Background: Previous research suggests Kyolic-aged-garlic-extract to be effective in reducing blood pressure in a large proportion of hypertensive patients similar to first-line standard antihypertensive medication. High blood pressure has been linked to gut dysbiosis, with a significant decrease in microbial richness and diversity in hypertensives compared to normotensives. Furthermore, gut dysbiosis has been associated with increased inflammatory status and risk of cardiovascular events.Objective: To assess the effect of Kyolic aged GARlic extract on Gut microbiota, Inflammation, and Cardiovascular markers, including blood pressure, pulse wave velocity and arterial stiffness.Methods: A total of 49 participants with uncontrolled hypertension completed a double-blind randomized placebo-controlled trial of 12-weeks, investigating the effect of daily intake of aged-garlic-extract  or placebo on blood pressure, pulse wave velocity and arterial stiffness, inflammatory markers, and gut microbiota.Results: Mean blood pressure was significantly reduced by 10 ± 3.6 mmHg systolic and 5.4 ± 2.3 mmHg diastolic compared to placebo. Vitamin B12 status played a role in responsiveness to garlic on blood pressure in 17% of patients. Garlic significantly lowered central blood pressure, pulse pressure and arterial stiffness (p < 0.05). Trends observed in inflammatory markers TNF-α and IL-6 need to be confirmed in larger trials. Furthermore, aged-garlic-extract improved gut microbiota, evident by higher microbial richness and diversity with a marked increase in Lactobacillus and Clostridia species after 3 months of supplementation.Conclusions: Kyolic-aged-garlic-extract is effective in reducing blood pressure in patients with uncontrolled hypertension, and has the potential to improve arterial stiffness, inflammation, and gut microbial profile. Aged-garlic-extract is highly tolerable with a high safety profile as a stand-alone or adjunctive antihypertensive treatment, with multiple benefits for cardiovascular health.Trial Registration: Australian New Zealand Clinical Trial Registry ACTRN12616000185460  Arte2S) production  of healthy adults in Australia with sub-optimal vitamin B12 levels (< 500 pg/l)  and hydrogen sulfide  . TherefoFirmicutes-to-Bacteroidetes ratio (F/B ratio) in hypertensives compared to normotensives  compared to normotensives. In general, higher relative abundance/bacterial mass/microbial richness and diversity of microbial species is associated with better health  and diversity  and a significant increase in the tensives . In thisr health –16.p < 0.001] (n = 21 vs. 20: F/B ratio 12.5 vs. 2.5)  ratios have been associated with obesity in mice and humans . Also, T< 0.001] . Naturalvs. 2.5) .Moreover, gut dysbiosis has been associated with increased inflammatory status, chronic inflammatory diseases and increased risk of cardiovascular events . Biochem2S)  , 26, gar2S) , and to 2S) . The tim2S) . In addi2S) .Our 3-month randomized controlled double-blind trial (RCT) aimed to assess the effect of Kyolic aged GARlic extract on Gut microbiota, Inflammation, and Cardiovascular markers, including blood pressure, pulse wave velocity and arterial stiffness.Adults with uncontrolled hypertension [systolic BP (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg] were sought to participate in the double-blind randomized placebo-controlled parallel 12-week trial investigating the effect of aged garlic extract on blood pressure, central haemodynamic measures including pulse wave velocity, inflammatory markers, and the gut microbiome. Participants were eligible, if they were on an established plan of blood pressure medication for at least 2 months, or were not taking any blood pressure medication, and their doctor was not planning to change current treatment during the trial. We excluded adults with unstable medical conditions or serious illness, at the discretion of the GP, pregnancy, severe hypertension (mean sitting SBP ≥ 180 mm Hg and DBP ≥ 110 mm Hg), those planning surgery in the next 3–4 months, or with a history of intestinal surgery, inflammatory bowel disease, celiac disease, lactose intolerance, chronic pancreatitis, or diagnosed malabsorption disorder. Additionally, participants were not enrolled, if they had been on antibiotic treatment within the last 2 months of study enrolment, taking prescribed anti-inflammatory agents, glucocorticoids, or other immune regulating prescription medication. Potential participants were advised to cease any probiotics or garlic supplementation at least 2 months prior to trial enrolment.We recruited through the NIIM clinic newsletter, NIIM website, and flyers distributed in the local area in Melbourne. The study was approved by the NHMRC-endorsed NIIM Human Research Ethics Committee, and participants provided written informed consent.Consenting eligible patients were randomly allocated to the garlic or placebo group using a computer-generated permuted random number table provided by an independent researcher not involved in patient recruitment, patient care, data collection, and follow-up.Patients were assigned either two capsules daily of Kyolic aged garlic extract , associated with its blood pressure reducing properties –33. GarlPlacebo capsules were matched in appearance to the active capsules, and packaged in identical containers by the manufacturers off-site. Activated carbon-sachets were added to each container to disguise any odor. Patients, investigators and research assistants were blinded to treatment allocation. Blinding success of patients was assessed at the end of the trial by questionnaire.Patients' appointments were made at NIIM 4-weekly for blood pressure and cardiovascular measurements. Eligible participants were required to fast (6–8 h) for blood testing at baseline and 12 weeks. A collection kit was provided for stool microbial analysis at baseline and 12 weeks.Participants were instructed to start the trial capsules after blood and stool collection at baseline, and to continue until the day of stool collection at 12 weeks. Patients were given a 4-week supply of trial capsules at the baseline, 4 and 8 weeks appointments.Participants were advised to take the trial capsules in the evening with food to minimize belching. Participants were reminded to take their usual prescription medication as instructed by their doctor, and not to alter their general diet and exercise regimen throughout the trial. Compliance was assessed by questionnaire and by pill count at the end of each visit.The baseline questionnaire assessed patient's demographics, BP and other medications, supplements, family history of cardiovascular and chronic diseases. Tolerability of trial capsules was assessed at each 4-weekly appointment using our previously developed questionnaire , 2. The Primary outcome measures were SBP and DBP at 4, 8, and 12 weeks compared with baseline. BP was measured by a trained research assistant using two independent devices, (a) a calibrated and validated digital sphygmomanometer , and, (b) an oscillometric ambulatory BP monitor , with appropriate sized brachial cuffs.The displays of the sphygmomanometers was positioned away from the patient to assure blinding to the BP readings. BP measurement was taken with the patient in seated position with the arm supported at heart level, after 5 min rest, after abstinence from food, nutritional supplements, caffeinated beverages, and smoking for a minimum of 2 h prior to BP measurement at Approximately the same time/day of the week, as per standard BP measurement guidelines . BP was With the Mobil-O-Graph device we also assessed central hemodynamic measures, including central blood pressure, pulse-wave-velocity (PWV), pulse pressure, and arterial stiffness at baseline, 4, 8, and 12 weeks. The Mobil-O-Graph, used in our previous trial , is a brAs PWV, a measure for arterial stiffness and a strong predictor of cardiovascular morbidity, is more accurately measured directly by the assessment of the distance traveled over time from carotid to femoral artery 7, we also used the validated SphygmoCor Xcel  for PWV. Here, the patient is in a supine position, and the distance from the carotid to femoral pulse is measured, and the time for the pulse wave to travel from carotid to femoral artery is assessed by applanation tonometry.The research assistant, trained in phlebotomy, took a fasted blood sample at baseline and 12 weeks to assess the red blood cell active Vitamin B12 and inflammatory markers TNF-α and interleukin-6 (IL-6).www.gtx.net) at baseline and at 12 weeks, and were instructed to collect a stool sample within a few days of their baseline appointment and to send this to Genova Diagnostics for a Microbial Ecological Profile (GI-Effects-Stool-Profile), providing a validated comprehensive profile of commensal bacterial species in colony-forming-units (CFU)/g stool by multiplex PCR-DNA analysis. The report was used to calculate Relative Abundance (RA)/ microbial richness, Shannon diversity, and Firmicutes/Bacteroidetes ratio.Enrolled patients were provided with a commercially available test kit from Genova Diagnostics, USA (Primary outcome measures were blood pressure change over time (SBP/DBP) at 12 weeks compared to baseline, and secondary outcome measures were central hemodynamic measures, including pulse wave velocity, changes in gut microbiota measured by relative abundance/ microbial richness, microbial diversity, and Firmicute/Bacteroidetes ratio, and changes in inflammatory markers TNF-α and IL-6.Vitamin B12 blood levels were explored as potential confounding variables.p < 0.05.Analyses were performed using IBM SPSS version 24. Statistical significance was set at Descriptive analysis was carried out for baseline variables. Normality of data distribution was assessed by the Shapiro–Wilks test. Differences between the groups at 12 weeks compared to baseline were assessed by chi-square test for binominal variables, and by one-way ANOVA with Bonferroni adjustment for continuous and normally distributed variables. Potential confounding variables were included in the analysis using ANCOVA , e.g., baseline blood pressure, or age and gender were relevant for central hemodynamic measures, e.g., pulse wave velocity. Primary analysis was conducted with all participants following protocol, excluding data points owing to BP medication change. Subgroup analyses of changes in SBP/DBP overtime by BP medication at baseline were also undertaken.We compared Vitamin B12 levels to BP change between groups by scatterplots. As previously described, we defined responders to garlic as mean BP reduction by more than 3% in SBP (≥5 mm Hg) or DBP (≥3 mm Hg) over time compared to baseline, which is clinically and statistically meaningful and similar to the definitions by others .Changes in cytokines TNF-α and IL-6 levels were analyzed by ANOVA excluding high values/outliers due to infection , and by subgroups (≥50 and < 50% percentile). Cytokine ratios IL-6/ TNF- α were also calculated.www.gtx.net). Results were presented as colony-forming-units (CFU) per gram of stool of 21 bacterial species, grouped into four main phyla: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria phyla.Microbial Ecological Stool Profile was done by validated multiplex PCR by Genova Diagnostics, USA , microbial richness, or “total” bacterial mass as the sum of all analyzed bacteria groups in colony forming units per gram (CFU/g), calculated changes over time (12 weeks vs. baseline) by bacterial group, and compared statistical significant differences between groups by ANOVA.H=SUM[(pi)*ln(pi)] with SUM = Summation, and pi = number CFU/g in individual bacterial group/sum of all bac in CFU/g. Changes over time between the groups were assessed by ANOVA.Diversity of species, Shannon diversity was calculated as the sum of the number of individual species relative to the total number of bacteria using the formula: Correlations between BP change and gut microbiota change were analyzed by the non-parametric Spearman correlation.n = 25) and control (n = 25) with 80% power and 95% confidence  in BP change between the active treatment  were not significantly different between the groups , were of 62 ± 10 years of age with a high average BMI of 29 ± 7 kg/mn = 1) did not change their blood pressure regimen throughout the trial. About half of the participants took other prescription medications, and did not change these over the period of the trial (Table Two-thirds of participants took standard blood pressure medication (63%), most took only one type (59%), with angiotensin-converting-enzyme-inhibitors (ACEI) being the most often prescribed type (47%). Of those participants all but one n =  did not Our sample was a homogenous group of people with uncontrolled hypertension and of similar age. Testing for normality of data distribution by Shapiro–Wilk test confirmed normal distribution of SBP, DBP and hemodynamic markers , in the garlic and the placebo groups.n = 49) revealed a reduction in SBP over 12 weeks within the garlic group (−14.3 ± 13.9 mmHg) compared to placebo (−4.3 ± 11.4 mmHg), resulting in a mean difference SBPchange (SE) of −10.0 ± 3.6 mmHg between the groups with high statistical significance (p = 0.008).Analysis of all participants (change (SE) of −5.4 ± 2.3 mmHg with statistical significance (p = 0.02)  was reduced on average by 9.9 ± 6.8 mmHg within the garlic group compared to 4.4 ± 8.9 mmHg in the placebo group, providing a mean difference DBPThe trajectory of blood pressure change over time within both groups is in line with the findings in previous trials –3, wheren = 16/17) revealed a slightly greater reduction in SBP of 12.3 ± 4.7 mmHg compared with participants not on BP medication (n = 7/9) of 4.9 ± 5.4 mmHg (p = 0.014) , PP : −9.6 (3.4) mmHg, p = 0.008), cPP : −6.5 (3.0) mmHg, p = 0.04), MAP :−7.9 (4), p = 0.05), and age-and gender-adjusted pulse wave velocity , an indicator for arterial stiffness. PWV measured in m/s with both devices (PWVmobilo and PWVsphyg) but not adjusted for age and gender tended to improve in the garlic group compared to placebo albeit not statistically significant. In summary, Kyolic aged garlic extract significantly lowered central blood pressure, pulse pressure and adjusted pulse wave velocity, an indicator for arterial stiffness : −12.5 (4.6) mmHg, Vitamin B12 is one of the important co-factors in the mechanism of action for blood pressure reduction amongst other B-complex vitamins and genetic factors , we expln = 3 had Vit B12 concentrations below the optimal level of 500 pg/ml  non-responders in the garlic group (SBP change < 5 mmHg), and all had lower Vit B12 levels with n = 1 below the standard reference range of 200 pg/ml, and 00 pg/ml   bacteria and Clostridia species (Firm3) in the garlic group, while Faecalibacterium prausnitzii (Firm5) markedly increased in the placebo group. All marked observed changes were in the Firmicutes phylum albeit not statistically significant between the groups ; and Clostridia and F. prausnitzii: r = 0.639, p = 0.02).No significant correlations were obtained between BP and observed microbiotic changes within the groups. However, the observed changes in the Firmicutes phylum in the garlic group with an increase in numbers in F. prausnitzii increased, the Clostridia and Lactobacillus species decreased over time, with a significant correlation between Clostridia decrease and F. prausnitzii increase .Observed microbiotic changes in the placebo group followed an inverse direction compared to the garlic group, while Cytokines TNF-α and IL-6 were investigated. After excluding outliers, e.g., high values in participants presenting with an acute infection (common cold), we observed a trend toward a greater decrease in inflammatory marker TNF-α over time in the garlic group compared to the placebo group, albeit statistically not significant Table . In contAs each cytokine influences levels of other cytokines, and IL-6 has been shown to inhibit TNF-α , we alsoIn subsequent subgroup analyses we compared groups with high or low levels of inflammatory markers at baseline.p = 0.2] (Table For TNF-α we divided into two even subgroups (~50% percentile), low < 200 fg/ml and those above 200 fg/ml. A greater reduction in the subgroup with high TNF-α levels was observed in the garlic group compared to placebo, albeit not statistically significant  Table . For IL-2] Table .n = 5), but no participant found this bothersome.All participants tolerated the trial capsules well, and found it very easy/easy and very acceptable/acceptable to take the capsules . No participants experienced any adverse effects, and only few mentioned garlic taste and burping in the first week of the trial  in the garlic group and almost 85% in the placebo group being unsure or incorrect in guessing their allocated group (Table % in the p = 0.008), DBP by 5.4 mmHg (p = 0.02) in a group of 50–70 year olds, and was highly tolerated. Subgroup analysis of participants taking standard BP medication revealed a slightly greater reduction in SBP by 12.3 mmHg , while the low sample size in the subgroup of participants not taking standard BP medications limited interpretability.Our trial suggests Kyolic aged garlic extract to be effective in reducing blood pressure in patients with uncontrolled hypertension, in line with our previous trials –3. A dosThe average blood pressure reduction by Kyolic aged garlic extract alone or in combination with other blood pressure medications, is comparable to conventional standard blood pressure drug therapies, reducing the risk of cardiovascular disease such heart attack or stroke by 30–40% .In this trial, 83% of the participants responded to garlic with a SBP reduction of more than 5 mmHg, a slightly larger proportion than previously found (70%)  in this trial were below the optimal level of Vit B12 (< 500 pg/ml), none of the responders were below the standard level (< 200 pg/ml), but a proportion of BP responders (40%) were between standard and optimal levels (200–500 pg/ml) of VitB12, indicating a non-exclusive involvement of vitamin B12 in the BP reducing mechanism. While vitamin B12 may play a role in the responsiveness to garlic on blood pressure, other factors, such as vitamin B6 and folate, as well as genetic factors, such as the trans-sulfuration gene cystathione-β-synthase (CBS) are also important in the biochemical mechanism  registered NIIM Human Research Ethics Committee (HREC) with written informed consent from all subjects in accordance with the Declaration of Helsinki. The protocol was approved by the NIIM HREC.KR and AS conceptualized the study. KR acquired funding and oversaw data collection by NT. KR, and NT undertook data analysis. KR prepared the manuscript with contributions from co-authors. All authors approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background Blood viscosity is a determinant of vascular resistance, and it is expected to contribute to blood pressure. Arterial hypertension (HTN), in addition to other cardiovascular risk factors, contribute to cardiac morbidity. Our study aimed to establish the association between cardiovascular risk factors including HTN and whole blood viscosity in Ecuadorian patients.Material and methodsWe studied 132 patients with the diagnosis of HTN. Fifteen cardiovascular risk factors were analyzed. The association between whole blood viscosity (WBV) and the number of cardiovascular risk factors was studied. The association between blood viscosity and risk factors was analyzed.Results One hundred and thirty-two patients were analyzed. Blood viscosity was associated with a number of cardiovascular risk factors. Creatinine, uric acid, total cholesterol, and low-density lipoprotein (LDL) values were significantly higher in patients with high blood viscosity.Conclusion Blood viscosity is a physiological variable associated with a number of cardiovascular risk factors in hypertensive patients. Such risk factors are related to renal function and lipid profiles. In high-altitude residents, polycythemia is common, and the consequences of high hematocrit on cardiovascular morbidity in this setting deserve special attention and warrant further research. Whole blood behaves as a non-Newtonian fluid, whose viscosity depends on shear rate. At low shear rates, blood cells aggregate, increasing viscosity, whereas the opposite happens at a high shear rate -3. IncreIn the human microvasculature, shear stress induces nitric oxide-mediated vasodilation. This phenomenon is blunted in hypertensive patients. By contrast, small vessels of patients with hypercholesterolemia exhibit normal vasodilation induced by shear stress despite diminished nitric oxide activity . AtheromIn Ecuador, the morbidity rates for HTN in 2007 and 2011 were 6.20 and 6.83, respectively . Due to -1.After approval by the Ethics Committee of Pontificia Universidad Catolica del Ecuador, we studied a population of 180 patients with the diagnosis of HTN based on the criteria outlined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure . We retrt-test and Chi-square test for the different types of variables. A calculated p-value less than 0.05 was considered statistically significant. We also compared the WBW net values according to the number of cardiovascular risk factors present in each patient, through the statistical contrast of Kruskall-Wallis. All statistical analyses were performed with SPSS 20.We assigned records to one of two groups: group 1 included patients with increased WBV, and group 2 had normal WBV. We defined high WBV as being equal or higher than 19.02 centipoise. The association between WBV and the number of cardiovascular risk factors was analyzed using Student’s n = 18) of patients were found to have elevated blood viscosity as determined by the WBV equation described in the Methods section [One hundred and eighty patients met the inclusion criteria. One hundred and thirty-two patients had all the information needed for analysis. Eighty-three percent of patients were male. Table  section .n = 6) had only one RFs, 22% (n = 29) had two RFs, 35% (n = 46) had three RFs, 25% (n = 33) had four RFs, 13% (n = 17) had 5 RFs, and 1% (n = 1) had 6 RFs : age, family history, smoking, dyslipidemia, obesity, and kidney disease. We scored the average number of RF for each patient. In our sample, 5% of patients  is a significant risk factor for the development of cardiovascular disease and a major contributor to cardiac-related mortality. On the other hand, blood viscosity has been associated with decreased renal function and increased urinary excretion of albumin in hypertensive patients without renal disease . In a stHypertensive patients in our study exhibited a high prevalence of lipid profile abnormalities when blood pressure was poorly controlled. Gebrie et al. showed that red blood cell counts increase in parallel with the severity of HTN . TraditiBlood viscosity is elevated in conditions of decreased alveolar pressure of oxygen, as happens in high altitude cities. This study was conducted in Quito, Ecuador , where the atmospheric pressure level is lower compared to sea level (526 mm Hg). Although it would be expected that high hematocrit secondary to altitude results in increased endothelial shear stress, individuals living at high altitude exhibit increases in red cell deformability and endothelial production of nitrous oxide -24. AddiOur study has limitations. The retrospective nature of the data collection allowed us to draw conclusions regarding the association of blood viscosity and cardiovascular risk factors; however, since causality could not be determined, hyperviscosity could be just an epiphenomenon in the complex network of pathophysiological mechanisms underlying vascular disease. The lack of association of blood viscosity with systolic and diastolic blood pressure seems to be counterintuitive and could be related to the small sample size. We recommend that future research efforts focus on the conduction of randomized trials to elucidate the effect of interventions on blood viscosity to affect individual cardiovascular risk factors.Our results show that WBV is a physiological variable associated with a number of cardiovascular risk factors in hypertensive patients. Such risk factors are related to renal function and lipid profiles. In high-altitude residents, polycythemia is common, and the consequences of high hematocrit on cardiovascular morbidity in this setting deserve special attention and warrant further research.


The patient remained hemodynamically stable, on volume-controlled ventilation, with sedation by continuous propofol infusion. Blood gas tests revealed persistent acidemia without tissue hypoperfusion. Doppler ultrasound of the renal graft reported adequate blood flow and serum triglycerides were elevated. A diagnosis of propofol infusion syndrome was made, and infusion ceased. A decrease in serum lactate levels was observed, with normalization 4 h later. This case highlights the importance of considering adverse effects of anesthetic agents as the cause of post-operative complications when prolonged sedation is required.Sedation during medical procedures poses a risk to any patient, and the use of specific anesthetic agents should be carefully considered to avoid adverse outcomes. We report on a patient with propofol infusion syndrome diagnosed during the post-operative period of a renal transplant. A 58-year-old female on chronic hemodialysis due to end stage kidney disease secondary to microscopic polyangiitis underwent kidney transplant from a deceased donor. Anesthetic induction was performed with fentanyl, propofol, and cisatracurium, and maintained with continuous propofol infusion. In the recovery room, the patient developed somnolence, tachypnea, and thoracoabdominal dissociation secondary to residual neuromuscular block. An arterial-blood gas test indicated acidemia, high pCO Renal transplantation is currently the best therapeutic option for treating end-stage kidney disease (ESKD) , 2. Currµ/kg), propofol (1.5 mg/kg), and cisatracurium (100 µ/kg). Anesthesia was maintained with continuous infusion of propofol (100–200 µ/Kg/min). Two arterial anastomoses, one venous and one ureterovesical, were made without complications. Adequate perfusion of the graft was corroborated, and 200 ml of spontaneous diuresis was observed by the end of the surgical procedure. The patient remained hemodynamically stable during surgery, which lasted 3 h, with a cold ischemia time of 10 h and surgical bleeding less than 500 ml. In the recovery room, the patient developed somnolence, tachypnea, and thoracoabdominal dissociation secondary to residual neuromuscular block. An arterial-blood gas test revealed a pH of 6.8, pCO2 131 mmHg, pO2 212 mmHg, HCO3 19 mmol/L, and lactate 3.2 mmol/L. The patient was intubated and transferred to the intensive care unit (ICU) for mechanical ventilation support. In the ICU, the patient remained on volume-controlled ventilation, was hemodynamically stable, and remained sedated with continuous propofol infusion at 0.5 mg/kg/h. A venous-blood gas test performed 1 h later showed that pH increased to 7.10, pCO2 47 mmHg, pO2 59 mmHg, HCO3 14 mmol/L, and increased lactate levels (9.4 mmol/L) , despite maintaining hemodynamic stability, with MAP >65 mmHg without vasopressor treatment, urinary output 200–300 ml/h, and being afebrile without any clinical data demonstrating tissue hypoperfusion  , without any clinical or biochemical activity of microscopic polyangiitis in the past 6 months. She successfully completed the protocol for a kidney transplant from a deceased donor, which was performed in August of 2018. Crossmatch test was negative, blood type was A+ , and the induction immunosuppression regimen used was methylprednisolone  and basiliximab . The surgical procedure was performed under total general intravenous anesthesia, induced with fentanyl (3  mmol/L) . Common erfusion . No aurierfusion , and the mmol/L) . The patThe first cases of a rare, but potentially lethal complication associated with the use of propofol infusion were reported in pediatric patients in 1990 .The incidence rate of PRIS is difficult to assess due to the use of different diagnostic criteria. Roberts et al. prospectively studied 1,017 ICU patients at 11 academic medical centers treated with propofol infusion for at least 24 h, reporting an incidence of 1.1% . HemphilHemphill et al. also proposed to classify clinical features of PRIS into primary and secondary. Primary features include metabolic acidosis, electrocardiographic changes, and rhabdomyolysis, and secondary features include acute kidney injury, hyperkalemia, lipidemia, cardiac failure, fever, elevated liver enzymes, and increased lactate levels . AccordiThe primary features most frequently reported by the authors were metabolic acidosis (77%), electrocardiographic changes (62.8%), and rhabdomyolysis (62%). Secondary features most frequently observed were acute kidney injury (50.4%), hyperkalemia (33.6%), raised lactate serum levels (31%), arterial hypotension (31%), cardiac failure (25%), and lipidemia (22.1%) . MultisyFrom the first reported cases, a wide variety of risk factors for developing PRIS have been identified, including cumulative propofol dose , 13, infIn our case, the risk factors that likely contributed to the development of PRIS were severe respiratory acidosis during post-anesthetic recovery, use of high doses of methylprednisolone during the induction of immunosuppression, and ESKD. The latter may have caused accumulation of propofol, despite using the recommended doses and a short infusion time. Ickx et al. documented that the pharmacokinetics and pharmacodynamics of propofol are not affected during the induction and maintenance of general anesthesia in patients with ESKD, and that the kidneys do not contribute significantly to extra-hepatic clearance . Howeverβ-adrenergic receptors and blocks cardiac calcium channels, which results in a shock state that can evolve to refractory cardiogenic shock, requiring intravenous catecholamines, which can also trigger or aggravate kidney damage and acidosis [The pathophysiology of PRIS is complex and multifactorial. It is characterized by injury and cell death secondary to imbalance between energy supply and demand within the cells. Propofol interferes with mitochondrial fatty-acid oxidation by inhibiting the enzymatic activity of palmitoyl-transferase I, which causes an energy deficit within cells, and accumulation of free fatty acids in the serum and various organs , 22. Thiacidosis , 23, 24.The prognosis of PRIS is variable and depends of severity and degree of systemic involvement. Hemphill et al. documented a mortality rate of 48% in adult patients and 52% in pediatric patients with the main factors related to mortality being propofol infusion rate, accumulated dose, and infusion duration . ClinicaTreatment of PRIS includes immediate suspension of propofol infusion, general support measures, and cardiopulmonary and renal support, if necessary . There iPRIS is a rare but potentially lethal complication that usually occurs in patients receiving propofol infusions at either high doses (>5 mg/kg/h) or for long durations (>48 h). Clinical features and systemic involvement are variable; therefore, awareness of the clinical entity and high level of suspicion are the best measures for early diagnosis. PRIS should be considered as a differential diagnosis in patients on propofol infusion who develop unexplained severe lactic acidosis.


Our pilot results suggest that retrogradely-transmitted venous pressure might be involved in the mechanisms mediating the relationship between cardiac diseases and brain functions.Cardiac diseases with elevated central venous pressure have higher frequency of jugular venous reflux (JVR), which is associated with decreased cerebral blood flow and white matter hyperintensities. Whether patients with severe mitral-regurgitation (SMR) have poorer cognitive functions and whether JVR is involved were determined in this pilot study. Patients with SMR and age/sex-matched controls were prospectively recruited. Neuropsychological tests such as global cognitive , verbal memory, executive, and visuospatial domains were performed. Cardiac parameters by cardiac catheterisation and echocardiography, and the frequency of JVR by colour-coded duplex ultrasonography were obtained. Forty patients with SMR and 40 controls  were included. Compared with the controls, patients with SMR had lower scores in all neuropsychological tests but only MMSE and visuospatial test scores were statistically significant after adjusting for age, sex, and educational level. We further adjusted for cardiovascular risk factors; the significance remained in the visuospatial test but diminished in MMSE. Multivariate linear regression analyses adjusted for age, sex, and educational level showed that JVR combined with high right-atrial-pressure  was significantly associated with poorer performances in both MMSE [right JVR: B coefficient(95% confidence interval, Cerebral venous drainage impairment with elevated venous pressure would decrease cerebral blood flow (CBF), damage the blood–brain barrier (BBB), and lead to brain dysfunctions ,2. InterContinuous or repeated elevated venous pressure proximal to IJV might result in wear and tear of the IJV valves and lead to valvular incompetence ,7,8. IndPatients with SMR, referred for surgical intervention in a tertiary medical centre, were eligible for this study. Every patient underwent transthoracic and transoesophageal echocardiography and cardiac catheterisation to confirm the diagnosis and to evaluate the feasibility for surgery. Patients who had disease durations of 1 year or longer from the initial diagnosis to the time of catheterisation and echocardiography were included. Among the eligible patients, those who met the following criteria were excluded from this analysis: (1) had concomitant severe aortic valve disease, mitral stenosis, acute coronary syndrome, or pericardial disease; (2) had unstable haemodynamics, or New York Heart Association functional class IV symptoms; (3) had existing neurological diseases, such as stroke, brain tumour, dementia, or other neurodegenerative diseases; and (4) had significant stenosis (>50%) over the cervical internal carotid and vertebral arteries using neck duplex sonography. Cardiac diseases other than mitral valvular disease were excluded because they might have different mechanisms and effects on the cognitive functions. A total of 40 individuals were included based on these criteria. We also recruited 40 age- and sex-matched normal controls from outpatients who visited our neurological clinics. These normal controls had no cardiac, neurological, or malignant medical histories.2 [Cardiovascular risk factors were either measured or assessed through self-report. The presence of hypertension was determined by a self-report of current antihypertensive medication prescription or by a measurement of either systolic BP of ≥140 mmHg or diastolic BP ≥90 mmHg . Diabete2), and cardiac output were obtained. Cardiac output was then divided by body surface area (BSA) to obtain the cardiac index.Cardiac catheterisation was performed in all patients with SMR using a percutaneous approach via the radial artery for coronary angiogram and right IJV for right heart catheterisation. Data of mean pulmonary artery wedge pressure (PAWP), pulmonary artery pressure (PAP), right ventricular pressure (RVP), RAP, mixed venous oxygen saturation  following a standardised protocol. The severity of mitral regurgitation was evaluated according to the effective regurgitant orifice, which was calculated by analysing the proximal isovelocity hemispheric surface area (PISA) of the convergence on the atrial side. According to the AHA/ACC guideline, and an effective regurgitant orifice of ≥ 0.4 cmd as SMR . The sevd as SMR .Both lefNeck colour-coded duplex sonography was performed in all patients with SMR using a 7-MHz linear transducer  by the same technician who was blinded to subjects’ characteristics. On examination, subjects were in a head-straight, flat supine position after a quiet 10-min rest. The IJV was initially insonated longitudinally and thoroughly from the proximal part of the neck base rostrally to the distal part of the submandibular level to detect any possible spontaneous JVR at baseline. Then, the VM was performed by forcible expiration by the subject via the mouth into a flexible rubber tube connected to a manometer. Subjects were asked to reach the 40 mmHg Valsalva pressure and maintain it for at least 10 s. During the VM, the distal margin window of the colour signal was placed at the tip of the flow divider of the internal carotid artery. The coloured box was adjusted to include the entire lumen of the IJV; if retrograde colour appeared in the centre of the lumen, the retrograde flow would then be confirmed by Doppler spectrum. JVR was determined when the retrograde-flow colour in the centre of the lumen and the Doppler-flow waveform demonstrated reversed flow for >0.5 s spontaneously or/and during VM –6.Routine cervical arterial examination including examination of internal carotid and vertebral arteries was also performed in all patients with SMR.All patients with SMR and normal controls underwent a face-to-face neuropsychological examination carried out by trained interviewers. In addition to the global cognitive performance, which was examined using the Mini-Mental State Examination (MMSE), three different cognitive domains  were assessed using extensive neuropsychological tests as follows:Verbal memory: delayed (10 min) free recall in the Chinese Version of the Verbal Learning Test (CVVLT) .Visuospatial function: the copy of the Taylor complex figure test .Executive function: digit backward test .Analyses were performed using SPSS software . All continuous variables are described as mean ± standard deviation (SD) and discrete variables as percentages. Comparisons of case and control were made using non-parametric Mann–Whitney tests. When appropriate, chi-square (χ2) or Fisher’s exact tests were performed for categorical variables. Univariate and multivariate linear regression analyses of neuropsychological test scores as the dependent variable were performed. Adjusted confounding factors were age, sex, educational level, cardiovascular risk factors  and the status of TR .To test our postulation that cerebral venous return status might be involved in the relationship between cognitive impairment and SMR, we analysed the hemodynamic parameters that may affect cerebral venous return, e.g., the RAP and presence of JVR, as independent variables individually. We also used the 50th percentile of the mean RAP, with 12 mmHg as a cut-off point. Three kinds of binary category variables, (1) RAP ≥ and <12 mmHg, (2) the presence or absence of JVR, and (3) the presence or absence of combined JVR and high RAP (≥12 mmHg), were individually analysed as independent variables. Furthermore, since decreased cardiac output is commonly postulated as a contributor to cognitive impairment in cardiac diseases, we also put cardiac index and LVEF into analyses.p = 0.046) but lower in MMSE (p = 0.058).The patient group had lower scores in all neuropsychological tests compared with control group, but only statistically significant in MMSE and Taylor complex figure test and borderline significant in digit backward test after adjusting for age, sex, and educational level. We further adjusted for cardiovascular risk factors, with significance remaining in the Taylor complex figure test  poorer global cognitive (MMSE) and visuospatial (the Taylor figure test) functions compared with those in normal controls and (2) JVR combined with high RAP was associated with these cognitive impairments. The present pilot study was of limited scope, having a small sample size. Therefore, our findings should be interpreted with caution and no firm conclusions should be made regarding the general applicability of our findings at this moment in time. Future studies including larger sample size are needed to confirm the validity of our findings.We previously reported that the prevalence of JVR in the general population (16–89 years old) is approximately 18–36% on the right side and 6–29% on the left side . The preAlthough retrogradely transmitted venous pressure by JVR has been shown to reach the cerebral venous system and influence CBF –6, the eSeveral studies on brain–heart axis have emerged, and they have shown a relationship between cognitive impairment and cardiac diseases . Most stCerebral circulation includes artery supply and venous drainage. Both of them are responsible for adequate CBF and brain metabolic homeostasis ,24. ReceWe noticed that CI and LVEF in our patients were relatively higher than patients with heart failure. The study population was composed of patients with degenerative and functional MR, while patients with degenerative MR generally have preserved LV functions and cardiac index. We also acknowledged that cardiac output could be over-estimated using either thermos-dilution or indirect Fick’s method. There was also one case who had mean PCWP less than 10mmHg (9mmHg). This patient was a case of severe MR along with severe TR. Even though the PCWP and RAP were low, the presence of prominent V wave confirmed the diagnosis of severe MR and TR. The other possible mechanism for low PCWP was over-diuresis status.th percentile of mean RAP as the cut-off point to test our postulation whether a higher RAP with JVR was associated with cognitive impairment in patients with severe MR. This value would need further studies with a larger sample size to validate before applying to clinical settings.Given a relatively small sample size and to avoid inadequate size in any classified group (as independent variables), we choose 50The present study has limitations. The study sample size was relatively small. Heterogeneous profiles of cardiovascular risk factors and hemodynamic parameters might decrease statistical power or confound the current results. Furthermore, the cross-sectional study setting could not establish a causal relationship. A larger and longitudinal study is necessary to validate our postulation. In addition, more investigated tools such as brain imaging are needed to further evaluate the underlying mechanisms between the cerebral venous drainage impairment and cognitive abnormalities in SMR.Patients with SMR had poorer cognitive function, particularly in the visuospatial domain, and JVR combined with high RAP was associated with poorer visuospatial function in these patients. The results suggest that retrogradely transmitted venous pressure but not low cardiac output might be involved in the mechanisms mediating the relationship between valvular heart disease and brain functions. In addition to management for decreasing RAP, IJV valve repair might be a potential treatment option for cardiac disease-related brain dysfunctions.


Current policy in South Africa requires measurement of blood pressure at every visit in primary care. The number of patients regularly visiting primary care clinics for routine care is increasing rapidly, causing long queues, and unmanageable workloads.We used data collected during a randomised control trial in primary care clinics in South Africa to estimate how changes in policy might affect workloads and improve identification of undiagnosed hypertension.The prevalence of raised blood pressure increased with age; 65% of individuals aged over 60 years had a raised blood pressure, and 49% of them were not on any treatment. Over three months, eight health facilities saw 8,947 individual chronic disease patients, receiving 22,323 visits from them. Of these visits, 60% were related to hypertension, with or without HIV, and a further 35% were related to HIV alone. Long waits for blood pressure checks caused friction at all levels of the clinics. Blood pressure machines frequently broke down due to heavy use, and high blood pressures readings were often ignored. If chronic disease patients without a diagnosis of hypertension had their blood pressure checked only once a year, the number of checks would be reduced by more than 80%. Individuals with hypertension had a blood pressure check on average once every 7 weeks, but South African guidelines recommend that this should be done every 3 months at most.The numbers of chronic disease patients in primary care clinics in South Africa is rising rapidly. New policies for measuring blood pressure in these patients attending clinics are urgently needed.ISRCTN12128227 5th March 2014.Current Controlled Trials  South Africa’s health services are managing one of the largest epidemics of HIV in the world . At the Despite the increasing numbers receiving care for hypertension, there is also a large proportion of the population where individuals have raised blood pressure but are not receiving any treatment . This maRecognising the pressures of increasing demands on primary care, the South African Government has introduced a new system of managing chronic conditions in primary care, the Integrated Chronic Disease Management system , which aAt the time that the Integrated Chronic Disease Management system was introduced, there was no review of an existing policy on screening patients arriving at the clinics. This policy, which did not distinguish between acute and chronic clinic attendances, recommends that all patients attending clinics undergo routine health checks on every visit to “routinely check and record weight, blood pressure, pulse and temperature” . In thisThe data we have used in this paper was collected during a randomised trial and its accompanying process evaluation. Between 2013 and 2015, we examined whether the introduction of trained local lay health workers to assist in the management of chronic care, and particularly the management of patients with hypertension, would relieve some of the pressure on the nurses, thus allowing them to focus more on clinical decision making and hence reduce the prevalence of untreated raised blood pressure in the community.Four clinics in the Agincourt Health and Demographic Surveillance System site were randomised to receive the extra assistance, while four other clinics acted as controls, with no extra assistance . The resAs part of the process evaluation alongside the randomised trial, we installed a system to collect information on all visits to the clinics for management of chronic disease, and undertook repeated observations in clinics, and interviews with all cadres of clinic staff. We observed that an important source of tension in all the clinics was the ‘vital signs queue’ where all patients who have arrived at the clinic that day have their weight, blood pressure, pulse and blood pressure measured. Moreover, we observed that the blood pressure machines often broke down and the cuffs wore out quickly, leading nurses to sometimes disregard the blood pressure measurement as unreliable .In this paper, we have used quantitative data that we collected during the trial to explore the implications of the current policy for screening for hypertension in primary care clinics, and for managing diagnosed cases of hypertension. We were interested in the potential for reducing the number of checks, which would free nurses’ time to focus on identification and treatment of people with hypertension.We used data on current activity in the clinics to estimate the change in workloads in different possible scenarios: if patients with a diagnosis of hypertension had their blood pressure checked just four times a year, and chronic disease patients without a diagnosis of hypertension had their blood pressure checked once a year instead of every time they returned for a repeat prescription. We also used the population level data we had collected to estimate the number of people with raised blood pressure not currently on treatment but attending clinics for other chronic diseases (mainly HIV) and hence to estimate the potential yield of new diagnoses of hypertension that could be acted upon by nurses if they had more time available.During the Nkateko trial we collected information on patients who used any of the eight primary care clinics that were participating in the trial. In each clinic, a data entry clerk equipped with a laptop collected identifying information  from consenting patients attending for chronic disease appointments and used those data to uniquely identify each patient. The data clerk recorded every subsequent visit by a patient who had been entered into the database, and collected information from clinic records on the reason for the visit, diagnosis and treatment. No information was collected on visits by patients with acute (as opposed to chronic) conditions.We discarded the first three months of data collection in the clinics when the database was being built up. We collected data on chronic disease clinic activity from May 2014 to July 2015 (the end of the intervention). We found a very rapid increase in the number of routine visits for chronic diseases over these 15 months , partly due to the continued roll-out of antiretroviral therapy to be delivered in primary care, and partly to an on-going hospital policy of referring stable out-patients back to primary care to relieve pressures on hospital out-patient services. Because of this rapid increase in numbers, which we believe to be real and likely to be sustained, we used just the last three months of available data (May to July 2015) to estimate the number of patients attending the clinic each year (denoted as “n” in ‘Diagnosed with hypertension’: when the clinic file recorded a diagnosis of hypertension at any time. We treated these people as requiring regular blood pressure checks for management of their condition.‘Available for screening for hypertension’: when the clinic file did not record a diagnosis of hypertension. We assumed that a proportion of these people had raised blood pressure but had not been identified and put on treatment. We derived the relevant proportion (“p”) from the findings of the two cross-sectional surveys.Two population samples were drawn from the Agincourt Health and Demographic Surveillance System (Agincourt HDSS) population  in 2013 ‘Hypertension not on treatment’: those with a systolic pressure equal to or above 140 mmHg or a diastolic pressure equal to or above 90 mmHg and not taking any medication for hypertension.‘Hypertension on treatment’: those who were taking any medication for hypertension including those with normal blood pressure on treatment.‘Normal blood pressure’: those with a systolic pressure below 140 mmHg and a diastolic pressure below 90 mmHg and not on treatment.We calculated the prevalence of the first of these three categories for each five year age and sex group  , the University of Warwick Biomedical and Scientific Research Ethics Committee , and the Mpumalanga’s Provincial Research and Ethics Committee . The clinic manager of all the clinics taking part in the trial consented for their clinic to participate. All individuals interviewed in the population survey gave written informed consent to the interview. All clinic patients whose details were entered in the clinic database gave written informed consent.Data collected in the clinics show that 8,947 patients attended one of the eight clinics for chronic disease management between May and July 2015, with a total of 22,323 visits over the three months. Nearly half, 45%  of these clinic users had a diagnosis of hypertension; these patients were markedly older than the other patients . The vasThere were 8,957 individuals sampled for the two surveys. We discarded the second survey result for those 591 who were sampled twice, leaving 8,366 individuals in the sample. Of these, 6,641 (79%) individuals completed the questionnaire and are included in this analysis. There were 789 patients who were identified by the lay health workers in the intervention clinics as having a raised blood pressure, but not a current diagnosis of hypertension. Most of them (around 85%) were patients visiting the clinic for an acute problem; the rest had a chronic condition other than hypertension. Of the 789 identified, 23 had no age recorded and six were aged less than 18 years, leaving 760 patients. Of these, 394 (51.8%) returned within 3 months for a second blood pressure check, and of those who returned, 301 (76.4%) were given a diagnosis of hypertension .once a stable target BP has been achieved, follow-up BP measurement should be performed every 3–6 months” (page 79) [In the year August 2014 to May 2015, patients diagnosed with hypertension attended a clinic, on average 7.1 times (approximately every seven weeks) and had their blood pressure measured every time, creating a workload for primary care staff of 28,736 blood pressure checks . HoweverWe considered different scenarios which would relieve the pressures caused by the large numbers of blood pressure checks, while maintaining systematic screening for hypertension. Our hypothesis is that if fewer blood pressure checks were carried out then there is a greater likelihood of a raised blood pressure being noted and acted upon.Using the numbers of patients seen in the clinics during May to June 2015, we calculated the effect of screening for hypertension once a year in those without symptoms and without diagnosed hypertension. Because of the HIV epidemic, there are large numbers of younger patients attending the clinics; 13% of women and 7% of men attending with a chronic condition were aged between 18 and 30 years, We therefore considered some possible age cut-offs for screening. On the basis of our observation in eight clinics from May to July 2015, we estimate that the current system will result in 27,356 blood pressure checks being required in the eight clinics every year. If appropriate action was taken on all those with a raised blood pressure, that is, patients are asked to return for a second blood pressure check and then diagnosed if raised, this would result in 418 new diagnoses of hypertension. If those chronic disease patients without a diagnosis of hypertension had their blood pressure checked only once a year, then the number of checks would be reduced by more than 80% to 5,456, without any reduction in the number of new diagnoses .Hypertension has a lower prevalence in younger people , so we aall patients attending clinics undergo health checks to “routinely check and record weight, blood pressure, pulse and temperature” on every visit [South Africa’s primary care clinics have been facing an unmanageable workload for some time . The numry visit , has notDuring the process evaluation of a randomised control trial in eight rural primary care clinics, we observed very long queues of patients waiting to have their blood pressure checked. Patients would arrive long before the clinic opened to get an early position in the queue. There could be as many as over 100 patients in the queue. Chronic disease patients with hypertension using the control clinics in the trial reported having been in clinic for an average 3 hours and 20 minutes . The lonIn this paper, we have used some of the data we collected to construct a spreadsheet which showed first, estimates of the workload that could be reduced by a change in policy on screening for hypertension and the frequency of checks to manage diagnosed hypertension. Secondly, we have estimated the number of new diagnoses of hypertension that might be made if staff were to respond appropriately to high readings observed in patients without a diagnosis of hypertension, and if the blood pressure machines were reliable. Reducing the number of patients each day who must have their blood pressure measured would shorten the queues and reduce waiting times. It would also reduce the wear and tear on the blood pressure machines, although a system for calibration and maintenance of the machines would still be needed.Although our spreadsheet results also showed that an extra reduction in workload could be achieved by limiting the age range to be screened, this would be achieved at the expense of missing around 4% of all the cases on undiagnosed hypertension, and arguably some of those it is most important to treat since they have already developed hypertension at such a young age.Even though the model used for the estimates was not sophisticated, it shows very large effects of a potential change in policy that are unlikely to be changed by more sophisticated modelling. Because we had access to electronic records of each patient’s clinic attendances we were able to give a much clearer picture of activity in a rural primary care clinic than had previously been possible. However, we only collected data from patients attending the clinics for management of chronic diseases and cannot include the workload generated by patients visiting for other reasons.Although our model points to the benefits of a change in policy, such a change would require some investment of resources for the new system to work well. The enrolled or staff nurses who take the blood pressure measurements at the vital signs stations would have to actively consider whose blood pressure to screen, rather than just screening everybody. This would require staff training. Also, the blood pressure machines would need to be serviced regularly to ensure reliable readings. The staff nurses would need to take note of raised blood pressures, and ensure that patients were followed up for a second assessment and enrolled in care when necessary.Hypertension represents a major health burden throughout South Africa. We have found that 60% of all visits to primary care clinics in the research area for chronic disease management were from people with a diagnosis of hypertension, while our two cross-sectional surveys showed the very high prevalence of hypertension 46.3%) in the adult population (age 18 plus). This accords with national data. The World Health Organization’s study on Global Ageing and Adult Health (SAGE) assessed the prevalence of hypertension in people aged over 50 years in six countries  between 2007 and 2010. South Africa had the highest prevalence of all countries, at 77.9% (95% CI 76.4–79.4). Moreover, only 38.0%  of the South African respondents were aware of their diagnosis 6.3% in t. Using mThe challenge of managing chronic diseases, and particularly hypertension and HIV, within primary care services is not unique to South Africa. Hypertension is increasing in prevalence throughout sub-Saharan Africa, and somAs the numbers of chronic disease patients continues to rise, a review of the current policy for measuring blood pressure in primary care clinics becomes increasingly urgent. This paper provides data that can assist policy makers undertaking such a review, showing the likely effect of some alternative strategies.


TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3  G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives  were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3  genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3  AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved . Against that, we found that TRIB3  AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change . Although no significant difference in antihypertensive effect between TRIB3  genotypes in patients treated with α, β-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, β-ADRs. In conclusion, our data supported that TRIB3  genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.Tribbles homolog 3 ( TRIB3) is organized as four exons, encoding a 358-amino-acid protein. TRIB3 proteins disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase, which contributes to insulin resistance and other physiological processes of vessel  by activating TRIB3 gene transcription  can be defined as a rise in blood pressure for unknown cause. It can increase risks for cerebral, cardiac, and renal events. It usually clusters with other cardiovascular risk factors such as aging, being overweight, insulin resistance, diabetes, and hyperlipidaemia . Human tf vessel . AKT medf vessel . Other sf vessel . Accumulcription . Homocysfunction .TRIB3 exon 2, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding, resulting in reduced Akt phosphorylation (TRIB3 missense Q84R (rs2295490) polymorphism and insulin resistance or its related cardiovascular events  variant in human rylation . Since Pr events , numerouRIB3 R84 . Among penotypes , individenotypes . In humaoduction . These veNOS accompanying with NO production via cAMP/cGMP/adrenalin signaling pathway  may cause a variability of antihypertensive drug therapy. Our previous findings have suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (rs2295490) G allele with good glucose and blood pressure control (TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in patients who received intensive glucose treatment as compared to those receiving standard glucose treatment in type 2 diabetic patients  ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg were included. Patients with secondary hypertension, coronary heart disease, diabetes, obesity (BMI.30 kg/m2), stroke, renal or liver dysfunction, malignant tumor or pregnancy and those whose blood pressure measurements above 180/110 mmHg or remaining lower than 140/90 mmHg during the wash-out period, were withdrawn from the study. In our study, a total of 368 unrelated subjects with primary mild to moderate EH, aged from 26 to 81 years were recruited for genetic screening. All the patients were enrolled after a run-in period of 2 weeks and assigned to receive the drugs for 4 weeks or more. The patients were followed up every 2 weeks at the weekend, and details of the protocol were shown in The study protocol was approved by the Ethical Committee of the Institute of Clinical Pharmacology, Central South University . Clinical study was registered at the Chinese Clinical Trial Register with the registration number ChiCTR-RO-12002612Blood pressure determinations were performed on the morning after a light breakfast with subjects in the seated position and following a 30 min quiet resting period. Blood pressure and heart rate were measured by trained nurses, with an automatic blood pressure monitor with intellisense, which allows the detection of alteration of the heart rate by greater than or equal to beat/min and the blood pressure by greater than or equal to 1 mmHg. Detected results were then validated by supervisors with the mercury sphygmomanometer. The blood pressure values were determined by the average of three measurements taken every 10 min. Values of SBP and DBP were defined by Korotkoff phase I and V, respectively. Pulse pressure was calculated as PP = (SBP- DBP); mean arterial pressure (MAP) was calculated as MBP = DBP + (PP/3) .TRIB3  were shown as follows: the sense primer, 5′GTTGCCCCTGAGCCCACCTACT3′; and the antisense primer, 5′TCCCTGGATGCTTCCCCACTAA3′. The product length was 286 bp. The reaction mixture (25 μl) contained: 10 × PCR buffer (2.5 μl), 10 × dNTP (2.5 μl), 10 μM for each of the sense and antisense primers (0.5 μl), H2O (16.8 μl), gDNA (2 μl), Taq polymerase (0.2 μl). Temperature cycling was proceeded as follows: initial denaturation for 5 min at 94°C, followed by 36 cycles of denaturation 30 s at 94°C, annealing at 57°C for 30 s, and elongation at 72°C for 30 s, and a terminal extension for 5 min. Genotypes were determined without knowledge of the status of patients, Ten percent blinded, random DNA samples from the patients were genotyped twice, with 100% concordance. And sequencing was assisted by Shanghai Majorbio Bio-pharm Technology Company.Tribbles homolog 3  genotypes were determined by sanger sequencing. The PCR primers for 2-test. Difference in baseline characteristics among the phenotypes were assessed by independent-samples T-test.All the analyses were performed with SPSS . Allele frequencies were determined by the genotypes of all the participants. Continuous data were presented as mean values ± standard error (SE), and categorical variable was shown as frequencies and percentages. The Hardy–Weinberg equilibrium analysis was carried out for the genotypes of participants using the χTRIB3 . This allowed the use of time-dependent and time-independent covariates within the model to be analyzed. Furthermore, this model has been found to work well for small sample sizes with missing data  genetic variation. Our data showed that the frequency of TRIB3  G allele was 18.5% in Chinese population. Genotype frequencies of TRIB3  AA, AG and GG were 66.0, 31.0 and 3.0%, respectively. All the allele frequencies were in Hardy-Weinberg equilibrium (P > 0.05). Owing to the low frequency of the GG genotype, we combined the AG and GG genotypes as one group for the following analysis. Baseline characteristics of the patients stratified by TRIB3 genotypes are shown in In this study, 368 patients were genotyped unambiguously for TRIB3  variant was significantly reduced (AA genotype compared to AG/GG genotype carriers) after CCBs administration. A similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment . Inversely, DBP change from baseline after ARBs prescription was significantly increased for the AA genotype carriers compared to AG/GG genotype  genetic polymorphism and α-ADR or β-ADR drug response was observed in our study cohort  genetic variation had a significant clinical relevance to the efficacy of certain class of antihypertensive drugs in individuals with EH treatment. It has been demonstrated that a better effect on BP response was observed in TRIB3 Q84R  AA genotype carriers than AG/GG carriers after taking a routine dosage of ACEI and CCBs antihypertensives. After stratification analysis for age and sex, we found a more significant difference between these two genotype carriers. Studies have shown that CCBs and ACEI have an excellent antioxidant stress effect via increasing eNOS expression and NO synthesis  genetic polymorphism. In addition, ARB could down-regulate TRIB3 mRNA level and a dual function of ARB on eNOS expression may also lead to the opposite relationship between TRIB3 G allele and antihypertensive effects of ACEI and ARBs  can elevate blood pressure by promoting pro-inflammatory and pro-thrombotic effects. Moreover, Ang IV can activate AT4R, and may contribute to cardiac damage . Likewisand ARBs .TRIB3 genotypes became more significant as time went on, which may be due to an increase in local eNOS mRNA expression and a decrease in angiotensin II in the LV, leading to the amelioration of myocardial remodeling in hypertensive condition  variance was associated with α, β-ADRs monotherapy in Chinese population with EH in an age-dependent and sex-specific manner. And between the age groups and the sex groups, there is a significant difference in BP-change from baseline only limited to patients with TRIB3  AG/GG genotype, while the mechanism is unclear. In addition, our study has shown that among G allele carriers, males or youngers are more likely to have a better antihypertensive effect  whose function and potential biological relevance have never, so far, been addressed. These may lead us to speculate that rare and common variants in TRIB3 may act together to alter drug efficacy.In recent years it became evident that the vast majority of genetic variants in genes of importance for drug treatment are rare, with minor allele frequencies <1%. Also, recent approximations based on analyses of population-scale sequencing projects estimate that such rare variants account for 30–40% of the interindividual variability in drug response . Some lo variant . Other s variant . SeveralOur study was a well-controlled drug clinical trial in which patients received monotherapy. Nevertheless, some limitations should be considered in the interpretation of our findings. On the one hand, diet habits, lifestyle factors may affect the antihypertensive effect of drugs. Such as a daily mean of 30 min of vigorous exercise, a DASH style diet, modest alcohol intake up to 10 g/day, non-narcotic analgesic use less than once per week, and intake of 400 μg/day or more of supplemental folic acid may lead to lower risk of hypertension . These fTRIB3  polymorphism was associated with the response of antihypertensive drugs therapy in Chinese EH patients,. Although this data may prove TRIB3  genetic variation is useful in clinical therapy, combining other genetic markers to identify individuals at high risk of cardiovascular abnormalities may bring a better clinical outcome. Further pharmacogenomics studies on TRIB3 merit attention.In conclusion, the results of the present study suggest that the JZ, FH, JL, LX, and WZ were responsible for the study design. JZ, FH, and BS were responsible for the experiments. JZ and FH did the data processing and statistical analysis. JZ, FH, and BS wrote and interpreted the manuscript. FH and BS were responsible for data management and contributed reagents and materials. RL, YG, HR, YS, XC, ZL, HZ, SD, and HX calibrated and discussed the manuscripts.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hypercortisolemia is associated with increased risk of hypertension. Natural and synthetic glucocorticoids (GCs) have different effects on blood pressure (BP). The effect of synthetic GCs on BP depends on the dose, treatment duration, type of GCs, and route of administration. Intravenous methylprednisolone (IVMP) pulse therapy is the first line of treatment for severe Graves’ orbitopathy (GO). The aim of this study was to evaluate influence of IVMP pulses on BP and N-terminal pro-brain natriuretic peptide (NT-proBNP) dynamics. A total of 32 patients with GO were treated with one IVMP pulse every week for 12 weeks. We performed 48-h BP monitoring (24-h before and 24-h after IVMP) and measured NT-proBNP before, 24 h, and 48 h after the 1st, 6th, and 12th IVMP pulse. Mean BP did not change after any of the pulses. We did not observe an increase in maximal systolic BP or mean nocturnal BP, except after the last pulse. Additionally, the dipping phenomenon was less frequent after the last pulse. We found a significant increase in median NT-proBNP levels after all analyzed pulses. Our study suggests that IVMP may have an unfavorable cumulative effect on BP. Variation in NT-proBNP concentration indicates a compensatory effect of brain natriuretic peptide secretion. High dose intravenous (i.v.) glucocorticoid (GC) pulse therapy is an effective immunosuppressive treatment used in various inflammatory and autoimmune diseases . One of However, a major concern was raised given reports of fatal side effects that may be associated with this therapy ,3. In a Synthetic GCs on BP appear to have a lesser impact than endogenous hypercortisolemia. Synthetic GCs with minimal mineralocorticoid activity stimulate the increase in BP without any urinary sodium retention, increase in body weight, or plasma volume . HoweverA consensus on the monitoring of patients during and after IVMP pulse administration has not yet been established ,10. The Results from 48-h ambulatory blood pressure monitoring (ABPM) were available from 22 patients. p = 0.024), as well as the 1st and 12th IVMP pulses (p = 0.0016).The baseline median value of NT-proBNP before the treatment was 70 (39–98) pg/mL . There was a statistically significant increase in median NT-proBNP levels between before, and 24 and 48 h after IVMP pulse in all of the analyzed pulses  . The higThe basic values of TnI were in the normal range in all patients. Only one of the participants reached normal TnI cutoff level (0.056 ng/mL) during any of the analyzed pulses. The increase in TnI level to 0.07 ng/mL was observed in one woman 48 h after the 12th IVMP pulse, but without any clinical symptoms of coronary heart disease. There were no statistically significant changes in TnI levels across the analyzed IVMP pulses.n = 8) patients , a decrease in 41% (n = 9) patients , and EF in 23% (n = 5) patients remained unchanged. Patients underwent echocardiographic examination before the 1st and after the 12th pulse (measurements were available in 22 participants). Median values of ejection fraction (EF) remained almost unaffected by the GC therapy: 65% before treatment (range: 56–71) vs. 65% after treatment (range: 55–73). The increase in EF was observed in 36% , and myocardial injury (TnI), as well as the echocardiographic parameter (EF). We did not observe any changes in the 24-h mean BP in all three evaluation periods  or in mean nocturnal BP and maximal SBP after first and sixth pulse of IVMP. However, after the last (12th) IVMP pulse, we observed an increase in mean nocturnal BP, maximal SBP, and a trend in a non-dipping BP profile. This is the first study suggesting the potential cumulative effect of IVMP administration on the circadian BP profile. The fast reaction of BP to IVMP pulses was analysed in a retrospective study by Yong et al. (1.0 g of IVMP)  and a prBNP gene results in the production and secretion of prohormone proBNP1-108. This is cleaved into the biologically active BNP1-32 and biologically inert and more stable NT-proBNP [Simultaneously, we observed a statistically significant increase in median NT-proBNP in all of the analyzed pulses, the greatest occurring 24 h after the administration of IVMP. The median increase in NT-proBNP levels during first 24 h was less pronounced after the 12th pulse. We observed a decrease in median NT-proBNP between basal values, before administration of the 1st, 6th, and 12th IVMP pulses. The increase in NT-proBNP after IVPM pulses indicated the elevated release of brain natriuretic peptide (BNP) that is secreted by cardiomyocytes in response to stretch . BNP mayT-proBNP . The samT-proBNP . Lack ofT-proBNP . LauridsT-proBNP . The autT-proBNP . FinallyT-proBNP .We did not analyze the influence of IVMP in subgroups of patients  as the study group was too small to perform such analysis. However, it would be interesting to include such analysis in a larger group of patients according to sex, age, and comorbidities. According to previous studies and our results, we consider therapy with IVMP pulses administered weekly as safe according to BP changes in normotensive patients and patients with well-controlled BP before treatment. However, during the cycle of treatment, an unfavorable cumulative effect on BP was observed after the last pulse. The study indicates a compensatory increase in BNP after every pulse of IVMP. We hypothesize that this effect could be reduced when the therapy lasts longer. This could explain why we observed the increase in maximal SBP and mean nocturnal BP and higher prevalence of non-dipping BP profile with lower median increase in NT-proBNP in the last evaluated pulse of IVMP. This is the first study concerning fast and cumulative influence of IVMP pulses on circadian BP.We did not observe any changes in echocardiography before and after treatment. We found no clinical symptoms of heart failure or acute exacerbation of heart failure in our patients. This study was a prospective, open, non-randomized, clinical study involving consecutive patients with active, moderate-to-severe GO treated with IVMP pulse therapy according to European Group On Graves’ Orbitopathy (EUGOGO) recommendations . PatientAfter enrolment, all participants were qualified for treatment with 4.5 g IVMP pulses (cumulative dose of methylprednisolone (MP)), treatment duration 12 weeks in once-weekly intravenous pulses, with each pulse in the first 6 weeks 0.5 g MP, and next 6 weeks 0.25 g MP) .Laboratory tests, such as NT-proBNP and TnI, were performed before, and 24 and 48 h after IVMP infusion during the following pulses: 1st, 6th, and 12th. Patients underwent echocardiographic examination before the 1st and after the 12th pulse. The 48-h ABPM (for 24-h before and 24-h after IVMP infusion) was recorded during the following pulses: 1st, 6th, and 12th. Standard monitoring and prophylaxis were performed before every pulse: evaluation of clinical status, symptoms of infection, BP monitoring, glucose level monitoring, monitoring of liver enzymes, and prophylaxis of osteoporosis. The primary endpoint was the change in BP and laboratory-documented change in cardiovascular biomarkers, which indicated the influence of IVMP on the cardiovascular system. The secondary endpoints included adverse cardiovascular events . The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee . The study was registered on clinicaltrials.gov with the number NCT03590080.We performed 48-h BP monitoring . All measurements of ambulatory BP were recorded by devices certified by the British Hypertension Society. ABPM recorders were programmed to register one BP measurement every 20 min during the awake period and every 30 min during the sleeping period. Bedtime and wake-up time were set to each patient according to their individual sleeping and waking habits. The parameters evaluated by ABPM and analyzed in the study were: mean BP from 24-h of BP monitoring and calculated as follows: (SBP-DBP) × 1/3 + DBP, mean nocturnal BP , and maximal SBP . The measurements, techniques, and device settings were in agreement with the current guidelines for hypertension diagnosis and management . The appThe absence of BP dipping phenomenon during sleeping was defined as a reduction in nocturnal SBP equal to or less than 10% in relation to the SBP when awake according to ABPM readings. Thus, we categorized individuals as dippers when the sleep-time-relative SBP decline was ≥10% and non-dippers when SBP decline was <10%.® Reagent Cartridge and Dimension® EXLTM integrated chemistry system  with a LOCI® Module . The cutoff value of NT-proBNP typical for hemodynamic stress in the left ventricle was defined as ≥125 pg/mL [All assays were performed in sera obtained from venous blood samples and analyzed immediately after blood sampling in The Central Laboratory in our hospital. NT-proBNP was measured using a Flex25 pg/mL . In addition to NT-proBNP, TnI was measured. Analysis of TnI was performed on Siemens Dimension System . TnI values ≥0.056 ng/mL above the 99th percentile were reported as positive. All echocardiographic examinations were performed using the Philips Medical Systems  with a sector 5-1-MHz. Measurements were performed according to the American Society of Echocardiography chamber quantification guidelines .The two-dimensional echocardiography studies were performed and interpreted by a board-certified cardiologist certified in transthoracic echocardiography. The parameter examined and analyzed in this study was the ejection fraction, which was calculated from end diastolic volume (EDV) and end systolic volume (ESV) estimates, using the following formula: EF = (EDV − ESV)/EDV.p value < 0.05 were considered statistically significant. All statistical analyses were made using STATISTICA ver.12.0 .Continuous variables are expressed as median values (lower quartile (Q1)—upper quartile (Q3). Categorical variables are presented as numbers (N) or percentage values (%). Comparisons between continuous variables  were assessed before and after selected IVMP pulses using a non-parametric Wilcoxson matched Pairs test. Analysis of paired nominal data, such as presence of BP dipping during sleep before and after IVMP pulses, was performed using McNemar’s test. Results with Our study suggests that treatment with intravenous methylprednisolone once every week may have an unfavorable cumulative effect on BP. Variation in NT-proBNP concentration after IVMP indicates the compensatory effect of brain natriuretic peptide secretion.


Hypertension is a highly prevalent co-morbidity in pediatric kidney transplant recipients. Undertreated hypertension is associated with cardiovascular complications and negatively impacts renal graft survival. Thus, the accurate measurement of blood pressure is of the utmost importance for the correct diagnosis and subsequent management of post-renal transplant hypertension. Data derived from the general population, and to a lesser extent from the pediatric population, indicates that ambulatory blood pressure monitoring (ABPM) is superior to blood pressure measurements taken in the clinical setting for the evaluation of true mean blood pressure, identification of patients requiring antihypertensive treatment, and in the prediction of cardiovascular outcome. This Educational Review will discuss the clinical value of ABPM in the identification of individual blood pressure phenotypes, i.e., normotension, new-onset hypertension, white-coat hypertension, masked hypertension, controlled blood pressure, and undertreated/uncontrolled hypertension in pediatric kidney transplant recipients. Finally, we examine the utility of performing repeated ABPM for treatment monitoring of post-renal transplant hypertension and on surrogate markers related to relevant clinical cardiovascular outcomes. Taken together, our review highlights the clinical value of the routine use of ABPM as a tool for identifying and monitoring hypertension in pediatric kidney transplant recipients. Hypertension is a central risk factor for the development of cardiovascular disease and a major cause of morbidity and mortality in the general adult population –3. HyperIn recent years, there has been renewed interest in the field of pediatric hypertension and post-renal transplant hypertension. This has been reflected by the publication of international guidelines for the optimal diagnosis and management of hypertension in children and by a growing number of review articles on the topic of childhood hypertension post-renal transplantation –19.In the adult population, the introduction of ambulatory blood pressure monitoring (ABPM) has changed the way we look at blood pressure . In sharAlthough the use of ABPM in the workup of children with hypertension has gained increasing attention , 23–27, This Educational Review will consist of an examination of contemporary clinical studies on the assessment of blood pressure in pediatric kidney transplant recipients. The main objective is to highlight the clinical value of ABPM after renal transplantation, thus enhancing the accuracy of blood pressure readings and facilitating clinical decision-making. Although our review is primarily based on cross-sectional studies, it also focuses on published longitudinal studies applying ABPM. Specific areas such as the pathophysiology of post-renal transplant hypertension and the treatment of pediatric hypertensive kidney transplant recipients will not be covered here since these topics have been extensively discussed in recently published review articles , 18, 19.Finally, we highlight the disadvantages of ABPM, including limited availability at certain centers and the impracticability of ABPM for patients required to travel long distances. We thus conclude that rigorous blood pressure measurements taken in the clinical setting are still useful provided that they are strictly performed according to validated protocols , 29–31. It should be recognized that blood pressure taken in the clinical setting is highly variable and influenced by several factors such as position of the arm and back, respiration, emotion, exercise, pain, disease, drugs as well as the circumstances of the measurement itself –40.If blood pressure variability is ignored by the observer, then the risk of an erroneous diagnosis becomes high. The analysis conducted by Myers et al. showed that in adult blood pressure measurements obtained outside of the clinician’s office are systematically and significantly lower than blood pressure readings obtained in the clinical setting . In ordeHaving briefly examined the inherent limitations of measuring blood pressure in the clinical setting, it becomes apparent that less biased and more accurate methods of representing patient’s actual blood pressure patterns are needed.The technique of non-invasive ABPM was initially conceived for evaluating antihypertensive drug efficacy . An impoHome blood pressure monitoring also provides more useful information than blood pressure measured in the clinical setting . HoweverSeveral pediatric studies sought to assess whether blood pressure readings taken in the clinical setting are sufficiently reliable when compared to ABPM in adequately categorizing a recipient’s blood pressure status after renal transplantation. Pooled data from four pediatric studies, including 188 untreated kidney transplant recipients, showed that the point estimate prevalence  of recipients with normotension in the clinical setting, who in fact were diagnosed as having true or sustained hypertension by ABPM criteria, was 30%  –57. AlsoIn treated hypertensive pediatric kidney transplant recipients, we and others have observed that readings taken in the clinical setting are not a solid surrogate for ABPM in identifying true responders to antihypertensive therapy. The point estimate prevalence of uncontrolled hypertension defined upon ABPM criteria in 457 treated hypertensive recipients was 54%  , 67–75. In this section, we have shown that the application of ABPM in pediatric kidney transplant recipients provides a better estimate of true or mean blood pressure level than blood pressure readings obtained in the clinical setting. Undoubtedly, all the above-mentioned studies provide supportive evidence for a real problem when attempting to define a recipient’s actual blood pressure status solely by means of blood pressure obtained in the clinical setting.Before going further, we need to consider what has been shown on the reproducibility of ABPM. It should also be acknowledged that ABPM devices have become more precise, with measurements now more reproducible than blood pressure taken in the clinical setting , 80. ValThere is a diurnal rhythm of blood pressure that mainly depends on the pattern of physical activity . A normaNocturnal blood pressure and circadian rhythm is often abnormal in adult and pediatric patients with chronic kidney disease as well as after renal transplantation . This shThere are, as described in the next sections, additional significant aspects from the clinical perspective.Presently, the question of controlled blood pressure is of great importance since, as previously mentioned, many treated hypertensive patients have undertreated hypertension.n = 98) [In our experience, controlled blood pressure in pediatric kidney transplant recipients was more than doubled when ABPM is performed yearly, thus conveying the message to pediatric healthcare providers and researchers of the usefulness of this technique . Recentln = 98) . Therefon = 98) .Since high blood pressure is commonly asymptomatic unless the child has severe hypertension that is left untreated , 98, theIn adult patients with chronic kidney disease, controlled blood pressure slows the further loss of renal function . Similarn = 23), the estimated graft function remained stable whereas in recipients with uncontrolled hypertension (n = 8) allograft function decreased significantly over time [Although all transplant patients experience a decline in their renal function over time, adult studies have shown that for every 10 mmHg higher systolic blood pressure graft loss is increased by 12–15% , 102. Cover time .More recently, Hamdani et al. observed that allograft function was significantly lower in recipients with sustained hypertension when compared to normotensive recipients in a large retrospective multicenter cross-sectional study including 221 participants that also used ABPM to assess blood pressure status and plasma creatinine to estimate renal function .n = 44) and recipients that were normotensive or had controlled blood pressure throughout the entire post-transplant follow-up (n = 24) [We explored the effect of hypertension, assessed by ABPM performed annually after transplantation, on the loss of renal function over a mean follow-up of 6.2 years by means of allograft function measurements, according to our local protocol, either by the renal clearance of inulin or iohexol . Since t(n = 24) . In the (n = 24) .In hypertension, left ventricular hypertrophy is the heart’s response to the presence of increased left ventricular load and neurohumoral stimuli, which results in an augmentation of oxygen consumption. In fact, myocardial ischemia is a hallmark of hypertensive heart disease . As suchSince the introduction of the ultrasound-derived assessment of the combined intimal and media layers of the common carotid artery, the technique has gained acceptance as a marker of asymptomatic target organ damage and displayed prognostic value among subjects with hypertension , 109. InBased on cross-sectional data derived from a large pediatric cohort including patients with advanced chronic kidney disease as well as renal transplant recipients, Litwin et al. speculated that successful renal transplantation could partially reverse the arteriopathy associated with chronic exposure to the uremic milieu . Later, Hypertension-related organ damage is a chronic process that takes years to manifest. Hence, reducing the cumulative burden of uncontrolled hypertension and cardiovascular injury should be a priority for clinical care and research in pediatric renal transplant recipients. Here, we emphasize that the routine use of ABPM offers advantages in terms of the accurate diagnoses of hypertension and refining risk-stratification when compared to traditional blood pressure measurements taken in the clinical setting. This makes ABPM an indispensable technique in the daily clinical practice for the management of hypertension following renal transplantation. In addition, economic factors also favor ABPM, for example up to 14% savings in the cost of healthcare provision has been calculated when ABPM is incorporated in the diagnosis and treatment process of hypertension in adults . PediatrIn broad terms, our cut-off points to define ambulatory hypertension are based on percentiles derived from healthy children and adolescents rather than in relation to outcomes . For manFinally, further larger studies capable of generating robust statistical data, i.e., knowledge, are required to investigate whether the repeated use of ABPM significantly improves the physician’s decision to initiate or intensify antihypertensive therapy and to determine if this practice translates into important clinical benefits for the pediatric kidney transplant population.Ambulatory blood pressure monitoring is more accurate than blood pressure readings taken in the clinical setting to estimate an individual’s true mean blood pressure.Several international professional groups have ascertained the utility of ABPM in the workup of pediatric hypertension, including post-renal transplant hypertension.ABPM has the ability to identify patients with white-coat and masked hypertension and when performed at regular intervals, offers guidance for additional titration of antihypertensive medication as well as to confirm controlled hypertension.Nocturnal hypertension and decreased blood pressure fall during sleep are well-described conditions after pediatric renal transplantation that can only be detected by ABPM.ABPM is inferior compared to blood pressure measurements taken in the clinical setting for improving a subject’s risk stratification.ABPM identifies patients with white-coat hypertension.ABPM identifies patients with masked hypertension.ABPM provides a better estimate of a subject’s true mean blood pressure than blood pressure measurements taken in the clinical setting.All statements below regarding the use of ABPM are true except one:Home blood pressure measurements.ABPM.Blood pressure measurements taken in the clinical setting.All of them are alike.What is the best method of measuring blood pressure for the diagnosis and treatment monitoring of hypertension in renal transplant recipients?Confirm hypertension by ABPM.Start antihypertensive treatment without delay and monitoring treatment with ABPM.After confirming hypertension by means of ABPM, treatment monitor should only rely upon blood pressure measurements taken in the clinical setting.Answers a) and c) are correct.What should be done in a recipient with hypertension that is diagnosed in the clinical setting and who has verified hypertensive-related organ damage?The annual loss of renal allograft function is expected to be similar to normotensive recipients.In hypertensive recipients with initially diagnosed left ventricular hypertrophy it is most likely to observe a regression of left ventricular mass under successfully long-term controlled blood pressure.Uncontrolled hypertension has been shown to be associated with increased carotid intima-media thickness.All answers are correct.In treated hypertensive renal transplant recipients with ambulatory controlled blood pressure: