the appearance of automatic or semi-automatic devices that have used a plethysmographic method instead of the classical auscultatory method described by Korotkoff. Part of this change has been motivated by restrictions on using mercury in health care devices.The two ways of measuring out-of-clinic BP, self-measurement at home and ambulatory BP monitoring (ABPM), were developed to obtain BP measurements outside health care settings, since those settings have a significant influence on BP in some individuals. Furthermore, especially in the case of ABPM, obtaining a higher number of measurements in a period containing the main sources of BP variability (activity/rest) provides a more precise approximation of an individual’s true BP.ABPM research has been particularly focused on epidemiological and diagnostic aspects. In this regard, the main indicators obtained during the course of ABPM correlate better with an individual’s organ damage and cardiovascular prognosis –4. MoreoApplying ABPM to therapeutic assessment has had less of an impact, both on the part of the investigators as well as on the part of the investment made by the sponsors of antihypertensive drugs and devices. A large part of this is motivated by the fact that the regulatory authorities continue to consider clinic BP measurement as the central element for approving antihypertensive drugs and devices. Nevertheless, the BP measurement indicators obtained using ABPM, the patient phenotypes during hypertensive treatment, dipping patterns, and BP variability over 24 h of monitoring, are of equally high interest when analyzing the effects of antihypertensive therapies . FurtherThis article describes the main indicators, direct or derived, from monitoring itself or combined between ABPM and clinic measurement that may be of interest in patients during antihypertensive treatment. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by the author.The mean 24-h, daytime, and night-time indicators have classically been the most used for both the relationship between ambulatory BP and cardiovascular prognosis, as well as for assessing the antihypertensive effect of drugs. Daytime BP, or BP during the period of activity, was one of the first parameters studied, since it is considered the closest to in-office BP. The current guidelines for diagnosing and treating HTN from the National Institute for Health and Care Excellence (NICE) of the British Government advises practicing ABPM during the day to confirm the HTN diagnosis when the clinic figures are high . DaytimeOne study has used daytime BP to guide antihypertensive treatment adjustment and monitoring in comparison with clinic BP . Thus, pThe mean BP of all measurements made over 24 h of monitoring is considered to be the one that provides better information. A larger number of measurements are included in its calculation. As such, it is less affected by sporadic situations that may arise during the day or night or by sporadic errors. It takes into account daytime activity, work, and the changes in pressure caused by those activities, as well as rest and the quality of it, and the night-time pressure dip. Its relationship with cardiovascular prognosis, as well as the presence and severity of organ damage, are clearly better than clinic pressure. From a therapeutic point of view, several meta-analyses have evaluated the correlation between the decrease in clinic BP or 24-h BP induced by antihypertensive treatment. Thus, in one of them that included 44 studies with more than 5000 patients, the mean decreases in clinic BP were 19/10 mmHg, while those corresponding to the 24-h figures were 13/8 mmHg. The percentage of 24-h BP reductions compared to clinic BP was 65% and 81%, respectively, for systolic and diastolic BP [Another conclusion reached in that meta-analysis was that the definitions of responders and patients achieving BP control were not able to be extrapolated to the values obtained in 24-h ABPM. Thus, the final in-office BP values 143/90 mmHg) were only slightly better than the normal values (<140/90 mmHg), suggesting that a high percentage of patients managed to achieve BP control. Conversely, the final 24-h BP values (139/86 mmHg) were clearly above the limits of normal (<130/80 mmHg), suggesting that achieving 24-h control was far below the clinic control achievement. These results were later confirmed in another meta-analysis that included studies with clinic measurement, home measurement, and ABPM. The BP reduction was greater in the clinic than at home, and higher at home than in the 24-h values [3/90 mmHgNight-time BP measurements have been progressively acquiring more importance. Of all the indicators obtained during ABPM, it is the one that is best correlated with the prognosis –4. Its mJointly using clinic measurement and ABPM has resulted in the creation of new patient categories that have expanded the hypertensive/normotensive dichotomy. Thus, the consistency between normal figures in clinic BP and those obtained through ABPM is called normotension, whereas the consistency between high figures in the clinic and ABPM constitute sustained HTN. The two new types represent the presence of discrepancies between both forms of measurement. Thus, high figures in the office and normal ones in ABPM constitute the phenotype known as white-coat HTN or isolated clinic HTN. This category, in principle, restricted to the diagnosis of patients without treatment, is also used in patients on treatment in whom ABPM figures are controlled, but not those in the clinic. At the opposite extreme are individuals with normal clinic BP figures but with high ABPM figures. This situation is known as masked HTN in untreated individuals or as masked uncontrolled hypertension (MUCH) in those who are on treatment.Though there is a general consensus that the presence of masked HTN or MUCH confers a risk that may be comparable to that of sustained HTN , 19 , and 45% if only daytime normality is considered  The clinical features that are associated with these divergent phenotypes are, in the case of white-coat HTN, old age, the female sex, the absence of other risk factors such as smoking or diabetes, and cardiac or renal organ damage , 24; wheAt this time, there is no absolute consensus on the need for antihypertensive treatment in patients with divergent phenotypes. All the observational studies demonstrate that masked HTN or MUCH result in a high risk of developing future cardiovascular events. As such, it seems logical to think that those patients are suitable for starting antihypertensive therapy. Nevertheless, no study has demonstrated that this treatment will improve the prognosis in those patients; therefore, the therapeutic decision is completely empirical. Even more uncertainties exist about the follow-up for these patients, including target figures or regularity of repeating ABPM .As for subjects with white-coat HTN, as previously mentioned, there are discrepancies between the likelihood of having a major cardiovascular event or not. Moreover, treatment in those patients, even reducing the BP figures, seems to have little impact on the BP figures obtained by ABPM. The current guidelines recommend antihypertensive treatment in high-risk patients with known cardiovascular disease or with hypertensive organ damage. In the rest, a close follow-up and early detection of the appearance of sustained HTN seems to be the best option .The decrease in BP caused by rest and sleep, usually at night, has a favorable impact on reducing the pressure burden related to the organ damage. Almost 40 years ago, it was described that some patients in whom this night-time dip was less pronounced  had a worse risk profile and a higher probability of developing cardiovascular events and death . In geneThe data from the Spanish ABPM Registry have allowed us to determine that the prevalence of these “deleterious” patterns is very high, approaching 50% of untreated patients and exceeding this figure in those on treatment Fig. . Old ageThe main problem in assessing the dipping pattern is its association with night-time BP levels. Both elevated night-time BP as well as inadequate nocturnal dip have been related with a worse prognosis. Nevertheless, the fact remains that both situations are intimately related, which makes it difficult to separate their independent effects. A separate assessment of both phenomena has enabled these uncertainties to be cleared up. Thus, there have been patients with inadequate night-time BP dip who despite everything present normal night-time BP figures, and by contrast, there have been patients with night-time HTN but with a night-time BP dip above 10%. In this analysis, the non-dipper pattern in the absence of night-time HTN was associated with the female sex, impaired kidney function, and a history of cardiovascular events, whereas night-time HTN in the presence of a normal pattern was associated with the male sex, diabetes, and asymptomatic organ damage . Obviously the worse risk profile was observed in patients who presented both night-time HTN and a non-dipper pattern .After the sleep-induced night-time BP dip, the morning surge that accompanies waking is a physiological phenomenon. However, some studies have observed that an exaggerated morning BP surge is associated with a higher rate of cardiovascular events . The horAnother parameter of interest intimately related to the morning surge is known as morning HTN, which consists of high BP figures obtained just after waking. A recent study in patients being treated for HTN demonstrated that the BP figures obtained in the first hour of the morning through self-measurement had a greater prognostic impact than clinic BP figures. Values above 145 mmHg were associated with a higher rate of cardiovascular events .The main problems that arise when evaluating the phenomena of the morning surge and morning HTN are, on one hand, that most studies have been carried out in a Japanese population. Data in a Mediterranean population suggest that the morning surge in this population is less pronounced than in the Japanese population ; thus its prognostic impact is presumably less. On the other hand, morning surge and morning HTN are influenced not only by physiological or pathophysiological circumstances, but also by type of treatment, its posology, and the duration of action of the drugs. Thus, if we take into account that most drugs are administered in the morning, this morning surge coincides with the end of the period of the therapeutic window, and therefore only those drugs with a longer half-life will significantly reduce these parameters.Although there are not many comparative studies, not all antihypertensive drugs ensure 24 h of coverage. Olmesartan and telmisartan among the angiotensin receptor blockers, lisinopril among the angiotensin-converting enzyme inhibitors, amlodipine among the calcium blockers, and chlorthalidone among the diuretics are probably the drugs with the longest duration of antihypertensive effect in their respective classes. Some others with shorter coverage times may see that time extended with pharmaceutical modifications that slow down their absorption.BP is a dynamic parameter that fluctuates based on several circumstances, some intrinsic and other extrinsic . Long-teIn recent years, there has been a growing interest in assessing the impact of antihypertensive treatment on this short-term variability determined by ABPM. Initial studies have used modifications in the posology of the drugs  and assessed their impact on the dipping pattern. Thus, it has been demonstrated that this night-time administration promotes a larger night-time dip and, as such, a proportion of non-dipper or riser patients becomes dippers. In one of these studies, this phenomenon was associated with a better cardiovascular prognosis .In addition to all the above-described parameters used to assess the effect of antihypertensive therapy, some mathematical indices have been developed that combined potency, duration of action, and homogeneity of effect. This allows for a better assessment of the effects of antihypertensive treatment.T/P) ratio. Interest in this ratio appeared nearly two decades ago and consists of calculating the ratio between the decrease in BP obtained in the hours just before the end of the therapeutic window (with drugs administered once a day between 22 and 24 h after administration) and the maximum effect calculated after several hours (between 4 and 6 h after administration). In theory, the closer it is to unity, the greater the homogeneity of effect, suggesting that the residual effect of the drug is close to its maximum effect. However, the T/P ratio has two significant problems. The first is a result of poor reproducibility, caused by the need to extract short periods of monitoring from a 24-h ABPM that may be influenced by external factors. Thus, the peak period or maximum effect may coincide with a postprandial rest (nap), which will magnify it, or with a period of higher physical or mental activity, which will minimize it. For its part, calculating the trough effect may coincide with the last hours of sleep or with waking, both circumstances that may change it. In addition, the T/P ratio does not take into account the magnitude of the antihypertensive effect, so that minimal decreases in BP in the peak will be associated with high T/P indices  [The first of these indices is the trough-to-peak (round 1) .The second index that measures homogeneity of effect is called the smoothness index (SI) . It is cOne last index proposed very recently is the treatment-on-variability index (TOVI), calculated using the ratio between the 24-h decrease in BP and the change in the weighted standard deviation  . A recenBetween 10% and 15% of patients with HTN do not manage to normalize their BP values despite treatment with 3 or more antihypertensive drugs. They fall under the category of resistant HTN , 43. MosIn a broad study stemming from patients in the Spanish ABPM Registry, one-third of 8295 patients who could be categorized as resistant hypertensive had normal 24-h BP figures, where resistance was due to a white-coat effect. Compared with truly resistant hypertensive patients, the organ damage in these patients was less and the cardiovascular prognosis better [The need to demonstrate that the BP values obtained using ABPM are undoubtedly high in resistant hypertensive patients was recently supported by the appearance of more invasive therapies, such as renal sympathetic denervation or baroreflex stimulation as a treatment for patients with resistant HTN . The firABPM should be considered the standard measurement of BP, a starting point for assessing and treating patients with HTN, as some recent guidelines recommend , 8, 48. Supplementary material 1 (PDF 200 kb)Below is the link to the electronic supplementary material.