High resting heart rate is considered an important factor for increasingmortality chance in adults. However, it remains unclear whether the observedassociations would remain after adjustment for confounders inadolescents.To analyze the relationship between resting heart rate, blood pressure andpulse pressure in adolescents of both sexes.A cross-sectional study with 1231 adolescents (716 girls and 515 boys) aged14-17 years. Heart rate, blood pressure and pulse pressure were evaluatedusing an oscillometric blood pressure device, validated for this population.Weight and height were measured with an electronic scale and a stadiometer,respectively, and waist circumference with a non-elastic tape. Multivariateanalysis using linear regression investigated the relationship betweenresting heart rate and blood pressure and pulse pressure in boys and girls,controlling for general and abdominal obesity.Higher resting heart rate values were observed in girls (80.1 ± 11.0beats/min) compared to boys (75.9 ± 12.7 beats/min) (p ≤0.001). Resting heart rate was associated with systolic blood pressure inboys  and girls , withdiastolic blood pressure in boys  and girls , and with pulse pressure in boys .This study demonstrated a relationship between elevated resting heart rateand increased systolic and diastolic blood pressure in both sexes and pulsepressure in boys even after controlling for potential confounders, such asgeneral and abdominal obesity.  Thisrelationship could be mediated by other important cardiovascular risk factors suchas obesity,4 which, through inflammatory substances, couldincrease RHR.6In previous studies,7 has demonstrated a positive relationship betweenhigh RHR and PP in 227 healthy male African-American adolescents. However, as PP isaffected by both BP levels and obesity status, it remains unclear whether theobserved associations would remain after adjustment for these confounders.Another factor that has been associated with high RHR is pulse pressure (PP), animportant marker of vascular stiffness. A recent study8 havefound that male adolescents had significantly higher PP values than femaleadolescents. Higher values of heart rate variability were observed in men comparedto women.9 These findings show thathormonal and local fat deposition characteristics could influence RHR and othercardiovascular risk factors.Moreover the sex of adolescents should also be considered when analyzing theserelationships. Rosa et al.The purpose of this study was to analyze the association between RHR, BP and PP inadolescents of both sexes and to identify covariates of this association.This was a cross-sectional study carried out in the city of Londrina, Paranástate, situated in southern Brazil. A meeting was held with the Secretary ofEducation in the city of Londrina. As a result of that meeting, information wasobtained on the six largest public schools in the downtown area, which were mostlikely to include students from different regions of the city . Those schools were chosen for the study.Londrina has approximately 17,000 enrolled students. To calculate the sample size, weused a correlation value of 0.18, an alpha error of 5%, a power of 80% and a designcorrection of 2.0 . Considering 20% losses,a minimum sample size of 624 students was required. The sample was composed of 1231adolescents aged 14-17 years (515 boys and 716 girls). The inclusion criteriaconsisted in authorizing the consent form signed by parent/guardian allowing theiradolescent to participate in the study, not be ingesting any medication or being intreatment related to problems of BP or heart rate. This study was approved by theethics committee on human experimentation of the institution involved (process:203/2010).2). Adolescents were classified as normal weight oroverweight according to the cutoff points of the World HealthOrganization.10All anthropometric measurements were performed by the same researcher,according to standardized techniques. Waist circumference was measured usingan inextensible tape-measure, according to the values recommended byTaylor et al.,11considering the age and sex of the adolescents.Body weight was measured using an electronic scale , withthe subjects wearing light clothing, and height was measured with awall-mounted stadiometer . Body mass index (BMI) wascalculated from the values of weight divided by height squared, validated foradolescents.14Systolic BP (SBP) and diastolic BP (DBP) were measured concomitantly withRHR. The mean value was used. To indicate the presence of high levels of BP,the 95th percentile of the National High Blood Pressure Education Programcutoffs was considered, adjusted by age and height percentile.Pulse pressure was calculated (difference between SBP and DBP).The sample characterization data were described as mean and standard deviation.As there is no specific cutoff point for RHR or PP in adolescents, we chose toclassify the adolescents in the highest quartile as having a possible risk forthose outcomes.The number of adolescents classified according to the risk factors was analyzedby means of frequency and possible associations observed by using the Chi-squaretest. The multivariate analysis (Linear Regression) was applied and adjusted forsex and age (first model), overall fat determined by BMI (second model), andcentral fat (third model). The confidence interval was 95% and significancelevel, p < 0.05. All statistical analysis was performed using SPSSv.18.0.Younger age had higher RHR values . Higher RHR values were observedin girls (80.1 ± 11.0 beats/min) as compared to boys (75.9 ± 12.7beats/min) (p ≤ 0.001). Elevated RHR was observed in 131 male adolescents(25.4%) and in 231 female adolescents (32.2%) (p = 0.011). There was no differencein BMI between boys and girls, but boys classified as having high RHR had higherBMI. The boys had higher waist circumference than girls, and the boys classified ashaving high RHR had higher waist circumference values. The sample characteristicsare shown in A low correlation was observed between BMI and RHR (r = 0.06). Adolescents withhigher RHR had a higher prevalence of high BP . Therewas no significant difference in RHR in adolescents when stratifying for nutritionalstatus (p = 0.174) or PP values (p = 0.158). The linear regression models adjusted for sex, age, overall fat and central obesityindicated that RHR was associated with SBP (p ≤ 0.05) and DBP (p ≤0.05) for both sexes, and with PP (p = 0.05) only for boys  and 4.This study's results indicate that adolescents with higher RHR values have higher SBPand DBP values. High RHR was associated with higher SBP and DBP in males andfemales, and was inversely related to PP only in male adolescents.15 who, assessing more than 8,000individuals from different countries, aged 48-56 years, have found that high RHRassociated with high BP values. Similar findings were observed by Kwok etal.,4 who evaluated therelationship between high values of RHR and of BP in young Chinese individuals.Corroborating our study, Fernandes et al.3 have demonstrated similar relationships in 356 maleadolescents. Even after controlling for different variables in the cited studies,high BP values were associated with high RHR. One reason is that heart rate and SBPand DBP are modulated by the central nervous system through sympathetic activity inthe heart and vessels.16This study's results are in agreement with those reported by Liu et al.,17 This study's results indicatedthat RHR was correlated with PP only in male adolescents, which is in agreement withthose reported by Song et al.18 ina representative sample of Korean adolescents. One possible mechanism is the factthat PP is an indicator of arterial stiffness, which contributes to heart ratechanges mediated by increased velocity of the pulse wave from the aorta to theperipheral vessels; in this case, the higher the speed of the anterograde wave, thehigher the successive retrograde wave, causing cardiovascular overload.19Pulse pressure is an indicator of arterial stiffness of different arteries andvessels and has been related to arteriosclerotic processes.20 have observed that RHR wasstrongly associated with obesity, added to which, average values of heart rateincreased according to the degree of obesity. Adipose tissue releases a variety ofsubstances, including adiponectin, which could contribute to changes in thesympathetic nervous system and decreased parasympathetic nervous system,21 increasing RHR values. Therefore,obesity is an important confounding factor to be considered in the analyses. Thecorrelation between RHR and PP remained significant after adjustment for age, age +BMI, and age + BMI + waist circumference in males, suggesting an independentrelationship between PP and RHR. A previous study16 has found no correlation between total fat massand cardiovascular variables  in male adolescents,unlike abdominal fat. On the other hand, in female adolescents, the relationshipsare absolutely inverse, the cardiovascular variables are directly related to total fat mass and unrelated to waistcircumference.18Another factor to be considered in this study is the relationship between obesity andincreased heart rate. In a study of over 30,000 young people, Babba et al.8 afterevaluating 456 adolescents, with higher PP values found in male adolescents. Onepossible difference to be considered is the age range of students in the currentstudy (14-17 years), menstruation is a period of intense activity in girls and mayalter the autonomic system due to intense hormonal production,22 leading to differences compared toboys. The location of body fat could also be related to higher RHR values. This hasbeen clearly observed by Song et al.,18 who have found a direct relationship between cardiovascularvariables  and waist circumference in maleadolescents.Concerning sex, the present study demonstrated associations between high RHR, SBP andDBP in both sexes; however, when considering RHR and PP, this relationship wasobserved only in male adolescents. Pulse pressure differences in boys and girls wereobserved by Rosa et al.23 and in addition to their ease of use, they typically providevalues of BP and heart rate, which could be assessed in the school environment,enabling the early control of those risk factors.Regarding practical applications, it should be emphasized that such assessments needto be conducted from the earliest ages, aimed at preventing future cardiovasculardiseases. Oscillometric devices have been used in several studies,24 Another limitingaspect is the fact that PP was measured indirectly from the SBP and DBP values, andnot from the pulse wave speed.One limitation of this study was its cross-sectional design, which does not allowassessment of the possible cause and effect relationships. Heart rate and BP wereevaluated on the same day, which is known to cause overestimation ofvalues.In conclusion, male adolescents with higher RHR had higher SBP, DBP and PP values. Infemale adolescents, RHR was associated with SBP and DBP, but not with PP. Thus,health promotion activities should be encouraged in young populations, becausecardiovascular risk factors interact. However, inherent characteristics of sex mustbe considered.


Central blood pressure level is not always consistent with peripheral blood pressure level, and especially their joint effect on incident hypertension is not well established. A total of 1607 non-hypertensive subjects from an atherosclerosis cohort in Beijing, China were included. Central systolic blood pressure (cSBP) was obtained using Omron HEM-9000AI machine and peripheral systolic blood pressure (pSBP) was measured using Omron HEM-7117 electronic sphygmomanometer, separately. Hypertension was defined as BP ≥ 140/90 mmHg or self-reported hypertension or taking any antihypertension drugs at the follow-up survey. After a median follow-up of 2.3 years, incident hypertension was 13.1%. Every 1 standard deviation increase of cSBP and pSBP was associated with 1.98 (95%CI: 1.69–2.33) and 2.84 (95%CI: 2.30–3.52) times of incident hypertension after adjustment for confounders. Moreover, hypertension risk in single pSBP ≥ 120 mmHg group, single cSBP ≥ 120 mmHg group, and both pSBP and cSBP ≥ 120 mmHg group was 2.83 (95%CI: 0.98–8.16), 3.28 (95%CI: 1.24–8.70), and 11.47 (95%CI: 4.97–26.46) times higher than both pSBP and cSBP < 120 mmHg group, respectively. The joint effect of cSBP and pSBP is superior to either cSBP or pSBP to predict incident hypertension in a Chinese community-based population. Screening of central blood pressure should be considered in non-hypertensive population for the purpose of primary intervention, especially for subjects with pSBP ≥ 120 mmHg. Early identification of high risk population is obvious in its importance for primary prevention of hypertension, especially in less developed countries. Conventional measurement of blood pressure relies on brachial cuff sphygmomanometer due to its convenient and non-invasive characteristic – a practice having been introduced into medical practice for over 100 years. However, arterial blood pressure varies continuously when moving from the aorta to the periphery because of pulse wave amplification across the arterial tree4.Hypertension is a challenging public health problem worldwide for its high incidence and strong correlation with cardiovascular disease, strokes, and renal outcomes5. Growing evidence suggests that central pressures are more relevant in predicting cardiovascular risks and target organ damage than brachial pressures9. Moreover, the reduction of central pressures in hypertensive population appears to be more effective in preventing cardiovascular morbidity and mortality11, indicating that central blood pressure may be a new worthwhile treatment target for hypertension management. However, few studies have accessed the relation of central blood pressure with future hypertension risk. Recent studies suggest that central blood pressure may be a powerful predictor for future hypertension independent of conventional risk factors13, but more compelling evidence is still needed. In addition, there are no previous trials investigating the joint effect of central blood pressure and peripheral blood pressure on hypertension risk, so whether central blood pressure can provide incremental value over peripheral blood pressure in risk profile for hypertension prevention remains to be elucidated.Central blood pressure, pressure at the aortic root, can now be reliably estimated by a variety of non-invasive validated devices and is highlighted as the “true pressure” exerted on target organs such as the heart, kidney, and brainTo better understand the different role of central and peripheral blood pressure in the prediction of hypertension, we herein designed this prospective study to investigate the impacts of central systolic blood pressure (cSBP) and peripheral systolic blood pressure (pSBP) on incident hypertension separately and jointly in a Chinese community-based population without hypertension at baseline.Among the 1,607 subjects enrolled at baseline, 211 (13.1%) subjects were found to be hypertensive after 2.3-year follow-up at 2014. Table In the spline model adjusted for potential confounders, the predictive risk of new-onset hypertension generally increased with rising level of cSBP and pSBP Fig. . A roughTable Joint effect of cSBP and pSBP on hypertension risk based on the four defined groups is shown in Table 14.The present study shows that both cSBP and pSBP were independently associated with future hypertension incidence, while different patterns were observed in the spline model. More importantly, combined detection of cSBP and pSBP would considerably improve the identification of people with elevated hypertension risk, thereby lending support to the hypothesis that central blood pressure measurement may be an attractive approach for primary prevention of hypertension. Our study also provides additional support for the recent perspective that central blood pressure not only served as an endpoint, but could also be a predictor of future cardiovascular risk in clinical practice15. In this substudy, differential effects on central pressures were reported for different blood pressure lowering drugs despite similar effects on brachial pressures, which might explain the “beyond blood pressure benefits” of cardiovascular stroke and survival in the calcium channel blocker (amlodipine) group compared with the beta-blocker (atenolol) group. Subsequent studies pointed out that central pressures were more closely correlated with intermediate measures of cardiovascular risk  than corresponding brachial blood pressures17. Further, some longitudinal observations demonstrated that central pressures were more predictive of cardiovascular events and mortality than brachial pressures9. However, much less is known for central blood pressure in the prediction of hypertension risk. In this context, the present work would contribute to the knowledge of the role of cSBP as potential complementary to brachial blood pressure in hypertension prevention and management.The value of brachial artery pressure in the epidemiology of hypertension has been firmly established, embodied in guidelines for hypertension management. As non-invasive devices introduced to medical practice, greater emphasis has been placed on central pressures recently for they can more exactly reflect the pressures loading on target organs such as the central nervous system, the heart and the kidney. The most influential study drawing attention to the potential superiority of central blood pressure over brachial blood pressure was the CAFÉ substudy of the ASCOT trial12. Another prospective observational study conducted in a cohort of young to middle-aged participants with stage 1 hypertension reported that central blood pressure was an independent predictor of future antihypertensive treatment13. However, the combined effect of cSBP and pSBP on incident hypertension has not been described in prior studies. Data from our cohort suggest that central blood pressure could provide increment predictive value in addition to brachial blood pressure for future hypertension risk as seen by the significantly higher hypertension incidence in the both pSBP and cSBP ≥ 120 mmHg group.Our findings of an association between cSBP and an increased risk of hypertension are consistent with previous studies. In a recent study of middle-aged Japanese men, Tomiyama suggested that central aortic systolic blood pressure could predict future hypertension more reliably than brachial-ankle pulse wave velocity independent of traditional risk factors18. Because cuff measured brachial blood pressure underestimates catheter brachial blood pressure by approximately 18 mmHg19, the SBP2 would substantially underestimate cSBP whenever the cuff measured brachial blood pressure was used for calibration. To relieve the influence of the cuff pressure on cSBP estimation and bridge the gap between noninvasive and invasive measurements, the Omron device introduced a regression equation to calculate the non-invasive cSBP with SBP2 asserting into the equation as a major independent variable18. As a result, cSBP provided by the Omron device is usually higher than corresponding cuff measured brachial systolic blood pressure under many instances, but is more closely to the invasive cSBP19.As to our knowledge, central blood pressure is invariably lower than corresponding brachial blood pressure based on invasive catheter measurement. Contrary to this fact, in our study, the average cSBP of total population was higher than corresponding pSBP and 270 (16.8%) subjects were assigned to the pSBP < 120 mmHg and cSBP ≥ 120 mmHg group. This can be explained by the cuff errors of brachial blood pressure measurement and the technological approach of Omron device. The Omron device records the radial pulse waveform and obtains the second peak of the peripheral systolic pressure (SBP2) by calibrating the radial waveform with brachial blood pressure5. The disparity between central and peripheral blood pressure is mainly determined by the pulse pressure amplification. Therefore, any factors causing increased stiffness of aortic artery and wave reflection would augment central blood pressure independently of brachial blood pressure20. Indeed, recent cross-sectional studies have reported a stronger association of central aortic pressure with carotid wall remodeling and increased arterial stiffness than brachial blood pressure, even in normotensive subjects23. In light of the fact that increased aortic arterial stiffness would proceed hypertension27, it is reasonable to deduce that central blood pressure as a surrogate maker of arterial stiffness may provide valuable instructions for hypertension prevention24. Further, in the Anglo-Cardiff Collaborative Trial II Study, McEniery observed that individuals presented with higher central blood pressure had more cardiovascular risk factors or diseases despite similar peripheral blood pressure, and over 70% of individuals with high normal peripheral blood pressure had similar central blood pressure as those with stage 1 hypertension, >30% of men and 10% of women with normal peripheral blood pressure had central blood pressure in common with subjects with stage 1 hypertension28. On condition that hypertension shares similar risk factors with cardiovascular disease 31, a higher central blood pressure level might indicate a greater potential of progression to hypertension. Results of our study reinforced this hypothesis for a higher odds ratio for incident hypertension was observed in the single cSBP ≥ 120 mmHg group compared with the single pSBP ≥ 120 mmHg group.This observational study does not provide a causal relation between cSBP and the development of hypertension. However, there are several possible pathophysiological mechanisms supporting an association between cSBP and hypertension risk. Specifically, the pressure wave generated by the left ventricle travels from the high elastic aortic artery to the stiffer periphery and is reflected at bifurcations and caliber disparitiesSeveral limitations in this study should be addressed. First, until now, there is no established standard reference value for cSBP. In this study, we defined subgroups with a cut-off value of 120 mmHg for both pSBP and cSBP based on guidelines of peripheral blood pressure and previous works on central blood pressure. This would inevitably cause diminished accuracy for central blood pressure categorization. Besides, technological differences between different validated devices would also lead to differential results in various studies. Second limitation of this study was the heterogonous definition of new-onset hypertension, defined as brachial blood pressure ≥140/90 mmHg or self-reported hypertension or taking any antihypertension drugs at the follow-up survey. In case subjects taking antihypertension drugs for other reason (i.e. cardiovascular disease), we performed a separate multivariate analysis. Exclusion of individuals taking any antihypertensive drugs at follow-up visit did not alter the results (data not shown). Third, although not necessarily a limitation, the correlation between blood pressure indices and incident hypertension did not indicate causal relationships given the nature that this is a longitudinal observational study.32. Briefly, from December 2011 to April 2012, residents aged above 40 years in the Gucheng and Pingguoyuan communities of the Shijingshan District were enrolled either by responding to the study recruitment posters or by inviting phone calls if the community health centers had their health medical records. A follow-up survey was conducted among subjects who had gene chip data in the year of 2014, from May to July. Participants fulfilling the following criteria were included in this substudy: (1) completed both the baseline and follow-up visit; (2) had no established hypertension and baseline brachial blood pressure <140/90 mmHg; (3) did not take any antihypertensive drugs at baseline visit; (4) had successful central and peripheral blood pressure measurements. Finally, a total of 1607 eligible subjects were included in our final analysis. All participants gave informed consent and the study was approved by the ethics committee of both Peking University and Peking University First Hospital. The methods were carried out in accordance with relevant guidelines and regulations.The study population was from a community-based atherosclerosis cohort in Beijing, China, details of which have been published previouslyParticipants completed a standardized written questionnaire concerning socio-demographic and medical data including age, gender, occupation, education, lifestyle factors, comorbid conditions and medical history. Current smoking was defined as cigarette consumption of one cigarette per day for at least half a year. Current drinking was defined as alcohol intake once per week for at least half a year. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m).33. Diabetes mellitus was defined as fast blood glucose ≥7.0 mmol/L, or oral glucose tolerance test (OGTT) ≥11.1 mmol/L, or any self-reported history of diabetes.Overnight fasting blood samples were drawn for glucose, lipid, serum creatinine and other biochemical measurements. All baseline laboratory variables were tested using the Roche C8000 Automatic Analyzer . Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to determine glomerular filtration rate (eGFR) based on serum creatinine18. Left radial artery pressure waveforms and right brachial blood pressure were measured simultaneously after the subjects enduring a rest in sitting position for at least 5 min. Then we obtained the first and second peaks of the peripheral systolic pressure (SBP1 and SBP2) by calibrating the radial waveform with brachial systolic blood pressure. Finally, central blood pressure was automatically calculated with a linear equation for SBP2.Measurements of central blood pressure were conducted with an automated device  using the method of radial artery applanation tonometryPeripheral blood pressure was measured using a validated automatic arm device  with appropriately sized cuffs following a standard protocol. With the participant being seated in a quiet room for a 5-minute rest, three blood pressure readings were obtained at intervals of no less than 1 minute. The average of the 3 consecutive readings was recorded as the final pSBP and peripheral diastolic blood pressure (pDBP) value. Simultaneously pulse at rest was obtained. New onset of hypertension was defined as blood pressure ≥140/90 mmHg or self-reported hypertension or taking any antihypertension drugs at the follow up survey.www.empowerstats.com, X&Y solutions, Inc. Boston MA). Data were expressed as mean ± standard deviation (SD) for continuous variables and percentages (%) for dichotomous variables. Comparison of continuous variables was performed using an independent t-test, and categorical variables were compared using chi-square analysis. Multivariate logistic regression models were used to investigate the independent and joint relations of cSBP and pSBP to new onset of hypertension. Covariates adjusted in the models included age, sex, BMI, current smoking and drinking status, dyslipidemia, diabetes mellitus, history of cardiovascular disease, lipid-lowering medications, hypoglycemic medications and baseline eGFR. The spline curves were also plotted to obtain additional insights into the association between cSBP, pSBP and hypertension risk.All statistical analyses were carried out using SPSS 19.0  and Empower (R) : pSBP < 120 mmHg, cSBP < 120 mmHg;Group 2 (G2): pSBP ≥ 120 mmHg, cSBP < 120 mmHg;Group 3 (G3): pSBP < 120 mmHg, cSBP ≥ 120 mmHg;Group 4 (G4): pSBP ≥ 120 mmHg, cSBP ≥ 120 mmHg.To examine the joint effect of pSBP and cSBP on new onset of hypertension, we defined four subgroups according to their baseline cSBP and pSBP levels. Current hypertension guidelines recommended <120/80 mmHg as normal, and 120–139/80–89 mmHg as prehypertensive for peripheral blood pressureThe datasets generated during the current study are available from the corresponding author on reasonable request.In conclusion, our findings suggest that the joint effect of cSBP and pSBP is superior to either cSBP or pSBP to predict incident hypertension in a Chinese community-based population without hypertension. Thus, non-invasive central blood pressure screening should be considered in non-hypertensive population as a routine health examination for the purpose of primary prevention of hypertension, especially for people with pSBP ≥ 120 mmHg.


In patients with obesity-related hypertension (ORH), reaction to antihypertensive medication is likely influenced by patientcharacteristics.Effects of aliskiren, moxonidine and hydrochlorothiazide on 24-h blood pressure (BP) were compared to placebo. Linear mixed effect models were used to analyze the effect of patient characteristics on BP levels and treatment response.Systolic BP response to aliskiren was higher in patients with a BMI > 30.7 kg/m2 compared to patients with a BMI ≤ 30.7 kg/m2 (−21 mmHg versus -4 mmHg). In patients with a hsCRP > 1.8 mg/L the systolic BP response to aliskiren was higher than in patients with a low hsCRP (−15 mmHg versus −7 mmHg). Hydrochlorothiazide (HCTZ) treatment effect on systolic BP was −13 mmHg when heart rate > 71 beats/min compared to -3 mmHg when heart rate was ≤ 71 beats/min.In patients with ORH, BP response to aliskiren is positively related to BMI and hsCRP. Systolic BP response to HCTZ is positively related to heart rate and negatively to renin levels.NCT01138423. Registered June 4th, 2010. Subjects who are either overweight or obese have a 2 time higher risk of developing hypertension as compared to persons with a normal BMI , 2. In pPatient characteristics linked to the underlying pathophysiological mechanisms of ORH could also influence blood pressure. The major underlying mechanism linking obesity to hypertension is thought to be adipose tissue dysfunction, defined as an imbalance between the release of pro- and anti-inflammatory adipokines, resulting in activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic overdrive, low-grade inflammation and oxidative stress –7. EventKnowledge of patient characteristics that influence the blood pressure response to antihypertensive treatment in patients with ORH may help to identify the most effective blood pressure lowering treatment in individual patients. Response to anti-hypertensive medication varies significantly in patients with previously untreated primary hypertension –12 and iIn the present study we evaluated which patient characteristics influence the blood pressure-lowering effect of the direct renin inhibitor aliskiren, the sympathicolytic agent moxonidine and the diuretic hydrochlorothiazide in patients with ORH.We used data from a cross-over trial in which 31 previously untreated patients with ORH were successively treated with aliskiren, moxonidine, hydrochlorothiazide (HCTZ) and matching placebo, in random order, each for 8 weeks. A detailed description of the methods has been published earlier . In summ(Pre)hypertension was defined as office systolic blood pressure (SBP) > 130 mmHg and/or office diastolic blood pressure (DBP) > 85 mmHg during two screening visits on separate days. Blood pressure was measured two times on both arms in sitting position after the subject had been seated for some minutes using an appropriately sized arm-cuff and an automated oscillometric blood pressure device . Blood pA linear mixed effect model was used to determine which characteristics modified the relationship between treatment  and 24-h systolic and diastolic blood pressure (DBP), adjusted for time since randomization, age and gender. Patient characteristics considered were gender, BMI, waist, age, fasting glucose, mean 24-h heart rate, aldosterone, renin, muscle sympathetic nerve activity (MSNA), 24-h urine sodium excretion, hsCRP, adiponectin and leptin. These characteristics were measured during placebo treatment (in fasting condition between 7 and 9 am), except BMI and waist circumference, which were only measured at study baseline. MSNA was only performed in a subgroup of 15 patients due to the invasiveness and time-consuming nature of the measurement. Adiponectin, leptin and hsCRP levels were logtransformed due to their skewed distribution. All available follow-up data were included in the analyses even when patients did not complete all four treatments. The 95% confidence intervals (95% CI) were approximated on the basis of the coefficients’ standard errors.p-values for interaction. Analyses were performed with the statistical package R, version 2.11.1 .In the analysis determining characteristics influencing reaction to medication, scale variables were dichotomized at the median level and treatment effect was presented accordingly, combined with 2 (IQR 27.7-32.2 kg/m2) and a median office blood pressure of 153/88 mmHg , a median BMI of 30.7 kg/mTable 2 versus a decrease of 4 mmHg (95% CI −9 to 1 mmHg) in those with a BMI below the median, (p for interaction = 0.01).SBP response to aliskiren was significantly related to BMI. SBP decreased with 21 mmHg (95% CI −27 to −14 mmHg) in patients with a BMI above the median of 30.7 kg/mSBP response was also significantly related to hsCRP in patients with > 1.8 mg/L  compared with patients with ≤ 1.8 mg/L . None of the other patient characteristics was an effect modifier in the relation between treatment with aliskiren and blood pressure reduction.Table Table During moxonidine use, women  tended to have larger blood pressure reductions than men .Also, participants ≤ 60 years  compared with participants > 60 years  tended to have larger reductions in SBP.None of the other patient characteristics was an effect modifier in the relation between treatment with moxonidine and blood pressure reduction.In patients with a screening blood pressure of > 140/90 mmHg, results were not significantly different from those in the patients with a screening blood pressure > 130/85 mmHg.In patients with obesity-related hypertension the characteristics BMI and hsCRP influence the blood pressure lowering effect of the RAAS inhibitor aliskiren. Heart rate and renin levels influence the effect of the diuretic HCTZ and age and gender influence the effect of the sympatho-inhibitor moxonidine.The positive association between adipose tissue and blood pressure is mainly driven by visceral adipose tissue in males and by adipose tissue deposited elsewhere in females . As a reOne of the other mechanisms underlying ORH is an inappropriately normal or even elevated RAAS activity. An increasing BMI is correlated to an augmented activity of the RAAS system , 25 as r2, suggesting that there is a linear association between BMI and RAAS-activation. Inhibiting RAAS could therefore be more effective in terms of blood pressure reduction in individuals with the highest BMI [Renin and aldosterone levels drop significantly with weight loss, even when the BMI remains > 25 kg/mhest BMI . Aliskirhest BMI  and alsohest BMI . Since ehest BMI , this mahest BMI , 30. Thehest BMI , 33. A shest BMI . In our hest BMI .In ORH, due to impaired pressure natriuresis, volume overload can be an underlying pathophysiological phenomenon . Both hiIn this study, patients with the lowest plasma renin concentrations, an indication for high volume status, responded most to HCTZ therapy with respect to systolic blood pressure lowering. This is in line with observations in overweight hypertensive patients . ContrarStrengths and limitations of our study need to be considered. The influence on blood pressure response of possible effect modifiers could be analyzed during treatment with three different classes of antihypertensive medication, aimed at different pathophysiological mechanisms. Blood pressure and heart rate were measured very accurately with 24-h ambulant blood pressure measurements. An important limitation of this study is the relatively small sample size, especially the amount of women participating in the trial. In this study, participants were regarded hypertensive with a relatively low blood pressure of > 130 mmHg systolic or > 85 mmHg diastolic. In this patient category, there is no proof of better outcome with lowering blood pressure. However, the aim of our study was not to investigate the change in outcome of lowering blood pressure, but to study the pathophysiological reactions in patients with obesity and hypertension to different antihypertensive drugs. Moreover, not treating patients with a higher blood pressure and concomitant risk (metabolic syndrome) is unethical, and would undermine the careful design with a placebo period in this study.Since many determinants were measured, some of the significant results might be false-positive due to multiple testing. However, determinants were not chosen and analyzed in a random way, but were chosen on their pathophysiological link with hypertension.The blood pressure-lowering response of antihypertensive medication is for aliskiren influenced by BMI and hsCRP, for HCTZ by heart rate and renin levels and for moxonidine by gender.This emphasizes the multi-factorial mechanism of development of ORH, with activation of the RAAS system, sympathetic activation and volume overload being causative factors. Patient characteristics may guide choice of blood pressure-lowering medication in patients with ORH.


Evaluation of diagnostic accuracy of an oscillometry-based device (VascAssist) combining fully automated ankle-brachial index (ABI) and pulse-wave velocity (PWV) assessment for detection of peripheral arterial disease (PAD).n = 41) and healthy PAD-free participants (n = 69) were recruited. All subjects underwent standard manual Doppler-based ABI (sABI) and oscillometry-based automated ABI (aABI) measurements (VascAssist). Oscillometry by the VascAssist included central and peripheral PWV assessment. Additionally, arterial stiffness (AS) was evaluated by flow-mediated vasodilation (FMD) of the brachial artery in all patients. All symptomatic PAD patients underwent catheter angiography for endovascular intervention and post-interventional acquisition of sABI, aABI, PWV and FMD.110 consecutive subjects including symptomatic PAD patients  and for non-diabetics r = 0.77; (P < .001). Bland–Altman-analysis revealed a difference (95% CI) for diabetics of 0.09  and significant increase of pre-/post-interventional PWV analysis (P < .001).Sensitivity, specificity, PPV and NPV of aABI for detecting PAD was 73%, 100%, 100%, and 86% as compared to 80%, 96%, 92%, and 89% for sABI. Pearson-correlation for diabetics was Combined automatic ABI and PWV acquisition with the VascAssist device showed excellent diagnostic accuracy for detection of PAD. Compared to FMD, AS analysis may serve as an investigator-independent (screening) tool for determination of functional vascular damage in atherosclerosis. Atherosclerosis is the major reason for cardiovascular-related death in western countries. The disease is mostly asymptomatic at an early stage. Screening for peripheral artery disease (PAD) is usually made by non-invasive measurement of ankle-brachial index (ABI) –3. In coEarly detection of initial vascular damage is achievable by assessment of endothelial function . In addiMoreover, arterial stiffness is evaluable by pulse-wave analysis (PWA) of aortic/brachial pulse-wave velocity (PWV). Increased aortic PWV, augmentation index (AUI), and decreased arterial elasticity are typically present in patients with PAD , 12. TheThe beforehand mentioned diagnostic tests use different approaches to assess arterial distensibility as a surrogate for vascular function. Reduced distensibility, or arterial stiffness (AS) can essentially be expressed by the relationship between aortic compliance and total peripheral arterial resistance, which are derived from PWV analysis of oscillometrically acquired blood pressure curves .The purpose of our study was to validate the diagnostic accuracy of a dedicated oscillometric automated device (VascAssist) in patients with known PAD and healthy volunteers. The primary objective was to compare manual ankle-brachial index (sABI) measurement using Doppler-ultrasound and mercury-sphygmomanometry as the reference standard vs. investigator-independent automated ABI (aABI) measurement. Secondary objectives included AS compared to  sABI, aABI and FMD.n = 20 diabetics] with symptomatic PAD and impaired walking capacity <200 m (intervention-group), and 69 voluntary participants (control group) presumably free of PAD . Table Overall, 110 subjects were consecutively recruited including 41 patients [female 15%, mean age 69.0 ± standard deviation 11.4 (range 40–94) years, Exclusion criteria included at least one of the following: participation in another study, malignancy, cardiac pacemaker, limb surgery, current or pregnancy <12 months, necrosis at any measurement location, axillary lymphadenectomy, convulsions, spasms, tremor of any kind.intervention-group were characterized by symptomatic PAD with an impaired walking capacity <200 m. All these patients had been consecutively referred to our angiography department for transfemoral catheter angiography combined with endovascular interventions. ABI, AS, and FMD measurements were performed before and after angiography. Interventional procedures (n = 44) included iliac stenting (n = 10), femoro-popliteal (n = 25) balloon-angioplasty or stenting, or endovascular aortic repair EVAR (n = 9). Three patients underwent combined procedures.Individuals in the control group encompassed PAD-free participants with a non-compromised, normal walking capacity. All these participants underwent only non-invasive ABI, AS, and FMD measurements.The In both groups, all measurements were performed in the morning by the same experienced investigator in a temperature-controlled room (24 ± 1 °C) with the subject in a supine position, and after having rested supine for 15 min prior to measurements.Appropriately sized sphygmomanometric cuffs were used for sABI and aABI measurements. The participants rested supine for 15 min before pressure measurements were obtained.Measurements for sABI were performed with a commercially available unidirectional Doppler device . A brachial pneumatic cuff was applied to the left upper arm, inflated to supra-systolic pressure and deflated slowly until a Doppler-flow signal was detected. Determination of ankle pressure was determined similarly at both ankles with flow detection over the dorsal pedal and posterior tibial arteries. ABI was calculated as the higher of the two pedal pressures divided by the arm pressure. Measurements were taken in triplicate.Measurements for aABI were also performed in triplicate, immediately following the sABI measurements, using the VascAssist device (VA) . Four pneumatic cuffs were applied to both arms and distal lower legs. aABI was calculated for each extremity as the relevant ankle pressure divided by the higher of the two arm pressures.The FMD measurements were performed with patients in the supine position. Patients were instructed to avoid caffeine-, nicotine- and alcohol-containing products for at least 12 h before measurements. A blood pressure cuff was placed around the upper arm distal to the brachial artery segment that was explored. Ultrasound images were acquired using a commercially available ultrasound system with an 18 MHz high-resolution linear-array transducer . The cuff was continuously inflated 50 mmHg above the patient’s systolic blood pressure for 5 min. Brachial artery diameter and flow velocity were recorded using 2D echography prior to cuff inflation, at deflation and after deflation at 1 min intervals for 5 min. The probe was angulated at 90° for optimal morphologic B-mode imaging and <60° for optimal velocity acquisition. Diameter measurements were made with electronic calipers at the end of ventricular diastole .Analyses were performed offline, using STATA 11 software  by an investigator blinded to test conditions and patient identity. Demographic variables are presented as mean ± standard deviation and computed measures as mean ± standard deviation; categorical variables  are presented as absolute frequencies and percentages.P ≤ = 0.05, and assuming a correlation coefficient at r ≥ 0.3, 110 subjects provide a power of ≥0.89. Discrepancy of subject number in control and intervention group is based on the level of significance.A power analysis was conducted before recruitment to determine the appropriate number of study subjects. With significance set at Correlation between measures was determined by linear regression. Agreement between aABI and sABI measurements was investigated using the Bland–Altman method .t tests were conducted to analyze pre-intervention vs. post-intervention differences in AS. Shapiro–Wilk tests were performed to determine normality of differences between both measures. Since sABI was derived using left arm blood pressure values only, aABI was recalculated  accordingly for statistical analyses. To avoid the effects of interrelatedness of measures, within-subject ABI values were entered as independent observations for each leg.Pearson’s correlations were calculated between each ABI measurement mode, and to evaluate correlations between FMD and AS measurements. Paired samples’ Selection of ABI measurements for statistical analyses: The VascAssist software (VascViewer) alerts the investigator to potential invalidity of individual pressure recordings based on a plausibility assessment of the detection of (a) end-diastolic nadir, (b) systolic peak pressure and (c) pulsatility of the ankle pressure curves.Overall, 278 ABI measurements were obtained in 110 participants. Twenty-eight measurements were excluded: In nine instances, ABI acquisition was impossible for aABI and possible for sABI. In 11 instances, ABI acquisition was possible for aABI and not possible for sABI. Furthermore, in eight instances, ABI acquisition was neither possible for aABI nor for sABI. The reason for technical failures of ABI determination is speculative. Severe (media-)sclerosis and vessel occlusion should be the most probable assumption.z = 1.18 (P = .24). None of the healthy controls (n = 69) was misclassified by aABI vs. 3 misclassifications (4.3%) by sABI, which constitutes a non-significant difference at z = 1.69 (P = .09). Expressed as sensitivity, specificity, positive predictive power and negative predictive power, the aABI method scored at 73, 100, 100, and 86%, respectively, whereas the sABI method had corresponding values of 80, 96, 92, and 89%, respectively.The number of patients misclassified as healthy was 11 (26.8%) vs. 8 (19.5%) for aABI vs. sABI, respectively, which constitutes a non-significant difference at r = 0.81 the agreement between sABI and aABI was highly significant (P < .001).Figure Before application of Bland–Altman analysis the distribution of the differences between the methods was inspected regarding normality. The differences were found to be normally distributed. Bland–Altman analysis performed on all 250 measurements indicates a mean difference of 0.04, and 95% limits of agreement between the two methods ranging from −0.25 to 0.33  we became interested in a subgroup specific comparison of the two ABI measurement methods as described above.r = 0.81 (P < .001) and r = 0.77 (P < .001) for diabetics and non-diabetics, respectively , which highlights the power of automated oscillometric measurement even in patients with clinically relevant PAD and, therefore, only low ABI.When measurements were separated into diabetic and non-diabetic subgroups  in the respective values for bias and limits of agreements were 0.09 and −0.22 to 0.4 for diabetics, and 0.022 and −0.25 to 0.295 for non-diabetics, respectively Figs. b, 4b. Pely Figs. a, 4a. FiR = 0.386, P = .043. No correlation was observed between post-interventional FMD and AS (R = −0.06. P = .76). FMD increased non-significantly by 0.15% from pre- to post-intervention .Pre-intervention FMD and AS showed a borderline significant correlation, with t = 3.82, P < .001), reflecting a mean increase by 51 ± 54.1%, with 82% of patients (23 of 28) witnessing an increase in AS.Conversely, the increase in AS from a pre-intervention mean of 504.2 to a post-intervention mean of 704.4 was highly significant (p < .01) [a priori definition of the acceptable limits of agreement to support or reject interchangeability of measurement methods [Assessment of ankle-brachial index (ABI) is recommended for PAD screening by the current guidelines of the European Society of Hypertension and Cardiology. ABI acquisition is usually made by non-invasive measurement with a very high sensitivity and specificity and considered as the method of choice –23. Howep < .01) . Oscillop < .01) . Oscillop < .01) , while ip < .01) . Simultap < .01) , 5. Datap < .01) . The simp < .01) , 5. Sinc methods . The resIncreased AS is identified as an independent factor for cardiovascular mortality. It is typically associated with age, hypertension, diabetes, end-stage renal disease and peripheral arterial disease . CentralAlthough a pathologic PWV has been described as preceding or accompanying cardiovascular diseases, evidence for such relationship in PAD is only less well documented , 33. TheThe limitations of the study consist of practical constraints on participant selection, which did not allow us to draw a random sample of the population in general or of the medical center’s patient population. Hence, the analysis of sensitivity, specificity, positive and negative predictive power may not apply to settings with substantially different proportions of diseased vs. healthy subjects. The conducted power analysis revealed 110 study subjects to be appropriate for adequate statistical hypothesis testing. The number of recruited subjects per group is limited , and consequently the number of diabetics for sub-analyses.aABI measurement using the VascAssist device is interchangeable with manual ultrasound-based sABI measurement.Arterial stiffness, as a result of total peripheral resistance and arterial compliance determined by PWV acquisition is a promising indicator of arterial health status and function, warranting further investigations for early detection of PAD in terms of secondary prevention.


Involvement of agrochemicals have been suggested in the development of chronic kidney disease of unknown etiology (CKDu). The association between CKDu and blood level of organochlorine pesticides (OCPs) in CKDu patients has been examined in the present study.n = 300) were divided in three groups, namely, healthy control (n = 100), patients with chronic kidney disease of unknown etiology (n = 100), and patients with chronic kidney disease of known etiology (CKDk) (n = 100). Blood OCP levels of all three study groups were analyzed by gas chromatography.All the recruited study subjects  and positively with urinary albumin of CKD patients. Logistic regression analysis revealed association of γ-HCH, Increased blood level of certain organochlorine pesticides is associated with the development of chronic kidney disease of unknown etiology. Chronic kidney disease (CKD) is a complex pathophysiologic process with multiple etiologies frequently leading to end-stage renal disease (ESRD). Currently, 10% of the global population regardless of ethnic origin is affected by chronic kidney disease. CKD is characterized by progressive loss of functional glomerular tissue, defects in the glomerular filter function, and subsequent proteinuria [CKD may develop as a consequence of (i) systemic disease such as diabetes 30.6%) and hypertension 13.2%), (ii) glomerulonephritis (9.9%), and (iii) other causes including the action of drugs, toxins and metals, infections, mechanical damage, ischemia, obstruction of the urinary tract, and genetic alterations [3.2%,  are banned in most of the countries, yet they persist in the environment due to their long half-life and human exposure has been detected in general population in various geographical regions around the world.p, p′-dichlorodiphenyldichloroethylene  and endosulfan in them [p, p′-DDE were detected among the participants of Canadian study of health and aging [p, p′-dichlorodiphenyltrichloroethane , and p, p′-DDE have been detected in mother’s plasma as well as in the umbilical cord plasma among mother-infant pairs from rural Mexico [p, p′-DDT, p, p′-DDE, heptachlor, β-endosulfan, and endrin aldehyde have been reported among the inhabitants of Southern Mexico and p, p′-DDE and β-endosulfan are the most frequently found OCPs in them [Carreno et al. has detected 14 different OCPs among young males from Southern Spain and have reported all the blood samples contain  in them . In anotnd aging . In a rel Mexico . Recentl in them .Exposure to OCPs has been shown to be associated with adverse reproductive outcome , cardiov1C (<6.5%), and blood pressure <160/100 mmHg untreated or <140/90 mmHg on up to two anti-hypertensive medications. Age-sex-matched healthy controls (n = 100) were recruited mostly from nonrelated persons accompanying different patients at the renal clinic and staff of the hospital. Age matching was done in intervals of 5 years. Subjects occupationally exposed to pesticides and industrial chemicals such as those belonging to farming communities were also excluded. The study was approved by the Institutional Ethics Committee for Human Research (IEC-HR) of University College of Medical Sciences. Written informed consent was obtained from all participants. Routine investigations including different lipid fractions  were measured at the Hospital Laboratory Services (HLS) at GTB Hospital, Delhi. Body mass index (BMI) was measured by weight/height2 (kg/m2). Total serum lipid levels were calculated by using the formula: total lipids = 2.27 total cholesterol + triglycerides + 0.623 [We recruited 100 patients each of CKDk and CKDu, aged between 30 and 50 years among the patients who attended to the nephrology clinic at University College of Medical Sciences and Guru Teg Bahadur Hospital (G.T.B.H.), Delhi, India, during the period of January 2014 to March 2015. CKD was defined as deranged renal function for more than 3 months with/without evidence of proteinuria and having estimated glomerular filtration rate (eGFR) ≤60 mL/min at least on two different occasions 3 months apart . CKD patVenous blood samples were drawn after overnight fasting and collected in sterile EDTA containing vials. Immediately after sampling, 3 mL of blood was sent to HLS for routine biochemical analysis and 2 mL of whole blood was used for pesticide extraction.Extraction of OCPs from blood was done in duplicate by using HPLC grade hexane and acetone (1:1) according to the method of Bush et al. followed by cleaning up procedure which was done by USEPA method using florisil . In brie63electron capture detector as described by Siddharth et al. [Quantification of OCP residue levels was done by using Perkin Elmer Gas Chromatograph equipped with Nih et al. . Elite-GStatistical analysis was carried out using SPSS software version 17.0. Normally distributed data were expressed as mean ± SD, and the three groups were compared using one-way ANOVA followed by Tukey’s test. Non-parametric data such as urinary albumin excretion and blood level of OCPs were expressed by median and interquartile range. Kruskal-Wallis test was applied for comparison among three groups. Relationships between OCPs and eGFR were tested using Spearmen’s correlation analysis. For association of OCPs with risk of CKD, blood level of OCPs was distributed in tertiles using control group tertile as cutoff points and binary logistic regression analysis was used to calculate the risk of CKD. Odds ratio was adjusted for age, sex, BMI, and total lipid content. We analyzed the data in three different models .k), and healthy control subjects. CKD patients enrolled in this study mostly were in stage 3 or 4 as per National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKFKDOQI) classification. CKD patient of known etiology were mostly having nephropathy along with retinopathy due to diabetes mellitus.The present study was carried out using three groups of study subjects, namely CKD patients of unknown etiology (CKDu), CKD patients with known etiology , the results were depicted as median and interquartile range as shown in Table p, p′-DDE, were found significantly higher as compared to healthy control, whereas in CKDu patients, significantly increased level of four pesticides, namely α-HCH, aldrin, β-endosulfan, and p, p′-DDE, were found as compared to healthy controls. When the blood level of pesticides were compared between CKDk and CKDu patients, increased concentration of two pesticides, namely β-endosulfan and p, p′-DDE, were found in CKDu patients.Following pesticide extraction from blood samples and analysis by gas chromatography, we detected nine OCPs, namely the different isomeric forms of HCH  and endosulfan , aldrin, dieldrin along with p, p′-DDE, exhibited significant negative correlation with eGFR, whereas in CKDk patients, only two OCPs, namely γ-HCH and p, p′-DDE, significantly and negatively correlated with eGFR. These pesticides also showed significant positive correlation with 24-h urinary albumin excretion (UAE) indicating that as the pesticide level increases eGFR tend to decrease with concomitant increase in UAE.Correlation analysis of eGFR and 24-h urinary albumin excretion with blood OCP level is presented in Table p, p′-DDE (OR = 1.63) showed significant association with CKDk. In model 2, the association of blood OCP level with the risk of CKDu was examined taking healthy control as reference group. Three pesticides, namely γ-HCH (OR = 2.05), β-endosulfan (OR = 1.92), and p, p′-DDE (OR = 2.13), showed significant association with CKDu. Model 3 examined association of blood OCP level with the risk of CKDu taking CKDk as reference group. Two pesticides, namely β-endosulfan (OR = 2.16) and p, p′-DDE (OR = 3.20), exhibited significant association with CKDu.Binary logistic regression analysis was applied to find out the association of blood level of OCPs with CKD using first tertile data as reference. The results were presented as odds ratio and 95% CI Table . No signp, p′-DDE, and aldrin, in the two groups of CKD patients as compared to healthy control (Table p, p′-DDE and HCH in uremic patients although there is no mention of the type of CKD patients used in their study [In the present study, we detected nine organochlorine pesticides in the blood samples of our study subjects. There are significant differences in the level of four pesticides, namely α-HCH, β-endosulfan, ol Table . The quair study . In a reir study . TherefoIt is difficult to put forward any mechanism to link OCP accumulation and development of CKD as no definite etiology have been assigned towards development of CKDu. A number of animal studies have demonstrated the nephrotoxic nature of some of the OCPs , 21. AlsTherefore, it is possible that accumulated pesticides may induce oxidative stress leading to development of CKD. The view of OCP accumulation and occurrence of CKDu is further evidenced by the fact that biopsy reports of CKDu patients reveal tubulointerstitial injury . In a reIn conclusion, the present study reveals association between increased blood levels of certain organochlorine pesticides and the occurrence of chronic kidney disease of unknown etiology for the first time to the best of our knowledge among urban population of Delhi who are not directly involved in agricultural activity or manufacture of pesticides and are probably exposed through environmental contamination. However, the data does not prove causality of the association. Despite strong body of evidences to suggest, defining the precise role of OCPs in the development of CKDu remains a challenge till date. Prolonged cumulative exposure in conjugation with other contributory factors possibly lead to renal dysfunction and CKDu. Further studies with improved study design involving larger population are required for better understanding of the etio-pathogenesis of CKDu and the role of OCPs in this context.


The incidence of chronic kidney disease (CKD) is increasing worldwide, with more than 26 million people suffering from CKD in the United States alone. More patients with CKD die of cardiovascular complications than progress to dialysis. Over 80% of CKD patients have hypertension, which is associated with increased risk of cardiovascular morbidity and mortality. Another common, perhaps underappreciated, feature of CKD is an overactive sympathetic nervous system. This elevation in sympathetic nerve activity (SNA) not only contributes to hypertension but also plays a detrimental role in the progression of CKD independent of any increase in blood pressure. Indeed, high SNA is associated with poor prognosis and increased cardiovascular morbidity and mortality independent of its effect on blood pressure. This brief review will discuss some of the consequences of sympathetic overactivity and highlight some of the potential pathways contributing to chronically elevated SNA in CKD. Mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and to date, not completely understood. Identification of the mechanisms and/or signals leading to sympathetic overactivity in CKD are crucial for development of effective therapeutic targets to reduce the increased cardiovascular risk in this patient group. Stages 2, 3 and 4 show progressive renal dysfunction with an eGFR of 60–89, 30–59 and 15–29 mL/min/1.73 m2, respectively. Stage 5 CKD is renal failure or end-stage renal disease which is characterized by eGFR of <15 mL/min/1.73 m2 or dialysis. Moderate to severe CKD (stage 3–5) is associated with a significantly higher risk of cardiovascular (CV) morbidity and mortality [More than 26 million people in the United States suffer from chronic kidney disease (CKD) with thousands of new cases diagnosed each year . CKD hasortality . This br2) in group I and lowest quartile of eGFR (31.4 ± 1.8 mL/min/1.73 m2) in group IV. There was a significant and progressive increase in resting MSNA from the highest quartile to the lowest quartile of eGFR  by angiotensin-converting enzyme (ACE). Activation of renin–angiotensin system increases renin secretion ultimately leading to high circulating plasma concentrations of Ang II, a common feature of CKD ,51,52. AThe kidneys are richly innervated by chemoreceptors and baroreceptors which send feedback to the brain to regulate sympathetic outflow and systemic blood pressure. Evidence from both animal and human studies indicates that neural signals originating from the kidney play a role in increasing sympathetic outflow in CKD ,62. Ratsl-arginine to l-citrulline [Another potential mechanism for chronic sympathoexcitation in CKD is reduced nitric oxide (NO) bioavailability. NO is produced by nitric oxide synthase (NOS) during oxidation of trulline . There atrulline ,75,76. Itrulline ,78. ThusG-monomethyl l-arginine (l-NMMA) directly into the RVLM of anesthetized animals increased renal SNA and consequently, blood pressure, while microinjections of l-arginine and sodium nitroprusside (NO donor) reduced renal SNA and blood pressure [l-NMMA into the nucleus tractus solitarius (NTS) showed similar changes in renal SNA and blood pressure [l-arginine causes a dose-dependent increase in neuronal activity of ~40% of NTS neurons, and this response is attenuated by l-NMMA. Hemoglobin, which endogenously binds to NO, blocks the increase in neuronal activity evoked by l-arginine, suggesting that NO diffuses out into the extracellular space to excite the adjacent neurons from which the neural activity was measured. They further extended their findings by using methylene blue, a guanylate cyclase blocker, to investigate whether these effects of l-arginine were mediated by cyclic guanosine monophosphate (cGMP). Methylene blue inhibits the increase in neuronal activity in the NTS elicited by both l-arginine and sodium nitroprusside. These data indicate that NO produced from l-arginine in the NTS neurons diffuses out to nearby target neurons where it increases neuronal activity through cGMP. Other animal studies involved intravenous infusion, interacisternal injection or microinjection of NOS inhibitors into the paraventricular nucleus (PVN) and the NTS, demonstrating acute increases in renal SNA and blood pressure [There is increasing evidence that suggests NO is a key signaling molecule involved in regulation of sympathetic outflow from the brainstem. Shapoval et al.  performepressure . Microinpressure . Tagawa pressure  used ratpressure ,80,82. Fpressure ,84. Togel-nitroarginine methyl ester (l-NAME) in barointact animals caused a biphasic response in renal SNA, an initial decrease followed by an increase in renal SNA. In barodenervated animals, NOS inhibition caused a progressive and significant increase in renal SNA uncovering the role of central NO in restraining sympathetic outflow. Our laboratory has also provided evidence for NO in central sympathetic control in humans. To overcome the confounding inhibitory influence of the arterial baroreflex on SNA, we directly measured skin SNA, which is not under baroreceptor control. Systemic l-NAME infusion in healthy adults caused progressive and sustained increases in skin SNA [Initial studies performed to extrapolate these findings from direct central injections to systemic infusions of NOS inhibitors observed a reduction in SNA. Indeed, when NOS inhibitors were infused systemically in animals and humans, there was a rapid and large increase in blood pressure along with a decrease in SNA ,86. The skin SNA .l-NAME in animals with and without sympathectomy showed that both groups had a similar increase in blood pressure during the first hour of infusion primarily due to inhibition of peripheral endothelial NO production. Importantly, blood pressure in the sympathectomized animals after 8 h and after 6 days of l-NAME infusion was significantly lower than the control group, indicating a delayed but significant role of the sympathetic nervous system in the blood pressure-raising effect of NOS inhibition , the primary endogenous NOS inhibitor . Plasma ADMA is produced in all cell types and can pass the blood–brain barrier ,99. It iCKD patients are reported to have higher oxidative stress ,105,106,Sympathetic overactivity is a hallmark of CKD and therapeutic strategies to reduce this heightened sympathetic activation are needed. In this review we have identified some of the potential pathways contributing to elevated SNA in CKD that warrant consideration when discussing therapeutic targets to reduce SNA in this high risk population. Ang II receptor blockers and ACE inhibitors have been shown to lower resting MSNA and blood pressure but neither normalizes MSNA in CKD and thus, other therapeutic strategies are needed ,16. SympAside from the aforementioned pharmacological strategies, there are therapeutic interventions such as renal denervation and carotid baroreflex stimulation that may also be used to reduce SNA in CKD. Renal denervation has been primarily utilized to treat resistant hypertension. Several studies in hypertensive patients and experimental animal disease models showed a significant reduction in blood pressure following renal denervation ,142,143.Chronic sympathoexcitation is a major contributor to increased CV risk and mortality in CKD. Despite recent advances in research, our understanding of the mechanisms causing sympathetic overactivity in CKD is still incomplete. As discussed in this review, various studies have proposed a role for the renin–angiotensin system, renal afferent stimulation, reduced NO concentrations due to elevated ADMA, and increased oxidative stress in contributing to chronic sympathoexcitation in CKD. Further research is needed to better clarify the individual and interactive roles of each of the aforementioned pathways in contributing to sympathetic overactivity in CKD patients.


Hypertension is a major risk factor for cardiovascular disease and prevalence varies by ethnic group. The diagnosis and management of blood pressure are informed by guidelines largely based on data from white populations. This study addressed whether accuracy of blood pressure measurement in terms of diagnosis of hypertension varies by ethnicity by comparing two measurement modalities (clinic blood pressure and home monitoring) with a reference standard of ambulatory BP monitoring in three ethnic groups.Cross-sectional population study (June 2010 - December 2012) with patients (40–75 years) of white British, South Asian and African Caribbean background with and without a previous diagnosis of hypertension recruited from 28 primary care practices. The study compared the test performance of clinic BP (using various protocols) and home-monitoring (1 week) with a reference standard of mean daytime ambulatory measurements using a threshold of 140/90 mmHg for clinic and 135/85 mmHg for out of office measurement.A total of 551 participants had complete data of whom 246 were white British, 147 South Asian and 158 African Caribbean. No consistent difference in accuracy of methods of blood pressure measurement was observed between ethnic groups with or without a prior diagnosis of hypertension: for people without hypertension, clinic measurement using three different methodologies had high specificity (75–97%) but variable sensitivity (33–65%) whereas home monitoring had sensitivity of 68–88% and specificity of 64–80%. For people with hypertension, detection of a raised blood pressure using clinic measurements had sensitivities of 34–69% with specificity of 73–92% and home monitoring had sensitivity (81–88%) and specificity (55–65%).For people without hypertension, ABPM remains the choice for diagnosing hypertension compared to the other modes of BP measurement regardless of ethnicity. Differences in accuracy of home monitoring and clinic monitoring  were also not affected by ethnicity.The online version of this article (doi:10.1186/s12872-017-0491-8) contains supplementary material, which is available to authorized users. Hypertension is the leading risk factor for cardiovascular disease (CVD), accounting for approximately 45% of global CVD morbidity and mortality . The preThe diagnosis and management of BP in the UK are informed by guidelines largely based on research from white populations . These gThe design and results of the BP in different ethnic groups (BP-Eth) study has previously been published , 9. ThisThe study population comprised two groups aged between 40 and 75 years: The first group were not known to be hypertensive (NHT) and the second had been previously labelled as hypertensive via a clinical code (HT). Participants were drawn from one of four ethnic groups namely WB, SA, AC and White Irish (WI). WI participants were excluded from this analysis due to insufficient numbers recruited (51). Patients that were unable to give consent to the study, belonged to a different ethnic group or whose general practitioner (GP) felt they were unable to take part were excluded.The study compared BP monitored in a clinic setting and from home-monitoring with ambulatory measurements. Recruitment was from those responding to a postal survey who indicated a willingness to participate in a validation study , 9. RespFollowing informed consent and a five minute rest, six sets of BP measurements were taken by the research nurse at each of three clinic visits  .Participants were fitted with an ambulatory monitor (Spacelabs 90217-1Q)   and hourly overnight and the mean daytime BP calculated. Home measurements were taken twice each morning and evening for 1 week, the first days readings discarded and the mean of the remaining readings calculated. For both home-monitored and day time mean ambulatory blood pressure, standard editing criteria were applied: ABPM readings were considered to be valid if there were 14 or more day-time (7 am to 11 pm) readings for a patient (threshold 135/85 mmHg) [nd and 3rd reading averaged over the 3 days  representing recommended clinic BP measurement for diagnosis; the mean of the 2nd to 6th reading averaged over three occasions  and the first reading taken on the first day , which was expected to accentuate any white coat effect.Clinic measurement was defined in three ways: the mean of the 2The primary outcome was the diagnostic test performance of various measures of clinic and home-monitored BP compared to the reference standard (mean daytime ambulatory BP) considering both diagnosis of hypertension in those not previously diagnosed and identification of poor control in those known to be hypertensive, using a threshold of 140/90 mmHg for clinic readings and 135/85 mmHg for out-of-office measurement . The samPeople with and without a previous diagnosis of hypertension were analysed separately and the impact of ethnicity was assessed.The continuous response variable was systolic or diastolic BP. The study design involved clustering effects (BP readings nested within days and patients), so we used a hierarchical linear statistical model to reflect the design. A 3-level hierarchical model was developed, with level 1 as the BP readings, level 2 as the day (the readings were taken) and level 3 as the patient. All models had a pre-specified set of covariates: ethnicity, age, sex, marital status, deprivation (IMD 2007), body mass index, smoking status, alcohol consumption, cholesterol, cardiovascular disease, chronic kidney disease, diabetic status, and hypertension status. Five separate models were constructed, one for each method—ABPM, clinic23, clinic26, clinic D1R1 and home monitoring. For clinic D1R1 there was no hierarchical structure as there was a single observation per participant (a simple linear regression model was used). Participants with complete data were included in the analyses. All analyses were undertaken in Stata (release 12) , 16.Sensitivity, specificity, likelihood ratio of a positive test (LR + ve) and likelihood ratio of a negative test (LR –ve) for either a diagnosis of hypertension or confirmation of raised BP in those known to be hypertensive, were calculated for each ethnic group and also for all samples for Clinic23, Clinic26, ClinicD1R1 and home monitoring using mean day-time ABPM as a reference standard.A total of 551 patients had complete records in the study   specific enough – just short of 90% - for daily practice.This leads us to conclude that for people without hypertension, ABPM remains the choice for diagnosing hypertension compared to the other modes of BP measurement because no other method has sufficient combined sensitivity and specificity on which to base lifelong treatment. Given that systematically measured repeated clinic BP had high specificity, it may be reasonable to treat people with raised mean clinic BP on multiple occasions, but clinic BP could not adequately rule out hypertension and casually measured BP performed poorly. Home-monitored BP was reasonably sensitive and specific but probably not enough so to provide an adequate replacement for ABPM. Sensitivity analyses using BP thresholds of 135/85 mmHg and 140/90 mmHg were undertaken and showed no difference between the ethnic groups.For people with established hypertension, a sensitivity of 84% from home monitoring is high enough to accept evidence of good control but specificity was low enough to reduce confidence about reacting to high readings.This is the first and largest study reporting four modes of BP measurement compared to ambulatory BP monitoring in three different ethnic groups. Participants were both hypertensive and not known to be hypertensive and importantly were not recruited on the basis of previously raised BP which has confounded much of the work on out of office measurement in the past. The attempt to recruit a White Irish group – known to have increased cardiovascular risk – failed due to a lack of numbers of people self-defining as White Irish, despite choosing areas previously identified by census ethnicity responses. This may reflect changes in population since 2001 (the study recruited before 2011 data were available). In light of the results in the groups considered, it seems unlikely that WI would be markedly different. Similarly, people with hypertension responded in greater numbers to our invitations to take part resulting in fewer without a previous diagnosis participating. The key results presented – namely a lack of difference between ethnic groups - were low in heterogeneity between the groups and largely consistent across methods and with or without a diagnosis so appear robust.The measurement of BP in this study was undertaken in a consistent manner by trained research nurses and facilitators and probably reflects better practice than common outside of specialist centres. Whilst this was a prerequisite for the study, it arguably did not represent usual practice and hence the results might not be generalizable to daily practice. The use of a single reading taken at the first research clinic was designed to both accentuate any white coat effects and also to represent the potential practice of BP measurement in busy clinical settings and proved suboptimal for both diagnosis and ongoing management.Patients included were chosen to be aged within the range used in NHS Health Checks (40–74) as this is the key age group for whom primary prevention is particularly relevant and for which decisions are commonly made in terms of diagnosis and treatment . InclusiThe overall performance of clinic (sensitivity 41%/specificity 90%) and home monitoring (73%/76%) for the diagnosis of hypertension are consistent with the receiver operating curves in our previous systematic review which found respectively sensitivities and specificities of clinic (75%/75% (86%/46% for patients around the threshold for diagnosis)) and home (86%/66%) .Since that review, Nasothimiou  has founNo comparative studies amongst different ethnic groups for the diagnosis of hypertension were apparent from a review of the literature although some studies have grouped together whites with people of Hispanic and/or African origin , 22. TheWith greater numbers of individuals in primary care now undergoing out of office BP measurement prior to a diagnosis of hypertension, then this work is reassuring in that it appears appropriate to extend thresholds developed in white populations to South Asian and African Caribbean populations at least.When making a diagnosis of hypertension in an unselected primary care population, the low sensitivity of clinic measurement means that it cannot reliably be used to rule out hypertension but with high specificity, those found to have high BP on multiple occasions in clinic can be reliably identified and treatment commenced.In terms of ongoing management of hypertension, the mode of measurement appears more important than the population being measured in terms of variation. In any case, home monitoring would appear to be a reasonable method of ruling out raised BP and in combination with careful clinic measurement provides high specificity in addition. Such a result resonates with the ever growing evidence of improved BP control with the use of home-monitoring, with or without other interventions .In the future, alternative methods of measurement of BP such as central arterial pressure may have increased clinical utility as data accumulate . The feaOverall the findings confirm those of our previous review  that in


Trefoil factor family (TFF) peptides are increased in serum and urine in patients with chronic kidney disease (CKD). However, whether the levels of TFF predict the progression of CKD remains to be elucidated.2). We determined the TFF levels using peptide-specific ELISA in spot urine samples and performed a prospective cohort study. The association between the levels of urine TFFs and other urine biomarkers as well as the renal prognosis was analyzed in 216 CKD patients ; however, TFF3 alone predicted CKD progression in a multivariate logistic regression analysis . The Kaplan-Meier survival curves demonstrated that patients with a higher TFF1 and TFF3 alone, or in combination with macroalbuminuria, had a significantly worse renal prognosis. The data suggested that urine TFF peptides are associated with renal progression and the outcomes in patients with CKD. All proAccording to the protocol, we excluded any patients with established atherosclerotic complications . Patients with nephrotic syndrome, acute kidney injury, acute infection, and malignancy including gastric cancer , 25, actg for 5 minutes in a refrigerated centrifuge, and the supernatants were immediately transferred to new screw-top cryovial tubes and frozen at −80°C. All urine aliquots used in this biomarker study had undergone no previous freeze-thaw cycle. Samples for this study were obtained from 216 participants who were free of ESRD at the time of urine collection.All urine samples were obtained from patients from spot urine in the morning . SamplesμL of assay buffer  and 50 μL of sample or human TFF standard were added to the wells. After incubation overnight at room temperature, the plate was washed, and diluted biotin-labeled anti-TFF polyclonal antibodies  were added to each well. After incubation for 2 h, the plate was washed, and diluted horseradish peroxidase-conjugated streptavidin  was added to each well, followed by a further 2 h incubation at room temperature, after which the plate was washed. Tetramethylbenzidine (TMB) solution  was then added, stop solution  was added 10 min later, and the absorbance at 450 nm was measured. Concentrations of human TFFs in the samples were calculated from a standard curve constructed from recombinant human TFFs. The assay sensitivities for TFF1, TFF2, and TFF3 were 7, 30, and 30 pg/mL, respectively. Each TFF antibody reacted specifically and showed no cross-reactivity for the other TFFs [The mean storage duration between collection and measurement was a median of 29 months . The TFF peptide  concentrations were measured using an ELISA system, as described previously , 25. Anther TFFs , 25. Theα1-microglobulin (α1-MG), β2-microglobulin (β2-MG), and N-acetyl-β-D- glucosaminidase (NAG) were also determined . The serum and urinary creatinine levels were measured according to the enzymatic colorimetric method. Each subject's arterial blood pressure was measured by a physician after a 10-minute resting period to obtain the systolic and diastolic blood pressures . The mean blood pressure (MBP) was calculated as DBP + (SBP − DBP)/3 [The concentrations of clinical parameters were measured using routine laboratory methods . The urinary levels of albumin, − DBP)/3 .The primary outcome was CKD progression, defined as a composite endpoint of incident ESRD  or doubling of serum creatinine . Patient t-test and the Mann–Whitney U test as appropriate. Receiver operating characteristic (ROC) curves were constructed to determine the optimum sensitivity and specificity, and the area under the curve (AUC) was calculated [p values, odds ratios, and corresponding two-sided 95% confidence intervals for the predictors are presented [p < 0.05 was considered to be statistically significant.Statistical analyses were performed using the JMP software package . Data are expressed as the mean ± standard deviation for continuous parametric data, median and interquartile range for continuous nonparametric data, and frequencies for categorical data. A linear regression analysis of the data at baseline was performed using the least-squares method. Variables showing a positively skewed distribution were transformed using the natural logarithm (ln). Differences between groups were analyzed using Student'slculated . A multilculated . The p vresented . A Kaplaresented , 31. Renμg/gCr, respectively. The baseline characteristics are shown according to early (stages 1 and 2), middle (stages 3a and 3b), and later (stages 4 and 5) CKD stages   and urine α1-MG  at the start of the study were significantly associated with the CKD progression (The parameter with the largest area under the ROC curve (AUC) for predicting the progression of CKD ≥ 3b was urine TFF3 (0.879), followed by urine  (0.874) . Regardigression .μg/gCr) or in their combination with albuminuria (<300 or ≥300 mg/gCr) in Kaplan-Meier survival analyses n = 14) or ESRD requiring renal replacement therapy (n = 8). Compared with the remaining 190 patients , the renal endpoint group had significantly higher levels of urine TFF1 and TFF3 but significantly lower levels of urine TFF2  TFF1 and TFF3 were significant predictors of the progression of CKD ≥ 3b in an ROC analysis, and TFF3 alone, but not TFF1 or TFF2, was a significant predictor in a multiple logistic regression analysis; and (4) in a survival analysis, TFF1 and TFF3 either alone or in combination with the level of albuminuria were a significant predictor of the renal outcome in patients with CKD.In this study, we measured the urine TFF levels in early, middle, and later CKD patients and determined the relationships between the urine TFF level and the CKD progression and outcomes. Based on analyses of urine samples from CKD patients, we found that (1) the TFF1 and TFF3 levels significantly increased with progression of CKD stages, while TFF2 did not; (2) TFF3 to a better degree and TFF1 to a lesser degree correlated with the decline in the eGFR and other urine markers of tubular injury, including We showed that the urine levels of both TFF1 and TFF3 significantly increased with the progression of CKD, while the urine levels of TFF2 did not . Regardiλ light chain, but not after exposure to fatty acid-free human serum albumin [κB binding site [κB, both of which are proposed as central regulators of CKD progression [The origin of urine TFF peptides has yet to be fully elucidated. TFF3 mRNA is expressed in the cortex of the human kidney , in cont albumin . The pro albumin  as well ing site . Possiblgression , 36.The exact role of TFF in the kidney is still uncertain. TFF3, also known as intestinal trefoil factor (ITF), a peptide expressed in goblet cells of the intestines, colon, and kidney , plays e tff3 mRNA expression in rodents [ tff3 transcript in rodents [The kidney tubules of the outer stripe of the outer medulla are a major site of rodents . Histoch rodents , and agi rodents . In the  rodents . In the  rodents . These r lrp2 encodes megalin, a multiligand endocytic receptor localized in the renal proximal tubule, TFF3 might be a megalin ligand, such like α1-MG or β2-MG [The renal distribution of TFF3 protein in CKD patients is very scant. Immunohistochemistry of renal biopsy specimens showed aberrant expression of TFF3, which was localized to the tubular epithelial cells in the renal cortex but not to the glomeruli, arterioles, or interstitium . The recor β2-MG , leadingor β2-MG , suggestor β2-MG .In the survival analysis of this study, TFF1 and TFF3 either alone or in combination with the level of albuminuria were found to be a significant predictor for the disease progression and renal outcome in patients with CKD . In an aα1-MG, urine β2-MG, and hemoglobin, were also shown to be good predictors (The ROC analysis of this study showed that urine TFF3 was a useful biomarker for predicting the progression of CKD ≥ 3b. Although other biomarkers, such as urine edictors , the AUCµg/mL [Our study has several limitations and strengths that should be kept in mind when interpreting the results. First, we lacked enough data in patients with diabetic nephropathy, which was the most frequent cause of ESRD in modern countries. However, including diabetic patients in the CKD cohort might have influenced the TFF levels, as other biomarkers such as serum Klotho are lower in diabetic patients than in nondiabetic patients . Second,µg/mL , 48. Theµg/mL .Our data showed that urine TFF peptides are associated with other urine tubular injury markers and the renal outcomes in patients with CKD. Further studies are required to elucidate the precise localization and function of TFF in the human kidney and its role in the progression in CKD patients. Interventions that can modulate the level of urine TFF in such patients may be useful, since improving the outcome is the ultimate goal of biomarker studies.


Direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP) could improve the hemodynamic status of septic shock patients. As PMX-DHP is an invasive and costly procedure, it is desirable to estimate the therapeutic effect before performing the therapy. However, it is still unclear when this therapy should be started and what type of sepsis it should be employed for. In this study, we retrospectively examined the clinical effect of patients treated with PMX-DHP by using central venous pressure (CVP).n = 33, CVP < 12 mmHg) and a high CVP group . The primary endpoint was vasopressor dependency index at 24 hours after starting PMX-DHP, and the secondary endpoint was the 28-day survival rate. Additionally, we performed a multivariate linear regression analysis on the difference in the vasopressor dependency index.Seventy patients who received PMX-DHP for septic shock during the study period were recruited and divided into a low CVP group  but not in the high CVP group , and there was a significant difference between the two groups in the index at 24 h (p = 0.02). The 28-day survival rate was higher in the low CVP group . Multivariate linear regression analysis showed that CVP (p = 0.04) was independently associated with the difference in the vasopressor dependency index.The vasopressor dependency index significantly improved at 24 h in the low CVP group  might be limited and that the initial CVP when performing PMX-DHP could function as an independent prognostic marker for the hemodynamic improvement.The online version of this article (doi:10.1186/s40560-016-0186-8) contains supplementary material, which is available to authorized users. Both the 2008 and 2012 Surviving Sepsis Campaign Guidelines (SSCG) recommend the rapid infusion of intravenous fluids until a central venous pressure (CVP) of 8–12 mmHg is achieved during initial resuscitation –5. In paDirect hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP), which can effectively adsorb bacterial endotoxin and lead to an earlier recovery from shock state, was first reported in 1994, and it has been used for the treatment of septic shock in many countries –11. AlthThe utility of CVP as a marker of intravascular volume has been questioned for many years , 14. HowIn this study, in order to clarify the application of PMX-DHP for septic shock patients, we retrospectively examined the hemodynamic improvement and the mortality of patients treated with PMX-DHP by using CVP values. Moreover, we investigated whether the CVP values at the start of PMX-DHP could function as an independent prognostic factor for the hemodynamic improvement of the hemoperfusion.We conducted a retrospective cohort study among all consecutive patients who received PMX-DHP for septic shock between May 2008 and April 2013 in the intensive care unit (ICU), high care unit (HCU), and cardiovascular care unit (CCU) at the Japanese Red Cross Kyoto Daini Hospital and the Kyoto University Hospital in Japan. After initial resuscitation to achieve the early goal directed therapy (EGDT), PMX-DHP was applied along the Japanese health insurance system, as follows [The Ethics Committee of Kyoto University Graduate School and Faculty of Medicine approved the protocol (E2153). This study was retrospective and used only a data bank while employing the highest privacy policy standards. Therefore, the requirement of informed consent was waived.Vascular access was placed at the femoral or the internal jugular vein. PMX-DHP with PMX-20R  was performed for at least 120 min per session once or twice per patient per day for 2 days. The blood flow volume was 80–120 mL/min. The duration of hemoperfusion was decided by the attending physician. The therapy was terminated when the attending physician deemed it appropriate to conclude PMX-DHP for any reason. The anticoagulant used in PMX-DHP was nafamostat mesilate, low molecular weight heparin, or unfractionated heparin. All other cardiovascular management, including cardiac output management, setting of blood pressure goals, and fluid and inotropic therapy, were performed on the basis of SSCG recommendations by the attending physician.In this study, we classified the patients into two groups: patients with CVP values greater than or equal to (≧) 12 mmHg when starting PMX-DHP were placed in the high CVP group, while the remaining patients whose CVP values were less than (<) 12 mmHg were placed in the low CVP group. CVP was measured using the standard method when starting PMX-DHP and expressed as mmHg, as described previously , 17. ThiWe employed three parameters in order to compare hemodynamic status among the patients in this study: mean arterial pressure (MAP), inotropic score, and vasopressor dependency index, as described in the preceding studies , 18. NamAnd, vasopressor dependency index was calculated as the inotropic score/MAP. The parameters were calculated before the first PMX-DHP, immediately thereafter and 24 h after the first PMX-DHP.2)/fractional inspired oxygen (FiO2) ratio (P/F ratio), positive end-expiratory pressure (PEEP), renal replacement therapy, surgery, hemoglobin, platelet count, C-reactive protein (CRP), total bilirubin, total protein, Acute Physiologic and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, time from admission to care units until starting PMX-DHP, duration of PMX-DHP, total fluid dosage from ICU admission until starting PMX-DHP, site of infection, and microorganism types. Cardiac output and cardiac index were measured by an arterial catheter attached to the FlotracTM pulse counter device  or a pulmonary artery catheter attached to VigilanceTM monitor .Relevant clinical background, medical history, and clinical data of all patients were collected at appropriate times during the treatment for sepsis. Basic cardiopulmonary data and laboratory data obtained at the time of starting PMX-DHP were considered baseline values. These included age, sex, body mass index, systolic blood pressure, diastolic blood pressure, dopamine infusion rate, noradrenaline infusion rate, inotropic score, vasopressor dependency index, heart rate, central venous pressure, cardiac output, cardiac index, body temperature, arterial pH, lactate, arterial oxygen tension . Comparison of continuous variables between the two groups was conducted with the t test or the Mann-Whitney U test, according to the distribution of the variables. Evaluation of significance between groups over time points was done by repeated measure ANOVA. As post hoc analysis, the three pair-wise comparisons of the hemodynamic status within a single group among different time points were made using Bonferroni adjustment. Therefore, p values less than 0.016 were considered significant only in this comparison. In the other comparisons, statistical significance was defined as p values <0.05. Kaplan-Meier curves were constructed for the comparison of the survival rate in the two groups and were tested for difference using the log-rank test.Statistical analysis was performed using JMP for Macintosh version 10.0.2 software . Categorical variables are expressed as the number of patients (%) and were analyzed by using the p values <0.20 in the univariate analysis were included in the multivariate analysis. To ensure that the assumptions for regression analysis were not violated, an analysis of residuals was carried out. Moreover, we performed multivariate Cox regression analysis to assess the covariates that were associated with time to mortality.To ensure the assumption that the CVP at the beginning of PMX-DHP could be an independently prognostic factor for the hemodynamic improvement of the hemoperfusion, we performed a multivariate linear regression analysis that focused on the difference in the vasopressor dependency index before PMX-DHP and 24 h after hemoperfusion. The relationships between the parameter and continuous variables were examined using Pearson’s correlation coefficient, and categorical variables were examined using Spearman’s R test. All variables with Although 112 patients received PMX-DHP for septic shock during the study period, 70 patients met the inclusion criteria, while 42 patients were excluded for a variety of reasons . Of these 70 patients, the initial CVP of 33 patients when receiving PMX-DHP was <12 mmHg, and the initial CVP of the other 37 patients was ≧12 mmHg, as shown in Fig. Table p < 0.01)  but not after PMX-DHP  in the low CVP group whereas the decrease was observed neither after PMX-DHP  nor at 24 h  in the high CVP group. Additionally, we could observe a significant difference in the index at 24 h between the two groups (p < 0.05)  Fig. . As for p < 0.01), as determined by log-rank test.The survival rates of both groups after 28 days were analyzed by the Kaplan-Meier method Fig. . The surp = 0.03). Subsequent multivariate linear regression confirmed CVP (p = 0.04) and age (p = 0.03) as independent prognosis factors regarding the hemodynamic improvement of PMX-DHP  may be limited and that the initial CVP in performing PMX-DHP could be an independent prognostic marker for hemodynamic improvement. Further study is required to clarify the mechanisms of PMX-DHP that affect sepsis treatment.