Misuse of anabolic androgenic steroids in athletes is a strategy used to enhance strength and skeletal muscle hypertrophy. However, its abuse leads to an imbalance in muscle sympathetic nerve activity, increased vascular resistance, and increased blood pressure. However, the mechanisms underlying these alterations are still unknown. Therefore, we tested whether anabolic androgenic steroids could impair resting baroreflex sensitivity and cardiac sympathovagal control. In addition, we evaluate pulse wave velocity to ascertain the arterial stiffness of large vessels.Fourteen male anabolic androgenic steroid users and 12 nonusers were studied. Heart rate, blood pressure, and respiratory rate were recorded. Baroreflex sensitivity was estimated by the sequence method, and cardiac autonomic control by analysis of the R-R interval. Pulse wave velocity was measured using a noninvasive automatic device.Mean spontaneous baroreflex sensitivity, baroreflex sensitivity to activation of the baroreceptors, and baroreflex sensitivity to deactivation of the baroreceptors were significantly lower in users than in nonusers. In the spectral analysis of heart rate variability, high frequency activity was lower, while low frequency activity was higher in users than in nonusers. Moreover, the sympathovagal balance was higher in users. Users showed higher pulse wave velocity than nonusers showing arterial stiffness of large vessels. Single linear regression analysis showed significant correlations between mean blood pressure and baroreflex sensitivity and pulse wave velocity.Our results provide evidence for lower baroreflex sensitivity and sympathovagal imbalance in anabolic androgenic steroid users. Moreover, anabolic androgenic steroid users showed arterial stiffness. Together, these alterations might be the mechanisms triggering the increased blood pressure in this population. Misuse of anabolic androgenic steroids (AASs) in bodybuilding athletes is a common strategy to enhance strength and skeletal muscle hypertrophy. However, AASs are associated with negative impacts on health, such as muscle sympathetic hyperactivation, reduced vasodilatation, and increased blood pressure (BP) In several cardiovascular diseases such as hypertension and heart failure, lower baroreflex sensitivity (BRS) is one of the main mechanisms leading to increased sympathetic hyperactivation In a previous microneurography study, it was demonstrated that AASUs showed higher muscle sympathetic nerve activity (MSNA) than AAS nonusers (AASNUs) Likewise, rats treated with high doses of AASs showed dysfunction in tonic cardiac autonomic regulation, as evaluated by spectral analysis of heart rate variability Therefore, the present study was performed to test whether AASU athletes showed impaired BRS and an imbalance in cardiac sympathovagal control. In addition, we evaluated pulse wave velocity (PWV) to ascertain the arterial stiffness of large vessels.This is a prospective, cross-sectional comparison study of AASUs and AASNUs. This study was designed to ascertain the influence of AASs on BRS, cardiac autonomic control, and PWV. To show the effect of AASs on these parameters, all the measurements were obtained when the subjects were at the peak of their AAS use. To avoid the influence of exercise on the measurements, all participants were instructed to refrain from exercise 48 hours before the experimental protocol. Moreover, they abstained from caffeine-containing products, fatty foods, and any sports supplements for at least 24 hours before the measurements.In the present study, from November 2013 to January 2015, 14 male AASUs and 12 healthy age-matched male AASNUs were invited to participate.Anamnesis was taken from all participants to obtain information about their exercise training regime, AAS usage, medications, and eating habits, e.g., use of dietary supplements and percentages of macronutrients .The inclusion criteria for both groups were 1) healthy subjects and 2) strength training (hypertrophy) for at least 2 years. Exclusion criteria for both groups were 1) smoking, 2) alcohol intake, 3) use of medication , and 4) liver and kidney disease.All the measurements were obtained when the subjects were at the peak of their AAS use . The AAS cycles of the AASU group lasted from 8-12 weeks. In addition, the subjects had been using AASs for at least 2 years with 2-4 cycles per year. The self-reported most used AASs were stanozolol, testosterone propionate, testosterone cypionate, nandrolone decanoate, boldenone undecylenate, and methenolone enanthate.The study protocol was approved by the Local Human Subject Protection Committee (number 569.389), and written consent was given by each individual. The study was performed in accordance with the principles of the Declaration of Helsinki.All participants were enrolled in traditional bodybuilding strength-training exercises consisting of 3-4 sets of 8-12 repetitions for approximately 2-4 exercise muscle groups 5 days per week. Division of the training consisted of 2-3 muscle groups exercised per day . All participants were asked about their perceived exertion during the training sessions, which should have been 8 to 10 (hard to extremely hard) in accordance with OMNI-Resistance Exercise Scale (OMNI-RES) ® , which provides noninvasive measurement of the beat-to-beat BP. Respiratory rate was monitored using a piezoelectric thoracic belt  placed around the upper abdomen.For 10 minutes of baseline recording, the heart rate was monitored continuously through lead II of an electrocardiogram. Simultaneously, arterial blood pressure  was monitored using a Finometer PRO® has a 1 second delay to convert the analogic signal to digital signal. To correct this delay between RR interval and SBP, we extracted similar and correspondent amounts of RR interval and SBP. Signals refer to sequences during which the SBP and RR interval of the following beat changed in the same direction, either increasing or decreasing (baroreflex sequences).Spontaneous BRS was determined using the sequence method 2, and the power spectral density is calculated in n.u. The normalization was performed by dividing the power of the LF or HF component by the total spectral power, as previously described The electrocardiogram signal to extract the time series for the heart rate  and the beat-to-beat BP were recorded with a computer program . The cardiovascular RR interval fluctuation was assessed in the frequency domain using autoregressive spectral analysis as described previously The breathing was spontaneous, and the breathing of 2 AASU and 1 AASNU subjects was uncoupled in the HF range; these subjects were excluded from the cardiac autonomic evaluation.Carotid-femoral PWV was measured using a noninvasive automatic device  as previously described All procedures were performed in a quiet, temperature-controlled (21°C) room in the morning at approximately the same time of day. All measurements were assessed in the supine position. The participants were instructed to restrain from exercise 48 hours before the experimental protocol and to eat their breakfast normally. However, they abstained from caffeine-containing products, fatty foods, and any sports supplements for at least 24 hours before the measurements.Normality (Shapiro-Wilk) and homogeneity (Levene) tests were conducted to test the distribution of the data. Data are presented as the mean ± SD or median (interquartile range – IQR – 25%-75%). Possible differences between groups were analyzed using an unpaired Student’s t-test or Mann-Whitney-Wilcoxon test for parametric or nonparametric data, respectively.Univariate correlation (Pearson correlation) between MBP, age, BRS-, BRS+, mean BRS, PWV, LF, HF, and LF/HF was conducted to test the association between parameters.p<0.05. All data were analyzed using SPSS version 18.0.An analysis of covariance (ANCOVA) was conducted to test the possible influence of age and body mass index (BMI) on MBP and mean BRS. Differences were considered significant at p=0.47) or BMI (p=0.13).The physical characteristics, heart rate, BP, and PWV are shown in p=0.23) or BMI (p=0.94). For the heart rate variability, there were no significant differences between AASUs and AASNUs in the variance and LFabs. Notably, AASUs showed lower HFabs and HFn.u., whereas LFn.u. was higher, indicating cardiac sympathetic hyperactivation and loss of cardiac parasympathetic control in this group.The spontaneous BRS and heart rate variability are shown in Single linear regression analysis showed significant correlations between MBP and BRS+, mean BRS, and PWV . HoweverOur study evaluated the influence of AASs on BRS and cardiac autonomic control to investigate their potential roles in the mechanisms underlying increased BP in athletes misusing AASs. In addition, we evaluated arterial stiffness by PWV. Our main findings were that spontaneous BRS and cardiac sympathovagal balance were impaired in AASUs compared to AASNUs. Moreover, we found a correlation between BP and spontaneous BRS and arterial stiffness.In older subjects, a reduction in arterial compliance is one of the main mechanisms of impaired cardiovagal BRS Baroreceptors control moment-to-moment variations in BP by mechanical transduction of pressure into barosensory vessel stretch and neural transduction of stretch into vagal outflow Another interesting finding of our study was that AASUs showed higher PWV than AASNUs. Assessment of arterial stiffness is a recommended measurement in the European Society of Cardiology guidelines because PWV is associated with future fatal and nonfatal cardiovascular events, even in younger people p=0.002) with elevated mean 24-hour BP Autonomic imbalance in AASUs, especially muscle sympathetic hyperactivation, was previously demonstrated 2, which could influence sympathetic outflow and, consequently, BP. However, when we performed an ANCOVA to test the possible influence of BMI on MBP, we observed no significant differences (p=0.13), showing that BMI is not correlated with higher BP in AASUs. In fact, higher BMI in bodybuilders is due to higher muscle mass than fat mass There are several studies showing that higher BMI in overweight and obese populations is associated with increased sympathetic nerve activity We recognized limitations in our study. We do not know if these results persist if the baroreflex is tested using vasoactive drugs, such as phenylephrine and sodium nitroprusside. We did not compare our results to a sedentary control group, and we are cautious about drawing conclusions from our study group only compared to a strength-training exercise group without AAS use. However, our results show alterations in BRS, cardiac autonomic nervous system, and BP in AASUs. Someone could argue that strength-training exercise, especially acute bouts of exercise, could influence arterial stiffness. However, all participants were instructed to refrain from exercise 48 hours before the experimental protocol. We did not perform body composition measurements in the participants. However, all of them were strength athletes, and they visually presented large muscle mass and low fat composition. Finally, although we demonstrated a correlation between BP and BRS in AASUs, we cannot at this moment support a cause-effect relationship. Future studies should be designed to address this issue.In conclusion, our results provide evidence for lower BRS and sympathovagal imbalance in AASUs. Moreover, AASUs showed arterial stiffness. Together, these alterations might be the mechanisms triggering the increased BP in this population.Santos MR, Sayegh AL, Armani R and Alves MJ were responsible for the study design, manuscript writing and statistical analysis. Costa-Hong V, Souza FR, Toschi-Dias E, Bortolotto LA, Yonamine M and Negrão CE were responsible for the writing of the Methods section and manuscript review.


In Group B, there was a statistically significant decrease of lung function parameters FEV1 (3.80 vs. 3.71) (p < 0.001), forced vital capacity (FVC) (4.43 vs. 4.37) (p < 0.001), FEV1/FVC (88.2 vs. 85.3) (p < 0.05), PEF (8.05 vs. 7.51) (p < 0.01), PEF variability (17.85 vs. 18.33) (p < 0.001), increased BHR (PD20 1.04 vs. 0.62) (p < 0.05), and symptom scores (0.46 vs. 0.62) (p < 0.01), as well as the use of rescue medication during the day (p < 0.001). Early introduction of low doses of ICS may be more beneficial than β2 agonists alone in patients with intermittent asthma.International guidelines advocate the early introduction of inhaled corticosteroids (ICS) in all types of persistent asthma. Our study was undertaken to assess the effects of ICS on bronchial hyperresponsiveness (BHR) as a hallmark of inflammation, and to assess the symptoms, the use of rescue medications, and the parameters of lung function in patients with mild intermittent asthma. The patients with intermittent asthma (n = 85) were randomly allocated to a treatment with ICS, beclomethasone dipropionate 250 μg/day and short-acting β2 agonists salbutamol as needed  or to a treatment with only short-acting β2 agonists as needed  during the 6-month treatment period. At the end of the study, in Group A, we found a statistically significant decrease of BHR (PD


Background: Asthma is a chronic disease appeared to be associated with depression. But the underpinnings of depression in asthma remain unknown. In order to understand the neural mechanisms of depression in asthma, we used cerebral blood flow (CBF) to probe the difference between depressed asthmatic (DA) and non-depressed asthmatic (NDA) patients.Methods: Eighteen DA patients, 24 NDA patients and 57 healthy controls (HC) received pulsed arterial spin labeling (pASL) scan for measuring CBF, resting-state functional magnetic resonance imaging (rs-fMRI) scan, severity of depression and asthma control assessment, respectively.Results: Compared to NDA, DA patients showed increased regional CBF (rCBF) in the right cerebellum posterior lobe. Compared to HC, DA, and NDA patients all showed significantly decreased rCBF in the right cerebellum posterior lobe.Conclusions: We showed the first evidence of altered rCBF in the right cerebellum posterior lobe in asthma using pASL, which appeared to be involved in the neuropathology in asthma.Clinical Trial Registration: An investigation of therapeutic mechanism in asthmatic patients: based on the results of Group Cognitive Behavioral Therapy (Registration number: ChiCTR-COC-15007442) (http://www.chictr.org.cn/usercenter.aspx). Asthma was a chronic inflammatory condition that swelled and narrowed the airways, leading to dyspnea, coughing, and tightening of the chest. To et al.  showed tOver the past decades, functional magnetic response imaging (fMRI) proved itself a useful technique to detect and quantitate sites of activation in the brain and to map circuits that might be associated with or involved in the underpinnings of emotion in asthma. Rosenkranz et al. –8 explor2, a potent cerebral vasodilator  patients were not found, although the abnormalities were identified in both depression  of certain brain regions in depressed patients, such as hippocampus , right podilator . Considepression  and asthpression  patientspression , to invepression , 19. Pulpression .To the current study's best knowledge, the pattern of rCBF changes in DA patients has not been characterized by pASL studies. So, a data-driven analysis was chosen to study the data according to the complexity and multidimensional causes of DA together with variability between individuals. We identified regions of interest (ROI) with abnormal rCBF between DA and non-depressed asthmatic (NDA), healthy controls (HC) groups. ROIs were then used as seeds to find out the rCBF alterations in DA patients and provided evidence for exploring the mechanism of depression in asthma.According to the scores of 17 items Hamilton depression rating scale (HDRS-17), asthmatic patients were divided into DA (HDRS-17 ≥ 7) and NDA (HDRS-17 < 7) group. As shown in Figure Participants who met the following criteria entered asthma group: (1) met the diagnostic criteria of bronchial asthma and during non-acute attacks; (2) 18 years old or above; (3) right handedness; (4) education to junior high school or above; (5) there is no electronic and metal equipment in body ; (6) participants sign the informed consent form. Inclusion criteria of HC: HDRS-17 < 7 and the above item (2) ~ (6) in the inclusion criteria of asthmatic patients.Participants with one of following items were excluded: (1) other serious disease of the respiratory system; (2) history of other mental disorders, alcohol, and drug dependence; (3) organic brain disorders and cardio, hepar, kidney abnormality; (5) women during pregnancy or lactation.2; thickness = 1.0 mm, gap = 0; time = 4 min 18 s]. ASL perfusion MRI was performed using the Siemens product pASL PICORE Q2T sequence .Imaging was performed on a 3-Tesla Siemens Magnetom Symphony scanner using a homogeneous birdcage head coil. Subjects laid supine with the head snugly fixed by a belt and foam pads to minimize head motion. High-resolution 3-dimensional T1-weighted scans were performed using the Siemens product magnetization prepared rapid gradient echo (MPRAGE) sequence . The post-hoc two-sample t-tests were conducted within a mask showing significant differences obtained from the ANCOVA analysis, with AlphaSim corrections .CBF comparisons were processed with REST software . StatistP < 0.05 (two-tailed).Brain regions were selected as ROI only when they were exhibiting significant differences both between the DA and NDA groups and between DA and HC groups. Mean CBF values were extracted within each of these ROIs, then Pearson correlation coefficients were computed between the extracted CBF values within these ROIs and the clinical assessments of DA patients by PASW 18.0, and the significance level was set at P < 0.05). It would be a covariate in the following statistical analysis of CBF. There was a significant difference in HDRS-17 scores among the three groups (P < 0.001). And the ACT scores were significantly different between DA and NDA group (P < 0.01).Table As displayed in Table The present study used partial correlation analysis to explore the relationships between mean CBF values in the right CPL and two scales (HDRS-17 and ACT). It revealed that no significant correlations were found between CBF values and HDRS-17, ACT scores respectively either in DA or NDA group.To our knowledge, this study at the first time used pASL method to explore the relationship between altered rCBF and depression in asthmatic patients. DA patients exhibited increased CBF values in the right CPL compared with NDA patients, and reversed result compared with HC.Stoodley and Schmahmann  highlighStoodley et al. , 33–36 mEvidence of aberrant activities in ACC and insula were often discovered whatever in emotion disorders or asthma , 40, 41.Significantly correlations between CBF values of the right CPL and HDRS-17 scores were not found whatever in DA or NDA group in the current study. A regional cerebral metabolism study suggested that different depressive symptom clusters might have different neural structures in unipolar depression, and depression symptom clusters predominantly correlated with the cerebral metabolism in right insula, temporal cortex, and ACC . CPL wasThere are some limitations to our study. First, since the current study mainly focused on the differences of rCBF between asthmatic patients with and without depression, we adopted only HDRS-17 and ACT for the evaluation of depressive- and asthma control- level in participants. More cognitive-related tests were required to adequately describe patients cognitive profile, and to confirmed the speculations that the abnormal rCBF in right CPL might reflect impaired cognitive function in asthmatic patients. Second, our study involved a relatively small sample, and the number of the subjects in the three groups did not match perfectly. To control for the effects of the differences in age among the three groups, this variable was considered as covariates and regressed out in the statistical analysis.In summary, this was the first study to explore the potential mechanism of depression in asthma using pASL. The findings demonstrated that the increased rCBF in the right CPL would be involved in the neuropathology of depression in asthma.YZ took responsibility for the content of the manuscript; YZ and ZW were responsibility for the data and analysis; YZ, YYang and RB were charge for patient recruitment; WJ, YYin, YYue, ZH provided language help for this study; YYuan was responsibility for experimental design.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Current data provide evidence for efficacy of NHF in patients with hypoxemic respiratory failure. Preliminary data suggest that NHF may decrease hypercapnia in hypercapnic respiratory failure. The aim of this study was to evaluate the mechanism of NHF mediated PCO2 > 45 mmHg), hypercapnia was evaluated by capillary gas sampling 1 h after NHF breathing under four conditions A to D with different flow rates and different degrees of leakage . Under identical conditions, mean airway pressure was measured in the hypopharynx of 10 COPD patients.In 36 hypercapnic COPD patients (PCO2 > 55 mmHg (n = 26), PCO2 additionally decreased significantly by increased leakage and/or flow rate in comparison to lower leakage/ flow rate conditions . The highest mean airway pressure was observed in patients breathing under condition B .Hypercapnia significantly decreased in all patients. In patients with capillary PCO2 reduction with NHF therapy in stable hypercapnic COPD patients. This effect does not correlate with an increase in mean airway pressure but with increased leakage and airflow, indicating airway wash out and reduction of functional dead space as important mechanisms of NHF therapy. These results may be useful when considering NHF treatment in hypercapnic COPD patients.This study demonstrates effective PCOClinical Trials: NCT02504814; First posted July 22, 2015. These devices create a gradient between atmospheric pressure and airway pressure, thus establishing a driving pressure during inspiration as well as a variable amount of positive end expiratory airway pressure. Respiratory frequency and a minimum minute volume may be specified. This kind of ventilator support improves alveolar ventilation and consecutively reduces PCO2 . The aimA novel development in non-invasive ventilation support is the application of a constant high nasal airflow with 20 to 60 L/min. This technique is known as nasal high flow (NHF) therapy. Patients tolerate flow rates in this order of magnitude when gas is warmed and humidified close to body standard temperature and humidity before entering the nose. In addition, the gas mixture may contain any fraction of oxygen set from 0.21 to 1.0.NHF therapy has become frequently used in the treatment of neonatal patients as an alternative to nasal continuous positive airway pressure (nCPAP) therapy . However2 during NHF, as opposed to the situation in NIV, did not correlate with tracheal pressure but was more efficient, when leakage of gas from the nose was increased. The authors therefore suggested that wash out of nasopharyngeal dead space by nasally applied high flow improves CO2 removal in the piglet model. The high flow generated by NHF can pass functional dead space more easily and may therefore economize the work of breathing [Few studies have investigated the effect of NHF therapy on e.g. hypercapnia in patients with chronic obstructive pulmonary disease (COPD), but the number of patients recruited in these studies is limited –13. In areathing –21. The 2, PO2, and mean airway pressure during various flow rates and leakage conditions.This study had a prospective, unblinded, and single-center design. Outcome parameters were changes in capillary PCO2 > 45 mmHg, chronic ventilatory insufficiency with hypercapnia without additional metabolic alterations, > 18 years of age, and a stable stage of disease. Patients with acute ventilatory insufficiency (pH < 7.35), instable disease , incomplete or untapped medical therapy, other lung diseases, inadequate compliance to any kind of treatment, as well as fertile women and patients participating in other trails were excluded.For this study, 46 patients were recruited in the department of respiratory medicine of the University hospital Leipzig in 2015. The study was approved (414–14-06102014) and registered  by the ethics committee of the Medical Faculty, University of Leipzig. All patients gave written informed consent to participate in the study. Criteria for inclusion in the study were a diagnosis of COPD (GOLD), PCOIn this study, the TNI20s oxy device  was used. The system was equipped with an additional humidifier/heater  to ensure the intended higher flow rates because the original humidifier was not able to sufficiently humidify when flow rates were higher than 24 L/min. Flow rates were additionally verified with an electronic flowmeter . With these modifications, the NHF system provided stable flow rates of up to 50 L/min and allowed the admixture of oxygen.2 prior to NHF therapy was considered as baseline PCO2. If more than one of the four possible NHF conditions were tested in one patient at 1 day, a treatment-free interval of at least 2 h between the two conditions was assured. Note that if patients were given continuous oxygen insufflations within the scope of their regular therapy, oxygen supply was neither altered nor interrupted during the duration of NHF treatment.Patients were randomly assigned to undergo sequences of treatment conditions. Randomization was computer-generated with a sequence of numbers, and each number was associated with a character . Some patients were treated by all conditions. Changes in hypercapnia were measured in 36 COPD patients who had undergone NHF therapy for 1 h. Capillary blood gas samples were taken prior to NHF therapy, 30 min after the beginning, and immediately after completion of one condition at 60 min. The starting PCOThe leakage and flow combinations tested (conditions A – D) were combinations of two different flow rates (20 L/min and 40 L/min) and two degrees of leakage . All measurements were performed with constant oxygen supplementation as indicated.Mean airway pressure was measured in 10 patients with COPD. First, a water-filled thin flexible tube  was connected to a pressure sensor . The free end was inserted in the nasopharynx under visual control. The electronic pressure sensor was hooked to a computer. A total of 10 breaths were recorded during spontaneous breathing (baseline) and another 10 breaths were recorded during each of the experimental conditions.2 of 5%. Data were analyzed using single factor ANOVA. If F > F crit, we rejected the null hypothesis. Additionally, we used Student’s t-test  to compare each pair of means (in case of rejecting null hypothesis). A p-value <0.05 was considered as significant.The sample size of 36 had 85% power, with a type I error rate of 5%, to detect a difference in capillary pCO2 in comparison to baseline in all patients . No significant differences were observed between the four experimental conditions with regard to PCO2 after treatment.Demographic data are presented in Table 2 measurements had a baseline PCO2 > 55 mmHg. In this hypercapnic subgroup of COPD patients, PCO2 was significantly reduced by all conditions (A-D). The reduction of capillary PCO2 by condition A was more pronounced when the flow rate was increased from 20 to 40 L/min (condition A = > B). The increase of leakage and the reduction of the effective flow rate (by using only one nostril) to 20 L/min (condition C) resulted in an even greater decrease. Yet, the largest reduction of capillary PCO2 was obtained after increasing the flow rate in a single prong to 40 L/min by occluding the prong that was located outside the nostrils (condition D). Between conditions A and D, there was an additional significant decrease in PCO2  due to pulmonary causes and in the prevention of postextubation respiratory failure –7. In adLittle is known about the mechanisms that underlie NHF therapy. Previous studies have demonstrated increases in airway pressure  but the 2 should achieve its minimum when mean airway pressure rises to its maximum, but this is not what was observed in this study. In contrast, in our study, PCO2 achieved its minimum with condition D, whereas mean airway pressure reached its maximum with condition B. Increased leakage (B = > C) resulted in a greater decrease in PCO2 that went along with a decrease of mean airway pressure, demonstrating that the reduction in PCO2 is not due to an increase in mean airway pressure. Rather, it relies on a higher degree of leakage and a concomitant airway wash out. This wash out affects the upper airways, as shown by Möller et al. who demonstrated CO2 elimination from nasal dead space and reduction of CO2-rebreathing under NHF therapy [2 wash out may extend to the lower airways. Our data confirm previous data obtained by Frizzola et al. who demonstrated that the reduction of PCO2 with NHF therapy in piglets similarly depends on the degree of leakage [If the increase in airway pressure was the principal reason accounting for the clinical effects of NHF therapy in adults, capillary PCO therapy . A model therapy  indicate leakage .2 decreased by applying higher amounts of room air and stable oxygen supplementation. We aimed at integrating this observation into our study because of both insufficient literature data and the hypothesis that reduction in oxygen can lead to a reduction in PCO2. Interestingly, there was no change in PO2 under low flow/low leakage of condition A. This study supports the observed necessity to increase rates of supplemented oxygen to keep FIO2 constant at higher flow rates. The non-significant decrease in oxygen cannot be the reason for decreased PCO2 levels in this study because of (1) constant oxygen values in different settings and regardless decreasing PCO2 values  [2 and decreased PCO2 values when using 20 L/min (condition A) [2 reduction [As shown in this study, oxygen saturation tended to slightly decrease when using higher flow rates and constant oxygen supplementation. This observation is not surprising because FIOB, C, D) , (2) staition A) , 12, 21,eduction , 10, 22.NHF therapy partially relieves the work of breathing in COPD patients , 13, 21.Our study has three limitations. Since experiments were time consuming and some patients tolerated only few measurements, it was not possible to test all four conditions within the clinical setting. Bias cannot entirely be excluded because patients as well as investigators could not be blinded regarding the different experimental conditions. The fact that only COPD patients were tested could limit the generalizability of our findings.2 in COPD patients. Higher flow rates and increased leakage of the upper airways appear to increase the effectiveness in reducing PCO2. At the same time, an increase in airway pressure is not required. Our data indicate that airway wash out is the major mechanism of action in NHF breathing.In the present study, we showed that NHF therapy significantly reduces capillary PCO


Acute Page Kidney (APK) phenomenon is a rare cause of secondary hypertension, mediated by activation of renin-angiotensin-aldosterone system (RAAS). Timely intervention is of great importance to prevent any end organ damage from hypertension. We present a unique case of three episodes of APK in the same renal transplant allograft. A 42-year-old female with hypertension (HTN), ESRD, secondary to IgA nephropathy and a history of deceased donor renal transplant, presented with acute kidney injury (AKI). Her AKI was presumed to be prerenal due to ongoing gastroenteritis. Her S Cr was elevated to 3.3 mg/dL (from baseline of 2–2.2 mg/dL) and admission blood pressure (BP) ranged with 190/100–210/110 mmHg. She was on mycophenolic acid 360 mg QID, sirolimus 1 mg daily, prednisone 5 mg daily, and carvedilol 50 mg BID. Her renal transplant ultrasonography (USG) showed normal resistive indices (RI) with no hydronephrosis. An allograft biopsy was performed to rule out transplant rejection, as her S Cr continued to be elevated at 3.3 mg/dL even after 72 hours of hydration and negative GI workup. Her antihypertensive regime was adjusted with the addition of nifedipine, clonidine, and minoxidil and her blood pressure ranged within 140–160/80–95 during 48 hours prior to procedure. On postprocedure day 1, her blood pressure was again elevated (170–210/90–110 mmHg) and she had a noticeable drop in her hemoglobin (Hgb) from 10 g/dL to 8.5 g/dL. Her CT scans showed large subcapsular hematoma. Renal allograft angiography failed to show any active bleeding, an AV fistula, or any pseudoaneurysm formation. On postbiopsy day 2, her BP remained high and the S Cr peaked at 4.2 mg/dL prompting the drainage of subcapsular hematoma and a Jackson-Pratt (J/P) drain placement for continuous drainage. This resulted in significant improvement in blood pressure  and her Unfortunately, six weeks later she was readmitted with severe anemia (Hgb 6.4 g/dL), AKI (S Cr of 8.3 mg/dL), and hypertensive emergency (BP range of 190/90–210/110 mmHg). Her CT scans confirmed recurrence of the subcapsular hematoma. Again, renal allograft angiography failed to show any active bleeding or any AV malformations. This time, the hematoma was surgically drained to ensure the bleeding stopped after drainage. A J/P drain was again placed which was removed after 2 weeks. She required four sessions of hemodialysis treatments for this episode of AKI but her renal function stabilized at discharge with S Cr of 3.1 mg/dL and improved BP control . A repeaShe was admitted again seven weeks later, for a large perinephric seroma with uncontrolled HTN (190/90–200/110 mmHg). The collection was drained emergently with an immediate and significant improvement in her BP (range 110–130/60–70) . Her renThe phenomenon of worsening of blood pressure from compression of the renal parenchyma by either a subcapsular collection or extrarenal collection causing renal hypoperfusion/ischemia and triggering of the renin-angiotensin-aldosterone system (RAAS) is known as Page Kidney. Dr. Page first described it in 1939 [APK most commonly is associated with perinephric hematoma. In one case series  blunt trThe management of APK and treatment need to be individualized to case-by-case basis and should be guided by extent of organ damage and severity of presentation. In cases with HTN emergency, a more aggressive approach including surgical drainage or arterial embolization  may be rIn conclusion, APK is a rare but very serious complication that can be seen after renal allograft biopsy. New onset of acute pain over the graft, uncontrolled blood pressure, and reduction of Hgb could be the ominous signs. High risk patients such as patients with coagulopathy and uncontrolled HTN should be followed up closely after APK episode as recurrence of hematoma and new perinephric collections including seroma are possible. Our case report is the first case of Recurrent Acute Page Kidney phenomenon in the same allograft and emphasizes the need for close follow-up of such patients even after initial management.


Recent clinical studies have suggested an increased risk of elevated arterial pressure in patients with hydronephrosis. Animals with experimentally induced hydronephrosis develop hypertension, which is correlated to the degree of obstruction and increased oxidative stress. In this prospective study we investigated changes in arterial pressure, oxidative stress, and nitric oxide (NO) homeostasis following correction of hydronephrosis.n = 15) before and after surgical correction, and the measurements were compared with arterial pressure measurements in two control groups, i.e. healthy controls (n = 8) and operated controls (n = 8). Markers of oxidative stress and NO homeostasis were analyzed in matched urine and plasma samples.Ambulatory arterial pressure (24 h) was monitored in pediatric patients with hydronephrosis (p < 0.05), and surgical correction of ureteral obstruction reduced arterial pressure . Markers of oxidative stress  were significantly increased (p < 0.05) in patients with hydronephrosis compared with both control groups, and these were reduced following surgery (p < 0.05). Interestingly, there was a trend for increased NO synthase activity and signaling in hydronephrosis, which may indicate compensatory mechanism(s).The preoperative mean arterial pressure was significantly higher in hydronephrotic patients  than in healthy controls (74 mmHg; 95% CI 68–80 mmHg; This study demonstrates increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which can be restored to normal levels by surgical correction of the obstruction. Once reference data on ambulatory blood pressure in this young age group become available, we hope cut-off values can be defined for deciding whether or not to correct hydronephrosis surgically. The kidneys play a key role in whole body fluid and electrolyte homeostasis and hence in long-term regulation of the arterial pressure. Abnormal renal autoregulation of glomerular perfusion and filtration as well as intrinsic renal disease can either cause hypertension or be a consequence of this condition . ObstrucRecently, we showed for the first time in a prospective case study that surgical relief of hydronephrosis, secondary to ureteral obstruction in children, is associated with a lowering of arterial pressure . MoreoveIn this prospective study, our aim was to further study ambulatory arterial pressure (24 h) and different markers of NO homeostasis and oxidative stress in blood or urine in pediatric patients with congenital hydronephrosis before and after surgical correction of the ureteral obstruction. Specifically, we investigated the hypothesis that preoperative arterial pressure is higher in children with hydronephrosis, which can be reduced by surgical management, and that this reduction in arterial pressure would be associated with attenuated oxidative stress and normalized NO homeostasis.n = 8) and operated controls  were included in this prospective study. The subjects were recruited between 2007 and 2016 at the Pediatric Surgery Department of Uppsala University Children’s Hospital in Uppsala and the Pediatric Surgery Department of Astrid Lindgren’s Hospital in Stockholm  was also included who had undergone general anesthesia for a minor day ward operation, but were otherwise considered to be healthy . In the hydronephrotic group matched samples were obtained before and 6 months after surgery when arterial pressure measurements were conducted. In the hydronephrotic group, anteroposterior diameter of the renal pelvis was measured by ultrasound a few weeks to a few days preoperatively to confirm the diagnosis of hydronephrosis. Preoperative evaluation of bilateral renal function was performed by mercaptoacetyltriglycine (MAG3) scintigraphy. Tc-99 m-labeled MAG3 renography with forced diuresis was also performed in all patients. Following intravenous injection of the tracer (1 MBq/kg body weight), registration  continued for at least 30 min, and furosemide (0.5 mg/kg body weight) was given intravenously after 15 min. The renography curves were classified according to O’Reilly  as normag, 5 min, 4 °C), and collected aliquots of both plasma and urine were stored at − 80 °C for later analyses of markers of NO homeostasis and oxidative stress, as described in detail in the following sections.Blood samples were immediately centrifuged (4700 A high-performance liquid chromatography (HPLC) system dedicated to the assessment of nitrite and nitrate  equipped with an auto-sampler  were used  was within the accepted range (%CV < 15) for all reported compounds.Plasma levels of arginine, citrulline, ornithine, and asymmetric and symmetric dimethylarginine  were measured by HPLC tandem mass spectrometry (LC-MS/MS) as previously described, with minor modifications , 22. BriCreatinine was quantified in 10 μl of urine as previously described . Laboratiso-iPF2α-VI, 8-isoprostane (8-iso-PGF2α), and its excreted urinary metabolite, 2,3-dinor-8-iso-PGF2α. Three additional urinary eicosanoids  were also quantified. Fortified laboratory urine reference material was used as a QC to ensure reproducibility of quantitation within the study. The reproducibility according to the QCs (%CV <12) was within the accepted range (%CV < 15) for all reported compounds.Isoprostanes were quantified in 300 μl of urine using an urinary eicosanoid LC-MS/MS platform as previously described . Three dr correlation was used to test for the association between MAG3 and mean arterial pressure. Statistical significance was defined as p < 0.05.Statistical analyses were performed using GraphPad Prism 6 for Mac OS X . The comparisons of the arterial pressure and markers in urine and plasma among groups were analyzed by using analysis of variance  followed by Dunn’s multiple comparisons test. Wilcoxon matched-pairs signed rank test (two-tailed) was used to analyze the effect of surgical management on the hydronephrotic group. Data are shown as a box and whiskers (5–95 percentile) graph. Linear regression analysis and the Pearson p = 0.08) higher than that in the operated control group (preoperatively). Moreover, there was no difference in arterial pressure between the two control groups. Surgical correction of the hydronephrosis was associated with significantly lower arterial pressure  was significantly higher in the hydronephrotic group than in the healthy control group Fig. a–c, but ure Fig. d–f. Posture Fig. g-h.Fig. Anteroposterior diameter preoperatively ranged from 15 to 50 mm in the hydronephrotic kidney . The renal functional share of the hydronephrotic kidney ranged from 11 to 55% Table a, but noSeveral different markers of NO homeostasis and oxidative stress level were measured in the plasma and in urine before and after surgical correction of hydronephrosis in children.2−) and nitrate (NO3−), and hence the levels of these inorganic anions have been widely used as an index of NO generation. No differences were observed for plasma nitrate  activity], ornithine/arginine (arginase activity), and citrulline/ornithine (relative NOS vs. arginase activity) were calculated Fig. a–f. TakeN-monomethyl arginine (NMMA) [Previous experimental and clinical studies have shown that renal disease and associated hypertension is associated with abnormal regulation of the endogenous NOS inhibitors ADMA, SDMA, and e (NMMA) , 25, 26.2, PGF2α, 8-iso-PGF2α, 8,12-iso-iPF2α-VI) were significantly elevated in hydronephrotic patients compared with healthy controls and these were normalized following surgery  and reduced antioxidant capacity. This oxidative stress is prevalent in patients with kidney disease and has been suggested as an important pathogenic mechanism associated with an increased risk of cardiovascular disease –30. Seve2-isoprostanes) [The measurement of oxidative stress in body fluids is complicated because of the very short half-life of ROS. Isoprostanes, which are mainly formed through free-radical catalyzation of arachidonic acid, are now considered to be reliable biomarkers of oxidative stress . Here weostanes) , 40, werOxidative stress due to the increased generation of ROS from vascular NADPH oxidase and mitochondria is often associated with reduced NO levels due to scavenging  . HoweverIn conclusion, this novel prospective study demonstrates significantly higher arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls. The elevated arterial pressure can be normalized by surgical correction of the obstruction, which supports our previous experimental and clinical case report studies. Currently, normalized reference values of 24-h ambulatory blood pressure in very young children are limited , 42, 43.


All participant blood samples were tested against the same TRPM extract, in addition to purified bacterial endotoxin and pyrogen-free water, which served as positive and negative WBA controls, respectively. The innate and adaptive cytokine responses were evaluated in cell-free supernatants of the whole blood incubations. Comparatively similar levels were recorded for nine out of the 10 cytokines measured , regardless of study participant asthma status. However, IL-8 levels in TRPM-stimulated blood from children with uncontrolled asthma were diminished, compared to subjects without asthma ; IL-8 responses for subjects with controlled asthma were also reduced, but to a lesser degree . These relationships were present before, and after, adjusting for age, sex, obesity/overweight status, C-reactive protein levels, and residential proximity to the study area’s major roadway. For tests conducted with endotoxin, there were no discernible differences in cytokine response between groups, for all cytokines measured. The WBA testing conducted for this study highlighted the capacity of the TRPM extract to potently elicit the release of IL-8 from the human whole blood system. Although the small sample size of the study limits the capacity to draw definitive conclusions, the IL-8 responses suggest that that asthma control may be associated with the regulation of a key mediator in neutrophil chemotaxis, at a systemic level, following exposure to PM derived from traffic-related sources.This study sought to investigate if acute phase immune responses of whole blood from Peruvian children with controlled and uncontrolled asthma differed from children without asthma, following exposure to traffic-related particulate matter (TRPM). TRPM, including particulate matter from diesel combustion, has been shown to stimulate acute airway inflammation in individuals with and without asthma. For this study, a whole blood assay (WBA) was used to test peripheral whole blood samples from 27 children with asthma, and 12 without asthma. Participant blood samples were stimulated,  Asthma is a respiratory disease characterized by recurrent episodes of airway inflammation, bronchial hyperreactivity, increased mucus production, and airflow obstruction . These s2.5) are primarily derived from combustion sources and have been associated with elevated risks of asthma and respiratory inflammation (2), have similarly been reported in mechanistic studies to stimulate acute inflammatory immune activity through ROS and oxidative stress , including PM from diesel combustion sources, has been shown to stimulate acute airway inflammation in individuals with and without asthma . TRPM exammation . Two othe stress . Like PMhe World .2.5 and black carbon (BC) (a marker of combustion) have been found to persist within 75 – 100 meters (m) of highway traffic, and decrease to background levels after distances of 150 – 300 m , offer opportunities to holistically assess the immunostimulatory activity of complex exposures  within integrated host-specific biologic systems.However, the task of evaluating the immunomodulatory characteristics of TRPM exposures is complicated by the inherently heterogeneous composition of anthropogenic, biologic, and crustal elements that may comprise the TRPM matrix . TRPM ma2.5, black carbon, and NO2 within the indoor air of neighborhood households were often equivalent to levels detected outside of the home, in the ambient air, suggesting these traffic-related pollutants easily permeated the home environment.In Peru, the prevalence of childhood asthma is among the highest of all Latin American countries . Lima, PFor this study, we utilized a human WBA to evaluate the potential of ambient PM from this neighborhood to stimulate conserved inflammatory immune responses, and tested peripheral whole blood from local children with and without asthma. The WBA served as a unique field-applicable test with which to test individual immune responses to both standard inflammatory agents  and complex environmental matrices (TRPM) from the local study area environment. The cytokine responses generated in the WBA were contrasted among groups of subjects, with and without asthma, in order to determine if asthma status  was associated with an altered acute phase immune activity. The human whole blood system serves as a suitable reaction medium for this work as it carries an array of immunologic defense mechanisms  that recognizes a wide array of biologically relevant stimuli . Moreoveex vivo incubation of human whole blood with environmental PM is an approach that is similar to other studies, which have employed monocytic cell lines and isolated peripheral blood mononuclear cells (PMBCs) to assess the cytokine inducing potential of air pollutants  from blood monocytes, increased cellular phagocytic activity, and the production of ROS . The ex llutants . While tllutants , the challutants , and forllutants .More recently, 2.5 was sampled from ambient air in the Pampas study area, at locations adjacent to the roadways that cut through the neighborhood from which our subjects were recruited. We collected filter samples of this PM and developed a single aqueous extract of stimuli for WBA tests, which were conducted using blood donations from children with and without asthma. Acute phase cytokine release was measured in peripheral whole blood, following 24-h of ex vivo exposure to TRPM extract, under controlled conditions. Post-incubated blood was assessed for a panel of cytokines that reflected innate and adaptive responses.For the present study, PMOur primary hypothesis was that levels of TRPM-stimulated acute phase inflammatory cytokines, associated with the innate immune response, would be enhanced in whole blood from children with either controlled or uncontrolled asthma, as compared to blood from children without asthma.The Institutional Review Boards of the Johns Hopkins University (JHU) School of Medicine  (Study # CIR00007480) and A.B. PRISMA  approved this study. Written informed consent for participation was obtained from the parents or guardians of each participant and assent was obtained from children.Figure 1). The Pampas community encompassed low-to-middle income households, with a dense population of approximately 60,000 people  conducted during the GASP study (collected between August of 2011 and March of 2012). The ASQ contained asthma severity questions that were derived from the International Study on Asthma and Allergies in Childhood (ISAAC) , as well as baseline spirometry tests (FEV (ISAAC) , and gui (ISAAC) . Partici2. Our analysis also categorized children as overweight/obese vs. normal weight, based on BMI thresholds developed by Atopy status was determined with an ImmunoCAP Phadiatop test , based on three panels of allergens . A positive result (IgE > 0.1 kUa/L) to any of the allergen panels was considered atopic. Height and weight were measured and body mass index (BMI) was calculated in kg/m2.5 samples were collected onto 37 mm polytetrafluoroethylene (PTFE) filters  using SKC PEM PM2.5 impactors . Samplers were calibrated to run at a flow rate of 4.0 l per minute, and operated continuously for a 7-day period of time. Flow rates were checked at the beginning and end of the sampling period. Gravimetric analysis of air filters was performed at JHU, in Baltimore, MD, USA. All filters were conditioned for 24 h in a temperature and humidity controlled room to record pre- and post-sampling weights on a Mettler Toledo XP2U microbalance . Data pertaining to these filter samples are summarized in Table 1.Prior to the enrollment of subjects, TRPM was sampled from ambient air at five different locations within the Pampas study area, within a two-kilometer radius of each other and participant homes. PM2.5 particles were eluted from PTFE filter membranes into a solution of pyrogen-free water (PFW) , containing 0.05% Tween20 by volume . Air filter samples were aseptically transferred into 12 ml non-pyrogenic glass vials , using clean, gloved hands and forceps. Ten milliliters of the PFW/Tween20 solution was then pipetted into each vial to fully submerge filters in liquid. These vials were capped, vigorously mixed for 1 min, and then sonicated in a room temperature water bath  for 60 min. Lastly, each vial was vortexed for 1 min and the entire volume of each of the filter eluates was combined in a single pyrogen-free 50 ml falcon. This solution was vortexed to thoroughly to mix the eluates, after which they were aliquoted into sterile 10 ml cryovials and frozen at -20°C for shipment to the field lab in Peru. The TRPM extract used for these WBA tests contained a particle mass concentration of 60 μg/ml, with an endotoxin content of 50 pg/ml. For reference, in vitro cellular studies ranged between 50 and 100 μg/ml.PM® Lot #2041204, Associates of Cape Cod Inc, E. Fallmouth, MA, USA), per the manufacturer’s instructions. LAL testing was conducted since endotoxin is a known pro-inflammatory agent and a contaminant of PM from many environments  to block potential false-positive interference from β-glucans in the sample matrix. Since the kinetic chromogenic LAL test requires clear, particle-free samples for testing, 1.0 ml aliquots of the TRPM extract were centrifuged in sterile 1.5 ml microcentrifuge tubes at 1,000 × g for 15 min to pellet insoluble particles. Dilutions of the TRPM extract were assayed in duplicate in endotoxin-free 96-well tissue culture plates . The LAL testing included dilutions of control standard endotoxin from Escherichia coli O113:H10 , as well as media blanks and spiked samples. The limit of detection for the LAL test was 15 pg/ml.Bacterial endotoxin content of the pooled TRPM extract was quantified using a kinetic chromogenic Limulus Amebocyte Lysate (LAL) test , and 300 μl of heparinized whole blood. Diluted peripheral whole blood from each study participant was challenged with the TRPM extract, as well as a positive control , and a negative control (pyrogen-free water).Each participant provided a single blood donation for this study. Subjects arrived at a field lab in Pampas on Sundays, between the hours of 6 am and 10 am, where blood draws were completed within a regular schedule to control for the influence of circadian rhythms on whole blood cytokine release . A certiWhole blood incubations were prepared and started within 1 h of each respective participant’s blood draw. Each vial of diluted whole blood and stimulus was gently mixed by slowly inverting the vial threes times. These vials were then placed upright in a thermoblock incubator , set to operate at 37°C. After 24 h, the blood samples were removed from the incubator, re-mixed, and then aliquoted to 1.5 ml microcentrifuge tubes. The incubated blood was immediately frozen at -20°C and transferred on the same day to a lab at the University of Cayetano  for storage at -70°C.Aliquots of heparinized plasma were also retained following each blood draw and were frozen at -20°C for C-reactive protein (CRP) analysis. Complete blood cell (CBC) counts, with a white blood cell (WBC) differential were also completed for each participant . All blood and plasma samples were then shipped on dry ice to labs at JHU and stored at -80°C.× g for 15 min to sufficiently pellet cellular debris and particles. The lower limits of detection (LOD) for the assay were: IL-1β: 0.04 pg/ml, IL-6: 0.06 pg/ml, TNFα: 0.04 pg/ml, IL-8: 0.04 pg/ml, IL-10: 0.03 pg/ml, IL-2: 0.06 pg/ml, IL-4: 0.02 pg/ml, IL-13: 0.24 pg/ml, IL-12p70: 0.11 pg/ml, IFNγ: 0.20 pg/ml. Measurements below the LOD were assigned a value of ½ the respective detection limit.Cytokine determination was conducted using the cell-free supernatants of the whole blood incubations. Tests were completed with a high-sensitivity electrochemiluminescent multiplex cytokine assay and a 10-plex cytokine panel (V-PLEX Proinflammatory Panel 1 (human) Kit, Catalog # K15049D-1, Meso Scale Discovery, Rockville, MD, USA). This commercially available kit measured cytokines from both the innate and adaptive response, and was specific for Interleukin (IL)-1β, IL-6, Tumor Necrosis Factor alpha (TNFα), IL-8, and IL-10, as well as IL-2, IL-4, IL-13, IL-12p70, and Interferon Gamma (IFNγ). Prior to analysis, whole blood incubation samples were thawed at room temperature and then centrifuged at 10,000 C-reactive protein levels were quantified from plasma samples with a commercial ELISA assay , per the manufacturer’s protocol. CRP is a biomarker of systemic inflammation and may modulate whole blood cytokine response through complement activation and binding of Fc gamma receptors . The senU-tests and Kruskal–Wallis tests, with Dunn’s multiple comparisons . Multiple linear regression methods were also used to compare WBA cytokine responses between participant groups, with adjustment for age, sex, overweight/obesity status, residential proximity to roadways, and plasma CRP. Cytokine responses were natural-log transformed for use as a continuous outcome in the regression analyses. Model assumptions were assessed via residual plots and post-regression diagnostics. For all tests, the two-sided p-value threshold for statistical significance was set at 0.05. Statistical analysis and the creation of figures was conducted using STATA 11.2  and GraphPad Prism version 5 .Summary statistics, with measures of central tendency, were computed for each subject group, with asthma subjects dichotomized for “controlled” and “uncontrolled” asthma, based on their respective ACT scores. Asthma Group A contained subjects with controlled asthma and Group B contained subjects with uncontrolled asthma. Between-group differences were assessed with Chi-squared tests for categorical data. Continuous variables were evaluated with non-parametric Mann–Whitney Table 2. Those with asthma were more likely to be male, although there was no difference in age or BMI. Group A subjects had higher cell counts than healthy controls for total WBC, eosinophils, and monocytes. Group B subjects only differed from the control group by their eosinophil count. No participants reported the use of long-term controller medications, such as inhaled corticosteroids. One participant with uncontrolled asthma reported use of oral corticosteroids in the previous 2 weeks and one participant reported active cigarette smoking upon their enrollment in the GASP cohort.Forty-five children from Pampas were enrolled in this study. Whole blood incubations for six of the 45 study participants were discarded due to improper adjustment of temperature settings on the thermoblock incubator. Thus, WBA data was available for 27 subjects with asthma and 12 controls. Summary statistics for these participants are presented in Figure 2 summarizes WBA cytokine responses for all participants (N = 39), and represents the absolute levels detected in the cell-free supernatants of incubations. The TRPM-stimulated release of acute phase inflammatory cytokines was measured at levels significantly above the pyrogen-free media control for all cytokines except IL-4, IFNγ and IL-12p70, which were therefore excluded from further analysis. Overall, the cytokine-stimulating potential of the TRPM extract was less potent than that of the endotoxin control.Table 3 summarizes TRPM, PFW, and endotoxin-stimulated cytokine responses for healthy controls and Asthma Groups A and B . For most cytokines, Group B subjects were associated with the lowest cytokine responses for WBA tests conducted with TRPM extract, while response estimates for Group A subjects were measured at levels between those of Group B and the healthy controls. In particular, IL-8 response levels in TRPM-stimulated blood from Group B subjects were diminished, in comparison to the control group . IL-8 estimates for Group A subjects were also reduced from controls, but to a lesser degree . For WBA tests conducted with endotoxin, no clear trend in cytokine response was evident between the asthma and control groups.Table 4 summarizes Spearman rank-order correlation coefficients between cytokine responses of WBA tests conducted with endotoxin (the positive control) and TRPM. While modest evidence of correlation exists for cytokines such at TNF-α, IL-1β, and IL-6, there is a notable lack of correlation evident for the IL-8 responses to endotoxin and TRPM, whether the study subjects were considered as a single group, or as sub-groups based on asthma control status. Overall, this relationship, or lack thereof, suggests that a participant’s IL-8 response to endotoxin was not predictive of the IL-8 response to the TRPM extract.-0.47= 0.63, p = 0.01) lower responses (geometric mean) to TRPM stimulation than the control group, without asthma. Group A subjects, with controlled asthma, had an intermediate IL-8 response between control subjects and those in Group B. There was no statistically significant difference in TRPM-stimulated IL-8 response between subjects with Group A and those without asthma .Whole blood assay cytokine responses were also investigated using multiple linear regression analysis to evaluate relationships between asthma control status and cytokine release. We observed no difference in the release of TNFα, IL-1β, IL-6, IL-10, IL-2, or IL-13 between the control group and either Groups A or B. For IL-8, subjects from Group B, with uncontrolled asthma, had 37%  in blood samples from all study participants.The present study investigated the systemic immune function of children with and without asthma through a priori hypothesis, we found that TRPM-stimulated WBA cytokine responses were generally equivalent across subject groups, regardless of asthma control status. The most notable exception was for TRPM-stimulated levels of IL-8, where children with uncontrolled asthma were found to have the lowest levels, both before and after adjusting for age, sex, obesity/overweight status. The relationship between IL-8 responses and the asthma control category was also not influenced by plasma CRP levels, or residential proximity to the study area’s major roadway. Similarly, IL-8 response estimates for subjects with controlled asthma were less pronounced than those of the control group, although the difference was not statistically significant. For ex vivo WBA tests conducted with purified bacterial endotoxin, there were no discernable differences between groups, for any of the cytokines that were measured.However, contrary to our in vivo, with effects that include signaling for chemotaxis, especially for neutrophils, and the promotion of angiogenesis , primarily driven by oxidative stress  was positively associated with increased levels of IL-6 from urban PM-stimulated whole blood, suggesting that chronic traffic pollutant exposure may enhance the innate cytokine response to PM in blood from children with asthma.In the context of the WBA model, our analysis is most similar to that of A primary limitation of the 2.5 particles, derived from samples collected in the community where the children lived, over a 2-week period in 2014. In one manner, the evaluation of these children’s systemic responsiveness to TRPM derived from their local environment was a unique strength of this study and the results add to the existing literature base on traffic pollution and pediatric asthma. However, we also acknowledge that the composition of ambient PM is known to vary over time in any single environment, and thus the pro-inflammatory potential of PM may fluctuate as well  biomarkers  may have provided added depth to assess and contrast relationships between WBA cytokine responses, asthma severity, peripheral blood cell counts, and markers of airway inflammation. Previous studies have associated a variety of EBC biomarkers with asthma severity and lung function  While maWe do acknowledge that immune cells in the peripheral circulation are relatively short-lived and have a rapid turnover, which may not accurately mirror the reactivity status of the airways. While our study results indicate that asthma control was associated with a differentially lower IL-8 response to TRPM exposure, additional mechanistic study is necessary (beyond WBA testing) to delineate the pathways activated by complex environmental stimuli, such as the TRPM extract used in this study. Genotyping candidate genes in participant whole blood would also allow for cytokine responses to be evaluated as a function of potential genetic polymorphisms.The literature on cytokine changes in asthma remains a subject of debate, and serum IL-8 is regarded as a poor indicator of disease activity in acute asthma . Our finDepressed IL-8 responses in the whole blood system may also suggest impaired cellular phagocytosis, oxidative burst, and neutrophil chemotaxis, which could compromise the strength of innate immune defenses against microbial infection . If sucha priori study hypothesis. However, for WBA tests conducted with TRPM stimuli, we found that subjects with uncontrolled asthma were associated with lower levels of IL-8, on average, as compared to children without asthma. Although the small sample size of our study limits definitive conclusions, the IL-8 responses from our testing suggest that that asthma control may be associated with the regulation of a key mediator in neutrophil chemotaxis, at a systemic level, following exposure to PM derived from traffic-related sources. However, there remains a need to further evaluate the correlation between acute phase WBA cytokine response and measures of asthmatic and non-asthmatic airway inflammation.This study provided insight toward the capacity of TRPM to elicit the release of acute phase pro-inflammatory mediators from the whole blood systems of Peruvian children. We observed comparatively similar levels of acute inflammatory markers  in TRPM-stimulated whole blood from children with and without asthma, which was contrary to our NH, WC, RG-P, TH, DW, and PB contributed to the grant proposal and conceptual design for this study. KR directed subject recruitment, blood draws, data and field lab management, and the Spanish translation of study protocols. JN and KR trained field staff for the whole blood assay testing and conducted the statistical analysis of the data. JN, NH, AS, DW, TH, and PB prepared the manuscript, which was reviewed and approved by all other authors, prior to journal submission.It is declared that TH holds patents for the whole blood assay pyrogen test used in this study and described in the body of the manuscript. TH also holds patents for whole blood pyrogen tests completed with cryopreserved blood, which are also referenced in the manuscript. TH is also an Associate Editor for Frontiers in Pharmacology. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Proteinuria is well recognised as a marker of chronic kidney disease (CKD), as a risk factor for progression of CKD among those with known CKD, and as a risk factor for cardiovascular events and death among both the general and CKD populations. Which measure of proteinuria is most predictive of renal events remains uncertain.We conducted a prospective study with 144 proteinuric CKD and kidney transplant recipients attending an outpatient clinic of a tertiary care hospital in Australia. We concurrently collected morning spot urine protein-to-creatinine ratio (UPCR), albumin-to-creatinine ratio (UACR) and 24-h urinary protein excretion (24-UPE) from each participant at baseline. The primary outcome was a composite of death, ESKD or > 30% decline in eGFR over 5-years. Secondary outcomes were each component of the composite outcome. For each proteinuria measure, we performed a Cox Proportional Hazards model and calculated the Harrell’s C-statistic and Akaike’s Information Criterion (AIC).After a mean follow-up of 5 years (range 4.4–6), 85 (59%) patients met the primary composite outcome including 23 deaths (16%). The multivariable analysis showed strong evidence of an association between each log-transformed proteinuria measurement and the primary composite outcome. . The C-Statistic were similar for all three measures of proteinuria  as were the models’ AIC . For secondary outcomes, no proteinuria measure was significantly associated with death alone (, whilst UACR and 24-UPE demonstrated marginally better association with ESKD and > 30% decline in eGFR respectively. .In patients with stable, non-nephrotic CKD, all three measures of proteinuria were similarly predictive of hard clinical endpoints, defined as a composite of death, ESKD and > 30% decline in eGFR. However, which measure best predicted the outcomes individually is less certain. Proteinuria is an established marker of kidney damage, a risk factor for progression of chronic kidney disease (CKD) and a potent risk factor for cardiovascular events and mortality amongst the diabetic and non-diabetic population , 2. PrecWe conducted this single-centre prospective longitudinal study at a metropolitan tertiary care teaching hospital in Sydney, Australia. At baseline in 2008–2010, we studied 270 CKD and kidney transplant patients collecting spot UACR, UPCR and 24-h urinary protein excretion as previously described , 13. In We obtained the following baseline variables at recruitment: age, sex, ethnicity, cause of CKD, eGFR, serum creatinine, kidney transplant status, angiotensin converter enzyme inhibitor or angiotensin receptor blocker use, history of diabetes mellitus (DM) , hypertension (defined by a history of diagnosed hypertension or the use of antihypertensive medications) and smoking history. The predictor variables were baseline UPCR, UACR and 24-h urinary protein excretion. The primary outcome was a composite of all-cause death, ESKD requiring dialysis or preemptive kidney transplantation or > 30% decline in eGFR. We chose a composite outcome as the primary outcome, after balancing the consideration of statistical precision, with the clinical significance of the composite outcome . SecondaThe first author and data assistant manually searched the electronic medical record database of the local area health district, supplemented by the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) to obtain dates of death, dialysis commencement and patient disposition at five years. If a patient was alive and had not reached ESKD, we recorded their serum creatinine and eGFR within 3 months of the 5-year follow-up date. The Sydney Local Area Health district ethics committee approved the study (protocol no. X16–0269).For descriptive statistics, we reported normally distributed continuous variables as means (standard deviation [SD]) and skewed continuous variables as medians (interquartile range [IQR]). For categorical data, we reported absolute numbers and percentages. We performed a Cox proportional hazards model for the primary composite and individual secondary outcomes. Because the data for the predictor variables UPCR, UACR and 24-h total protein excretion were highly skewed, we performed log-transformations on these variables. We excluded cases with missing predictor or outcome variables in the analysis.p-value of less than 0.1 in the univariable analysis. To check whether the association between the predictor variables and the primary outcome was modified by whether the patient had a functioning transplant at the time of study enrolment, we created an interaction term between each of the predictor variables and the transplant status. We checked the proportional hazard assumption of each model by plotting the Schoenfield residuals against time. We considered a two-tailed P value of < 0.05 as statistically significant. We performed a sensitivity analysis by excluding patients who had a functioning kidney transplant at study recruitment. We assessed the linearity of each predictor variable using Martingale Residuals and by plotting the residuals against the predictor variable using LOWESS . We analysed the data using Stata, version 14.1 .To decide which measure of proteinuria is most predictive of the primary composite outcome, we constructed a Cox regression model and calculated the Harrell’s C-statistic and Akaike’s Information Criterion (AIC) for each measure of proteinuria. The C-statistic is a measure of predictive power (where 0.5 = random concordance and 1 = perfect concordance) and the AIC is a measure of the model’s goodness-of-fit. For the Cox model, we first performed a univariable analysis using the predictor variables. For the multivariable models, we added variables that were known risk factors for progression of CKD including age, baseline eGFR, hypertension and diabetes mellitus and any predictor variable with a Figure n = 81, 56.3%), followed by Mediterranean  and Asian . The median baseline eGFR estimated by the CKD-EPI equation was 44 ml/min/1.73m2 (IQR 28–65.5 ml/min/1.73m2). 50 (34.7%) of the patients had microalbuminuria (3–30 mg/mmol), whilst the majority of the patient [79 (54.9%)] had macroalbuminuria (> 30 mg/mmol) . The models are summarised in Table 2 and no history of hypertension or diabetes mellitus. With increasing baseline albuminuria and proteinuria, there is a separation of curves in both measurements of proteinuria.Univariable analysis of log UPCR, UACR and 24-h protein excretion showed very strong evidence of association with the primary composite outcome . These are summarised in Table p = 0.3, log-UACR = 1.19 (1.00–1.55), p = 0.2, log-24-h protein excretion = 1.19 (0.83–1.71), p = 0.3]. Of the three measurements, 24-h protein excretion showed the strongest evidence of association with > 30% decline in eGFR per log-increment [24-h protein excretion adj HR = 1.54 (1.13–2.09) p = 0.005]. Finally, all three measurements were strongly associated with ESKD in the univariable analysis, with UACR and 24-h protein excretion remaining significant in the multivariable model after adjusting for age, baseline eGFR, diabetes and hypertension. , p <  0.001 and log-24-h protein excretion adj HR = 1.43, (1.09–1.88), p <  0.001]. All baseline measures of proteinuria were also similarly predictive of the primary outcome (Harrell’s C statistic 0.77 vs. 0.78 vs 0.78 respectively) , In this single-centre study of 144 patients with CKD, our study showed that all three measures of proteinuria were strongly associated with the composite outcome of death, ESKD or > 30% decline in eGFR and were similarly predictive of clinically relevant renal outcomes as demonstrated by a similar Harrell’s C statistic .Proponents of the untimed or spot proteinuria measurement method point out that UPCR is a reasonably accurate indicator of 24-h proteinuria and is a simple and less time-consuming way of measuring proteinuria excretion . On the Our study is unique due to the availability of both spot and 24-h proteinuria measures within the same individual. Only a handful of studies have directly compared all three measures of proteinuria in their ability to predict clinically significant events. These are summarised in Table Our study showed some mixed results on individual secondary outcomes, which should be interpreted in the context of a small number of events for each outcome. In the multivariable model, we did not detect a significant association between death and any of the proteinuria measures. For ESKD, we found a significant association with UACR and 24-protein excretion. In contrast, only 24-h urinary protein excretion was significantly associated with a >  30% decline in eGFR in the multivariable model. Spot UACR has been conclusively shown to be associated with both death and ESKD risk in the CKD prognosis consortium meta-analyses which included both the clinical and general population cohorts , 2, 23. Our study is limited by being a single-centre study with a relatively small number of patients, the majority being white males. Despite 270 patients initially enrolled, only 144 completed all three baseline proteinuria measurements. We measured eGFR change over 5-years, rather than 2-years, which is a generally more accepted surrogate endpoint . The proIn conclusion, our study supports the current clinical practice of collecting spot UACR or UPCR for prognostic information in patients with stable CKD with non-nephrotic range proteinuria. All three measures of proteinuria were similarly predictive of hard clinical outcomes over 5 years, defined as a composite of death, ESKD and > 30% decline in eGFR. The evidence is less certain when we consider each outcome individually. In a bid to assess the utility of UACR or UPCR as surrogate measures of hard outcomes, future research should focus on whether changes in the quantity of proteinuria over time in response to treatment or natural history, is predictive of a similar change in the risk of hard outcomes.


Background. Hemodialysis related hemodynamic instability is a major but an underestimated issue. Moreover, cardiovascular events are the leading cause of morbidity and mortality associated with blood pressure in hemodialysis patients. However, there have been many controversies regarding the role and management of hyper- and/or hypotension during hemodialysis that needs to be addressed. Objective. To critically review the available published data on the atypical role of hyper- and/or hypotension in cardiovascular associated morbidity and mortality in patients on hemodialysis and to understand the discrepancies in this context. Methods. A comprehensive search of literature employing electronic as well as manual sources and screening 2783 papers published between Jan 1980 and Oct 2015 was conducted to collect, identify, and analyze relevant information through peer-reviewed research articles, systematic reviews, and other published works. The cardiovascular events, including accelerated atherosclerotic cardiovascular disease (ASCVD), stroke, heart failure, myocardial infarction, myocardial ischemia, and stress induced myocardial dysfunction, leading to death were considered relevant. Results. A total of 23 published articles met the inclusion criteria and were included for in-depth review and analysis to finalize a comprehensive systematic review article. All the studies showed a significant association between the blood pressure and cardiovascular disease events in hemodialysis patients. Conclusions. Both intradialytic hypertension/hypotension episodes are major risk factors for cardiovascular mortality with a high percentage of probable causality; however, clinicians are faced with a dilemma on how to evaluate blood pressure and treat this condition. In chronic kidney disease (CKD) the kidney function is gradually reduced over a period of time. As a result, glomerular filtration rate (GFR) of the patient drops to <60 mL/minute and the albumin-to-creatinine ratio of patient's urine becomes >30 mg/g. The occurrence of a total, irreversible, and permanent kidneys' failure is termed as end-stage renal disease (ESRD) where fluid is retained by the patient's body resulting in the accumulation of harmful wastes. Consequently, the ESRD patients need suitable treatment in order to replace and compensate for the work of such failed kidneys.The prevalence of CKD and ESRD is increasing worldwide. According to the US National Kidney Foundation, 26 million American adults suffer from CKD, the precursor to ESRD, and millions more are at increased risk . It has Cardiovascular disease is the main cause of death in patients with ESRD , 6. It iZager et al. described a “U”-shaped relationship between postdialysis systolic blood pressure (SBP) and mortality  and in areverse epidemiology” which states that “conventional risk factors of cardiovascular disease and mortality in the general population such as body mass, serum cholesterol, and blood pressure are also found to relate to outcome in maintenance dialysis patients, but often in an opposite direction.”Kalantar-Zadeh and his coworker –23 preseChao et al. reported that safe and smooth achievement of ultrafiltration and solute removal goal in chronic dialysis patients is prohibited by a decrease of systolic or mean blood pressure  to a certain level. They have referred to various studies elucidating the potential mechanisms involved in the development of intradialytic hypotension, including excessive ultrafiltration and loss of compensatory mechanisms for blood pressure maintenance . HoweverThe aim of the current systemic review is to summarize and critically review the available published data related to the atypical role of hyper- and/or hypotension in cardiovascular associated morbidity and mortality in patients on hemodialysis, to understand the discrepancies in this context, and to, possibly, propose suitable strategies for management of patient care with special reference to blood pressure causing cardiovascular events leading to death in hemodialysis patients.The protocols and checklist of PRISMA  and PRISA comprehensive search of literature employing electronic as well as manual sources, published between Jan 1980 and Oct 2015, was conducted in order to collect, identify, and analyze relevant information and knowledge existing in the instant area of our search through relevant peer-reviewed research articles, systematic reviews, and other published works related to blood pressure and cardiovascular events, such as stroke, myocardial infarction, and heart failure, in hemodialysis patients.A strategic, systematic, and comprehensive way of search techniques was applied, by the first author in independent capacity, to extract relevant articles of interest employing electronic database system such as PubMed, International Pharmaceutical Abstracts (IPB), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Web of Science, Scopus, Current Content, Embase, All Evidence-Based Medicine (EBM) Reviews , and Google Scholar, using the Boolean operators for combinations of key words and terms relevant to the topic of this review article, such as patient care management in hemodialysis, cardiovascular morbidity and mortality in hemodialysis, management of cardiovascular events in hemodialysis patients, management of cardiovascular events and blood pressure in hemodialysis patients, the role of hypertension in cardiovascular associated morbidity and mortality in hemodialysis, the role of hypotension in cardiovascular associated morbidity and mortality in hemodialysis, the controversial role of hyper- and/or hypotension in cardiovascular events in hemodialysis patients, end-stage renal disease and hemodialysis, end-stage renal failure and hemodialysis, stage 5 CKD and hemodialysis, advanced CKD, and hemodialysis. Keeping in view the difficulty in translating our specific search questions into concise key word or search terms, all other possible strategies were also exhausted in order to capture all that relevant information that might have been skipped in the database searches. Moreover, the bibliographies of selected articles were reviewed for the said purpose. In addition to the above-mentioned search using electronic database systems, manual sources were also exploited for the said purpose. Similarly, several academic researchers and professional nephrologists were contacted for help. For getting access to full-text research/review articles the library and E-journals facility of University Sains Malaysia (USM) were used. In addition to these, the Higher Education Commission (HEC) sponsored digital library facility of Quaid-i-Azam University (QAU), Islamabad, was also utilized as alumni of QAU. Finally, abstracts and proceedings of several important meetings, conferences, workshops, and seminars organized by various renal societies of nephrology and other relevant bodies or individuals were also reviewed to get the most in this context.The articles were identified by the principal investigator/first author, independently, through all the electronic sources. After removal of the duplicates, the data were subjected to a two-staged screening process comprised initially of screening by titles followed by abstract screening. This process screened out a major fraction of the initially identified articles from the electronic database systems to be excluded, leading to a smaller sample of leftover articles being qualifying for the 3rd stage of full-text screening process. Eligibility assessment was conducted by Amjad Khan and Amer Hayat independently in an unblinded standardized manner. Disagreements between reviewers were resolved by consensus.For the purpose of this systemic review, the search was limited to be conducted within a specific period of publication (Jan 1980 to Oct 2015), including the studies with a minimum of 100 participants, published in English, and containing appropriate information and knowledge available in the area of our search question through relevant peer-reviewed research articles, systematic reviews, and other published works related to hemodialysis patients. All other studies lying outside the above narrated range and purview specified for this systematic review were excluded. The screening process has been summarized through PRISMA flow diagram as illustrated in To assess the study quality, a data extraction sheet was developed and refined after testing on ten randomly selected studies. Amjad Khan extracted the data from included studies and Amer Hayat checked the extracted data. Disagreements were planned to be resolved by mutual discussions; however, any such disagreement did not arise.n = 2778 + 5 = 2783). After removal of the duplicates (n = 997), the data (n = 1786) were subjected to a two-staged screening process comprised initially of screening by titles followed by abstract screening. This process screened out a major fraction of the initially identified articles from the electronic database systems to be excluded (n = 1694) leading to a smaller sample of leftover articles (n = 92) qualifying for the 3rd stage of full-text screening process. After screening of the 92 full-text articles, it was found that only 23 articles  and mortality caused by cardiovascular events in patients on hemodialysis. Moreover, these studies have also intensively evaluated relationship between different types of BP measurements and CVD based mortality in hemodialysis patients. Therefore, it was decided to divide and report the findings of this study into various parts as described below.Among the 23 articles included for qualitative synthesis , 12 artiOnly one article (s # 3) reports the strong association of hypotension, measured either predialysis or postdialysis, with increased mortality in patients on hemodialysis.Among the 23 reviewed articles, 10 studies  reported that both hyper- and hypotension are found to be associated with cardiovascular events based morbidity and mortality in patients on hemodialysis.In 18  out of the 23 articles reviewed, the blood pressure was measured at standardized hemodialysis units, that is, dialysis centers , while the remaining 5 studies  have discussed the blood pressure measurements obtained at home, either by the patient or using an ambulatory blood pressure monitor, and their relationship with CV morbidity and mortality.Management of patient care in hemodialysis patients is an important but complex task on the part of healthcare team members. In this connection, the randomized controlled trials conducted for reducing primary outcomes of cardiovascular disease events, mortality, and morbidity in such patients have so far not been proven very successful. The area of major concern in the management of hemodialysis patients as related to the above referred outcomes includes the cardiovascular disease burden, control of hyper- and/or hypotension, anemia, inflammation, and abnormalities in mineral metabolism. At times, these issues are further complicated by conflicting and controversial data obtained from observational and randomized controlled trials. The main reason for such controversies could be the limited treatment options for reducing these endpoints in maintenance hemodialysis patients. Therefore, for continuous management of advanced care in patient on hemodialysis it is essential to conduct, in future, well-planned randomized controlled trials in order to meet the goal of improving outcomes. Such trials should consider new therapies to better target these factors, consideration of additional risk factors that have not been well tested to date, and therapies with new targets.In the light of the literature studied, it is now well established that during hemodialysis treatment the changes occurring in hemodynamics act as a marker for higher risk of patient morbidity and mortality. The most common clinical problems include developments and management of hypertension or hypotension.It has been reported that accelerated atherosclerotic cardiovascular disease (ASCVD) has close association with high blood pressure  and thatIn contrast, another study showed that a blood pressure of 140/90 was associated with a decreased risk for left ventricular hypertrophy but an increased mortality risk . AccordiApart from these, some investigators found and reported a “U”-shaped relationship between postdialysis systolic blood pressure (SBP) and mortality . Accordi modest intradialysis declines in systolic BP (SBP) (−30 to 0 mm Hg) were associated with the best survival, whereas a pre- to postdialysis decline of less than −30 mm Hg and any pre- to postdialysis increase of more than zero mm Hg were associated with higher mortality. The greatest survival was associated with a pre- to postdialysis change in SBP of −14 mm Hg. They observed similar results for diastolic BP, too.In addition to the above, Park et al.  describereverse epidemiology” [The controversial theory of “miology” –23 repor “reverse epidemiology” of hypertension, which has logically raised concerns of the patients and practitioners regarding lowering of BP among hypertensive patients on hemodialysis.As described above in the results section, the authors of some studies have attributed the cardiovascular associated morbidity and mortality to the hypertension while others have related the same to hypotension in case of patients on hemodialysis. In fact high blood pressures measured either before or after dialysis are either not associated or minimally associated with increased mortality. In addition to this, the association of low BP and cardiovascular related mortality in hemodialysis is further magnified when BP is considered as a time-dependent covariate. Moreover, the phenomenon of lower BP being associated with increased morbidity and mortality in hemodialysis patients has been referred to asThese facts clearly indicate that proper control of blood pressure is critical in dialysis patients and its importance can never be overemphasized because the risk of other comorbidities will increase under such extreme changes. Therefore, proper knowledge and awareness is required against the effect of such abnormalities and to help in preventing their complications and recurrence .n = 997), only 1786 remained for screening and further processing and finally only 23 could meet the inclusion criteria. Moreover, we could not conduct any meta-analysis and the articles were therefore analyzed descriptively with an emphasis on trends because of wide variability in study populations and also due to different methods adopted for the measuring outcomes. In addition to the above, while conducting such studies, a judicial analysis and careful assessment of the baseline comorbidities are of utmost importance because the relationship between BP and mortality is stronger in diabetics than in nondiabetics [The major limitation of the instant review could be attributed to the possible but inadvertent selection biasness of the retrieved articles, although all possible efforts were made to ensure the inclusion of all relevant and exclusion of all the irrelevant articles. Accordingly, a total of 2783 articles could be retrieved from the databases; however, after removal of the duplicates (iabetics . HoweverBased on the critical review of the shortlisted articles , it was However, it is hereby recommended that in-depth studies are required to further explore the complex physiological and dialysis-related mechanisms influencing BP and also the yet poorly understood association between hyper- and/or hypotension and cardiovascular disease events for better management of BP in patient population on hemodialysis while focusing on both generally applicable plans and individualization in order to determine the BP target and the treatment regimen.The study of reviewed articles showed that both hypertension and hypotension episodes are major risk factors for mortality with a high percentage of probable causality. The clinicians are faced with a dilemma on how to evaluate blood pressure and treat this condition. Hypertension is common, difficult to diagnose, and poorly controlled among patients with ESRD. Patients with CKD and regular hemodialysis who experience moderate or severe intradialytic hypotension have significantly higher prevalence of myocardial ischemia and stress induced myocardial dysfunction than those who experience no or mild intradialytic hypotension. It is well established that there exists a relationship between pre- to postdialysis changes in BP and mortality. Both increases and decreases in BP from before to after dialysis would be associated with all-cause and cardiovascular mortality, independent of predialysis BP levels. Topics of major concern in the management of maintenance hemodialysis patients include the overall cardiovascular disease burden, blood pressure control, anemia, abnormalities in mineral metabolism, and inflammation. Overall, treatment options for reducing these endpoints in maintenance hemodialysis patients are limited, and future randomized controlled trials are essential to continuing to advance care in this population, with the goal of ultimately improving hard outcomes. Future trials should consider new therapies to better target these factors, additional risk factors that have not been well tested to date, and therapies with new targets, including inflammation. Further studies with larger numbers could be more conclusive.