Recent research indicates hypertensive patients with microalbuminuria have decreased endothelial progenitor cells (EPCs) and increased levels of endothelial apoptotic microparticles (EMP). However, whether these changes are related to a subsequent decline in glomerular filtration rate (GFR) remains unclear.2. The mean annual rate of GFR decline (△GFR/y) was −1.49±3.26 mL/min/1.73 m2 per year during the follow-up period (34±6 months). Flow cytometry was used to assess circulating EPC (CD34+/KDR+) and EMP levels (CD31+/annexin V+) in peripheral blood. The △GFR/y was correlated with the EMP to EPC ratio , microalbuminuria , and the Framingham risk score . When we divided the patients into 4 groups according to the EMP to EPC ratio, there was an association between the EMP to EPC ratio and the ΔGFR/y . Multivariate analysis indicated that increased EMP to EPC ratio is an independent predictor of ΔeGFR/y.We enrolled totally 100 hypertensive out-patients with eGFR ≥30 mL/min/1.73 mAn increased circulating EMP to EPC ratio is associated with subsequent decline in GFR in hypertensive patients, which suggests endothelial damage with reduced vascular repair capacity may contribute to further deterioration of renal function in patients with hypertension. It has been recognized that declining renal function, estimated by the glomerular filtration rate (GFR), is an independent risk factor for all-cause mortality It has become evident that the vascular endothelium is a highly active organ that affects vascular tone, smooth muscle cell proliferation, monocyte adhesion, and platelet aggregation 2. Hypertension was defined as a systolic blood pressure ≥140 mmHg, a diastolic blood pressure ≥90 mmHg, or use of antihypertensive drugs. Subjects with history or clinical evidence of angina, myocardial infarction, congestive heart failure, peripheral vascular disease, inflammatory disease, or any disease predisposing to vasculitis were excluded. Causes of secondary hypertension were excluded by appropriate investigations. Patients with stage 4 and 5 chronic kidney disease (GFR <30 mL/min/1.73 m2) were also excluded From April 2008 through December 2008, we consecutively recruited 100 outpatients with essential hypertension and a baseline estimated GFR ≥30 mL/min/1.73 mMedical history, including cardiovascular risk factors, previous and present cardiovascular events, and current medication regimen, was obtained during a personal interview and from medical files. All the measurements were made at the medical center after an overnight fast of at least 8 hours. Weight, height, and waist circumference were measured and body mass index (BMI) was calculated. Brachial blood pressure was measured by a physician with a mercury sphygmomanometer after patients sat for 15 minutes or longer. The average of 3 measurements was used for the analysis.2) were calculated with the new equation proposed by investigators in the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration 2, and it has been externally validated in Chinese populations with greater precision and accuracy in terms of eGFR Creatinine measurements were performed at baseline and at the end of follow-up using the Jaffe method implemented in an auto-analyzer. Estimated GFR values . Plasma NT-proBNP was determined by a sandwich immunoassay (EIMA) with two antibodies . Each standard and plasma sample was analyzed twice, and the mean value was used in all subsequent analyses. The intra-assay and inter-assay variation coefficients of the tests were <10% g for 2 minutes to generate platelet-poor plasma. Fifty microliters of platelet-poor plasma was incubated with 4 μL of phycoerythrin (PE)-conjugated monoclonal antibody against CD31 (Becton Dickinson) followed by incubation with fluorescein isothiocyanate (FITC)-conjugated annexin V according to the manufacturer’s instructions. IgG-FITC  served as the negative control. Fluorescence-activated cell sorting (FACS) analysis was performed immediately after staining using a FACSCalibur flow cytometer (Becton Dickinson). We used standard beads  to identify microparticles in gating cells by FACS. CD31+/annexin V+ microparticles were defined as particles positively labeled for CD31 and annexin V (CD31+/annexin V+). Representative flow cytometry analysis for quantifying the number of endothelial apoptotic microparticles is shown in bright, only CD31+ microparticles were selected +/annexin V+ and CD31+/CD42− microparticles in 104 patients  Plasma derived from 10 mL citrate-buffered blood was immediately centrifuged at 13,000 +KDR+CD133+. To assess the reproducibility of EPC measurements, circulating EPCs were measured from 2 separate blood samples in 10 subjects, and there was a strong correlation between the two measurements  Assessment of the circulating EPCs by flow cytometry was performed by the researchers masked to the clinical data. A volume of 1000-µL peripheral blood was incubated for 30 minutes in the dark with monoclonal antibodies against human kinase insert domain-conjugating receptor  followed by PE-conjugated secondary antibody, with the fluorescein isothiocyanate (FITC)-labeled monoclonal antibodies against human CD45 , and PE-conjugated monoclonal antibody against human CD133 , and with FITC-conjugated or PE-conjugated monoclonal antibodies against human CD34  and KDR . Isotype-identical antibodies served as controls (Becton Dickinson). After incubation, cells were lysed, washed with phosphate-buffered saline (PBS), and fixed in 2% paraformaldehyde before analysis. Each analysis included 100,000 events. As shown in t test, Mann-Whitney U test, or Chi square test, as appropriate. Comparisons of continuous variables among the 4 groups were performed by analysis of variance (ANOVA). Subgroup comparisons of categorical variables were assessed by Chi square or Fisher’s exact test. Variables associated with the annual rate of decline of eGFR were identified using Pearson’s correlation coefficient or Spearman’s correlation coefficient, as appropriate. Linear regression analysis was used as appropriate to assess the relationship between annual rate of decline of eGFR, traditional risk factors, medications, and CD31+/annexin V+ EMP to EPC ratio. Finally, we constructed multivariable models using △eGFR as the dependent coefficient. Regression model results are presented as correlation coefficients and their p values. Data were analyzed using SPSS software . A p value of less than 0.05 was considered to indicate statistical significance.The analysis was performed on the complete data set, and results were expressed as mean ± SD or as percent frequency. Comparisons between two groups were made by paired or unpaired Student 2, which decreased to 78.34±23.51 mL/min·1.73 m−2 by the end of the observation period. In the general population, the normal annual mean decline in GFR with age from the peak GFR (120 mL/min·1.73 m−2) attained during the third decade of life is 1 mL/min/1.73 m2 per year, reaching a mean value of 70 mL/min/1.73 m2 by age 70 2 per year, which was similar with the natural history of CKD and was not statistically different between males and females (p = 0.230).The mean age of the 100 hypertensive patients  was 62±14 years. The baseline characteristics of the patients are listed in p = 0.028). There were no significant differences in their antihypertensive therapy duration and medication usage among the 4 groups, including angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium-channel blockers, beta-blockers, statins, and thiazides.Based on the EMP/EPC ratio, the actual cutoff values for each quartile of the EMP/EPC ratio are 0.5, 2.0, and 11.7. We classified our patients into four groups according to quartiles, including 25 patients (25%) in group 1 (Q1) with EMP/EPC ratio ≤0.5, 25 patients (25%) in group 2 (Q2) with EMP/EPC ratio >0.5 and ≤2.0, 25 patients (25%) in group 3 (Q3) with EMP/EPC ratio >2.0 and ≤11.7, and 25 patients (25%) in group 4 (Q4) with EMP/EPC ratio >11.7. The baseline characteristics of the patients in each group are presented in 2, p<0.001).As illustrated in r = −0.465, p<0.001) and urine albumin/creatinine ratio . Moreover, circulating EMP concentration, EPC level alone, and Framingham risk score showed a marginal association with eGFR decline . Besides, the correlations between the EMP/EPC ratio and the annual decline rate in eGFR in patients with CKD were consistent with the result in the overall population .To further clarify the association between change in eGFR and EMP/EPC ratio after adjustment for other risk factors, we performed simple and multiple regression analyses that included demographic variables and cardiovascular risk factors. As demonstrated in r = −0.340, p = 0.003). Additionally, a marginal association between the EMP/EPC ratio and the urine albumin/creatinine ratio was noted .By multivariate analysis, EMP to EPC ratio, microalbuminuria, and the Framingham risk score were significant independent factors to subsequent decline in eGFR . The comTo the best of our knowledge, this is the first study to show that increased EMP to EPC ratio in hypertensive patients is associated with subsequent decline in GFR. Even when the relationship between the EMP/EPC ratio and eGFR is expressed by a moderate correlation coefficient, our data suggest that the association is as clinically important as that documented by the microalbuminuria and Framingham risk score. These findings demonstrate that the reduced vascular repair capacity and increased endothelial damage indicated by higher EMP to EPC ratios may exacerbate the decline in renal function in patients with hypertension, and that therapies to improve circulating EPC levels and reduce endothelial damage may help to prevent the progression of hypertensive kidney disease.Chronic kidney disease (CKD) is a major public health problem There are various etiologies thought to contribute to the pathogenesis of atherosclerosis in patients with CKD, including oxidative stress, inflammation, and endothelial dysfunction. It has become clear that the vascular endothelium is a highly active organ that affects vascular tone, platelet aggregation, monocyte adhesion, and smooth muscle cell proliferation Microparticles carry membrane proteins and phospholipids of the parent cell , and can also be derived from leukocytes, erythrocytes, or platelets However, there has been some controversy regarding whether EMPs are just the sequela of vascular injury or have a pathological role. Previous study in patients with end-stage kidney disease suggested that EMPs may play a pro-atherogenic role other than being a consequence of vascular damage et al. reported that EMPs from EPCs isolated from healthy subjects protect against acute and long-term consequences of ischemia-reperfusion injury in rats On the other hand, EMPs also stimulate angiogenesis and differentiation of EPC In this study, levels of hsCRP and NT-proBNP were not sufficient to predict short-term changes in renal function as significant independent factors. This suggested that the changes in the EMP/EPC ratio might be more sensitive than these biomarkers for predicting the progress of hypertensive kidney disease. Although not tested in the present study, the prevention of progressive renal disease in hypertensive patients may rely not only on rigorous blood pressure control, but also on other measures known to improve endothelial function and reduce endothelial damage by enhancement of circulating EPC levels.Some limitations of this study should be mentioned. First, the sample size is rather small, and was assembled from a single center. Therefore, further larger confirmative studies are needed to verify the current result. Second, no consensus or standardized assay for the measurements of EMP and EPC levels has been established for routine clinical testing, and the number of this study population was not estimated by power calculation. Further, although we used the newer equation from CKD-EPI for GFR estimation, which has demonstrated less bias at higher GFR values and has been validated in Asian and Chinese populations, we did not have a direct measurement of GFR in this study. At last, we cannot exclude the possibility that the EMP level and EMP/EPC ratio increased as the consequence of impaired kidney function and reduced EMP clearance. However, the impact of this clearance effect is difficult to be measured precisely because of lacking the reference data of EMP clearance in deferent stages of CKD according to the best of our knowledge.+/annexin V+ EMPs to EPCs is associated with subsequent declines in GFR in hypertensive patients. The results suggest that reduced vascular repair capacity and escalating endothelial damage may contribute to deterioration of renal function in hypertensive patients. These findings may explain the pathogenetic processes coupling the balance of endothelial injury and the subsequent pathogenetic progression of hypertensive kidney disease.In conclusion, this is the first study to show that an increased ratio of the levels of circulating CD31


RESPPP) has scarcely been reported. In patients with ARDS, the pathophysiology of ΔRESPPP may differ from that of healthy lungs because of low tidal volume (Vt), high respiratory rate, decreased lung and sometimes chest wall compliance, which increase alveolar and/or pleural pressure. We aimed to assess ΔRESPPP in a large ARDS population.Fluid responsiveness prediction is of utmost interest during acute respiratory distress syndrome (ARDS), but the performance of respiratory pulse pressure variation : 0.62 to 0.85), and a best cutoff of 5% yielded positive and negative likelihood ratios of 4.8 (CI95: 3.6 to 6.2) and 0.32 (CI95: 0.1 to 0.8), respectively. Adjusting ΔRESPPP for Vt, airway driving pressure or respiratory variations in pulmonary artery occlusion pressure (ΔPAOP), a surrogate for pleural pressure variations, in 33 Swan-Ganz catheter carriers did not markedly improve its predictive performance. In patients with ΔPAOP above its median value (4 mmHg), AUC for ΔRESPPP was 1 (CI95: 0.73 to 1) as compared with 0.79 (CI95: 0.52 to 0.94) otherwise (P = 0.07). A 300-ml volume expansion induced a ≥2 mmHg increase of central venous pressure, suggesting a change in cardiac preload, in 40 patients, but none of the 28 of 40 nonresponders responded to an additional 200-ml volume expansion.Among the 65 included patients (26 responders), the area under the receiver-operating curve (AUC) for ΔRESPPP performance was poor. Careful fluid challenges may be a safe alternative.During protective mechanical ventilation for early ARDS, partly because of insufficient changes in pleural pressure, Δ RESPPP)) ) ) .-1 kg-1 or PAOPtm >22 mmHg or 5% decrease in pulse oxymetry (SpO2)). Mechanical ventilation, vasoactive therapy, sedation and paralysis were set by the attending physician and not modified.The study procedure was stopped in case of changes in respirator settings or vasoactive therapy, occurrence of arrhythmia or respiratory intolerance to volume expansion (EVLWi >22 mlHemodynamic (heart rate (HR), blood pressure and cardiac output (CO)) and respiratory parameters  were measured at baseline, immediately after infusion of 300 ml of modified fluid gelatin over 18 minutes (to assess the respiratory tolerance) and an additional 200 ml over 12 minutes.CO was measured through end-expiratory injection of 10 ml or 15 ml  of an iced dextrose solution (using a closed injection system with in-line temperature measurement: CO-set+™ system (Edwards Lifesciences) or that which is included in the PiCCO™ system). Three consecutive measurements within 10%  were averaged.The correct placement of the pulmonary artery catheter was ascertained by visualization of concordant waveforms and calculation of the respiratory changes in PAOP (ΔPAOP)-to-respiratory changes in pulmonary artery pressure (ΔPAP) ratio .RESPPP was calculated by an observer blinded to other hemodynamic data as follows and averaged over three consecutive respiratory cycles:Central venous pressure (CVP) , PAOP  and blood pressure were measured with a disposable transducer , zeroed at the level of the midaxillary line. Offline, on high-resolution paper tracings, including airway and blood pressure waveforms and after their numerical enlargement, Δwithin one respiratory cycle . Other icor pulmonale .Echocardiography was performed within 6 hours of measurements to quantify valvular regurgitations and to detect intracardiac shunts or acute 2 [Patients were classified as responders if volume expansion induced an increase in CO ≥10% and as nonresponders otherwise. Indeed, a measured increase of CO above 9% (which we rounded to 10%) reliably reflects that a real change has taken place . To vali2  cutoff tn (%)) were compared using Student's t-test and Fisher's exact test (between responders and nonresponders), paired Student's t-test (for each patient), analysis of variance and the χ2 test (between centers). For each index , we calculated the area under the receiver-operating characteristic curve (AUC), determined positive and negative likelihood ratios (LR+ and LR-) for the best cutoff (Youden method) and for the widely used cutoff of 12% for ΔRESPPP [P < 0.05 was considered statistically significant. All statistical tests were two-tailed and performed using MedCalc software  and Statview software .Variables  or epinephrine . Volume expansion was interrupted in two patients after 300-ml intolerance (one because of a 6% drop in SpO2 and one because of an increased EVLWi >22 ml/kg). Data after 300-ml volume expansion were used for analysis of these two patients. Hemodynamic parameters at baseline and their evolution after volume expansion are detailed in Table RESPPP were similar between centers .Sixty-five patients were included Table . The meaRESPPP was associated with an AUC of 0.75 : 0.62 to 0.85) and a best cutoff value of 5% (LR+ and LR- of 4.8 (CI95: 3.6 to 6.2) and 0.32 (CI95: 0.1 to 0.8), respectively) (Table 95: 0.8 to 4.9) and 0.92 (CI95: 0.3 to 2.8), respectively.Δ.8 CI95: .6 to 6.2 CI95: 0. to 0.8, RESPPP for various estimates of extramural vascular pressure variations  did not lead to major improvement in predictive performance  and 0.81 (CI95: 0.64 to 0.93), respectively. Figures Adjusting Δe Figure . In the RESPPP might achieve better results, we performed a subgroup analysis. In case of respiratory variation in PAOP above its median value (>4 mmHg), ΔRESPPP was associated with an AUC of 1 (CI95: 0.73 to 1) as compared with 0.79 (CI95: 0.52 to 0.94) otherwise (P = 0.07), with a marked decrease of the visual overlap of baseline values of ΔRESPPP between responders and nonresponders  did not lead to marked difference in AUC and/or in the visual overlap , site of the arterial catheter  or femoral (n = 51)) , dDown (n = 45), CVP (n = 65), PAOP (n = 33) and PAOPtm (n = 33) were associated with an AUC below 0.78  its indexation, (2) analyzing different cutoffs for ΔRESPPP or fluid responsiveness definition or (3) identifying subgroups where ΔRESPPP may perform better.The main finding of this large multicenter study of 65 shocked ARDS patients with neither arrhythmia nor spontaneous respiratory activity is that the performance of Δet al.'s study [RESPPP performance in ARDS and reported a similar AUC (0.77) for ΔRESPPP as in our population (0.75 (CI95: 0.62 to 0.085)). In our study, the AUC was not good, as the lower bound of the 95% confidence interval was below 0.75 [et al.'s study [RESPPP remains a reliable predictor of fluid responsiveness for ARDS patients ventilated with low Vt and high PEEP) was a misinterpretation [et al. [RESPPP did not perform better than PAOP. Other authors also observed this low performance of ΔRESPPP in case of low Vt. One can reasonably assume that many patients in those studies had ARDS, despite the lack of specific subgroup analysis [RESPPP in ARDS patients.Huang 's study , includilow 0.75 . Partly 's study , it was retation ,29. In a [et al. , who fouanalysis ,30. Agaianalysis ,14,15 juRESPPP was low at baseline (5.2%) compared with most studies exhibiting values close to 12% [RESPPP value. First, it may be a consequence of including patients already resuscitated. Indeed, large volume expansion before inclusion (not recorded) may explain the low variations in blood pressure waveform we observed. However, despite this initial resuscitation, 40% of our patients were still fluid responders. Second, as previously shown [RESPPP may also be related to the low Vt used in our population (6.9 ± 0.95 ml-1 kg-1) compared with other studies reporting values of at least 8 ml-1 kg-1 [RESPPP (low Vt and high RR) often come together in particular in case of ARDS. Figure RESPPP in our population.Interestingly, our mean Δseline 5.% comparee to 12% ,17). Manly shown ,10,11, tl-1 kg-1 -36. Thirl-1 kg-1 . Again, l-1 kg-1 -33,36. IRESPPP, false-positive cases may also arise because of a common phenomenon during ARDS: pulmonary artery hypertension [cor pulmonale  than patients whom we included.Beyond these limitations (low Vt and high RR) causing false-negative cases of Δrtension ,38 and/ortension . We onlyefulness . It is nRESPPP, positively or negatively. Decreased chest wall compliance, observed in cases of intraabdominal hypertension (extrapulmonary ARDS) [RESPPP may be higher and present false-positive results in this situation. At the opposite, chest wall compliance may be increased through the use of muscle relaxants, which was the case in 40% of our patients, and then induce reduced intrathoracic pressure swings and therefore potential false-negative ΔRESPPP results. The lack of measurement of chest wall compliance in our patients  precluded precise analysis of this factor. Nevertheless, using PAOP as a surrogate for esophageal pressure measurements, we performed some physiological analysis which allowed us to gain some insight into this issue.Moreover, changes in chest wall compliance may also affect Δry ARDS)  increasery ARDS) ,15. ThusRESPPP to perform well in this population [RESPPP) have been shown to be the magnitude of Vt and chest wall compliance (both of them ruling the compression of the cardiovascular structures), regardless of lung compliance [RESPPP tended to perform markedly better in patients with high ΔPAOP , respiratory changes in PAOP represent the ratio of Vt/chest wall compliance  may cause sufficient changes in intrathoracic pressure, allowing Δpulation . Actuallpulation , but thempliance . Indeed,mpliance , we founP Figure , illustr95: 0.64 to 0.93)) that we found for ΔRESPPP/ΔPAOP (in the subset of Swan-Ganz catheter carriers) suggests that a more precise approach of pleural pressure swings may be a more interesting way to correct the crude ΔRESPPP and to improve its predictive ability. Not surprisingly, and as previously reported in case of low Vt [RESPPP performance when it was corrected for airway driving pressure. Moreover, there was no marked evidence of better performance of ΔRESPPP in cases of high airway driving pressure  [2:FiO2 ratio <70) for safety reasons. Of note, ΔRESPPP showed similar performance in patients with respiratory system static compliance below or above its median value  [RESPPP is mostly influenced by the Vt rather than the airway driving pressure [RESPPP than that reported in similar previous works.Our ARDS patients exhibited higher values of respiratory system static compliance  than values usually reported in ARDS patients (40 versus 26 to 30 ml/cmH2O) ,17,42. T7 cmH2O) ,17,42. H7 cmH2O) ,17,42. Apressure ,14, one RESPPP was 5%, that is, close to that previously reported in ARDS patients with low Vt [RESPPP to predict fluid responsiveness may be that this low cutoff exposes it to errors in measurements because of low signal-to-noise ratio [RESPPP in ARDS patients [In our population, the best cutoff value for Δh low Vt . Anotherse ratio . Of notepatients ,17 did nRESPPP, we found that the other breath-related, blood pressure-derived indices, dDown and SPV, were of similar poor performance in predicting fluid responsiveness in our ARDS population. Before using fluid responsiveness prediction tools, one has to identify patients who may actually benefit from having their CO increased by fluids. In an overall population, many fluid responders actually do not need any fluids . All of our patients were in acute circulatory failure and most presented signs of tissular hypoperfusion , suggesting that they may benefit from volume expansion, but baseline CVP (11 ± 4 mmHg) and PAOP (12 ± 4 mmHg) were unhelpful  perform poorly in predicting fluid responsiveness in patients with ARDS.• Respiratory variations of pulse pressure  and low HR:RR ratio downplay the performance of ΔRESPPP.• Respiratory changes in pleural pressure, but not airway driving pressure, are the main determinant of ΔRESPPP performance was found.• No simple means of improving Δ• Because optimal fluid management is of utmost importance in ARDS patients, clinicians have to rely on other means, such as fluid challenges, for this purpose.RESPPP: respiratory variations in pulse pressure; ΔPAP: respiratory changes in pulmonary artery pressure; ΔPAOP: respiratory changes in pulmonary artery occlusion pressure; ARDS: acute respiratory distress syndrome; AUC: area under the receiver-operating characteristic curve; CO: cardiac output; CVP: central venous pressure; dDown: difference between the average, over three consecutive respiratory cycles, of the minimal value of systolic blood pressure during a respiratory cycle and the value of systolic blood pressure during apnea; HR: heart rate; LR+: positive likelihood ratio; LR: negative likelihood ratio; LSC: least significant change; PAOP: pulmonary artery occlusion pressure; PAOPtm: transmural pulmonary artery occlusion pressure; PEEP: positive end-expiratory pressure; Pplat: plateau pressure; RR: respiratory rate; SPV: respiratory changes in systolic arterial pressure over three consecutive respiratory cycles; Vt: tidal volume.ΔThe authors declare that they have no competing interests.KL, SE and TB contributed to the conception and design of the study. KL, SE, DBL, IR, EM, PFD, AL and TB contributed to the acquisition of data. KL, SE, MW, BR and TB contributed to the drafting and revision of the manuscript.Additional data and figures. Impact of several clinical factors on the performance of ΔRESPPP: subgroup comparisons according to respiratory system compliance, norepinephrine dosage, neuromuscular blocking agent use and site of the artery catheter. Impact of the definition of fluid responsiveness on the performance of ΔRESPPP, individual values of baseline static and breath-derived indices in responders and nonresponders using the 15% cutoff for cardiac output to define fluid responsiveness, performance of ΔRESPPP using the 15% cutoff for cardiac output to define fluid responsiveness. Impact of chest wall compliance on ΔRESPPP provides additional comments to Figure 4. AUC, area under the receiver-operating characteristic curve; ΔRESPPP, respiratory changes in pulse pressure.Click here for file


Dynamic cerebral autoregulation after intracerebral hemorrhage (ICH) remains poorly understood. We performed a case-control study to compare dynamic autoregulation between ICH patients and healthy controls.i) was calculated as the ratio of MAP to MFV. Dynamic cerebral autoregulation was assessed using transfer function analysis of spontaneous MAP and MFV oscillations in the low (0.03-0.15 Hz) and high (0.15-0.5 Hz) frequency ranges.Twenty-one patients (66 ± 15 years) with early (< 72 hours) lobar or basal ganglia ICH were prospectively studied and compared to twenty-three age-matched controls (65 ± 9 years). Continuous measures of mean flow velocity (MFV) in the middle cerebral artery and mean arterial blood pressure (MAP) were obtained over 5 min. Cerebrovascular resistance index . The ICH group had higher gains than controls in the low  and high  frequency ranges. The ICH group also had higher coherence in the contralateral hemisphere than the control  in the high frequency range.The ICH group demonstrated higher CVRPatients with ICH had higher gains in a wide range of frequency ranges compared to controls. These findings suggest that dynamic cerebral autoregulation may be less effective in the early days after ICH. Further study is needed to determine the relationship between hematoma size and severity of autoregulation impairment. Cerebral autoregulation serves as a protective feedback mechanism to maintain relatively constant blood flow to the brain in response to changes in cerebral perfusion pressure (CPP) . HoweverThe understanding of cerebral autoregulation is especially important in ICH since blood pressure management is the mainstay of current treatment options . With imstatic cerebral autoregulation and captures the steady-state relationship between gradual changes in pressure and flow [dynamic cerebral autoregulation measurements assess the "robustness" of dynamic cerebral vessel caliber changes in response to sudden changes in blood pressure, which cannot be assessed with most static imaging techniques.Most of the early studies of cerebral autoregulation were assessed by gradually raising or lowering blood pressure and measuring the cerebral blood flow (CBF) responses to determine if steady-state CBF values have changed ,15. Thisand flow . Most ofTCD ultrasound is a noninvasive and readily available diagnostic tool that can be used to assess dynamic cerebral autoregulation. Recent developments in Doppler technology have enabled researchers to measure spontaneous beat-to-beat changes in mean blood flow velocity (MFV) of the major cerebral arteries in response to spontaneous mean arterial pressure (MAP) oscillations, allowing investigators to quantify the dynamic relationship between MFV and MAP without the substantial risk of manipulating blood pressure . This alThe study received approval from the Brigham and Women's Hospital institutional ethical standards committee on human experimentation for any experiments using human subjects. A written consent was obtained from the subjects or their healthcare proxies.From August 2007 to June 2009, we prospectively screened 37 patients admitted to the neurointensive care unit at Brigham and Women's Hospital with diagnosis of spontaneous ICH. Inclusion criteria were age greater than 18, evidence of acute ICH on admission by computed tomography (CT), symptom onset within 72 hours from the study and hemodynamic stability. Exclusion criteria included traumatic hemorrhage, history of chronic obstructive lung disease, unstable blood pressure requiring vasopressor agents, other central neurological co-morbidities  and inadequate TCD windows. All head CT scans were reviewed independently by one of the study investigators (K.N.) using a standardized protocol, blinded to cerebral hemodynamic data, and hematoma volume was calculated from the most recent brain CT prior to the TCD study by using the "ABC/2" volume method . The locTwenty-three age-matched healthy subjects (65 ± 9 years) with no history of stroke or major vascular risk factors were drawn from a group of control subjects involved in another study . In the Upon arrival to the emergency department, each patient underwent baseline brain CT and evaluation by a neurologist. The subjects were placed in a 30-degree recumbent position on a standard hospital bed. They were instrumented for measurement of heart rate and non-invasive beat-to-beat arterial blood pressure monitoring  as previously described . TCD ulti) was calculated as the ratio of MAP to MFV. Heart rate was determined from peak to peak times. All data segments for MAP and MFV were visually inspected and edited for artifact and ectopy, and only steady-state data were used for analysis.All data were displayed and digitized in real time at 500 Hz with commercially available data acquisition software . The beat-to-beat cycles were determined by detecting the peak of each arterial pressure waveform and flow velocity waveform. The MAP and MFV values were determined from the integrals of each waveform using a custom Matlab program to calculate the systolic and diastolic blood flow velocity from peak and minimum TCD values within each beat cycle. Cerebrovascular resistance index  × . Transfer functions were determined by dividing the cross-spectrum by the input autospectrum for each vessel insonated [A power spectrum analysis technique based on the Welch algorithm of averaging periodograms was used. The 5-minute time series were interpolated at 100 Hz to obtain equidistant time intervals. For fast Fourier analysis a Hanning window of 30 seconds was used with two-third overlap and transformed to its frequency representation squared. The periodograms were averaged to produce the spectrum estimate. Coherence between MAP and MFV were calculated from the cross-spectra and autospectra of steady-state data segments as follows: (cross-spectra)nsonated . With a nsonated .2 χtest for categorical data and t-test for normally distributed continuous variables. Within the ICH group, intra-individual differences in MFV, transfer function coherence, gains, and phases between the ipsilateral and contralateral sides were tested using a repeated measures two-way ANOVA using hematoma size as a covariate. Relationships between hematoma size and coherence, gains and phases were tested using Pearson correlation analysis. Data are presented as mean ± SD, and levels of p < 0.05 are considered statistically significant.Data were analyzed using commercially available statistical software . Descriptive statistics were used to describe patient characteristics, clinical data and hematoma sizes. Inter-group differences were tested using 3. None of the subjects required surgical evacuation of the space-occupying hematoma. The ICH group demonstrated lower MCA MFV on both sides and higher CVRi compared to controls  and high frequency range   in the high frequency range . The increased gain seen in the low frequency range in our study supports the concept that slow-responding dynamic cerebral autoregulation is less effective in the ICH patients.2 reactivity and also inversely correlated with the degree of proximal artery stenosis, [Interestingly, gains in the high frequency range (0.15-0.5 Hz), a frequency range that is considered a much faster response (2-7 seconds) than what is generally considered for dynamic cerebral autoregulation, were also greater in the ICH group. Panerai et al. have shown similar results in a group of neonates where those with normal cerebral autoregulation had lower transfer gain in the 0.25-0.43 Hz range (> 0.15 Hz range) compared to those with impaired cerebral autoregulation . Althougtenosis,  and thusOur findings are also consistent with the study by Schramm et al.  which shstatic cerebral autoregulation curve is thought to be shifted to the right in people with untreated hypertension [dynamic cerebral autoregulation has been shown to be preserved with those with controlled or uncontrolled hypertension [Since our measurements were made post ictus and we do not have any pre ICH measures, we can not rule out the possibility that dynamic cerebral autoregulation was already impaired in the ICH group prior to hemorrhage due to underlying vascular risk factors such as hypertension. In fact, the rtension . Howeverrtension . Therefoi between the two groups may have contributed to our observed differences in transfer gains. We speculate that antihypertensive and sedative medications administered to the ICH group as part of standard protocol [i compared to controls, suggesting that the small arteries and arterioles were likely more vasoconstricted in the ICH group. Since many studies suggest more effective cerebral autoregulation with vasoconstriction [i (more vasoconstriction) had higher transfer gains than controls. This further supports the hypothesis that compared to healthy controls, dynamic cerebral autoregulation of the ICH patients is intrinsically more impaired, independent of the effect of vessel caliber.Critical for the interpretation of our data is to understand the extent to which the differences in MFV and CVRprotocol  likely rprotocol ,31. The triction ,32,33; tAnother important factor to note is the potential effect of blood pressure variability on transfer gain. Theoretically, if patients have significantly higher blood pressure variability, it may be more difficult for even intact autoregulation to compensate for this variability. However, our ICH patients had lower blood pressure variability than the control group, and thus the higher gain seen in the ICH patients suggests that even with reduced blood pressure changes, autoregulation was still unable to compensate effectively.To date, there is no intervention that significantly improves clinical outcome after spontaneous ICH. Several clinical trials are currently ongoing to test whether aggressive blood pressure lowering prevents hematoma expansion and improves clinical outcome -36. Howe2 or end-tidal CO2 could have introduced variations in the vasomotor reactivity and cerebral blood flow between patients. Our study was conducted over a range of 72 hours from the ictus, which may have combined the hyperacute and early subacute stages of ICH, which may have differed. Given the dynamic nature of neurocritical care patients who may have fluctuating hemodynamic and autoregulatory status, one cerebral autoregulation measurement from a 5 minute recording may not be sufficient to capture their overall cerebral autoregulatory status.This was an exploratory case-control study to assess the differences in dynamic cerebral autoregulation between patients with acute spontaneous ICH and healthy controls. The lack of a separate control group with similar vascular risk factors is the major limitation of the study since we were unable to directly address whether our observation was due to their underlying chronic vasculopathy or due to acute deterioration as a result of acute ICH. Furthermore, since the patients treated in the intensive care unit may have other unaccounted factors not present in the control group that could affect the results of transfer function analysis, our results should be interpreted with caution. Although we excluded subjects with chronic obstructive lung disease, and none of the patients had oxygenation or ventilation problems during the study, alterations in PaCOIn conclusion, our study indicates that dynamic cerebral autoregulation may be less effective in patients with spontaneous lobar or basal ganglia ICH compared to healthy controls. Our findings also suggest that dynamic cerebral autoregulation may be further impaired in patients with larger hematomas; however, a larger prospective study is needed to confirm this observation.The authors declare that they have no competing interests.KN participated in the conception and design of the study, performed the TCD measurements on the ICH patients, conducted the statistical analyses, and was responsible for drafting and finalizing the manuscript. JMS performed the TCD measurements on the control group, conducted the Matlab analyses of the data, helped in the interpretation of the data, and helped to draft and finalize the manuscript. SLL participated in patient recruitment and coordination of the study, participated in the TCD measurements of the ICH patients, and helped to draft and finalize the manuscript. FAS participated in the conception and design of the study, analyses and interpretation of the data, and helped to draft and finalize the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/108/prepub


To study the influence of a nationwide albuminuria self-test program on the number of GP contacts for urinary complaints and/or kidney diseases and the number of newly diagnosed patients with kidney diseases by the GP.Data were used from the Netherlands Information Network of General Practice (LINH), including a representative sample of general practices with a dynamic population of approximately 300.000 listed patients. Morbidity data were retrieved from electronic medical records, kept in a representative sample of general practices. The incidence of kidney diseases and urinary complaints before and after the albuminuria self-test program was compared with logistic regression analyses.Data were used from 139 general practices, including 444,220 registered patients. The number of GP consultations for kidney diseases and urinary complaints was increased in the year after the albuminuria self-test program and particularly shortly after the start of the program. Compared with the period before the self-test program, more patients have been diagnosed by the GP with symptoms/complaints of kidney disease and urinary diseases (OR = 1.7 (CI 1.4 - 2.0) and OR = 2.1 (CI 1.9 - 2.3), respectively). The odds on an abnormal urine-test in the period after the self-test program was three times higher than the year before (OR = 3.0 (CI 2.4 - 3.6)). The effect of the self-test program on newly diagnosed patients with an abnormal urine test was modified by both the presence of the risk factors hypertension and diabetes mellitus. For this diagnosis the highest OR was found in patients without both conditions (OR = 4.2 (CI 3.3 - 5.4)).A nationwide albuminuria self-test program resulted in an increasing number of newly diagnosed kidney complaints and diseases the year after the program. The highest risks were found in patients without risk factors for kidney diseases. Because of the increasing prevalence rate of lifestyle-related diseases such as cardiovascular diseases and diabetes mellitus -3, but aWith advertisements on the radio, television, newspapers and the Internet, Dutch adults over the age of 18 were invited to order the free albuminuria self-test via the Internet or by telephone in the period September until November 2006. The presence of an increased amount of albumin in the urine is an indicator for worsening kidney function and increases the risk of developing CRF. In case of a positive test result, participants were advised to visit their General Practitioner (GP) for additional examination and treatment . In the In a previous study the usefulness of the albuminuria self-test program was investigated in a population of participants who ordered the self-test ,6. From Given the high awareness of the self-test program, it is likely that the program not only resulted directly in newly detected diseases, but also indirectly led to an increased number of newly detected kidney diseases, since 1) instead of self-testing, patients could have decided to visit their GP for testing the renal function, and 2) GPs could have become more focused on the detection of kidney diseases as a result of the program. In our previous study questionnaires of participants were used and therefore it was not possible to determine the consequences of the self-test program for the GP.Therefore, in this study we have investigated the influence of the screening program on the number of GP contacts for urinary complaints and/or kidney diseases and the number of newly diagnosed patients with kidney diseases by the GP. Accordingly, the following research questions were formulated: 1) Are there differences in the total number of GP contacts for urinary complaints and/or kidney diseases before and after the albuminuria self-test program?, 2) Are there differences in the number of newly diagnosed patients with kidney diseases by the GP before and after the albuminuria self-test program?, and 3) Are there differences in the number of newly diagnosed patients in persons with hypertension and/or diabetes mellitus and patients without these risk factors before and after the albuminuria self-test program?http://www.whocc.no/.Data were used from the Netherlands Information Network of General Practice (LINH). Data were retrieved from electronic medical records, kept in a representative sample of general practices with approximately 300.000 listed patients in 2008 . Data inThe study was carried out according to Dutch legislation on privacy. The privacy regulation of the study was registered at the Dutch Data Protection Authority. According to Dutch legislation, nor obtaining informed consent nor approval by a medical ethics committee was obligatory for observational studies.In this study the number of contacts with the GP for kidney diseases and/or urinary complaints and the number of newly diagnosed patients with kidney diseases were compared between the year before and after the albuminuria self-test program. The period before the program was from 1 September 2005 to 31 August 2006 (Period 1) and the period after the program was from 1 November 2006 to 31 October 2007 (Period 2). The two months in between were not included in the study, because there was a delay between the start of the program at 1 September 2006 and the first GP visits by participants with a positive test result .Data are used from a dynamic population and include all consultations from patients who were registered at a LINH practice at any time during the study period (1 September 2005 to 31 October 2007). We used a dynamic population, because the group of registered patients at a GP practices is not fixed . In case a patient was not registered the whole study period -when a general practice did not deliver data during the whole study period or when patients were registered temporarily-, a 'time at risk' was calculated. Patients who were under the age of 18 at the start of the self-test program (1 September 2006) were excluded, because the self-test was meant to be used by adults.Per selected patient we determined if they were diagnosed in a period of three years before the first study year with one of the following kidney diseases/urinary complaints: U07 , U14 (Kidney symptom/complaint), U27 (Fear of urinary disease), U29 , U98  and U99 ). Furthermore the presence of risk factors for chronic kidney disease, i.e. diabetes mellitus (ICPC code T90), hypertension (ICPC code K86 and/or K87), at the start of the study period was determined.Three different statistical analyses were performed. First, a descriptive analysis was performed to determine the course of the number of consultations per week with the GP for kidney diseases and urinary complaints  over the whole study period. The number of consultations was divided by the total number of contacts in that week to correct for seasonal fluctuations in the number of GP contacts. To adjust for outliers, a 4-week moving average was calculated and plotted.Second, per kidney disease/urinary complaint the absolute number of newly diagnosed patients was determined for the period before and after the self-test program. In addition, the absolute number of cases and the total 'time at risk' of all patients in the specified periods were used to calculate person-time incidence rates (IR) per 10,000 person years. The IR of both periods were used to calculate incidence rate ratio's (IRR) with 95% confidence intervals. IRs and IRRs were calculated for the total study population and stratified by age , presence of hypertension and presence of diabetes mellitus, which are all risk factors for chronics kidney diseases.Third, per kidney disease/urinary complaint the number of newly diagnosed patients by the GP in the period before the self-test program were compared with the number of newly diagnosed patients in the period after the self-test program with logistic regression analyses. The models were adjusted for age and gender and the presence of hypertension and diabetes mellitus. Odds ratios (ORs) are reported with 95% confidence intervals. In addition, it was tested if the presence of these risk factors for kidney diseases modified the effect of the self-test program on the number of newly detected kidney diseases by adding interaction terms to the model. If the interaction was statistically significant , ORs were presented for subgroups. All statistical analyses were performed with Stata 11.Data from 81 out of the 85 (95.3%) participating LINH practices in 2005 could be used for statistical analyses. Four practices had to be excluded because of missing data. In 2006 and 2007, 58 new general practices were included in LINH. In total, data were used from 139 general practices, including 444,220 registered patients. Of these patients, 227,393 were female (51%) and the largest age group was 36-45 years old , U14 (Kidney symptom/complaint), U98  and U99 ) with the highest OR for an abnormal urine test (OR = 3.0 (CI 2.4 - 3.6)). The effect of the self-test program on newly diagnosed patients with an abnormal urine test (ICPC code U98) was modified by both the presence of hypertension and diabetes mellitus. For this diagnosis, the highest OR was found for patients without both conditions (OR = 4.2 (CI 3.3 - 5.4)). Furthermore, for the diagnosis 'Urinary disease' (ICPC code U99), the odds of being newly diagnosed was higher in patients without diabetes mellitus (OR = 2.3 (CI 2.0-2.6) versus OR 1.4 (CI 1.1-1.9) in patients with diabetes).The number of GP consultations for kidney diseases and urinary complaints increased in the year after the albuminuria self-test program and particularly shortly after the start of the program. Compared with the year before the self-test program, 1.7 times more patients have been diagnosed by the GP with symptoms/complaints of kidney disease and 2.1 times more patients with urinary diseases. The odds of an abnormal urine-test in the period after the self-test program was 3.0 times higher than the year before. The effect of the self-test program on newly diagnosed patients with an abnormal urine test was modified by both the presence of the risk factors hypertension and diabetes mellitus. For this diagnosis the highest OR was found in patients without both conditions (OR = 4.2).In a previous study, the effects on participants of the albuminuria self-test program were evaluated using a questionnaire eight weeks after the start of the self-test program ,6. TherePrevious studies have shown positive effects of mass media campaigns on the effectiveness of screening. Awareness of a mass media campaign is not only associated with higher awareness of symptoms of a disease, but also increases the screening rate -12. Two In this study we estimated the impact of a nationwide self-test program on the number of newly diagnosed patients with kidney diseases in general practice. Although we used data from a large representative network of GPs, this study has also a few limitations. For instance, we could not correct for all potential confounding factors in the statistical analyses. Socio-economic status, ethnic background, blood glucose levels, high-density lipoprotein (HDL) levels and cigarette smoking are not recorded by GPs in a systematic way and therefore could not be used in this study ,14. FurtWe found that the risk of being newly diagnosed by the GP with kidney diseases and/or urinary complaints one year after a nationwide albuminuria self test program was higher, especially for patients without risk factors for kidney diseases (diabetes mellitus and hypertension). The latter could be a result of periodic screening on kidney diseases of patients with diabetes and hypertension by the GP. According to the guidelines of the Dutch College of General Practitioners, patients with hypertension and diabetes should be monitored every year by the GP -17.It can be concluded that a nationwide albuminuria self-test program resulted in an increasing number of newly diagnosed kidney complaints and diseases the year after the program. The highest numbers were found in patients without risk factors for kidney diseases.The authors declare that they have no competing interests.JDB and MMJN performed the study according to protocol, analyzed the data and wrote the manuscript. RAV and FGS initiated and supervised the study and developed the study protocol. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/12/81/prepub


Aim. To determine whether there is a significant correlation between the optic nerve head (ONH) circulation determined by laser speckle flowgraphy (LSFG) and kidney function. Materials. Seventy-one subjects were investigated. The estimated glomerular filtration rate (GFR) and serum creatinine, cystatin C, and urinary albumin excretion were measured. The ONH circulation was determined by an analysis of the pulse wave of LSFG, and this parameter was named blowout time (BOT). Chronic kidney disease (CKD) was defined to be present when the estimated GFR was <60 mL/min per 1.73 m2. Pearson's correlation coefficients were used to determine the relationship between the BOT and the kidney function. We also examined whether there were significant differences in all parameters in patients with and without CKD. Results. BOT was significantly correlated with the level of creatinine , the estimated GFR , cystatin C , and urinary albumin excretion . The BOT level in subjects with CKD was significantly lower than that in subjects without CKD (P = 0.002). Conclusion. BOT in ONH by LSFG can detect the organ damage such as kidney dysfunction, CKD. More 2 . This reOther factors reflecting kidney function are the levels of serum cystatin C and urinary albumin excretion. Evaluations of serum cystatin C and serum creatinine were reported to predict cardiovascular events in elderly persons without chronic kidney disease . In addiLaser speckle flowgraphy  is a method of determining ocular blood flow and is based on the changes in the speckle pattern of laser light reflected from the fundus of the eye , 9. LSFGThe purpose of this study was to determine whether there is a significant correlation between the optic nerve head circulation determined by LSFG and the estimated GFR, serum creatinine, serum cystatin C, and urinary albumin excretion. In addition, we examined whether there are significant differences in the optic nerve head circulation in patients with and without CKD.One hundred and thirty-six consecutive subjects who visited the Vascular Function Section of the Department of Cardiovascular Center of Toho University Sakura Medical Center between April 1, 2007, and October 1, 2010, were studied. The exclusion criteria were subjects who had diabetes mellitus, history of cardiovascular disease and heart failure, presence of cerebrovascular disease, arrhythmias , history of ophthalmic surgery, cataract which affects the corrected visual acuity, glaucoma, and vitreous and retinal diseases. Subjects who had systemic hypertension were included. In the end, 71 patients whose mean ± standard deviation (SD) age was 62.3 ± 10.5 years with a range from 39 to 86 years met the study criteria. There were 48 men and 23 women. And all subjects had a corrected visual acuity exceeding 20/20.The Institutional Review Board of Toho University Sakura Medical Center approved the protocol of this study, and we began the research after all subjects received information on the purpose and possible side effects of the research protocol and signed an informed consent form. The procedures used conformed to the tenets of the Declaration of Helsinki.The LSFG was measured after the patients rested for 10 minutes in a quiet and air-conditioned room maintained at 24°C. Measurements were made between 15:00 to 17:00 hours before a meal. All subjects abstained from alcohol, smoking, and caffeine for at least 12 hour prior to the measurements.2) = 194 × SCr−1.094 × age−0.287  [2 [Kidney function was assessed by determining the level of serum cystatin C and creatinine. The creatinine-based modified diet of renal disease of the estimated GFR was calculated using the equation for Japanese subjects recommended by the Japanese Society of Nephrology: estimated GFR  , 12, andmale) [2 . The uri2). The mean arterial blood pressure  was determined by the formula; MAP = DBP + (SBP-DBP)/3.The following systemic parameters were measured: age, systolic blood pressure , diastolic blood pressure , pulse pressure (mmHg), heart rate , and body mass index , and we measured the BOT of the optic nerve head area three times and used the average for the statistical analyses. All subjects were measured in seated position and pupils were dilated with 0.5% tropicamide eye drops. And only the data from the right eye were used for the analysis.The following ocular parameters were also studied: the intraocular pressure (IOP mmHg) measured by applanation tonometry and ocular perfusion pressure (OPP mmHg) which was defined as OPP = (2/3MAP) − IOP.t-test, and Mann-Whitney U test. A P value <0.05 was considered to be statistically significant. The Stat View version 5.0 program  was used for the statistical analyses.Data are presented as the means ± standard deviations (SDs) for the continuous variables. Pearson's correlation coefficients were used to determine the relationship between the BOT, kidney function, and other systemic and ocular parameters. In addition, we examined whether there were significantly differences in all parameters in patients with and without CKD. Statistical analyses were conducted using the Yates 2 × 2 chi-square test, unpaired The results of the systemic and ocular measurements are shown in r = −0.53, t  value = −5.13, P < 0.0001), SBP , pulse pressure , and heart rate . The IOP and OPP were not significantly correlated with BOT. All of the kidney function parameters were significantly correlated with BOT: creatinine, r = −0.24, t  value = −2.06, P = 0.04; estimated GFR, r = 0.42, t  value = 3.79, P = 0.0003; cystatin C, r = −0.29, t  value = −2.55, P = 0.01; and urinary albumin excretion, r = −0.29, t  value = −2.52, P = 0.01. The relationship between BOT and creatinine is shown in P < 0.0001) and incidence of hypertension , creatinine , and cystatin C  were significantly higher in the CKD cases than in the without CKD cases. There was no significant difference in urinary albumin excretion. The BOT in the subjects with CKD cases was significantly lower than that in subjects without CKD cases .The findings of kidney function are given in The increased risk of cardiovascular disease in patients with CKD is probably related to increased arterial stiffness measured by the pulse-wave velocity –21. In aIn an earlier study, we found that the BOT in the optic nerve head by LSFG was significantly correlated with age, bronchial pulse-wave velocity, intima-media thickness, and left ventricular diastolic function , 15. TheNagaoka and Yoshida reported relationship between retinal blood flow, using Laser Doppler Velocimetry System, and chronic kidney disease in patients with type 2 diabetes mellitus ; howeverP = 0.002). These findings indicate that BOT in the optic nerve head by LSFG may detect organ damage such as CKD. However, it is unknown whether kidney function affects ocular circulation directly or is a surrogate marker of kidney function. Thus, a more detailed investigation is needed. In current study, the region of measurement was set for the entire optic nerve head area. This area was selected because it had the highest correlation with all of kidney function in preliminary investigations than the other regions.Our results showed that all of the kidney function parameters were significantly correlated with BOT, and the estimated GFR had the highest correlation with BOT. From the above results, it was suggested that BOT in the optic nerve head by LSFG can detect early kidney dysfunction. In addition, estimated GFR may be reflecting the ocular circulation more sensitive than other kidney function parameters. It was reported that, in the study population, the prevalence rate of low GFR and CKD increased with age . And theBOT was also significantly correlated with age, SBP, pulse pressure, and heart rate but not with the IOP and OPP. It should be noted that these factors affect the results of BOT.There are limitations to this study. First, this study was cross-sectional with a small number of subjects. It will be necessary to conduct a prospective study with a larger number of subjects with and without kidney dysfunction. Second, in this study, patients who already developed coronary artery disease or heart failure were excluded, in order to standardize patient background. Thus, further studies will be needed to investigate the association between BOT and serious arteriosclerosis-related diseases such as cardiovascular diseases in comparison with parameters of kidney function.In conclusion, our results confirmed that measurements of BOT in the optic nerve head by LSFG can be a useful method to not only large vascular function, but also age-related organ damage such as CKD. In addition, ocular circulation by LSFG method may reflect the early stage of kidney dysfunction without severe atherosclerotic disease such as cardiovascular events.


The social and economic burdens of dialysis are growing worldwide as the number of patients increases. Dialysis is becoming a heavy burden even in developed countries. Thus, preventing end-stage kidney disease is of the utmost importance. Early detection and treatment is recommended because late referral is common, with most chronic kidney disease (CKD) patients remaining asymptomatic until a late stage. Three-quarters of dialysis patients initiated dialysis therapy within 1 year after referral to the facility. Since its introduction in 2002, the definition of CKD has been widely accepted not only by nephrologists but also by other medical specialties, such as cardiologists and general practitioners. Japan has a long history of general screening for school children, university students, and employees of companies and government offices, with everybody asked to participate. The urine test for proteinuria and hematuria is popular among Japanese people; however, the outcomes have not been well studied. We examined the effects of clinical and laboratory data from several sources on survival of dialysis patients and also predictors of developing dialysis from community-based screening . At an early CKD stage, patients are usually asymptomatic; therefore, regular health checks using a urine dipstick and serum creatinine are recommended. The intervals for follow-up, however, are debatable due to the cost. CKD is a strong risk factor for developing cardiovascular disease and death and also plays an important role in infection and malignancies, particularly in elderly people. People can live longer with healthy kidneys. Although kidney disease patients can survive without kidney function, dialysis is a life-saving procedure. However, many complications related to chronic kidney disease (CKD) have not been resolved, including cardiovascular disease (CVD), mineral and bone disorders (CKD-MBD), and infection . NephrolCKD is clinically defined by the presence of albuminuria and/or a decrease in kidney function for >3 months. Since its introduction in 2002, the definition of CKD has been widely accepted not only by nephrologists but also other medical specialties, such as cardiologists and general practitioners. Japan has a long history of universal screening for school children, university students, and employees of companies and government offices. The urine test for proteinuria and hematuria is popular among Japanese people; however, the outcomes have not been well studied.Chronic dialysis therapy was started in Okinawa in 1971, several years after it was initiated in other parts of Japan –5. The nWe examined the effects of clinical and laboratory data from several sources on survival –18. Amonn = 235) or a treatment other than an angiotensin receptor blocker or angiotensin-converting enzyme inhibitor (n = 234). Lowering blood pressure with an angiotensin receptor blocker did not significantly lower the risk of major cardiovascular events or death among patients with hypertension on chronic HD . Al. Al28]. Only a few studies outside Japan have examined the effect of microhematuria on developing ESKD. Microhematuria is relatively common, particular in elderly women. Compared to proteinuria, the risk of microhematuria was significant, but showed a weak dose–response relationship. The absolute risk of microhematuria was low but was a statistically significant predictor of ESKD . NotablyThe JSDT has been conducting a nationwide survey on chronic dialysis therapy and reporting annually as ‘an overview of regular dialysis treatment in Japan’. According to the 2011 report, the total number of dialysis patients was 304,592 , and the leading cause of ESKD was diabetes (44.2 %)  is becoming higher than ever before –47. The 2 , 49. The2 is considered to be normal for someone who is otherwise healthy. Albuminuria can only be measured and reimbursed for patients with early-stage diabetic kidney disease in Japan. Instead, the JSN advocates using dipstick proteinuria or measuring the daily amount of proteinuria.The JSN has published the ‘Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney Disease’ in 2007, 2009, and 2012 . The “EvThe JSN has been supporting the research project ‘Frontier of Renal Outcome Modifications in Japan’ (FROM-J) . To prevSince 2008, the special health check system  has been used to detect subjects with metabolic syndrome and direct them towards a healthy lifestyle. The target population is the 40–74 year age group. The new ‘Kidney Disease: Global Outcomes Improving Outcomes’ (KDIGO) CKD classification prevalence of hypertension was clearly dependent on eGFR and proteinuria Fig.  53]. Si. Si53]. Since the introduction of the concept of CKD, the definition has been challenged with several criticisms: (1) the classification was too simple, (2) lack of key outcomes of CKD, and (3) significance of testing eGFR and albuminuria. In this setting, the KDIGO-Controversies Conference was held from October 4–6, 2009 in London . We offeTo further examine the significance of the classification, the KDIGO CKD prognosis consortium (PC) was organized. We are privileged that the Okinawa 1983/1993 cohorts were involved in the KDIGO-PC. The phase 2 analyses have already been completed for seven major topics, such as hypertension, diabetes, gender, ethnicity, age, CKD epidemiology collaboration, and cystatin C –64. The CKD is common but treatable if detected early and properly managed. At an early CKD stage, patients are usually asymptomatic; therefore, regular health checks using a urine dipstick and serum creatinine are recommended. The intervals for follow-up, however, are debatable due to the cost. In this regard, subjects with hypertension, diabetes, anemia, and/or metabolic syndrome have the highest risk of CKD Fig. . Other fCKD patients are at risk of developing acute kidney injury due to contrast media, nephrotoxic drugs, surgery, and dehydration. CKD is a strong risk factor for developing CVD and death and also plays an important role in infection and malignancies, particularly in elderly people. People can live longer with healthy kidneys.Japan is a front runner in ‘the new society’ of a world where the elderly population (≥65 years) is the most prevalent, reaching 30 % in 2020 . Moreove


Background: Combination therapy with antihypertensive agents utilises different mechanisms of action and may be responsible for a more effective decrease in blood pressure. Objective: To review the recently published trials on efficacy and safety of the combination therapy with olmesartan and amlodipine.  Results: The double-blind American COACH (Combination of Olmesartan Medoxomil and Amlopdine Besylate in Controlling High Blood Pressure) study (2008) showed in 1,940 patients that after eight weeks of treatment the BP goals were most frequently achieved in the ‘combination therapy group’, with 56.3% (54.1–58.5%) and 54.0% (51.8–56.2%) of patients reaching adequate blood pressure of <140/90 mmHg with olmesartan/amlodipine 20/10 and 40/10 respectively. Combination therapy was generally well tolerated. The most common side effect was oedema . The frequency of oedema was lower in the groups combining amlodipine 10 mg with olmesartan 10 mg , 20 mg  or 40 mg . In 2009 three double-blind controlled European studies including 500–1,000 patients each and performed independently of one another have confirmed the above study, and have demonstrated similar efficacy-safety effects from the combination of olmesartan medoxomil with amlodipine, particularly for patients not achieving adequate blood pressure control with olmesartan monotherapy. Conclusions: Combinations of olmesartan and amlodipine were significantly more effective at reducing blood pressure and realising guideline blood pressure goals in patients with mild to severe hypertension than monotherapy (with a placebo component). Combination therapy is well tolerated and is associated with a lower incidence of side effects, such as oedema, compared to monotherapy with high amlodipine dosages (10 mg).  According to the most recent data from the National Health and Nutrition Examination Survey, the prevalence of (age adjusted) hypertension in the American population, estimated from 14,653 individuals, is 29.3% (28.6–30.0%)  and is increasing . The. The3]. A meta-analysis of 61 prospective, observational studies of over one million patients in total showed that there was a 7% 6.95–7.05%) risk reduction in cardiovascular mortality for every 2 mmHg decrease in systolic blood pressure (SBP) and even a 10% 9.94–10.06%) reduction in the risk of death from cerebro-vascular accidents  3,4]. I,4. I3,4]–10.06% r–7.05% riOne of the most significant reasons for poor control is insufficient medical treatment to intensify antihypertensive therapy in patients unable to attain the blood pressure goals . Extra aVarious extensive studies have demonstrated that it is certainly possible to achieve blood pressure goals in patients with hypertension. However, the great majority will eventually require two or more antihypertensive agents to achieve this . Both thCombination therapy with antihypertensive agents utilises different mechanisms of action and may be responsible for a more effective decrease in blood pressure . One of The treatment of hypertension increasingly involves a combination of an ARB and a dihydropyridine calcium antagonist, and, in the past few years, fixed drug combinations have been used in a dose that is below the dose normally prescribed when each drug is used on its own . The com®) against monotherapy in patients with mild to severe hypertension [The purpose of the COACH study (Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure) was to investigate the effectiveness and the safety profile of combinations of olmesartan and amlodipine (Sevikarrtension . The stu54.3% (52.1–56.5%) of the 1,940 randomised patients were male. The average age was 54 years and 19.8% were over 65 years of age. The average blood pressure at the start of the study was 164/102 mmHg, and 79.3% of patients had stage 2 hypertension. The combination therapy with olmesartan/amlodipine produced decreases in diastolic blood pressure (from –14.0 mmHg with olmesartan/amlodipine 20/5 mg to –19.0 mmHg with olmesartan/amlodipine 40/10 mg) and in systolic blood pressure  and 54.0% (51.8–56.2%) of patients reaching adequate blood pressure of <140/90 mmHg with olmesartan/amlodipine 20/10 and 40/10 respectively. Combination therapy was generally well tolerated. The most common side effect was oedema (olmesartan 20 mg 9.9% (8.6–11.3%), amlodipine 10 mg 36.8% (34.7–39.0%), placebo 12.3% (10.9–13.8%)). The frequency of oedema was lower in the groups combining amlodipine 10 mg with olmesartan 10 mg , 20 mg  or 40 mg .These findings of dose-dependent effectiveness with a combination of olmesartan and amlodipine are consistent with the results both from comparable studies of other fixed-dose combinations and from other studies specifically investigating a combination with a different ARB: valsartan with amlodipine .There are a number of fixed-dose antihypertensive combinations, such as ARBs combined with a diuretic agent (hydrochlorothiazide) and ACE inhibitors combined with a diuretic or a calcium antagonist. The treatment that underlies these combinations is consistent with the JNC 7 recommendation, which stipulates that combinations should comprise of antihypertensive constituents that work through different mechanisms of action in order to achieve maximum therapeutic effect . Both thFixed-dose combinations could be regarded as more patient friendly than taking two medicinal products separately. A recent meta-analysis demonstrated that compliance with fixed-dose antihypertensive combinations was significantly better than compliance with two separate medicinal products . actively investigates the development and the severity of oedema [When a higher dose of amlodipine was combined with increasing dosages of olmesartan, the lower incidence of oedema in the COACH study was consistent with other studies, where the use of a RAAS blocker combined with amlodipine reduced the probability of amlodipine-induced oedema ,15,16,17f oedema . Consequet al. reported 19% (16.3–21.6%) peripheral oedema while using amlodipine 5 or 10 mg in a study with a specific questionnaire actively asking after these symptoms [One study of valsartan and amlodipine, which followed a passive recording system , showed that 8.7% (2.1–26.5%) of patients developed oedema while using amlodipine monotherapy and 3.0% 0–17.2%) while using placebo .2% while. In contsymptoms . Another study (the CASTLE study), which followed a proactive monitoring system, even showed that 22.1% (16.8–27.0%) of patients who received amlodipine 5 or 10 mg had oedema . In the In the last year three double blind controlled European studies including 500–1,000 patients each and performed independently of one another have confirmed the above studies, and have demonstrated similar efficacy-safety effects from the combination of olmesartan medoxomil with amlodipine, particularly for patients not achieving adequate blood pressure control with olmesartan monotherapy ,22,23. WIn conclusion, combinations of olmesartan and amlodipine were significantly more effective at reducing blood pressure and realising guideline blood pressure goals in patients with mild to severe hypertension than monotherapy (with a placebo component). Combination therapy is well tolerated and is associated with a lower incidence of side effects, such as oedema, compared to monotherapy with high amlodipine dosages (10 mg).


Background. The purpose of this study was to answer the question whether a single testing for microalbuminuria results in a reliable conclusion leading costs saving. Methods. This current cross-sectional study included a total of 126 consecutive persons. Microalbuminuria was assessed by collection of two fasting random urine specimens on arrival to the clinic as well as one week later in the morning. Results. In overall, 17 out of 126 participants suffered from microalbuminuria that, among them, 12 subjects were also diagnosed as microalbuminuria once assessing this factor with a sensitivity of 70.6%, a specificity of 100%, a PPV of 100%, a NPV of 95.6%, and an accuracy of 96.0%. The measured sensitivity, specificity, PVV, NPV, and accuracy in hypertensive patients were 73.3%, 100%, 100%, 94.8%, and 95.5%, respectively. Also, these rates in nonhypertensive groups were 50.0%, 100%, 100%, 97.3%, and 97.4%, respectively. According to the ROC curve analysis, a single measurement of UACR had a high value for discriminating defected from normal renal function state (c = 0.989). Urinary albumin concentration in a single measurement had also high discriminative value for diagnosis of damaged kidney (c = 0.995). Conclusion. The single testing of both UACR and urine albumin level rather frequent testing leads to high diagnostic sensitivity, specificity, and accuracy as well as high predictive values in total population and also in hypertensive subgroups. Chronic kidney disease imposes a large financial burden on patients and society. Early diagnosis and treatment of these disorders can slow progression to end-stage renal disease leading to lowering mortality and morbidity as well as reducing the overall costs . TherefoP values of 0.05 or less were considered statistically significant.The current cross-sectional survey was a part of a large comprehensive population-based cohort named “the Isfahan Healthy Heart Program” (IHHP) with the aim to identify subjects at risk for cardiovascular diseases, to control of cardiovascular risk profile, and to modify lifestyle . In thisn = 88) were 73.3%, 100%, 100%, 94.8%, and 95.5%, respectively. Also, these rates in nonhypertensive groups were 50.0%, 100%, 100%, 97.3%, and 97.4%, respectively. According to the ROC curve analysis . Urinary albumin concentration in a once measurement had also high discriminative value for diagnosis of damaged kidney , while measurement of urine creatinine level had no acceptable value for discriminating damaged kidney function from normal function state .In overall and based on the diagnosis of microalbuminuria as UACR from 30 to 300 mg/g in two consecutive portions, 17 out of 126 participants suffered from microalbuminuria that, among them, 12 subjects were also diagnosed as microalbuminuria once assessing this factor with a sensitivity of 70.6%, a specificity of 100%, a PPV of 100%, a NPV of 95.6%, and an accuracy of 96.0% . The meaanalysis , once meSeveral studies have demonstrated cost-effectiveness of microalbuminuria screening in high-risk populations leading optimization of patients' care as well as future implementation of CKD screening programs , 9, 13. In our study, the diagnostic accuracy of the first-morning test for microalbuminuria was cost-benefcial for hypertensive patients as well as the total population. In fact, this once test can be beneficially used to screen microalbuminuria in both hypertensive and normotensive patients with the minimum cost. It has been previously shown that screening recommendations can be extended to include persons with hypertensive or diabetic patients , 13. ThiBesides assessing the diagnostic accuracy of the one testing UACR for detection of microalbuminuria, we test diagnostic performance of one estimating urine albumin level and also urine creatinine level for assessment of kidney damage. According to the obtained discriminative values, the value of UACR and urine albumin level determination was equal, but measurement of urine creatinine level alone was notably low for this aim. Urine albumin is the key marker for chronic kidney disease. However, it is useful to compare the amount of albumin in the sample against its concentration of creatinine. The UACR has been shown to be convenient, cost-effective, and efficient in screening patients for microalbuminuria when compared with 24-hour collections , 15. It The main limitation of the study was considering a partially small sample size leading to difficulties in high-power estimation of diagnostic accuracy  as well as diagnostic power measured by the ROC analysis. In another portion, considering other baseline variables especially socioeconomic level can help to explain more the affordability of the single testing. In addition, by considering different levels and severity of hypertension, assessment of affordability according to hypertension state can be achieved with more precision.In conclusion, our results showed that the detection of both urinary albumin concentration and also estimation of UACR in single urine sample is accurate and cost-benefit procedure to identify microalbuminuric subjects regardless of hypertension state.


P < 0.05), enhanced cardiovascular reactivity to norepinephrine (P < 0.05) and increased cytosolic calcium in platelets (P < 0.05) than controls. Pre-hypertensive patients with normocalcaemic PHPT had intermediate values of increased cardiovascular reactivity and cytosolic calcium. Normotensive patients with hypercalcaemic PHPT and normotensive controls had comparable pressor hormone concentrations and intracellular calcium levels. Successful parathyroidectomy was associated with normal blood pressure values and normalisation of pressor hormone concentrations, cardiovascular pressor reactivity and cytosolic free calcium. Our results suggest that parathyroid hypertension is mediated/maintained, at least in part, by functional alterations of vascular smooth muscle cells and can be cured by parathyroidectomy in those patients who do not have primary hypertension.Primary hyperparathyroidism (PHPT) may be associated with arterial hypertension. The underlying mechanisms are not fully understood and reversibility by parathyroid surgery is controversial. This study aimed to characterize pressor hormones, vascular reactivity to norepinephrine, and cytosolic-free calcium in platelets in 15 hypertensive patients with hypercalcaemic PHPT before and after successful parathyroidectomy and to compare them with 5 pre-hypertensive patients with normocalcaemic PHPT, 8 normotensive patients with hypercalcaemic PHPT and 15 normal controls. Hypertensive patients with hypercalcaemic PHPT had slightly higher levels of pressor hormones ( Sporadic primary hyperparathyroidism (PHPT) is an endocrine disorder usually characterized by persistent fasting hypercalcaemia attributable to autonomous overproduction of parathyroid hormone (PTH) by parathyroid adenoma or hyperplasia . However, a proportion of patients with PHPT (20%) show normal total and ionized serum calcium levels in the presence of persistently elevated PTH concentrations –3. InitiPHPT is associated with increased risk of arterial hypertension. Recent investigations have reported high blood pressure in 40 to 65% of patients with PHPT . DespiteAt present the mechanisms underlying parathyroid hypertension are not clear. Systemic hypertension accompanying hypercalcaemic PHPT is haemodynamically characterized by increased total peripheral vascular resistance , 13. ProRegardless of the precise nature of the operating factors, abnormal calcium metabolism at the level of the vascular smooth muscle cells may be the final common pathway for functional alterations of vascular tone and vascular reactivity and finally for increased total peripheral vascular resistance.The aim of this study was to evaluate circulating levels of vasopressor hormones, cytosolic calcium in platelets and cardiovascular pressor response to norepinephrine in patients with different forms of PHPT and to characterize the changes in blood pressure and in proposed causes of blood pressure dysregulation in patients with hypercalcaemic PHPT and hypertension before and after parathyroidectomy. Three groups of patients and one group of healthy subjects were included in the study. Group 1 were fifteen patients with hypercalcaemic PHPT and untreated chronic arterial hypertension (RR ≥ 140/90 mm Hg). Group 2 included 8 patients with hypercalcaemic PHPT and normotension (blood pressure less than 120/80 mm Hg). Group 3 included 5 patients with normocalcaemic PHPT and untreated prehypertension (RR 120–139 mm Hg/80–89 mm Hg), and Group 4 consisted of 15 healthy normotensive subjects . Patients with PHPT were accepted only if they had no family history of primary hypertension or known long-standing personal history of primary hypertension. The known duration of arterial hypertension was short in all patients (less than 6 months). Antihypertensive drugs were discontinued at least 4 weeks before the study. None of the participants of the investigation had taken any medication interfering with platelet function or production for at least 3 weeks. Informed written consent was obtained from all study participants, and the study protocol was approved by the local ethics committee . The three patient groups and the normal subjects did not differ in mean age, in the predominance of female participants, and had similar renal function. The two patient groups (Group 1 and 2) with hypercalcaemic PHPT did not differ in mean serum total calcium concentrations, mean serum phosphate concentrations, and mean iPTH levels. Compared to these two hypercalcaemic PHPT patient groups, the normocalcaemic patients from Group 3 had significantly lower PTH levels. The prevalence of left ventricular hypertrophy (LVH) was high in all patients affected by PHPT . Neither the prevalence of LVH nor its severity showed a correlation with high blood pressure. Hypercalcaemic PHPT was defined by persistent supranormal total serum calcium levels (more than 2.6 mmol/L) and supranormal ionized calcium (more than 1.35 mmol/L) together with supranormal serum intact PTH (iPTH) level (more than 55 ng/L). Normocalcaemic PHPT was defined by the repeated demonstrations of consistently normal serum total and ionized calcium levels with persistently abnormal serum iPTH. The diagnosis of normocalcaemic PHPT was made when vitamin-D deficiency by measurements of 25-hydroxy vitamin D3 (less than 20 ng/mL) was excluded. None of these patients had any family history of hypercalcaemia; they all had normal or high urinary calcium excretion to an extent excluding familial hypocalcuric hypercalcaemia. None of the patients with normo- or hypercalcaemic PHPT had reduced glomerular filtration (estimated by creatinine clearance) or was taking thiazides, lithium or other drugs known to affect calcium metabolism. Chronic arterial hypertension was defined by constant blood pressure values above 140/90 mm Hg documented on repeated readings at clinical visits or at home. Normotension was defined as blood pressure values below 120/80 mm Hg. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure, defined prehypertension as a predisease state with systolic blood pressures ranging from 120 to 139 mm Hg and diastolic blood pressures from 80 to 89 mm Hg . The claIn contrast to primary  hypertension, secondary hypertension was defined as high blood pressure which is caused by an identifiable underlying cause . Secondary forms of high blood pressure other than parathyroid hypertension were excluded by clinical examination and established tests including estimation of renal function, urinalysis, renal ultrasound, Duplex and Doppler ultrasound, determinations of haematocrit, serum electrolytes and fasting blood glucose, hormonal analysis of thyroid, and if appropriate of adrenal function and chest radiograph. Echocardiography was performed using two-dimensional guided M-mode echocardiography according to the recommendations of the American Society of Echocardiography . Left veBlood pressure recordings were performed using a standard cuff and sphygmomanometer, and blood samples were taken through an intravenous cannula for the determination of serum total calcium and inorganic phosphate , iPTH , plasma renin activityand plasma aldosterone (by radioimmunoassay), and plasma norepinephrine (by radioenzymatic method). Intracellular free calcium concentrations in platelets were measured by Quin-2AM .The cardiovascular pressor reactivity to intravenously infused norepinephrine (1-norepinephrine tartrate in 5% glucose) was determined while the participants were in the supine position as described previously . The ratThe cardiovascular pressor response to norepinephrine was studied in hypercalcaemic PHPT patients with hypertension prior to surgery and 3 months after surgical correction of PHPT. Normocalcaemic Patients with PHPT and normotensive controls were studied once. Study Group 1 was tested twice, that is, prior to surgery and after 3 months after surgery; Groups 3 and 4 were studied once, and Group 2 was not available for study.Hypercalcaemic PHPT with normotension were not available for this part of the investigations. U test. The Student paired test was used for comparison of the pre- and postoperative values in the hypertensive hypercalcaemic PHPT patients. Correlations were calculated by the Spearman rank method. P values less than 0.05 were regarded as significant. All statistical calculations were done with the SPSS version 10 . Results are given as means ± SD. Natural logarithmic transformation of plasma renin activity, plasma aldosterone, plasma norepinephrine and pressor dose was done, and comparisons between groups were performed using the Mann-Whitney Blood pressure, pressor hormones, cardiovascular norepinephrine reactivity, and cytosolic calcium in platelets in the study groups are given in Systolic, diastolic, and mean blood pressure levels in hypercalcaemic PHPT patients with hypertension (Group 1) were significantly higher than in hypercalcaemic PHPT patients with normotension (Group 2) or in healthy subjects (Group 4). Prehypertensive patients with normocalcaemic PHPT (Group 3) had intermediate values. Patients from Group 1 had significantly higher mean plasma renin activity, plasma aldosterone, and norepinephrine levels than matched healthy subjects from Group 4. There were no significant differences between healthy subjects and patients from Group 2 and 3. None of these pressor hormones correlated positively either with blood pressure or PTH levels. The pressor doses of norepinephrine were tested in Group 1, 3, and 4. They were significantly lower in Group 1  and in Group 3  by comparison with healthy subjects from Group 4. r = 0.9, P < .01).There were significant differences in mean platelet calcium concentrations between Group 1 and Group 3, respectively, compared to patients from Group 2 and Group 4. A close correlation between platelet cytosolic calcium levels and mean blood pressure was apparent when all 43 participants were included  parathyroid hypertension can be cured by normalization of the hyperactive parathyroid metabolism in patients who do not have primary hypertension.The pathophysiology of hyperparathyroid hypertension is still an area of research, but at least three theories have been proposed to explain increased total peripheral resistance , 13. FirSecondly, one major finding of our present study is the demonstration of a significantly enhanced pressor response of the cardiovascular system to norepinephrine, although circulating plasma norepinephrine levels were slightly increased or normal in all patients with PHPT. These data are in line with other observations , 15, 26 The concentration of intracellular calcium in platelets has been found to be elevated in primary and various forms of secondary hypertension , 27–32. If the results obtained in platelets are indeed representative for vascular smooth muscle cells, functional alterations characterized by an abnormal calcium metabolism at the level of vascular smooth muscle cells may be the final common pathway for the enhanced vascular reactivity to pressor hormones and the increased vascular tone and finally for increased peripheral vascular resistance. Thirdly, structural changes in the vessels may maintain high blood pressure in PHPT, but such changes may occur as a result of either longstanding hypertension, hypercalcaemia, or metabolic abnormalities associated with PHPT , or a combination of these. Structural changes can lead to impaired vasoreactivity in patients with PHPT which is not improved by successful parathyroidectomy . RodriguThe factors underlying the disturbances in cellular calcium metabolism found in hypertension due to PHPT are not well defined. There are objections against the hypothesis that hypercalcaemia per se or PTH causes enhanced cellular influx of calcium and raised cytosolic calcium. In fact, hypercalcaemic PHPT may be associated often with normotension, questioning the role of excess calcium or increased PTH. Moreover, preincubation of platelets of normotensive patients with exogenous iPTH in vitro had no effect on baseline cytosolic calcium , 28, 35.Left ventricular hypertrophy is a common finding in patients with PHPT although this finding may be related primarily to excess parathyroid hormone secretion and not to hypertension. Previous studies have shown that successful parathyroidectomy may lead to reversal of left ventricular hypertrophy even in PHPT patients with normal resting blood pressure . Given the high prevalence of chronic arterial hypertension (30% of the US population ) and theUndoubtedly, there is a need for further investigations to clarify the pathogenesis of parathyroid hypertension.