To investigate the predictors of intolerance to beta-blockers treatment and the 6-month mortality in hospitalized patients with acute coronary syndrome (ACS).This was a single-center, prospective, and longitudinal study including 370 consecutive ACS patients in Killip class I or II. BBs were prescribed according to international guidelines and withdrawn if intolerance occurred. The study was approved by the institutional ethics committee of our university. Statistics: the clinical parameters evaluated at admission, and the related intolerance to BBs and death at 6 months were analyzed using logistic regression (p<0.05)in PATIENTS.BB intolerance was observed in 84 patients and was associated with no prior use of statins  and Killip class II  in the model adjusted for age, sex, blood pressure, and renal function. There was no association with ST-segment alteration or left anterior descending coronary artery plaque. Intolerance to BB was associated with the greatest risk of death .After ACS, intolerance to BBs in the first 48 h of admission was associated to non previous use of statin and Killip class II and had a high risk of death within 6 months. Beta-blocker (BB) treatment decreases the mortality rate in patients with acute coronary syndrome (ACS). Therefore, its use is currently recommended as a class I-A indication in clinical practice guidelines,2. Several strategies have been developed to encourage the prescription of BBs early after the diagnosis of ACS. However, it has been reported that nearly 22% of eligible patients do not receive the medication –5. All p However, the nonprescription of BBs might be due to intolerance to the medication rather than to nonadherence to evidence-based therapy . The lit The present study aims to evaluate the characteristics associated with nontolerance to BBs in patients with ACS, and to identify its impact in the 6-month all-cause mortality. The procedures were approved by The Research Ethics Committee of the Botucatu School of Medicine  and were conducted in accordance with the Declaration of Helsinki. All participants had ability to consent and signed an informed consent form.  This is a prospective and longitudinal observational study comprising 377 consecutive patients older than 18 years and admitted to the hospital with unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI)  diagnose After the ACS diagnosis, the patients underwent clinical and laboratory evaluations, according to the standardized protocols implemented in the intensive care unit at Botucatu Medical School for patients with ACS. All patients were administered with acetylsalicylic acid as well as submitted to mechanical or chemical reperfusion when indicated. Patients who fulfilled the inclusion criteria were treated with BBs. The medication used in all cases was metoprolol, following the international guidelines. Briefely, Intravenous metoprolol tartrate was given in 5 mg increments by slow intravenous administration (5 mg over one to two minutes), repeated every five minutes for a total initial dose of 15 mg (three doses). Patients who tolerate this regimen then received oral therapy beginning 15 min after the last intravenous dose (25 to 50 mg every six hours for 48 hours of metoprolol tartrate) followed by a maintenance dose of 100 mg twice daily. Patients who do not receive a beta blocker during the first 24 hours because of early contraindications were reevaluated for beta blocker candidacy for subsequent therapy. Oral metoprolol tartrate 25 to 50 mg every 6 to 12 hours, titrating upward as needed [Gender, age, ST elevation, comorbidities , tobacco use, previous ACS, and pharmacological treatment at admission were recorded, as well as blood pressure, heart rate, Killip classification, and blood glucose level at admission. The culprit artery was determined with coronary angiography during the in-hospital period.In the first analysis, the primary outcome was the intolerance to BB during the hospitalization period and the 6-month mortality thereafter.Data management and analysis were performed using SYSTAT 12.0 (SYSTAT Software Inc. 2007). Summary data are expressed as either mean (SD) or proportions. Univariate regression analysis was performed in order to assess which variables were independently associated with either BB treatment intolerance or 6-month all-cause mortality. Those variables that showed a statistically significant association with each outcome were introduced into a multivariate model. The analysis of BB intolerance included the variables age, gender, SBP, Killip class, serum creatinine, and use of ACEIs and statins. For the 6-month mortality analysis, age, history of ACS, intolerance to BBs, and the presence of atherosclerotic plaque in the left anterior descending (LAD) coronary artery were considered. The level of significance was set at 5%. During the follow-up period, 7 patients lost contact with the service and were excluded from the analysis. Therefore, 370 patients  were consecutively included. The demographic and clinical characteristics of the studied population are presented in  Statistically significant differences were found between male and female patients in hypertension (p< 0.001), diabetes mellitus (p 0.001), smoking (p< 0.001), and dyslipidemia (p< 0.001). At the initial evaluation, 85.7% of men (n= 192) were in Killip I class, and 14.3% received the classification Killip II. Among the females, 72.6% (n= 160) were in Killip I and 27.4% (n= 40) were in Killip II (p= 0.002). Plasma creatinine was higher among males . Of the whole population, 76% received BBs . Among the female patients, 30% did not tolerate any dose of BBs, whereas only 20% among the males showed intolerance (p = 0.042). Coronary angiography was performed in 348 patients. An atherosclerotic plaque causing an obstruction >60% in the LAD coronary artery, right coronary artery, and/or circumflex coronary artery was observed in 243 (69.8%), 180 (51.7%), and 160 (46%) patients, respectively.  The univariate logistic regression for the outcome “BB intolerance” indicated that the Killip II classification more than doubled the risk for non-tolerance to this therapy as compared to Killip I class. In addition, for each unit increase in plasma creatinine, the risk of BB intolerance increased by 30%. The nonuse of ACEIs and statins increased the risk of intolerance to BB use .   The results of the multivariate logistic regression analysis for the outcome “BB intolerance” including age, gender, systolic blood pressure serum, creatinine, non-use of ACEI, and statin are presented in  Death at 6 months was associated with age, medical history of arterial hypertension, Killip II at admission, increased serum creatinine, and the presence of a >60% lesion in the LAD coronary artery. In addition, in-hospital intolerance to BB increased the risk of death during follow up by 4.5 times .  Multivariate logistic regression indicated that female gender, medical history of arterial hypertension, Killip II class, increased serum creatinine, atherosclerotic plaque in the LAD coronary artery, and nonuse of BBs and/or ACEIs were independently associated with death at 6 months.In the adjusted model including clinical variables and angiographic findings, we have found that intolerance to BBs and anterior descending coronary artery disease were the most important predictors of all-cause mortality . The present study aimed to identify variables associated with intolerance to BB use in hospitalized ACS patients. We here show that some clinical parameters easily obtained in the emergency department on admission can predict such intolerance. In addition, intolerance to treatment with BB increases the risk of death at 6 months in these patients. Our study found that 23% of the ACS patients eligible to did not tolerate BB treatment. This result is similar to those described by other researchers worldwide ,13. Howe The results of the present study suggest that the nonprescription of the drugs is due to the intolerance to their use rather than to the nonobservance of guidelines. The patients who did not tolerate BB use were those in Killip II class, with intolerance to ACEI, and were not under statin treatment. The univariate regression analysis showed that beyond the Killip II classification, impaired renal function is also a predictor for the nonuse of BBs. Several studies have analyzed the association between impaired renal function and the treatment of ACS –17. Most The nonuse of ACEIs and statins was associated with BB intolerance. Concerning ACEI, arterial hypotension would explain this association. However, the association of the lack of statin prescription with the nonuse of BB was intriguing. Patients who were not treated with statins had double the risk of nontolerance to BB. As our results do not allow us to explain such association, we discuss some considerations about the subject as follows.  The use of statins is recommended for patients with ACS and also as an adjuvant drug in the primary prevention of the disorder –21. The A gender-related difference was noticed in the treatment. This is in agreement with the reports of others stating that elderly female patients receive less aggressive therapies when hospitalized with ACS, maybe because aggressive prescriptions are discouraged in this specific patient group –26. It is known that immediate reperfusion therapy and the introduction of adjuvant medications such as BBs, ACEIs, and statins are highly relevant for the better management of patients with ACS . In addiACS patients presenting an unstable hemodynamic condition at admission or a history of previous ACS events, kidney failure, or overt heart failure received less adjuvant pharmacological approach, in accordance with other reports –32. Howe The overall 6-month mortality was associated with age, arterial hypertension, Killip II, elevated serum creatinine, atherosclerotic plaque in the LAD coronary, and the nonuse of BB. Notably, the lack of BB use during hospitalization more than quadrupled the risk of death, regardless of the ACS type. Altogether, the results of the present study suggest that the parameters associated with BB intolerance during hospitalization should be aggressively managed in order to allow the use of the drug. Therefore, we emphasize the need for an individualized therapeutic strategy that would allow enough hemodynamic stability to make BB prescription possible in ineligible patients.


Because of the various cardiovascular and metabolic activities of glucocorticoids, we tested the hypothesis that 11β-HSD1 is a common mechanism in the hypertension, dyslipidemia, and insulin resistance in metabolic syndrome. In obese and lean SHR/NDmcr-cp (SHR-cp), cardiovascular, metabolic, and renal functions were measured before and during four weeks of administration of vehicle or compound 11 (10 mg/kg/d), a selective inhibitor of 11β-HSD1. Compound 11 significantly decreased 11β-HSD1 activity in adipose tissue and liver of SHR-cp. In obese SHR-cp, compound 11 significantly decreased mean arterial pressure, glucose intolerance, insulin resistance, hypertriglyceridemia, and plasma renin activity with no effect on heart rate, body weight gain, or microalbuminuria. These results suggest that 11β-HSD1 activity in liver and adipose tissue is a common mediator of hypertension, hypertriglyceridemia, glucose intolerance, and insulin resistance in metabolic syndrome.Metabolic syndrome is a constellation of risk factors including hypertension, dyslipidemia, insulin resistance, and obesity that promote the development of cardiovascular disease. Metabolic syndrome has been associated with changes in the secretion or metabolism of glucocorticoids, which have important functions in adipose, liver, kidney, and vasculature. Tissue concentrations of the active glucocorticoid cortisol are controlled by the conversion of cortisone to cortisol by 11 Metabolic syndrome is a constellation of interrelated risk factors that promote the development of cardiovascular disease. The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) defined the characteristics of the metabolic syndrome as elevated blood pressure, insulin resistance (with or without glucose intolerance), abdominal obesity, atherogenic dyslipidemia , and prothrombotic and proinflammatory states . Rather β-hydroxysteroid dehydrogenase within tissues. There are two isozymes of 11β-hydroxysteroid dehydrogenase: type 1 (11β-HSD1) converts inactive cortisone to active cortisol and type 2 (11β-HSD2) converts active cortisol to inactive cortisone. 11β-HSD1 is most abundantly expressed in liver and adipose tissue -cortisone diluted in 80 nM in assay buffer  with 1 mM NADPH was dispensed to a 96-well plate. To start the reaction, 10 μL of tissue microsome preparation  was added to each well. As a control to determine assay background, assay buffer was added instead of microsomes. The plate was shaken briefly and incubated at 37°C for 2 hours. Meanwhile, a stop solution containing 5 mg/mL protein A-coated YS SPA beads resuspended in Superblock (Pierce), 10 μM 18β-glycyrrhetinic acid, and 1 μg/mL monoclonal cortisol antibody (East Coast Biologics) was prepared and incubated for 2 hours at room temperature to form the SPA bead complex. For each well, 70 μL of the stop solution containing SPA beads was added to terminate the enzyme reaction. The plate was then incubated for another 2 hours. The signal emitted by the SPA/product complex was measured on a TopCount (Packard). The measurements of 11eviously , 32. Briβ-HSD2 assay, 40 μL of [3H]-cortisol diluted in 80 nM in assay buffer with 2 mM NAD was dispensed to a 96-well plate. 10 μL of kidney microsomes (30 μg/mL) was added to the plate. The plate was shaken briefly and incubated at 37°C for 1.5 hour. The stop solution was prepared as described above, and 70 μL of the stop solution containing SPA beads was dispensed to all wells to terminate the enzyme reaction. The plate was then incubated for 1 hour at room temperature while slightly shaking to allow the capture of the remaining substrate, [3H]-cortisol, by the SPA bead complex. The signal emitted by the SPA/product complex was measured on a TopCount (Packard).For the 11t-test was used to evaluate statistical significance. P < 0.05 was considered to be statistically significant.Data are reported as mean ± SEM. Analysis of variance followed by Bonferroni multiple comparison test or Student's P < 0.05 versus obese) SHR-cp have significantly higher mean arterial pressure (MAP) than age-matched WKY . As shown in The blood pressure and heart rate responses to chronic administration of compound 11 or vehicle in obese and lean SHR-cp are illustrated in Figures The plasma lipid profiles of lean and obese SHR-cp before and after three weeks of vehicle or compound 11 administration are shown in The renin-angiotensin-aldosterone system was assessed by measuring circulating renin and aldosterone concentrations before and after chronic vehicle or compound 11 administration. At baseline, the plasma aldosterone concentration was significantly higher in obese (273 ± 59 pg/mL) compared to lean (130 ± 26 pg/mL) SHR-cp. Compared to vehicle treatment, compound 11 had no significant effect on the plasma aldosterone concentrations in either lean  or obese  SHR-cp. However, plasma renin activity was significantly reduced in obese SHR-cp treated with compound 11 . At baseline, obese SHR-cp had impaired glucose tolerance and insulin resistance compared to lean SHR-cp. The fasting blood glucose concentrations at baseline were similar among obese  and lean  SHR-cp. However, the fasting blood glucose response to glucose challenge was significantly impaired in obese compared to lean SHR-cp see . The maxFour weeks of compound 11 administration significantly improved glucose tolerance and reduced insulin resistance in obese SHR-cp. The maximum blood glucose concentration in response to glucose challenge , the areβ-HSD1 cortisone reductase activities in adipose tissue and liver tissues of lean and obese SHR-cp after chronic treatment with vehicle or compound 11. After four weeks of treatment with vehicle, 11β-HSD1 activity in obese SHR-cp was significantly higher by 31% in liver and lower by 76% in adipose tissue compared to lean SHR-cp. However, obese SHR-cp had a much greater abundance of visceral fat than lean SHR-cp (authors' observations at tissue harvest), so total adipose 11β-HSD1 activity may have been elevated in obese compared to lean SHR-cp. In lean SHR-cp with compound 11 treatment, 11β-HSD1 activity was significantly lower by 96% in liver and by 92% in adipose tissue compared to vehicle. Similarly, in obese SHR-cp with compound 11 treatment, 11β-HSD1 activity was significantly lower by 90% in liver and by 97% in adipose tissue compared to vehicle. The cortisol dehydrogenase activity of 11β-HSD2 in kidney was similar between lean (4587 ± 98 cpm) and obese (4228 ± 113 cpm) SHR-cp with vehicle treatment, and compound 11 had no effect .β-HSD1 inhibition in metabolic syndrome. Previous studies using either genetic models or pharmacological blockade uncovered a role for 11β-HSD1 in one or more of the risk factors in metabolic syndrome. However, no earlier study had investigated the comprehensive response, including blood pressure and renal function, to determine whether 11β-HSD1 is a common mechanism in the multiple risk factors. The results from this study show for the first time that pharmacological inhibition of 11β-HSD1 activity alone in adipose tissue and liver significantly decreases hypertension in a preclinical model of metabolic syndrome. Inhibition of 11β-HSD1 also reduces the glucose intolerance, insulin resistance, and elevated plasma triglycerides in metabolic syndrome. Together, these results expand upon previously published results and indicate that 11β-HSD1 is a common mechanism that contributes to the interrelated risk factors of metabolic syndrome. The major objective of this study was to determine the integrated cardiovascular, renal, and metabolic response to 11Clinical studies previously have shown an association between glucocorticoids and hypertension in the presence or absence of metabolic syndrome. In humans with essential hypertension, the vasoconstrictor sensitivity to glucocorticoids is increased  and the β-HSD1 inhibitor MK-0916 [β-HSD1 inhibition also reduced elevated LDL and body weight in these clinical studies using small cohorts [ Not only there is a strong association between glucocorticoids and hypertension, but also clinical trials have shown a therapeutic benefit of reducing glucocorticoid activity on blood pressure, in some cases on a background of metabolic syndrome. Hypertension associated with Cushing's syndrome was reversed with the antiglucocorticoid agent RU486 [ MK-0916 . Interes MK-0916 . In asso cohorts , 24.β-HSD1 suggested that the local  generation of cortisol plays an important role in the regulation of blood pressure in metabolic syndrome (see [β-HSD1 in mice caused a transgene dose-related increase in blood pressure [β-HSD1 specifically in adipose tissue also exhibited high blood pressure [β-HSD1 in selective tissues, Kotelevtsev et al. reported that the mean arterial pressure of 11β-HSD1−/− mice is the same as in wild-type mice [β-HSD1−/− mice in order to maintain blood pressure. These preclinical studies suggested that increased 11β-HSD1 activity can markedly elevate blood pressure, but is not required for hypertension. We show for the first time that the pharmacological inhibition of 11β-HSD1 activity alone in liver and adipose tissue is sufficient to reduce blood pressure in an animal model of metabolic syndrome. Prior preclinical studies using the genetic manipulation of 11ome (see  for revipressure . Furtherpressure . In contype mice . Other mβ-HSD1 decreases blood pressure through a natriuretic mechanism. The results indicate that inhibition of 11β-HSD1 activity tended to decrease sodium and chloride excretion in obese SHR-cp, an effect opposite to a natriuretic agent. However, the small reduction in salt excretion could have been due to the significant decrease in urine flow, which was secondary to the reduced glucose excretion, since glucose is an osmotically active solute in renal tubules. Glucocorticoids have a wide range of activities within the cardiovascular, renal, and endocrine systems. Previous studies have shown that glucocorticoids can affect insulin resistance, gluconeogenesis, liposynthesis, accumulation of visceral fat, vascular reactivity, vascular remodeling, renal sodium reabsorption, and blood pressure , 40, 41.β-HSD1 activity. The present data clearly indicate that long-term inhibition of 11β-HSD1 significantly improves glucose tolerance and reduces insulin resistance, which may contribute to the lowering of blood pressure. Previous studies have demonstrated that reducing 11β-HSD1 activity decreased glucose intolerance and hyperinsulinemia in diet-induced obese mice [An alternative explanation for the reduction in blood pressure may be found in the metabolic changes associated with inhibition of 11ese mice , 42 and ese mice . Howeverese mice .β-HSD1 decreases blood pressure in hypertensive SHR-cp independent of metabolic changes. Inhibition of 11β-HSD1 in adipose tissue and liver of obese SHR-cp decreases glucose tolerance, insulin resistance, hypertriglyceridemia, and hypertension. Yet in lean SHR-cp, inhibition of 11β-HSD1 similarly decreases hypertension in the absence of changes in glucose tolerance or insulin resistance. With the caveat that the metabolic response to 11β-HSD1 inhibition may simply not be manifested in lean SHR-cp because of their normal metabolic state, our results suggest that 11β-HSD1 is an independent mediator of hypertension in SHR-cp. Regardless, 11β-HSD1 is a common mechanism in multiple risk factors in metabolic syndrome. Our data suggests that inhibition of 11β-HSD1 activity in adipose tissue had increased plasma angiotensinogen, angiotensin II, and aldosterone concentrations and are hypertensive. The elevated blood pressure was abrogated by blockade of the angiotensin II type 1 receptor [β-HSD1 inhibition is likely due, at least in part, to a reduction in angiotensin II actions. Finally, the mechanism for the reduction of high blood pressure likely includes modulation of the renin-angiotensin system. Previous investigators showed that glucocorticoids increased hepatic synthesis of angiotensinogen  and angireceptor . Indepenreceptor  or minerreceptor , 47, inhreceptor , or antireceptor , 50 all β-HSD1 activity decreases hypertension, insulin resistance, glucose intolerance, and hypertriglyceridemia in obese SHR-cp. These are prominent features of the metabolic syndrome, and 11β-HSD1 appears to be a common regulatory mechanism among them. Longitudinal clinical studies have confirmed that metabolic syndrome is a risk factor for subsequent development of cardiovascular disease and mortality [β-HSD1 for the treatment of hypertension and other interrelated risk factors in metabolic syndrome.The present study shows that inhibition of 11ortality . The preortality . Althougortality , 53 and ortality , there a


Obstructive sleep apnea syndrome (OSAS), a chronic condition characterized by collapse of the pharynx during sleep, has been increasingly recognized as a health issue of growing importance over the last decade. Recently emerging evidence suggests that there is a causal link between OSAS and hypertension, and hypertension represents an independent risk factor in OSAS patients. However, the pathophysiological basis for patients with OSAS having an increased risk for hypertension remains to be elucidated. The main acute physiological outcomes of OSAS are intermittent hypoxia, intrapleural pressure changes, and arousal from sleep, which might induce endothelial dysfunction, sympathetic activation, renin–angiotensin–aldosterone system activation, lipid metabolism dysfunction, and increased oxidative stress. This brief review focuses on the current understanding of the complex association between OSAS and hypertension. Sleep-related breathing disorders lead to concomitant alterations in the central nervous and cardiovascular systems, and such alterations often induce additional health issues. Sleep-disordered breathing represents a wide spectrum of sleep-related breathing abnormalities. Obstructive sleep apnea (OSA) is a condition in which there is repetitive partial or complete collapse of the pharynx during sleep. OSA associated with excessive daytime sleepiness is commonly called obstructive sleep apnea syndrome (OSAS). OSAS is the most common sleep-disordered breathing abnormality  and ofteOur understanding of OSAS has evolved from initially regarding it as merely an annoying social situation to the recognition that OSAS may act through various mechanisms to increase cardiovascular risk and lead to increased morbidity and mortality . In partOSAS symptoms, including habitual and intermittent snoring, recurrent arousal during sleep, excessive daytime sleepiness, and witnessed apneas suggest the occurrence of OSAS. However, the gold standard diagnostic test for OSAS is the overnight in-laboratory polysomnography. Polysomnography uses multi-channel continuous recordings for electrocardiography, electromyography, electroencephalography, electro-oculography, nasal airflow, snoring sounds, blood oxygen saturation, thoracic and abdominal impedance belts for respiratory effort, and intra-esophageal pressure. The apnea-hypopnea index (AHI), defined as the average number of apneas and hypopneas per sleep hour, has always been used to evaluate OSAS severity. An apnea is defined as the complete airflow cessation for at least 10 seconds . HypopneThe prevalence of OSAS varies among study populations, due to the use of different variables, and is influenced by the criteria used to define OSAS as well as by the population characteristics. The first large epidemiologic polysomnographic study of OSAS was done in 1995 . Later, OSAS is widespread in the middle-aged and older population, while hypertension is also highly prevalent among the middle-aged and older population. This raises the possibility of considerable co-morbidity between hypertension and OSAS. A lot of experimental and clinical evidence has indicated that the extent of the co-morbidity of hypertension and OSAS is actually substantially greater than expected.In animal studies, direct evidence of the relationship between OSAS and hypertension has been well-established. Experimental OSAS resulted in acute transient increases in nighttime blood pressure (BP) and eventually produced sustained daytime hypertension . Acute nIn humans, a large number of studies have sought to determine the presence and extent of a causal relationship between OSAS and hypertension, independent of frequently co-occurring and possibly confounding variables including age, body weight, and body mass index. The most convincing evidence for the support of a causal relationship between OSAS and hypertension has come from numerous epidemiological data collected in community populations. Early studies indicated that hypertension was found in about 50% of OSAS patients , while aSome researchers have concluded that an increase in diastolic blood pressure might be the earliest hypertensive change associated with OSAS, evidenced by the fact that diastolic blood pressure was higher early in the course of OSAS , and diaThe pathophysiological pathways linking risk factors between OSAS and hypertension intersect with upper airway dilator muscle activity abnormalities, reduced arousal from sleep, reduced lung volume, and impaired ventilatory control stability . CommuniThe prevalence of OSAS increases with age . In oldeDuring the past three or four decades, the United States has witnessed a dramatic increase in the number of overweight or obese individuals, which has become a public health issue . EpidemiLongitudinal data from the Cleveland Family Study demonstrated that AHI was significantly associated with BMI and waist–hip ratio . RecentlHowever, in the Asian population, where visceral obesity is less prevalent, the prevalence of OSAS is not proportionately reduced. This phenomenon suggests that there may be a craniofacial effect interacting with body habitus . With obThis increasing prevalence of obesity and obesity-related hypertension has not only been described in the Western developed countries but also in developing countries such as China and India . AlthougMost of the clinical population-based studies on OSAS prevalence were conducted in USA, Europe, and Australia. Recently, in Asian countries, including China, India, and Korea, several studies have been undertaken to characterize the burden of OSAS . The preThe overall prevalence of sleep-disordered breathing was approximately equal in Caucasians (30%) and African-Americans (32%), but the severity was higher in the African-American population . The oddSimilarly, a cross-sectional study of New Zealand Maori (Polynesian) and European (Caucasian) men showed that small reductions in mandibular prognathism and a wider bony nasal aperture represent major factors associated with OSAS in Polynesian men, whereas in the Caucasian group OSAS was associated with a larger neck circumference and a reduced retropalatal airway size . In addiEthnicity is associated with hypertension prevalence and is an important independent contributor to OSAS prevalence . The preIn normal subjects, blood pressure decreases during sleep by 10%–20% of the awake value and increases promptly on waking. An absence of this nocturnal dip in blood pressure correlates directly with the amount of deep sleep and inversely with indices of sleep fragmentation . Thus, tA nighttime fall of blood pressure (dipping) is normal. On the contrary, reduced nocturnal BP (non-dipping) or even higher nocturnal BP than daytime BP is an undoubted risk factor for hypertensive patients due to the end-organ damage and subsequent cardiovascular events . A bluntIn the Wisconsin Sleep Cohort Study, Young and colleagues  found a Also, diastolic, systolic, and mean blood pressure values during sleep were significantly related to apnea-hypopnea index and age . AnotherMoreover, the relationship between OSAS and nocturnal hypertension might differ between males and females. Interestingly, Portaluppi et al. studied 100 new cases of hypertension in men and found that non-dipping individuals exhibited a blunting of nocturnal blood pressure dipping phenomenon and an increased variability in BP associated with OSAS . This suOSAS-related hypoxemia and hypercapnia, sleep fragmentation, increased sympathetic activity, chemoreflex activation, and nighttime blood pressure surges may be involved in the increased peripheral vascular tone  and subsequent cardiovascular events in OSAS patients . CardiovOSAS is an important secondary cause of resistant hypertension and is particularly common in patients with resistant hypertension . ResistaMasked hypertension is defined as a normal clinic blood pressure and elevated out-of-clinic blood pressure, assessed using self-monitoring of blood pressure by the patients at home . Masked A recent study revealed that among apparently normotensive male OSAS patients, masked hypertension is present in one-third of patients and there is a progressive impairment of arterial stiffness in OSAS patients with masked hypertension, indicating that the diagnosis of masked hypertension may be underestimated in OSAS patients and that OSAS has an association with arterial stiffness independent of masked hypertension . MoreoveThe first report regarding OSAS and pulmonary hypertension was in 1988. No significant correlation existed between pulmonary arterial pressure and the apnea index . HoweverThe main acute physiological consequences of OSAS are intermittent hypoxia, intrapleural pressure changes, and arousals, which might induce endothelial dysfunction, sympathetic activation, lipid metabolism dysfunction, increased oxidative stress, etc. . All of Intermittent hypoxia, particularly if associated with episodes of intermittent reoxygenation, is one of the most important features in OSAS . IntermiEndothelial dysfunction is a systemic pathological state of the vascular endothelium and can be broadly defined as an imbalance between vasorelaxation and vasoconstriction substances produced by the endothelium . EndotheA previous study showed that even mild OSAS was associated with reduced endothelium-dependent vasodilatation . GreaterNitric oxide (NO), the most important vasodilatory molecule synthesized by the endothelium, decreased in patients with OSAS . In addiThe evidence that OSAS is associated with increased oxidative stress and inflammation is based on findings from both animals and humans. Promoting inflammation and oxidative stress is a major cause of endothelial dysfunction by decreasing NO availability and reducing endothelial vasodilatation capacity. Cells exposed to intermittent hypoxia demonstrated selective activation of the pro-inflammatory transcription factor NF-κB, whereas the adaptive regulator HIF-1 was not activated . In addiMoreover, NF-κB could further stimulate the production of pro-inflammatory mediators such as IL-8 and intercellular adhesion molecule 1 (ICAM-1) . TNF-alpWeight loss is an effective treatment of obesity in OSAS patients. Weight loss improves significantly sleep apnea and has favorable effects on blood pressure and baroreflex sensitivity . The impThe most common and highly efficient therapeutic procedure of eliminating airway obstruction is continuous positive airway pressure (CPAP) therapy, a form of treatment first described in 1981 by Sullivan et al. . This thP < 0.05) (P < 0.05)  . Another < 0.05) .P = 0.23)  were modest and not statistically significant ( = 0.23) . The aut = 0.23) . ObviousOver the last decade, there has been increased interest in OSAS-related research and increased understanding of the OSAS-related cardiovascular complications. Because OSAS is associated with hypertension and hypertension associated end-stage organ diseases such as stroke, coronary heart disease, and arrhythmia, the employment of CPAP is highly encouraged as CPAP therapy seems to assist blood pressure control at least in those with severe apnea, resistant hypertension, and daytime sleepiness. This field continues to be updated monthly. A number of key questions, however, remains to be resolved. More clinical research is warranted to characterize more fully the underlying mechanisms and to develop practicable strategies for OSAS treatment.


Sidestream dark-field (SDF) imaging is an important new technology that has been used to demonstrate microcirculatory abnormalities in a variety of critical illnesses . The micSublingual SDF images were obtained from five groups of 20 participants: healthy volunteers under 25 years, healthy volunteers over 55 years, and stable patients over 55 years with one of diabetes mellitus (DM), cirrhosis and stage 5 chronic kidney disease (CKD). Microcirculatory parameters  between P for difference = 0.14). There were no significant differences in the proportion of perfused vessels and perfused vessel density between the groups. See Figure All DM patients were type 2, with mean glycated haemoglobin HbA1c) of 8.8% (SD 1.7%). Seventeen cirrhotic patients were Child- Pugh-Turcotte score A and one was score B. For CKD, the mean estimated glomerular filtration rate was 11.5 ml/minute (SD 2.9). Median microvascular flow index (MFI) was 2.85 (IQR 2.75 to 3.0) for participants aged <25, 2.81 (2.66 to 2.97) for those aged >55, 2.88 (2.75 to 3.0) for those with DM, 3.0 (2.83 to 3.0) for those with cirrhosis and 3.0 (2.78 to 3.0) for those with CKD (c of 8.8%Older age, diabetes, and chronic kidney and liver disease need not be considered confounding factors for comparison of SDF microcirculatory parameters in the critically ill.


Background. Stroke frequently leaves survivors with hemiparesis. To prevent persistent deficits, rehabilitation may be more effective if started early. Early training is often limited because of orthostatic reactions. Tilt-table stepping robots and functional electrical stimulation (FES) may prevent these reactions. Objective. This controlled convenience sample study compares safety and feasibility of robotic tilt-table training plus FES (ROBO-FES) and robotic tilt-table training (ROBO) against tilt-table training alone (control). A preliminary assessment of efficacy is performed. Methods. Hemiparetic ischemic stroke survivors  were assigned to 30 days of ROBO-FES (n = 38), ROBO (n = 35), or control (n = 31) in addition to conventional physical therapy. Impedance cardiography and transcranial doppler sonography were performed before, during, and after training. Hemiparesis was assessed using the British Medical Research Council (MRC) strength scale. Results. No serious adverse events occurred; 8 patients in the tilt-table group prematurely quit the study because of orthostatic reactions. Blood pressure and CBFV dipped <10% during robot training. In 52% of controls mean arterial pressure decreased by ≥20%. ROBO-FES increased leg strength by 1.97 ± 0.88 points, ROBO by 1.50 ± 0.85 more than control . CBFV increased in both robotic groups more than in controls (P < 0.05). Conclusions. Robotic tilt-table exercise with or without FES is safe and may be more effective in improving leg strength and cerebral blood flow than tilt table alone. Stroke poses enormous medical and social problems to societies worldwide. Stroke incidence ranges between 101 and 285 per 100.000 inhabitants per year depending on continent and region . Early mRobots can help early mobilization. Robots can assist the patient with altered states of vigilance enabling movement repetitions that may induce central nervous system reorganization processes that lead to functional recovery . RoboticNeither for robot nor FES therapy, safety, feasibility, and efficacy have been demonstrated in patients during the acute phase after stroke. The objective here was to assess safety—especially with respect to orthostatic reactions—of robot-assisted verticalization with and without FES shortly after a stroke. A preliminary assessment of efficacy was also conducted. This study evaluates safety and feasibility of robotic/FES acute rehabilitation in a convenience sample of patients that were assigned to one of three groups allowing for between-group (control) comparisons. The trial does not fulfill the CONSORT criteria of a randomized controlled trial and was therefore not registered.Inclusion criteria were ischemic stroke in the territory of the middle cerebral artery not longer than 7 days before enrollment participated in the trial. Patients with hemiparesis 4 or less points on the MRC scale were included. The diagnosis of ischemic stroke was verified by CT or MRI.We excluded patients with an NIHSS > 16 points, because we assumed that the severity of the disease would interfere with the accessibility of the patient for training. Additional exclusion criteria were severe cognitive impairment (MMSE < 10), severe aphasia, blood pressure (BP) persistently higher then 160/100 mmHg or lower than 90/60 mmHg, internal carotid artery stenosis > 60% by NASCET criteria, severe cardiac disease, intracardiac thrombus, severe medical conditions, contractures of lower extremities, thrombophlebitis, and lower extremity deep vein thrombosis. All patients gave written informed consent. Experimental protocols were approved by the institutional ethics committee.All patients received acute care for ischemic stroke according to institutional protocols in accordance with international guidelines. Conventional rehabilitation consisting of physical and physiotherapy  was delivered for 30 days (0.5–1 h/work day) other in addition to experimental and control treatments.In parallel to conventional therapy, participants received either robotic tilt table  combined with FES (ROBO-FES), robotic tilt-table alone (ROBO), or tilt-table training alone (control). Group assignment was determined by day of admission; that is, patients admitted on Mondays or Thursdays were assigned to ROBO-FES, those admitted on Tuesdays and Fridays to ROBO, and those admitted on Wednesdays and Saturdays to control.The robotic tilt table . Electrodes were placed over biceps femoris, quadriceps femoris and gastrocnemius of either leg. The stimulation was synchronized with robotic leg movements: biceps femoris, and gastrocnemius muscles were stimulated at the time of leg flexion; quadriceps femoris was simulated at the time of leg extension. Strength of stimulation varied between 5 and 100 mA. Hemiparesis was measured using British MRC strength scale. Systolic and diastolic blood pressure and stroke volume were measured using impedance cardiography . Cerebral blood flow was assessed using transcranial doppler ultrasonography (TCD) of the middle cerebral artery in the hemisphere affected by the stroke. TCD was performed using pulse-wave doppler and a range-gated 2 MHz probe  that was fixated over the temporal bone window by a helmet . The MCA was insonated at a depth of 55 mm. Maximum systolic velocity, minimum diastolic velocity, and the indexes of peripheral resistance (pulsatility index (PI) and resistance index (RI)) were measured. Both impedance cardiography and TCD were performed over a period of 30 minutes. All outcome measures were collected within 1-2 days before starting and after ending the 30-day training period. Additionally, cerebral blood flow and hemodynamic parameters were measured during the first training session.n = 9 tests . Dunn's multiple comparison test was used for comparisons between each intervention group and the control group. In case of significant between-group differences at baseline, the baseline variable was included as a covariate in the model. Two-tailed P values < 0.05 were considered significant.SPSS  was used for all statistical analyses. Because of the small sample size in each group, nonparametric tests  were used to assess the effect of group on the change of each outcome variable (postintervention baseline). Because no primary outcome variable was prespecified we present the results also corrected for multiple comparisons using Benferroni's correction for n = 8). These eight patients chose to terminate the study and were excluded from further analyses. A total of 128 patients were recruited. 24 patients dropped out for different reasons see . AdverseOf the 104 patients who completed the study, 38 were treated with ROBO-FES, 35 with ROBO, and 31 with tilt table (controls). Mean age of the 104 subjects was 58.3 ± 1.2 years (mean ± SD). In 52 patients, stroke affected the right hemisphere. Patient demographics, cardiovascular risk parameters, and baseline impairment and dependency pre group are presented in P < 0.0001, Bonferroni corrected P < 0.0001, P < 0.05). The difference between ROBO and control and between both robotic groups was not significant. Similarly, the Barthel index increased in ROBO-FES more than in ROBO or control, but the overall effect of group was not significant . There was a significant group effect on the resistance index , but the result was no longer significant when multiple comparison correction was applied (P = 0.42). Dunn's post hoc tests for comparisons between groups were insignificant  if multiple comparisons were not corrected for (P = 0.28). There was a significant difference between groups at baseline (P < 0.0001). If baseline values were entered as a covariate into an ANOVA model, the group effect disappeared  in combination with functional electrical stimulation (FES) is safe and may improve strength as well as cerebral blood flow and blood pressure. As an addition to conventional physiotherapy, ROBO-FES was more effective than verticalization only using a tilt table. ROBO training without FES induced smaller changes than ROBO-FES but was still superior to tilt-table in improving leg strength and cerebral blood flow.Early mobilization out of bed is generally desired to prevent systemic complications after stroke . The AVEDifferent rationales have been proposed for the use of robotic mobilization and FES. One is to improve orthostatic hypotension, which is common in patients with spinal cord or traumatic brain injury. Venous return and, hence, cardiac output increase during passive leg cycle exercise in healthy and in subjects with spinal cord injuries . SimilarIn addition to orthostatic reactions, verticalization may cause harm by decreasing cerebral blood flow, which depends on head position. Lowering the head has been suggested to improve blood flow in the acute phase after stroke . We therA second rationale is to improve vigilance. In comatose or vegetative patients, verticalization may improve the regaining of consciousness (reviewed in ). WhetheA third rationale is to reduce motor impairment by preventing long-term spasticity and improving strength. Our findings suggest that leg strength improves more after ROBO-FES as compared with ROBO and control. However, the study was not designed to evaluate the efficacy of the therapies to improve leg paresis. Its limitations (see the following) limit the interpretability of these findings.Thirty days of training in ROBO and ROBO-FES groups did induce lasting changes in cerebral perfusion. Comparing cerebral blood flow to the lesioned hemisphere before and after training showed greater improvement in the robotic groups. Pulsatility and vascular resistance improved likewise. Improved perfusion in certain brain regions has been observed in chronic stroke patients after constraint induced movement therapy using single photon emission computed tomography. These findings have been interpreted as evidence of therapy-related cortical reorganization . This inIn contrast to cerebral blood flow velocity, systemic blood pressure declined in all three groups over the 30-day training period, reflecting the expected time course of blood pressure evolution after acute stroke . We cannThis study has several limitations. Most importantly, a relatively crude assessment of strength using the MRC scale was the only functional outcome. As our main objective was to address safety, we focused on adverse events and physiological parameters. A simple functional outcome was added because we expected logistic problems with collecting a more sophisticated assessment of impairment, such as the Fugl-Meyer scale. Another limitation is the lack of followup data. Both questions—functional outcome and maintenance of therapy effects—are important to answer in future studies. A third limitation is the lack of randomization. This may explain the differences between the groups observed at baseline for various outcome measures. However, because we could not identify a systematic difference in the assignment to group, the differences may also have occurred by chance.In conclusion, this controlled study suggests that robotic tilt-table training with and without functional electrical stimulation is safe and feasible in the postacute period after stroke. It provides preliminary evidence that in combination with conventional physical therapy this training is more effective in improving leg strength as compared with tilt-table training alone.


Accurate blood pressure monitoring is critical for the management of chronic kidney disease, but changes in management in secondary care clinics may be based on a single blood pressure reading, with a subsequent lack of accuracy. The aim of this study was to evaluate a fully automated sphygmomanometer for optimising the accuracy of blood pressure measurements in the setting of secondary care renal clinics.Patients had routine blood pressure measurements with a calibrated DINAMAP PRO400 monitor in a clinical assessment room. Patients then underwent repeat assessment with a DINAMAP PRO400 monitor and BpTRU device and subsequent 24 hour ambulatory blood pressure monitoring (ABPM).The BpTRU systolic (± SD) reading (117.3 ± 14.1 mmHg) was significantly lower than the routine clinic mean systolic blood pressure  and the repeat blood pressure taken with a DINAMAP PRO400 monitor in a quiet room . The routine clinic mean diastolic (82.4 ± 11.2 mmHg) was significantly higher than the BpTRU reading . Clinic BpTRU measurements were not significantly different to the daytime mean or overall mean of 24 hour ABPM.In patients with CKD, routine clinic blood pressure measurements were significantly higher than measurements using a BpTRU machine in a quiet room, but there was no significant difference in this setting between BpTRU readings and 24 hour ABPM. Adjusting clinic protocols to utilise the most accurate blood pressure technique available is a simple manoeuvre that could deliver major improvements in clinical practice. Chronic kidney disease (CKD) affects up to 15% of the adult population  and is aPatients at highest risk from CKD are managed in secondary care renal clinics; however, the management changes that clinicians recommend in this setting are often based on a single clinic BP reading. Use of a single clinic measurement may over-diagnose hypertension in up to 30% of the general population -13; in mIn addition to the shortfalls of a single BP measurement, inaccuracies may be caused by operator errors; these include incorrect positioning of the patient, inappropriate cuff usage, an inadequate rest period and overly rapid deflation rate ,21-25. IAmbulatory BP monitoring allows BP to be measured over a prolonged period  and is currently considered the 'gold standard’ for the diagnosis of hypertension ,30. An aThe BpTRU device is a fully automated sphygmomanometer that takes six sequential BP readings at pre-set intervals; it automatically discards the first reading and produces an average BP from the last five readings. The BpTRU device has been clinically validated to British Hypertension Society (BHS) A/A grade accuracy . StudiesThe aim of this study was to investigate the clinical utility of the BpTRU device in people with CKD who are attending secondary care clinics. To address this, we have assessed the relationship between i) routinely taken single BP measurements and clinic BpTRU measurements and ii) clinic BpTRU measurements and 24 hour ambulatory BP measurements.This study was registered with the Trust Research & Development at University Hospital Birmingham as part of a clinical service evaluation (CA2-03382-10), and fully complies with the Declaration of Helsinki. The patients were adults attending nephrology outpatient clinics at the Queen Elizabeth Hospital Birmingham. Each patient had a routine clinic BP taken by a clinic nurse in a multi-use clinical assessment room, using a calibrated DINAMAP PRO400 monitor . The DINAMAP PRO monitor series have been validated  and showAfter the routine clinic BP check, patients were approached (by SB) and asked to participate in an assessment of the accuracy of BP measurements. All of the patients who were approached gave informed consent; they were then allocated into one of two groups: the first 45 consecutive patients are reported as 'Group A', a further 25 consecutive patients are reported as 'Group B’. Twenty one consecutive patients attending the outpatient department for ambulatory BP monitoring and who underwent BpTRU evaluation immediately before ambulatory BP monitoring are reported as 'Group C’. A flow diagram summarising the BP measurement schedule is shown in Figure Group A (n = 45) underwent repeat assessment with a separate calibrated DINAMAP PRO400 monitor and then assessment by a BpTRU device  in a quiet clinic room with only the operator present. Of this group, 24 patients had BP re-measured with the DINAMAP PRO400 monitor. They then had BP taken with a one-off reading with the BpTRU monitor. This was followed by a five-minute rest period (consistent with BHS guidelines), and then BP measurement with the BpTRU device, using the full six minute protocol. For BpTRU measurements, the patient was seated (back supported) and the appropriate cuff size, according to measurements on the BpTRU cuffs, was applied to the non-dominant arm (same arm as used for routine clinic BP measurement), at the level of the heart. The BpTRU device is a fully automated sphygmomanometer, which uses the oscillometric technique, and has been clinically validated to BHS A/A accuracy . It is dGroup B (n = 25) underwent immediate repeat assessment in a quiet clinic room with the BpTRU monitor, using the full six minute protocol and with no five minute rest. Group C (n = 21) also underwent immediate repeat assessment with the BpTRU monitor in a quiet room ; the patients in Group C then returned to the clinical assessment room to have their ambulatory BP device  fitted. After fitting the ABPM monitor, an initial BP reading was taken (patients sitting with their back supported and the cuff at the level of the heart). The ABPM device was then set to obtain automatic BP readings in accordance with published guidelines . The ABPDescriptive statistics were calculated for all patients involved in the study (n = 91) and the three groups. Continuous variables are reported as mean ± standard deviation throughout where normally distributed. The analysis focused on comparisons of different BP readings: i) BP measured with a DINAMAP PRO400 monitor in a clinical assessment room as part of routine clinic proceedings; ii) BP measured with DINAMAP PRO400 monitor in a quiet clinic room; iii) BP measured with a BpTRU device in a quiet room, with or without a five minute rest beforehand and iv) BP measured with the ABPM device.post hoc tests were then used to show specific differences between groups. Non-Gaussian data (descriptive statistics only) were analysed with non-parametric Kruskal-Wallis ANOVA tests. Paired Student’s t-tests were used to reveal significant differences between routine clinic and BpTRU BP readings (comparing two different readings only); noted in the relevant Figure legends. Correlation between eGFR and nocturnal ambulatory BP blunting was assessed using Pearson’s correlation coefficient (the data were confirmed as Gaussian prior to using this method). A critical P value of P < 0.05 was considered significant for the statistical tests used throughout this study. Graphically, P < 0.05 is denoted as *, P < 0.01 as **, and P < 0.001 as ***.GraphPad Prism  was used for all statistical analysis. Data were checked for Gaussian distribution prior to further analysis. For data that were normally distributed, we used analysis of variance  to reveal significant differences overall; Bonferroni’s multiple comparisons Ninety one patients were included in the study; 34 female (37.4%) and 57 male (62.6%). The mean age was 49 years (± 18.4), with a range of 16 – 83 years. There was no significant difference in age or gender between the groups.2. The overall mean albumin:creatinine ratio (ACR) was 54.6 ± 146.3 (0 – 1203.6) mg/mmol. There was no significant difference in eGFR or ACR between each group  was 45.1 ± 24.2 (range 4 – 92) ml/ min/1.73 mThe BpTRU systolic reading (122.0 ± 13.9 (96 – 150) mmHg) was significantly lower than the routine clinic systolic BP (149.7 ± 18.5 (117 – 209) mmHg; n = 45; P < 0.0001). The BpTRU diastolic reading (78.4 ± 10.0 (53 - 97) mmHg) was significantly lower than the routine clinic diastolic BP (82.4 ± 11.2 (49 – 100) mmHg; n = 45; P = 0.0033; Figure The mean BpTRU systolic reading (117.3 ± 14.1 mmHg) was significantly lower than both routine clinic systolic (143.8 ± 15.5 mmHg) and systolic BP taken with a DINAMAP PRO400 monitor in a quiet room . The mean BpTRU diastolic reading (74.1 ± 9.2 mmHg) was also significantly lower than both the routine clinic mean diastolic (78.9 ± 12.2 mmHg) and diastolic recorded with a DINAMAP PRO400 monitor in a quiet room  was significantly higher than the mean BpTRU average final reading . However, there was no significant difference between BpTRU systolic readings from Group A  and Group B  was significantly higher than the ABPM daytime mean systolic  and the ABPM overall mean systolic . The routine clinic diastolic reading (90.5 ± 16.2 mmHg) was significantly higher than the ABPM overall mean diastolic value  was not significantly different to either the ABPM daytime mean systolic , or the ABPM overall mean systolic . There was no significant difference between the BpTRU diastolic reading (89.1 ± 16.9 mmHg) and the ABPM daytime mean  or ABPM overall mean diastolic measurements ; 6.28 ± 2.83% for patients with an eGFR from 30-59 ml/ min/ 1.73 m2 (n = 10) and 12.80 ± 8.12% for patients with an eGFR ≥60 ml/min/ 1.73 m2 (n = 6). There was a positive correlation (non-significant) between eGFR and difference between day-time and night-time systolic BP ; the lack of statistical significance may reflect the relatively small numbers who underwent ABPM in the study.Patients in Group C n = 21) underwent routine clinic BP measurements, followed by BpTRU readings, prior to having 24 hour ABPM. The night-time mean ambulatory systolic BP (135.6 ± 20.1 mmHg) was significantly lower than both the day-time  and overall  ambulatory systolic BP readings (denoted as *** in Table 1 underweThis study showed that the use of BpTRU in an outpatient CKD clinic leads to significantly more accurate BP measurement (using 24 hour ABPM as a gold standard) than BP obtained with a conventional BP monitor (DINAMAP PRO400); in this study, there was no significant statistical difference between BP readings taken with BpTRU and daytime and overall 24 hour ABPM. The results show a hierarchy of increasing accuracy from single clinic BP measurements to BpTRU on full protocol; these differences in BP, when measured under different conditions, have important clinical implications and may lead to inaccurate BP management.In addition, we have shown that BpTRU measurements taken in a quiet clinic room are significantly lower than the readings obtained with a DINAMAP PRO400 device in the same setting. We have also demonstrated that, in the presence of an operator, the first BpTRU reading is still significantly higher than the average BpTRU reading.et al. (2011) compared BpTRU readings with the most recent manual routine office BP. Their study also showed that average BpTRU readings were significantly lower than the routine office BP readings [et al. (2008) compared BpTRU readings with mean office manual BP readings taken on the same day. For the office readings in their study, four consecutive readings were taken at one minute intervals; the first reading was then discarded and the mean of the last three readings was recorded. Their results showed that the average BpTRU reading was significantly lower than the mean office BP [A number of primary care studies have investigated the difference between routine office BP measurements and average BpTRU readings. Three studies restricted their subjects to patients with an existing diagnosis of hypertension ,33,34; office BP . Anotherffice BP . The resHowever, there are several differences between this study and previous studies carried out in primary care. Firstly, our measurements were taken in a secondary care outpatient clinic. Secondly, patients in this study were attending for routine appointments, rather than to participate in the study. Thirdly, all the patients had CKD; accurate BP assessment and management is particularly important in this patient group, as people with CKD are at very high risk of cardiovascular disease and hypertension is the major treatable risk factor for this complication. Finally, routine office BP measurements in previous studies have been taken with manual sphygmomanometers; this study compared average BpTRU readings to BP measurements taken with a DINAMAP PRO400 device, an automated sphygmomanometer which, like the BpTRU device, also uses the oscillometric technique.A recent study compared BpTRU readings with routine clinic BP measurements in secondary care clinics . The patSeveral previous studies showing a significant difference between BpTRU and routine clinic measurements have included a five-minute rest prior to carrying out measurements with BpTRU, as per the BHS guidelines ,29,54,60The first BpTRU reading was significantly higher than the average BpTRU reading. This is in agreement with results reported by previous studies ,55,61. INight-time ambulatory BP readings were significantly lower than the daytime and overall ambulatory BP readings. However, a blunted sleep-time decline  in BP was common; a finding consistent with other studies that have assessed people with CKD -35. BlunIn this study, there was no detectable difference between average BpTRU readings obtained in outpatient clinics and the daytime mean or overall mean readings from 24 hour ABPM; again, this is consistent with other published studies ,53-55. BOne shortfall of the study is the absence of 48-hour ABPM data. A recent consensus recommendation concluded that 48-hour ABPM should be utilised for assessment of hypertension, including patients with CKD . The datOther limitations to this study include: i) this study was performed in a clinical setting, rather than a research setting, unlike the majority of previously published work in this area. Therefore, BpTRU readings were always carried out following the routine clinic BP measurements; ii) previous studies have taken routine clinic BP measurements and BpTRU measurements in random order; this is clearly a more accurate way to compare the two techniques, and iii) routine clinic BP measurements were not consistently carried out following a five-minute rest period, unlike those reported in the literature. In a busy outpatient setting, some patients had their routine clinic BP measured as soon as they arrived at clinic; others had their routine clinic BP measured after sitting in the waiting room for a variable amount of time. This lack of control over the technique used for the routine clinic BP measurements may be responsible for some of the difference observed between these readings and the subsequent BpTRU readings. It is also important to emphasise that data from a single study carried out in one setting may not be applicable to other settings. However, in previous studies, where routine clinic BP measurements were carried out in a more controlled manner, average BpTRU readings were also significantly lower than routine clinic readings, suggesting that the data we present are broadly consistent with previous findings and also confirming that previous work carried out in a research setting may be applicable to routine clinical practice.In conclusion, our study demonstrates that routine clinic BP measurements are significantly higher than measurements using a BpTRU machine in a quiet room, and there is no significant detectable difference between BpTRU readings and the day-time mean of 24 hour ABPM in patients with CKD. Adjusting clinic protocols to utilise the most accurate BP device available is a simple manoeuvre that could deliver major improvements in clinical practice.The authors declare that they have no competing interests.SB contributed to the design and co-ordination of the study; undertook data collection and statistical analysis and drafted the manuscript. MD helped co-ordinate the study and reviewed the manuscript. CF critically reviewed the draft manuscript. PC and SS contributed to the conception and design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/218/prepub


Acute kidney injury (AKI) in hospitalized patients is independently associated with increased morbidity and mortality in pediatric and adult populations. Continued reliance on serum creatinine and urine output to diagnose AKI has resulted in our inability to provide successful therapeutic and supportive interventions to prevent and mitigate AKI and its effects. Research efforts over the last decade have focused on the discovery and validation of novel urinary biomarkers to detect AKI prior to a change in kidney function and to aid in the differential diagnosis of AKI. The aim of this article is to review the AKI biomarker literature with a focus on the context in which they should serve to add to the clinical context facing physicians caring for patients with, or at-risk for, AKI. The optimal and appropriate utilization of AKI biomarkers will only be realized by understanding their characteristics and placing reasonable expectations on their performance in the clinical arena. Acute kidney injury (AKI) is defined as an abrupt decrease in kidney function, which in its most severe form, acute renal failure, is manifested by changes in blood chemistry and decreased urine output . AKI ratThe AKI landscape has undergone a seismic shift in the last ten years. Prior to 2004, the definition of AKI was not standardized, with more than 30 different definitions used in the published literature -7, standOptimal therapeutic interventions require expeditious diagnosis for any disease state. The advancements in cardiac and oncological treatments over the past decades have in large part been enabled by the discovery, validation and implementation of new biomarkers of disease; these have included advanced imaging techniques as well as specific markers of cardiac myoblast injury or the genetic subtypes of specific cancers. The myocardial ischemia diagnostic paradigm has moved from electrocardiographic changes, to creatine phoshopkinase (CPK) measurement, to specific CPK subtype enzymatic changes, to the troponins and now to brain natriuretic peptide (BNP). As a result, the sensitivity and specificity to detect earlier myocardial ischemia has progressively increased, directing earlier intervention that has transformed the field and substantially decreased patient mortality ,17.Extensive research efforts over this past decade have been directed at the discovery and validation of novel AKI biomarkers to detect injury prior to changes in kidney function and potentially to aid in the differential diagnosis of AKI. The quest for such biomarkers has often been referred to as the 'search for the renal troponin I'. The analogy to troponin I and its acceptance for prompt evaluation and therapeutic intervention in at-risk patients with the clinical presentation of chest pain is an informative and potentially applicable model to the AKI field . NephrolThe purpose of this article is to review the relevant AKI biomarker literature in terms of a contextual framework to aid in the clinical diagnosis of AKI prior to changes in kidney function. In addition, the empiric prodrome of 'renal angina' will be discussed to highlight the need to direct AKI biomarker assessment only where it will optimize clinical care by detecting AKI early, refining AKI differential diagnosis and/or providing information regarding AKI severity. Finally, very recent data demonstrate that AKI biomarker 'positive' but serum creatinine 'negative' AKI has an equally poor prognosis with classical functional AKI , suggestAKI detection and differential diagnosis has been mired in reliance on the same functional marker, serum creatinine, used to diagnose chronic kidney disease. Unfortunately, serum creatinine concentrations do not change until significant injury and loss of nephron function has occurred. Chertow and colleagues demonstrated that a serum creatinine rise of ≥ 0.3 mg/dl in hospitalized adults was independently associated with a four-fold increased risk of mortality, even when controlling for diabetes, advanced heart failure, ethnicity and age . MultiplAn ideal AKI biomarker should be accurate, reliable, easy to measure with a standard assay, non-invasive, reproducible and sensitive and specific with defined cutoff values . Urine rMost early AKI biomarker validation studies have occurred in patients after cardiopulmonary bypass -27 or reThe initial prospective human study of urinary NGAL occurred in the pediatric CPB setting . SeventySubsequently, multiple studies have confirmed the predictive ability of NGAL in the pediatric CPB setting -31. In aSubsequent to the initial promising results observed for novel biomarker prediction of AKI development and severity after CPB, biomarkers  have beIn addition, other non-surgical or non-kidney specific disease states such as acute decompensated heart failure-associated cardiorenal syndrome may provide an excellent arena to study novel AKI biomarkers . The useAll of the AKI biomarker work performed to date has focused on discovery and validation of AKI biomarkers in a post-hoc manner; samples for biomarkers have been obtained and stored for later assessment of their ability to predict AKI development or severity. The next challenge for AKI biomarkers is to test their ability to direct therapeutic intervention or other clinical management. Yet, the heterogeneity of patient populations and varying precision of AKI biomarkers noted above presents a significant risk for inappropriate use of AKI biomarkers to decrease their utility. Recent statistical methods such as the net reclassification index must be used to ensure that biomarker concentration thresholds add predictive value to the clinical model alone in predicting the AKI spectrum. A recent concept of a prodome of 'renal angina' has been proposed to direct biomarker assessment only in patients who fulfill a combination of illness severity/risk and small changes in kidney function (creatinine changes or fluid overload) ,47. The As discussed above, AKI biomarkers have been validated retrospectively in multiple patient populations. The challenge for the future is to use these data to design preventive, interventional and supportive clinical studies to test the value of AKI biomarkers in improving the outcome for patients with, or at-risk for, AKI. Only after AKI biomarkers have been validated prospectively in the appropriate populations will widespread and rational adoption be possible.AKI: acute kidney injury; ATN: acute tubular necrosis; BNP: brain natiuretic peptide; CKD: chronic kidney disease; CPB: cardiopulmonary bypass; CPK: creatine phosphokinase; CRRT: continuous renal replacement therapy; eGFR: estimated glomerular filtration rate; HUS: hemolytic uremic syndrome; IL-18: interleukin-18; KIM-1: kidney injury molecule-1; L-FABP: liver-type fatty acid binding protein; NGAL: neutrophil gelatinase-associated lipocalin; RIFLE: risk; injury, failure, loss, end-stage kidney diseaseDr. Goldstein has no competing interests to declare with respect to this article.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/9/135/prepub


P = 0.9) over a median follow-up period of 4.5 years. The 1.2% of patients with extreme hypertension at recruitment and at 12-months had a significantly increased mortality risk . This association was not seen in patients with baseline extreme hypertension and improved 12-month blood pressures . Most CKD patients with extreme hypertension respond to pharmacological blood pressure control, reducing their risk for death. Patients with extreme hypertension in whom blood pressure control cannot be achieved have an approximate prevalence of 1%. These patients have an increased mortality risk and may be an appropriate group to consider for further therapies, including renal nerve ablation.Hypertension frequently complicates chronic kidney disease (CKD), with studies showing clinical benefit from blood pressure lowering. Subgroups of patients with severe hypertension exist. We aimed to identify patients with the greatest mortality risk from uncontrolled hypertension to define the prevalence and phenotype of patients who might benefit from adjunctive therapies. 1691 all-cause CKD patients from the CRISIS study were grouped by baseline blood pressure—target (<140/80 mmHg); elevated (140–190/80–100 mmHg); extreme (>190 and/or 100 mmHg). Groups were well matched for age, eGFR, and comorbidities. 77 patients had extreme hypertension at recruitment but no increased mortality risk (HR 0.9,  The global epidemic of chronic kidney disease (CKD) represents a significant challenge for healthcare providers . DespiteHypertension and CKD are inextricably linked with both cause and effect relationships. Uncontrolled blood pressure is associated with a more rapid loss of estimated glomerular filtration rate (eGFR) . As suchDespite these gaps in our knowledge, hypertension in CKD continues to be a focus for investigation. Much interest currently surrounds renal sympathetic nerve ablation—a technique shown to have significant effects on systolic and diastolic blood pressures in both the general and CKD populations with resistant hypertension –15. Howe2 and not requiring immediate referral for dialysis are approached for consent. Baseline demographic data  are recorded, as are annual measurements of blood pressure, prescribed medications, and laboratory data . Mortality data are obtained from the Office of National Statistics. All blood pressure measurements are made by trained staff in accordance with trust protocol. An automated sphygmomanometer with an appropriately sized cuff is used, with all measurements made after at least 5 minutes of seated rest. Patients are requested not to consume caffeine alcohol or undertake vigorous exercise prior to clinic visits. A minimum of two readings are obtained, with an average of these results recorded. For this analysis, patients were grouped into categories of blood pressure: target: systolic blood pressure <140 mmHg and diastolic blood pressure <80 mmHg. This group was used as the referent category; elevated: systolic blood pressure 140–190 mmHg and/or diastolic 80–100 mmHg;extreme hypertension: systolic blood pressure >190 mmHg or diastolic >100 mmHg. Although these values differ from classical definitions of, for example, stage III hypertension, they were selected as they identified the 5% of the study population with the highest baseline blood pressures and in part reflect the more rapid increases in vascular stiffness observed in CKD . The study population was drawn from patients recruited to the Chronic Renal Insufficiency Standards Implementation Study (CRISIS) prior to 31 January 2010. Approval for this study was granted by the regional ethics committee and all patients provided full written informed consent. Details of CRISIS have been published previously ; in brieP for inclusion and retention <0.3). Censoring occurred at death, last clinic visit, or 1 July 2012. Unless specified in the text, all presented hazard ratios are from multivariate analysis, with results presented as hazard ratio . Event rates were compared using negative binomial regression and correlations between variables assessed with Pearson's correlation coefficient. Unless otherwise stated, statistical significance was defined as P < 0.05. All analyses were performed in SAS version 9.2  under license to the University of Manchester (UK). Normally distributed data are presented as mean ± standard deviation, with non-parametric data presented as median (interquartile range). Survival analysis was performed using multivariate Cox proportional hazards regression with a forward stepwise methodology . When grouped according to baseline blood pressure, 722 (42%) had target blood pressure, 892 (53%) had elevated blood pressure, and 77 (5%) had extreme hypertension. In the extreme hypertension group, 45% of patients met the systolic blood pressure definition, 71% of patients met the diastolic blood pressure definition, and 16% of patients met both definitions. Primary cause of CKD was well matched between groups. In comparison between all groups, baseline characteristics were well matched between all three blood pressure groups, with significant differences only observed in urinary protein to creatinine ratio, which increased with blood pressure group ; hemoglobin, which also increased ; and history of myocardial infarction, which was inversely associated with increasing blood pressure . Complete baseline data are presented in 1750 patients were recruited to CRISIS prior to 31 January 2010, with complete baseline data available for 1691 patients, who formed the study population. At recruitment, median patient age was 67 years (IQR 55–75), mean eGFR 32 ± 15 mL/min/173 mP for both <0.01). When considered as a continuous variable, neither baseline systolic, or diastolic blood pressure was associated with a significant change in hazard ratio (HR) for death within 12 months of recruitment. Both, however, had minor associations with risk for mortality over the complete follow-up period . However, there was no association between baseline group of blood pressure and risk for mortality over the entire follow-up period, with neither baseline elevated blood pressure nor extreme hypertension reaching sufficient statistical significance to enter the multivariate model . Complete data are presented in When patients were considered by group of baseline blood pressure, there was a nonsignificant trend towards increased risk for death within 12 months for patients in the extreme hypertension group . Patients who continued to be classified as having extreme hypertension had significantly higher blood pressures than those no longer classified as such . Of the 77 patients in the extreme hypertension group at baseline, 5 (6.5%) died within the first 12 month followup. Of the 72 survivors at 1 year, only 9 (12.5%) still met the criteria to be classified as having extreme hypertension despite being prescribed more antihypertensive medications than the 55 patients with a documented blood pressure who had transferred into a lower category of blood pressure , HR for death 4.3 [1.5–12.7], P = 0.001. Notably, the patients who were no longer classified as having extreme hypertension at 1 year did not have an increase in risk for death compared to the remainder of the study population . These data are presented in In the 9 patients where extreme blood pressure elevations persisted at 1 year, a significant increase in risk for death was observed ). This increase was relative both to the patients who initially, but no longer, had extreme hypertension , with an HR for death 3.47 [1.1–11.0], P = 0.1). Complete data on antihypertensive medication use are presented in No significant differences in the distribution of baseline antihypertensive medications were observed between patients classified as having extreme hypertension and the remainder of the study population. The same overall finding was replicated when medication use at 12 months was considered, although here a trend towards higher rates of diuretic use in patients with persistent extreme hypertension was observed —91 dead and 191 discharged or lost to followup. Of these 1332 patients, 602 were in the target blood pressure group at baseline  and 730 patients were in the elevated blood pressure group at baseline . Overall 58 (4.4%) patients had sufficient increase in their blood pressure to move into the extreme hypertension category during followup. P = 0.9) or in the subsequent 12 months . Of the 58 patients who moved into the extreme hypertension group at 12 months, 24-month follow-up data were available for 45, with 6 of these patients continuing to be classified as having extreme hypertension and 39 having moved down to a lower blood pressure group. No significant increased risk for death was observed in the 6 patients who remained in the extreme hypertension group either when compared to the 39 patients who had moved to a lower category of blood pressure  or the remainder of the population . Overall blood pressure trends are described in Movement into the extreme blood pressure group at 1 year was not associated with an increased risk for death either throughout the complete followup  in this analysis, has extreme elevations in blood pressure that persist despite specialist intervention. This may have implications when designing the studies needed to compare hard clinical end-points between novel interventional and standard pharmacological therapies. Furthermore, this study raises questions about the value of considering hypertension in patients with moderate to advanced chronic kidney disease in a categorical manner. We have demonstrated an association between baseline blood pressure and mortality in an all-cause CKD population. This is consistent with previous studies that have shown that coexistent renal impairment is an independent risk factor for mortality for hypertensive patients  and thatP = 0.01), consistent with other studies in CKD populations [P = 0.6). This equal distribution has further relevance, given the potential links between these agents and an increased risk for death [Secondly, we have demonstrated that extremes of blood pressure are not restricted to patients with the most advanced CKD. Whilst an inverse relationship between eGFR and systolic blood pressure existed , the secondary care setting of this study makes ineffective prescribing unlikely. Potentially, the increased use of these agents is representative of a higher proportion of patients with CKD-related salt/water retention. As such the elevations in blood pressure may represent a volume-mediated process compounding increased systemic vascular resistance. As fluid overload in CKD has been associated with increased risk for death [Our most novel findings relate to patients with “extreme hypertension” at baseline. Although this subgroup was limited in patient numbers, there was a clear signal towards increased short-term but not long-term mortality in this cohort. We suggest that this related to significant improvements in blood pressure control in the majority of these patients in the 12 months following recruitment. By one year, 87% of surviving patients classified as having extreme hypertension at baseline no longer fitted in this category. These patients saw a mean blood pressure reduction of 36/23 mmHg in comparison to the 9 patients with persistent extreme blood pressure, who saw a mean change of 0/3 mmHg. These vast differences in blood pressure control related only to a modest increase in number of antihypertensive agents and small increases in the number of patients prescribed either angiotensin blockade or calcium channel blockers. As such, the most logical conclusions are that either dosing alterations or improved compliance facilitated the improved control. This highlights the benefits of specialist care given that patients with CKD are often underdosed and undertreated for fear of worsening renal function , 25. Givor death , 27, thiP < 0.0001), with a signal towards greater percentage of 2-year reductions in eGFR observed in patients moving into the extreme hypertension group versus those who remained in the target or elevated groups . Hence patients developing extreme hypertension during followup may have suffered the greatest decline in renal function. Given that renal function is one of the strongest predictors of mortality in CKD [Finally, we have demonstrated that the risks of extreme elevations in blood pressure appear to vary over time. Although it initially seems incongruous that patients with normal or moderately raised blood pressure at baseline who transit into the category of extreme hypertension do not have the same increased risks for death as patients with extreme hypertension at baseline, this may relate to several factors in addition to the small sample size in these categories. Firstly, it is highly probable that patients with extreme blood pressure at time of referral have been exposed to this vascular risk for a substantial period of time, whilst those who develop extreme hypertension during followup can be more readily identified and quickly treated. Secondly, increases in blood pressure during followup were strongly related to reductions in eGFR (Pearson's correlation coefficient 0.15, y in CKD , it is pThis analysis has several limitations. Firstly, the small patient numbers in some groups may have implications for model stability; as such the reproducibility of these findings needs to be assessed in another cohort. Secondly, due to the observational nature of this study, no data was available regarding compliance with medications, medication dosing, or dietary sodium restriction. Finally, despite the increased 12 month mortality risk shown in the “extreme hypertension” group, this study cannot directly answer the question of which subgroup of hypertensive CKD patients would be of greatest interest in a future study of interventional blood pressure therapy. In conclusion, this study suggests that failure to manage extreme elevations in blood pressure is more important than absolute baseline blood pressure as a predictor of mortality in CKD. Of the 77 patients with extreme hypertension at baseline, 14 either died within the first 12 months or had persisting extreme hypertension at this time. Another 6 patients progressed to develop persistent extreme hypertension from a less severe baseline category. Hence 1.2% patients in this secondary care CKD population in whom extreme elevations in blood pressure persisted despite specialist care would warrant further study both to understand why blood pressure cannot be controlled and also to identify their suitability for interventions that may mitigate their high adverse risk. This provides an estimate of the proportion of a CKD population that might be suitable for interventional techniques to lower blood pressure, such as renal nerve ablation therapy.


Hypertension plays a key role in chronic kidney disease (CKD), but CKD itself affects the blood pressure (BP) profile. The aim of this study was to assess the association of BP profile with CKD and the presence of cardiac organ damage.2. Cardiac organ damage was evaluated by echocardiography.We studied 1805 patients, referred to our Hypertension Centre, in whom ABPM, blood tests, and echocardiography were clinically indicated. The glomerular filtration rate was estimated (eGFR) using the MDRD equation and CKD was defined as eGFR<60 mL/min/1.73 m2.7 index, and a higher prevalence of left ventricular hypertrophy and diastolic dysfunction . Nocturnal SBP and PP correlated more strongly with cardiac organ damage (p<0.001). Patients with CKD had a greater Treatment Intensity Score (p<0.001) in the absence of a significantly greater BP control.Among patients with CKD there were higher systolic blood pressure (SBP) during the night-time, greater prevalence of non-dippers (OR: 1.8) and increased pulse pressure (PP) during 24-hour period, daytime and night-time . Patients with CKD had a greater LVM/hCKD patients have an altered night-time pressure profile and higher PP that translate into a more severe cardiac organ damage. In spite of a greater intensity of treatment in most patients with CKD, BP control was similar to patients without CKD. Our findings indicate the need of a better antihypertensive therapy in CKD, better selected drugs, dosages and posology to provide optimal coverage of 24 hours and night-time BP. Many individuals with CKD are hypertensive and receive medications for controlling BP. However, the majority of these patients seem to be undertreated. Optimizing blood pressure treatment in this high-risk population can have a great potential in decreasing renal disease incidence and cardiovascular mortality Several studies reported that patients with an altered circadian blood pressure pattern, as non-dippers, have a higher risk of major cardiovascular events compared with patients with a normal pressure pattern Patients with CKD may have a non-dipping BP pattern. The explanation for this is not clear, but many factors have been proposed (e.g. defective natriuresis during daytime and increased blood pressure/natriuresis during the night) To date, to the best of our knowledge, there is little data available, especially for the Italian population, regarding the inter-relationships between estimated glomerular filtration rate (eGFR), BP values and patterns  and echocardiographic parameters. Therefore, the rationale of our study was to investigate the associations between eGFR, BP values and patterns and echocardiographic parameters, to see how CKD and BP values and patterns may correlate with the presence of a cardiac organ damage.The main aim of our study was to assess 24-h BP values and patterns and their relationship with eGFR and cardiac damage, in a population referred to a single “Hypertension Excellence Centre” for BP evaluation, in the hope to improve the clinical management of these patients in the absence of similar published data.All participants have given their informed written consent and clinical investigations have been conducted according to the principles expressed in the Declaration of Helsinki. This study was approved by the local institutional ethics committee . We studied outpatients referred to our Hypertension Centre for BP related problems Inclusion criteria were: clinical indication to undergo ABPM, plasma creatinine measurement and echocardiography. Main exclusion criteria were: age<18 years, low-quality of pressure monitoring (rate of artifacts >25% and/or recording duration less than 20 continuous hours and/or <2 record per hour at daytime and 1 record per hour at night-time), and unreliable data regarding anti-hypertensive treatment. After exclusions, 1805 patients were studied; eGFR was estimated using the MDRD study equation 2 in patients having the clinical indication to at least two creatinine determinations, the second one obtained 3 to 6 months after the first one . No significant differences in creatinine/eGFR were found between the two time points (assessed by paired t-Test), supporting the notion that 15% of our patients truly had CKD.CKD was defined as the presence of confirmed eGFR <60 ml/min/1.73 mCKD stages were defined according to the international classification of National Kidney Foundation 2 test was used to analyze the differences between the categorical variables. Logistic and linear regression analysis and ANCOVA were used to create adjusted models.Data were analyzed with the Statistical Package for Social Science version 13 . A value of p<0.05 was defined as statistically significant. Quantitative variables were checked for normality. Normally distributed continuous variables were described as a mean ± standard deviation (SD). The unpaired t-test and ANOVA (for multiple comparisons) were used to compare normally distributed quantitative variables with Bonferroni correction for multiple comparisons. The χ2 and 270 (15.0%) CKD patients. Hypertension was present in 1680 (93.1%) patients; 1194 (71.1%) were on drug treatment: 311 (26.0%) were controlled, 883 (74.0%) were not controlled. CKD stages are shown in 2). Among the CKD patients 264  were hypertensives, 218 (82.6%) were currently drug-treated, but only 63 (28.9%) had controlled BP.General characteristics of the population with reliable ABPM and drug therapy are shown in As shown in Along with higher night-time SBP, patients with CKD showed higher prevalence of non-dipping pattern   and CKD 2.7  and higher prevalence of left ventricular hypertrophy   OR = 1.7 (CI:1.12–2.74).Patients with CKD had a greater TIS  without significantly better BP control but, on the contrary, a tendency toward worse control . Among hypertensive patients treated but with BP not controlled, there was a significantly higher percentage (87.3%) of CKD with uncontrolled night-time SBP; OR = 2.4 . Isolated uncontrolled night-time SBP were also increased in CKD  vs patients with eGFR ≥ 60 ml/min/1.73 mWe studied a large patient population with clinical indication to perform ABPM, lab test for plasma creatinine and echocardiography. The main findings in patients with CKD were an altered SBP profile at night-time (higher BP and a more frequent non dipper-pattern) and a higher PP which depends also on a significantly lower DBP. Higher SBP values in patients with CKD could be merely due to the higher prevalence of hypertension in these patients, as well as to a higher prevalence of severe hypertension in CKD. However, 24-hours and daytime pressures were not different between patients with and without CKD. Only night-time SBP and the dipper pattern were altered, leading to the hypothesis of a direct influence of CKD on nocturnal blood pressure profile. Impaired natriuresis in daytime may increase nocturnal SBP in order to compensate the diminished natriuresis with pressure natriuresis. Fujii et al In our study, the association between non-dipping pattern and CKD was independent of age, sex, BMI and TIS, highlighting a direct influence of CKD on circadian pressure profile. The rise in differential pressures and the reduction in DBP were independent of age and TIS; in patients with CKD, this could be due to an increase in arterial stiffness. Increased atherosclerosis and arteriosclerosis, as well as the metabolic alteration present in CKD with secondary calcifications of the intima and media layers of the artery wall, are likely contributors to this process Our patients with CKD had a higher prevalence of both myocardial hypertrophy and diastolic dysfunction, suggesting that the higher PP and the night-time SBP significantly increased the heart load. Linear regression analysis revealed a strong association between nocturnal blood pressure, PP and cardiac organ damage. CKD itself was also independently associated with cardiac damage, suggesting that other factors  in addition to BP are involved in the higher prevalence of cardiac damage and cardiovascular risk in these patients. Ad-hoc designed studies will be needed to investigate the association between metabolic alterations in CKD and cardiac damage, relevant aspects that were not the focus of our present work. Despite greater intensity of treatment in CKD, BP control is similar in the overall distribution. However, during night-time, there is a higher percentage of subjects with poor nocturnal control in CKD, a finding enlightened only by ABPM. Because of the lack of recognized pressure target for ABPM, we had to use arbitrary cut offs to define BP control, referring to the values in the range of normotension for ABPM in general population. Notwithstanding, according to initial evidences 2) had an altered 24-hour BP profile, especially at night-time. Higher night-time SBP, a more frequent non-dipper pattern and higher PP are related with more severe cardiac organ damage.Our “real-life patient” data are relevant for clinicians that often evaluate BP-related clinical problems on the basis of a single plasma creatinine value in the initial evaluation of outpatients. Our study shows that patients with a reduced eGFR . Although a selection of patients was unavoidable , patient selection was based only on the best clinical practice for the management of arterial hypertension.Overall, our analysis is based on one creatinine/eGFR and this is certainly a limitation. Nevertheless, our data fit in the context of current literature because most of the data available have been obtained with a similar approach. Our “real-life patient” data are relevant for clinicians that make their decisions most often on the basis of a single creatinine determination during the initial evaluation of “stable” outpatients coming for BP related problems. Moreover, patients having the clinical indication for at least two creatinine determinations, had the second one taken 3 to 6 months apart. There were no significant differences in creatinine values/eGFR between the two time points, supporting the notion that 15% of our patients truly had CKD.Our study is based on “real-life” clinical practice, and we have not been able to include all potential causes of non-dipping pattern in the statistical adjustments (e.g. presence of obstructive sleep apnoea documented by cardio-pulmonary monitoring), a limitation similar to other studies that investigated the relationship between lower eGFR and ABPM patterns. Moreover, we didn't study some CKD biochemical factors  and their role in influencing the association between CKD, BP profile and cardiac damage. This was because some metabolic parameters of CKD are not routinely assessed when patients are referred for BP evaluation in a cardiovascular setting. However, the overall night-time results  and increased 24 h PP in our large population, even after statistical adjustments, strongly indicate an altered pattern of night-time BP in CKD patients, with a negative impact on the heart and therefore with important clinical implications.