To assess the effects of single nucleotide polymorphisms (SNPs) on blood pressure control in patients with obstructive sleep apnea (OSA).JAG1, GUCY1A3-GUCY1B3, SH2B3, and NPR3-C5orf23 genes with systolic and diastolic blood pressure  in 1179 adults evaluated for OSA with overnight polysomnography. Genotyping was performed by unlabeled probe melting analysis.This prospective observational cohort study, conducted between 2004 and 2014, examined the associations of SNPs of JAG1 genotype was associated with SBP and DBP: compared with AA homozygotes, G allele carriers (pooled GG and AG genotype) had significantly higher morning SBP  and morning and evening DBP ; the differences remained significant after the correction for multiple SNPs testing. In multivariate analyses, oxygen desaturation index and JAG1 genotype independently predicted morning SBP  and DBP , and evening SBP  and DBP .The patients were predominantly male . Only JAG1 genotype is related to blood pressure control in OSA: G allele was associated with higher morning and evening SBP and DBP.This is the first replication study of the SNPs recently linked to arterial hypertension in general population by genome-wide association studies. Our findings suggest that  Blood pressure is a multifactorial trait. International guidelines for the management of arterial hypertension recognize obstructive sleep apnea (OSA) as the most prevalent cause of secondary hypertension  and the Another factor that profoundly affects blood pressure control is heredity. Approximate heritability of blood pressure ranges between 30%-50% . The matSH2B3 gene, rs1327235 of the JAG1 gene, rs13139571 of the GUCY1A3-1B3 gene, and rs1173771 of the NPR3c5orf23 gene) in individuals referred to a sleep laboratory for OSA evaluation. The selection of four distinct SNPs was guided by several previous studies that identified the relationships between these polymorphisms and blood pressure, arterial hypertension, and coronary artery disease in general population as summarized by Waken et al  for a diagnostic sleep study were recruited consecutively between 2004 and 2014. They were all clinically stable adults (age over 18 years) with or without OSA. Exclusion criteria were respiratory failure, arterial hypertension secondary to a disease different from OSA, and any cardiovascular instability including accelerated hypertension. The study was approved by the L. Pasteur University Hospital Ethics Committee, and all patients gave written informed consent.All patients underwent overnight polysomnography , which consisted of electroencephalography (EEG), electrooculography, electromyography, thoracic and abdominal impedance belts, thermistor flowmeter for nasal and oral airflow, microphone for snoring, and pulse oximetry. Records were scored manually following the criteria of the American Academy for Sleep Medicine (AASM) 2007 guidelines and 2012 update .Apnea was defined as a reduction of airflow of ≥90% from the baseline with duration ≥10 s; hypopnea was defined as a reduction in airflow of ≥50% of baseline for ≥10 s, followed by a decrease in oxygen saturation for ≥3%, arousal, or both. Alternatively, hypopnea was identified if reduction of airflow ≥30% from the baseline was present and accompanied with a decrease in saturation ≥4%. Apnea/hypopnea index (AHI) was defined as the total number of apneic and hypopneic events per hour of sleep. Oxygen desaturation index (ODI) was calculated as the number of episodes of reductions in oxygen saturation of ≥3% per hour of sleep, and arousal index was used as a marker of sleep fragmentation characterized as the number of arousals on EEG recording per hour of sleep.Patients with AHI less than five episodes per hour had no OSA. In patients diagnosed with OSA, its severity was classified based on AASM guidelines, with AHI≥5 and <15 episodes/h labeled as mild OSA, AHI≥15 and <30 episodes/h as moderate OSA, and AHI≥30 episodes/h as severe OSA .Blood pressure was measured in a sitting position by using a certified manometric device in the evening, immediately before the montage of polysomnographic leads after at least of 10 minutes of no physical effort  are shown in TM Software 4.1. Genotyping success rate for all examined variants was 100%, and duplicate genotyping concordance was 100% (5 samples for each genotype).Peripheral blood samples for leukocyte DNA extraction were collected by a trained nurse by venipuncture of the cubital vein in the morning after diagnostic polysomnography. DNA was extracted with the QIAamp DNA Blood Mini QIAcube Kit according to the manufacturer’s instructions on the QIAcube – robotic workstation for automated purification of DNA, RNA, or proteins . Four variants of interest were analyzed by high-resolution melting analysis (HRMA) after real-time polymerase chain reaction in the presence of LCGreen Plus dye  on Eco Real-Time PCR System . Specifically, post hoc pair-wise comparisons between groups with different OSA severity. Differences in proportions between groups were analyzed with χ2 test. A two-tailed P-value of <0.05 was considered significant for comparisons between groups with different OSA severity. The alleles of the selected SNPs that confer an increase in blood pressure were referenced according to the genome database in the project Ensebml GRCh38 . Graphic outputs of the blood pressure comparisons between genotype groups were created with SigmaPlot version 8  and Microsoft Powerpoint . Linear relationships between blood pressure and indices of OSA severity were analyzed by calculating the Pearson correlation coefficient. In multivariate analyses, multiple linear regression models were used with blood pressure as a dependent variable, and age, sex, body mass index (BMI), antihypertensive use, ODI, and genotype as independent variables. Associations in the linear regression models are presented as nominally significant (P < 0.05). All analyses were carried out using SPSS, version 14 .Normality of the distribution was assessed by Kolmogorov-Smirnov test. The data are presented as mean ± standard deviation (SD). Differences between groups were analyzed using one way ANOVA for parametric variables and ANOVA on ranks for nonparametric variables. Holm-Sidak test was used for l GRCh38 . For comhttp://www.oege.org/software/hwe-mr-calc.shtml). The genotypes were considered to be distributed as expected under Hardy-Weinberg equilibrium if the calculated χ2 was <3.84   .P value >0.05 for each respective genotype).The study involved 1179 participants (821 or 69.6% men) with mean age 52.0 ± 11.4 years  and mean AHI 34.4 ± 30.9 episodes/h , arousal index , desaturation index , and time spent in saturation under 90% , with P < 0.001 for all. Evening SBP and DBP were positively correlated with AHI , arousal index , and desaturation index , with P < 0.001 for all, and evening SBP was correlated with time in desaturation under 90% .Morning and evening SBP and DBP increased with increasing OSA severity, with the highest values in patients with severe OSA . MorningJAG1 gene. Alleles A and G of JAG1 gene polymorphism were distributed according to Hardy-Weinberg equilibrium. Sex distribution, age, BMI, AHI, ODI, antihypertensive medication use, and the proportion of patients according to OSA severity were similar in the two JAG1 genotype groups (Significant differences in SBP and DBP were observed between the genotype groups of polymorphism in the e groups .JAG1 polymorphism genotypes were associated with blood pressure in the entire cohort (P = 0.009), morning DBP , and evening DBP  than allele A homozygotes.e cohort . After aJAG1 polymorphism genotype groups. G allele carriers with severe OSA had significantly higher morning and evening SBP and DBP  than G allele carriers with no OSA. In addition, AA homozygotes with severe OSA had higher morning SBP and DBP (P < 0.05 for both), and evening SBP (P < 0.05) compared with AA homozygotes with no OSA  and blood pressure were observed (No significant associations between the further three tested SNPs (observed .JAG1 gene had significantly higher morning SBP and DBP, and evening DBP than AA homozygotes. The association of JAG1 genotype with blood pressure was independent of age, sex, BMI, and use of antihypertensive medication. Moreover, our data indicate that OSA severity has deleterious effects on blood pressure independently of the effect carried by the JAG1 genotype. Previously, several GWASs reported links between JAG1 genotype and increased SBP and DBP, and higher odds of hypertension and coronary artery disease in the general population (JAG1 gene and blood pressure control, and to suggest that the rs1327235 polymorphism of JAG1 gene may be involved in blood pressure regulation in patients with OSA.The present genetic association study revealed that among patients with suspected OSA, carriers of the risky G allele of the rs1327235 polymorphism of JAG1 genotype groups were 2.0-4.5 mm Hg for SBP and 0.9-3.5 mm Hg for DPB across different OSA severity groups. Interestingly, in a GWAS, the mean estimated effect size of singular polymorphism was 0.5 mm Hg for DBP and 1.0 mm Hg for SBP (The prevalence of hypertension in OSA ranges from 30 to 85%, while the prevalence of OSA among hypertensive patients is 40% . The ass for SBP  in their2-adrenergic receptor was also investigated: heterozygosity for the β2-adrenergic receptor was associated with a lower rate of post-myocardial infarction survival in patients with OSA and a high cardiovascular risk profile. However, functionally relevant polymorphisms of β2-adrenergic receptor did not modify blood pressure induced by OSA (1-adrenergic receptor gene Arg389Arg genotype was associated with an increased prevalence of hypertension in individuals with mild OSA (Several genetic association studies have reported links between genetic background and arterial hypertension in OSA. Lavie et al  reportedd by OSA . In anotmild OSA . The resmild OSA , in anotmild OSA . Interesmild OSA  observedmild OSA  reportedJAG1 gene polymorphism and morning and evening SBP and DBP in patients with OSA confirm and extend the previous results on the role of JAG1 genotype in blood pressure control. JAG1 gene is localized on chromosome 20. It codes jagged 1 protein that serves as a ligand for multiple Notch receptors. Notch signaling is an evolutionary conserved short-range intercellular pathway with a role in many essential processes, such as cell fate determination during embryonic development, vascular morphogenesis, angiogenesis, phenotypic switching, and vascular remodeling after injury (JAG1 has been implicated in the pathogenesis of pulmonary arterial hypertension by aggravating pulmonary vascular remodeling both in animal studies (JAG1 genotype and systemic hypertension might parallel those observed in pulmonary hypertension, but experimental data for this hypothesis are lacking. Of note, a human clinical condition with autosomal dominant heritability, termed Alagille syndrome, involves both major frameshift mutations of JAG1 gene and systemic arterial hypertension (JAG1 genotype and blood pressure control remain to be elucidated.Our study was the first to analyze, in patients with OSA, the potential role of polymorphisms originally identified in GWASs as being significant in blood pressure regulation in general population. Therefore, our results on the associations between the r injury . Recentl studies  and in p studies . Mechanirtension . NeverthJAG1 gene in blood pressure control in patients with OSA, investigation of the underlying mechanisms of the observed association was beyond the scope of the present study. Therefore, the present results should be considered hypothesis-generating, and further studies are needed to analyze the relationships between the JAG1 gene polymorphism and blood pressure control in OSA in more detail.The main strength of our study is a distinct cohort of patients who underwent full attended polysomnography, which is a fundamental method in diagnosing sleep disordered breathing. Nevertheless, several limitations to the current study need to be also acknowledged. First, only a minority of the genetic variants significantly associated with SBP, DBP, and hypertension in GWAS was near a gene with a recognized role in blood pressure control . MoreoveJAG1 genotype is associated with higher morning and evening SBP and DBP in patients referred to sleep laboratory for the evaluation of suspected OSA. Large-scale genetic studies are needed to elucidate the impact of susceptibility polymorphisms that contribute to hypertension in such patients.In conclusion, the present study suggests that the risky G allele in the


To compare kidney size  and kidney function outcomes between patients with tuberous sclerosis complex (TSC) and rAML treated and not treated with everolimus.Medical charts of adults with TSC-associated rAML followed at a specialty medical center in the Netherlands (1990–2015). Included patients treated with everolimus  and non-treated patients .Percent change in kidney size and kidney function from the index date to the best measurement in the two years post-index date (best response) compared between patients treated and not treated with everolimus.Compared with non-treated patients, significantly more everolimus-treated patients experienced a reduction in the size of their largest kidney in the two years post-index date . Also, there was a tendency towards more improvement in the estimated glomerular filtration rate (eGFR) among the everolimus-treated patients .The study results suggest that everolimus is effective in controlling and even reversing the growth of the kidneys, used as a proxy for rAML size, as well as preserving or improving kidney function in patients with TSC and rAML treated in a real-world, observational setting. Tuberous sclerosis complex (TSC) is a disorder characterized by the growth of non-malignant tumors in various body organs . ApproxiMedical charts of patients with TSC treated from 01/01/1990 to 31/12/2015 at University Medical Center Utrecht (UMCU), a kidney tumor major specialty center in the Netherlands, were reviewed.TSC diagnosis was based on the Revised 1998 Criteria . All paOf 371 patients with TSC-associated rAML managed at UMCU, 33 everolimus-treated patients and 39 patients not treated with mTORi were included in the study . This stAll patients had kidney size and/or kidney function assessments both in the year before and two years after an index date defined as (a) date of everolimus treatment initiation for everolimus-treated patients, and (b) date with kidney size or kidney function assessment  for non-treated patients. Patients with embolization or nephrectomy after the index date were excluded from the current study as these procedures could have confounded the kidney size and kidney function measurements post-index. When multiple potential index dates were available for a given outcome, logistic regression-based propensity scores models to select a single index date corresponding to the date when the patient had the highest propensity of receiving everolimus treatment. Since everolimus was first used for TSC at UMCU in 2008, the index date had to be in 2008 or afterwards. Because everolimus use in patients with rAML stage < 4 may target non-renal TSC manifestations, patients were also required to have rAML stage ≥ 4 at the index date . Of 33 eStudy outcomes were defined as the change in kidney size and kidney function from the index date  to the best value in the two years post-index . OutcomAnalyses were performed separately for each outcome. Patient characteristics and outcomes were described using descriptive statistics. Where applicable, outcomes were compared between cohorts using Fisher, chi-square, or t-tests. Statistical analyses were performed using SAS statistical software, version 9.3 .2, and stage 1 CKD 63.0% and 72.4%, respectively , significantly more everolimus-treated patients experienced a kidney size reduction compared with non-treated patients . The average change in kidney size was -8.8 mm for everolimus-treated patients and -1.7 mm for non-treated patients (p = 0.01). Among patients with a kidney size reduction, the magnitude of the reduction was similar in the two cohorts  and there were no statistically significant differences between cohorts in the proportion of patients with CKD of different stages  compared with the non-treated patients (median observation period: 24 months) but the difference did not reach statistical significance . In 37% of the everolimus-treated patients, the kidney size reduction amounted to ≥ 10%. More everolimus-treated patients also experienced an improvement in eGFR compared with non-treated patients (55.6% vs. 33.3%). These results strongly suggest that everolimus can lead to a reduction in kidney size–and thus potentially in rAML volume–, the preservation and improvement of kidney function, and the protection of organ loss.Real-world findings from the current study substantiate the results of the phase III EXIST-2 trial, in which rAML volume was reduced in 42% of everolimus-treated patients versus 0% of placebo-controlled patients . The perIn the current study, 37.9% of non-treated patients experienced kidney size reduction. Although unexpected, this could be explained by several factors. First, measurement variations may occur between consecutive assessments in the same patient . Indeed,A distinctive feature of the present study is the assessment of kidney function following everolimus treatment, an outcome not included in the EXIST-2 trial. Findings of this study showed a tendency towards less worsening, and possibly improvement, in kidney function in everolimus-treated patients compared with non-treated patients, even though differences between the two cohorts did not reach statistical significance. However, it is very possible that the current study lacked the statistical power to detect small, but clinically meaningful differences. The results of the EXIST-2 trial  current Overall, the current study provides real-world evidence of the relationship between everolimus and kidney size reduction in patients with TSC-associated rAML in a more advanced stage than previously reported. Furthermore, it also provides evidence of a potential link between everolimus and improved kidney function. By reducing rAML volume  and kidnSeveral limitations should be considered. First, this study included patients followed at a specialty center and results might not be generalizable to the entire TSC population. Second, kidney size was used as a proxy for total rAML size and the extent to which the two measures correlate is unknown. However, rAMLs located on the upper/lower kidney poles are likely captured well by the kidney size measure. While presence of renal cysts may also influence the kidney size, current evidence shows that everolimus has no effect on cysts in patients with TSC . TherefoThe results for this longitudinal observational study suggest that everolimus is effective in controlling and even reversing kidney growth, used as a proxy for rAML size, as well as preserving or improving kidney function.


P < 0.0001) in HR (70.4 ± 10.7 bpm to 91.6 ± 14.8 bpm), SBP (118 ± 8 mmHg to 138 ± 14 mmHg) and DBP (71 ± 7 mmHg to 91 ± 11 mmHg). Participants’ EDV (101.1 ± 15.8 ml to 104.2 ± 19.3 mL), ESV (38.7 ± 9.1 mL to 40.3 ± 11.6 mL), SpO2 (99.5 ± 0.79% to 99.5 ± 0.77%) and EF (61.9 ± 5.9% to 60.9 ± 6.4%) were only slightly changed (P > 0.05). However, cardiac output (4.3 ± 0.9 L/min to 5.4 ± 1.4 L/min) and cardiac index (3.7 ± 0.8 L/min per m2 to 4.5 ± 1.4 L/min per m2) increased significantly (P < 0.0001). We conclude that sympathetic stress induced by cold pressor test has marginal effect on ejection fraction and fractional shortening while increasing cardiac output and cardiac index in young healthy adults.There is a dearth of studies investigating the effect of sympathetic activation on left ventricular function. This study aimed to investigate the effect of sympathetic autonomic stress on left ventricular function in young healthy adults. Fifty‐six normotensive healthy participants (age 23.55 ± 3.82 years) took part in the study after giving informed consent. After obtaining baseline measurements, heart rate (HR), blood pressure (BP), peripheral saturation of oxygen (SpO2) and left ventricular function (assessed by means of ejection fraction (EF) obtained by transthoracic 2‐D echocardiography) were determined before and following sympathetic activation using cold pressor test (CPT). Exposure to CPT led to significant increase ( The cardiovascular system is prone to being affected by stress caused by many factors experienced in modern life. Stress elicits changes in sympathetic–parasympathetic balance  is an experimental cold stimulus used clinically as a stress test to evaluate cardiac autonomic function and to assess left ventricular function  by the Health Research and Ethics Committee of the Lagos State University Teaching Hospital (LASUTH), Ikeja. The study was carried out in accordance with the latest revision of the Fifty‐six (56) normotensive young healthy participants took part in the study after informed consent was obtained from them. The participants were informed of the protocol and details of the study before signing the consent form. Questionnaires were given to all of them where they stated if they had any family history of hypertension.2. They had no history of chest pain and they were not on any cardiovascular or respiratory medications.Healthy young adults aged 18 years to 35 years, and normotensive with a resting blood pressure <140/90 mmHg were continually enrolled into the study from Lagos State University College of Medicine (LASUCOM) and LASUTH community. They were nonsmokers with no history of smoking. They were nonobese with a body mass index (BMI) less than 30 kg/mIndividuals were excluded if their resting blood pressure was <110/60 mmHg; baseline plasma norepinephrine was high above the normal range or their enddiastolic volume and endsystolic volume below the normal range. Females in their menstrual flow, pregnant or on oral contraceptives were also excluded. Trained athletes were also excluded from this study, because they tend to have increased muscle mass , Ikeja and the Echocardiography Laboratory of the Lagos State University Teaching Hospital (LASUTH), Ikeja. Participants were asked to refrain from caffeinecontaining beverages for at least three h, and alcohol beverages and exercise for at least four h prior to experiment , measured to the nearest 0.1 m using a standard stadiometer (Seca 217) and body weight (kg) measured using a body weighing machine (Camry C200) were carried out. The participant was then asked to lie on the couch in a supine position, with their shoes taken off. The participant was connected to a Comen C80 patient monitor system  for the measurement baseline blood pressure (BP) using an automatic cycling noninvasive BP monitor and the standard oscillometric method. Heart rate (beat/min) of the participants was measured from Lead II of the 12‐lead ECG cable connected to the Patient Monitor after recording for 1 min at a speed of 25 mm/sec.Left ventricular function was assessed using a Vivid q Cardiovascular ultrasound machine . All ultrasound assessments were made by REA, a trained sonographer with LASUTH, Ikeja. With participants lying in the left lateral decubitus position, a phasedarray transducer with a frequency of 3.5 MHz was connected to the 2‐Dimensional transthoracic echocardiography machine and placed over the left border of the sternum. The image of the heart was reflected on a gray scale picture on the monitor of the echocardiography machine. Left ventricular function (LVF) was measured by using the motionmode (M‐mode) technique obtained at the left parasternal long axis view (the first echocardiography view). An Mmode cursor was placed through the septal and posterior left ventricular walls just beyond the tip of the mitral leaflets. The internal left ventricular dimensions were measured between the endocardial border of the septum and the endocardial border of the posterior wall in systole and diastole  of participants was carried out before and during exposure to the test using a Comen C80 adult finger clip SpO2 sensor, part of the Patient Monitor.Prior to the onset of this procedure, the participants were instructed to avoid performance of Valsalva maneuver or hyperventilating during the test. They were then asked to immerse their right foot up to the ankle for 1 min in ice slurry maintained at 4°C  was drawn through a 5 mL syringe and placed into a chilled lithium heparinized bottle before and after the exposure of participants to the CPT. Plasma samples obtained were immediately stored in a −80°C freezer until analysis later. Norepinephrine was analyzed with a 2‐CAT ELISA ‐ Fast Track  with a Norepinephrine kit  following the manufacturer's instructions.Q˙ (L/min) was calculated as the product of stroke volume, SV (mL) and heart rate, HR (beat/min). Total Peripheral Resistance (mmHg/L per min) was calculated as MAP/Q˙. Cardiac Index (L/min per m2) was calculated as Q˙/BSA.Mean Arterial Pressure, MAP (mmHg) was calculated as diastolic blood pressure (DBP) plus 1/3 pulse pressure. Stroke volume (mL) was calculated as LV end diastolic volume (mL) minus LV end systolic volume (mL). Cardiac output, t‐test. Correlation coefficients  between the different studied parameters were sought using Spearman's rank correlation. Statistical significance was accepted at 95% confidence interval.All statistical analyses were carried out using GraphPad Statistical software, Prism 5 for Windows . Data are expressed as mean ± Standard Deviation, (SD). Test for normality of distribution was carried out using the Shapiro‐Wilk test and where the test failed, the MannWhitney U test was carried out to detect differences between the nonparametric data. Differences in descriptive variables and cardiovascular responses before and after the CPT were determined using Student's paired The characteristics of the participants and baseline cardiovascular measurements are shown in Table P < 0.0001): SBP from 118 ± 8 mmHg to 138 ± 14 mmHg; DBP from 71 ± 7 mmHg to 91 ± 11 mmHg and MAP from 88 ± 7 mmHg to 105 ± 18 mmHg  as shown in Figure When participants were exposed to the cold pressor test, heart rate increased significantly (P = 0.31) from that at baseline.As shown in Figure P = 0.13) in enddiastolic volume     from 4.28 ± 0.93 L/min to 5.35 ± 1.44 L/min and 3.68 ± 0.83 L/min per m2 to 4.51 ± 1.37 L/min per m2 respectively  in fractional shortening from the baseline value of 33.28 ± 4.5% to 32.55 ± 5.01%.Following exposure to the CPT, there was no change  Fig. B, stroke29) Fig. C and Eje65) Fig. D. The paP = 0.28) from 195.7 ± 45.4 pg/mL to 315.8 ± 91.45 pg/mL  with pressor response to the CPT ; ∆DBP r = −0.40).Plasma norepinephrine (NE) following exposure to CPT was slightly increased  is assumed a simple ellipsoid with both orthogonal axes being equal.Stress response is contingent upon intensity, duration and type of stressors. In the present study, the model of sympathetic stress did not produce significant changes in the ejection fraction (EF). This agrees with reports of similar studies by Sagiv et al. Following exposure to the cold pressor test, enddiastolic volume (EDV) remained unchanged. In contrast, studies using radionuclide ventriculography have reported large increases in enddiastolic volume during increased sympathetic activation (La Gerche and Gewillig β‐adrenergic responsiveness) (Boluyt and Lakatta We report no change in endsystolic volume (ESV) in the present study. The ESV varies in relation to the force of ventricular contraction. Increased sympathetic activation would cause the ventricles to contract strongly and this allows more volume of blood to be ejected, thus the ESV would be lower. However, stress does not have the same effect on ESV in older persons as it has on younger individuals because of increased stiffness of the arteries, decreased cardiac contractility and decline in the response of the heart to sympathetic nervous system . Silber et al.  observedIn the present study, the cold pressor test was used as an experimental stimulus to activate the sympathetic nervous system (SNS). Activation of the SNS led to a marginal increase in plasma norepinephrine (pNE) when compared to baseline. Sympathetic stimulation may influence arterial wall mechanics by passively increasing arterial pressure or by changing smooth muscle cell tone , diastolic blood pressure (DBP) and mean arterial pressure (MAP) following exposure to the cold pressor test. This is consistent with earlier reports (Cui et al. The Simpson's Biplane Method which is a more accurate method to determine left ventricular volumes and ejection fraction could not be used due to the limitation on the time imposed by the duration of exposure to the cold pressor test. The cold pressor test needed to be done in 1 min while the recording of echocardiographic images by Simpson's biplane could only be carried out in a minimum of 3 min.Our findings have shown that stress induced by increased sympathetic activation has no effect on the indices of left ventricular function of Ejection Fraction and Fractional Shortening though Cardiac output and the blood pressure parameters were significantly increased.There are no conflicting interests.


Supplemental Digital Content is available in the text Acute compartment syndrome (ACS) is defined as a clinical entity originated from trauma or other conditions, and remains challenging to diagnose and treat effectively. The review was aim to present the controversy in diagnosing, treating ACS. It was found that there was no criterion about the ACS, and result unnecessary osteotomy. The presence of clinical assessment (5P) always means the necrosis of muscles and was the most serious or irreversible stage of ACS. Besides pressure methods, the threshold of pressure identifying ACS was also controversial.Immediate surgical fasciotomy was important to prevent severe suquelae of the ACS. However, there was still controversy about the right time that fasciotomy should be done to avoid irreversible ischemic changes. The most important thing to treat ACS was comprehension to the true injury mechanism, but a systemic classification about traumatic mechanism in most literature was not clear.After observations to fracture patients with blister, we recommended that surgeons dealing with such emergencies should be vigilant, and the indication for fasciotomy should be strictly controlled following with injury mechanism especially for patients without severe soft tissue injury.For those crushing and soft tissue injuries, the current evidence based strategies for managing patients was useful, but for those fracture related injury, more examination was necessary to avoid overtreatment especially for those patients with blister observed. In facing patients, medical history, injured mechanism should be paid special attention, and rigorous classification about traumatic etiology was the key for the treatment of these patients. With a character of increased intracompartmental pressure, it is a surgical emergency and commonly occurs in the lower leg, forearm, thigh, foot, gluteal region, hand, and abdomen. The incidence rate of ACS was reported 30.4% especially in shaft and proximal regions of tibia. The higher incidence of ACS in proximal tibia is directly related to high energy trauma causing comminuted fractures, especially those affecting the entity of medial tibial plateau and increased with the fracture line extended laterally.–5Acute compartment syndrome (ACS) is defined as a clinical entity originated from trauma or other conditions that cause bleeding, edema, or that compromises perfusion in limbs. It was described around 130 years ago, and remains challenging to diagnose and treat effectively.To prevent serious complications induced by ACS, fasciotomy should be done before irreversible tissue necrosis occurs, thus there is a strong clinic bias toward doing fasciotomy empirically or prophylactically in patients who are considered to be at high risk and/or who have concerning clinical findings. It is generally recommended that conducting a prophylactic fasciotomy, which may be unnecessary, is better than do it too late, or ignoring a true ACS, given the potential systemic risks (rhabdomyolysis and myonecrosis) and functional loss associated with untreated ACS . However, there were controversies regarding the diagnosis (method and pressure threshold), treatment (the time of fasciotomy), and injury mechanism of ACS. The aim of this review was to present the uncertainties in treating ACS and propose new solutions.2The patients’ photographs were collected from our institutional database, retrospectively, and all the methods were performed in accordance with the relevant guidelines and regulations of the Third Hospital of Hebei Medical University. It was approved by the committee of the Third Hospital of Hebei Medical University.–8The diagnosis of compartment syndrome is always controversial and is based on clinical assessment and pressure measurement in compartment. Compartment syndrome clinical hallmarks have been defined as the 5Ps: pain out of proportion, pallor, paresthesias, paralysis, and pulselessness. Someone considered 5Ps as the established diagnostic procedures monitoring ACS, but it is an unreliable determinant of the presence of the syndrome, and many of clinical symptoms and signs also occur in patients without ACS , perhaps due to direct tissue injury 10 to 18. It is also not useful in patients with a decreased level of consciousness, unconscious, or insensate who are unable to provide feedback. In fact, the presence of these signs always means the necrosis of muscles and was the most serious or irreversible stage of ACS. Furthermore, these signs are more often signs of arterial ischemia than ACS, and be elicited only in the fully alert patient. Ulmer found that clinical examination had poor sensitivity and a high negative predictive value, which means that it is better in excluding than confirming ACS. Therefore, subjective clinical assessments of compartments are unreliable even judged by experienced clinicians, the results was that unnecessary liberal fasciotomy which expose patients to an increased risk of complications from wound infection was more than we can image. In the case that the clinical diagnosis is equivocal, measurement of intracompartmental tissue pressure might be helpful because of the fact that the pressure changes pull ahead the clinical symptoms and signs. Through pressure monitoring, it reduces both the delay to fasciotomy and the development of sequelae, but the researches that identified the pressure as the measuring criteria was only 11.7%. An investigation reveals that only about half of the hospitals in Germany have the technical equipment to do this despite most surgeons’ agreeing that pressure measurement is the standard method.The surgeons concern mainly about clinical signs of ACS such as worsening pain that is out of proportion and increasing analgesic requirements, or anxiety, agitation. However, the subjective symptoms rely heavily on clinical expertise, are impossible to standardize, and meanwhile the early changes of ischemia in compartment was the increased pressure. The pressure adjacent to the damaged artery is substantially higher than a critical value, indicating the need for fasciotomy. However, at the same time, the pressure in regions far from the bleeding artery is substantially lower than the threshold value even after 2 hours from injury. Intracompartmental pressure was highest and should be measured within 5 cm of the site of fracture.,13 However, the standard whether one should obtain pressures near the fracture, or measure further away (outside the zone of injury) to obtain a more representative pressure to the majority of the compartment was not established.There are many methods of monitoring pressure, and the equipment was different from each other. Invasive choices of monitoring pressure include the Whitesides needle manometer, a slit or wick catheter. The deficiency of these devices was that it was easily to be blocked by lest muscle and blood clots. The STIC Monitor  is a portable monitor that uses a side port needle, a disposable syringe of saline flush, and a digital read out manometer to allow for simple measurement of compartment pressure. The measurement will be effected by position, measuring location and tissue in tip of needle. Through knee cadaveric specimens, large calculated interobserver technical variations, and errors in the measurement of compartment pressures, he found that even with proper technique, 40% of the measurements were >5 mm Hg from the actual pressure. Therefore, it was misleading to make the choice depending on pressure monitor; many patients may be wrongly diagnosed as ACS. Some researches considered that the pressure monitor by needle was technically wrong in clinic. Nudel et al found that ACS is not uniform about pressure distribution in the compartment. Levels ranging from 30 to 50 mm Hg are also proposed as critical level to diagnose ACS.–16 However, the value was proved to be inaccurate, and no correlation was found between high compartment pressure and clinical outcomes in patients treated primarily in plaster cast. More and more researches demonstrated that pressures more than 30 mm Hg can also be tolerated without sequel, and proposed that instead of an absolute threshold, the difference between diastolic pressure and compartment pressure was accepted as indication for fasciotomy (diastolic pressure minus compartment pressure <30 mm Hg).–21 However, along with pressure measurement, it is important that the diagnosis of ACS should take into account time factors, and single pressure measurements alone reflect instantaneous blood perfusion. The tissue and blood pressure was dynamic equilibrium, and pressure in different compartment was various from each other. Bussell et al reported that pressure in the anterior compartment was higher compared to all the other compartments within the healthy and fractured leg in children. McQueen et al monitored pressure for 2 hours and demonstrated excellent sensitivity (94%) and specificity for ACS after tibia fractures. On the contrary, there was also researches reported that continuous compartment pressure monitoring was not advocated in alert patients. Diagnosis based on pressure measurements (diastolic pressure minus compartment pressure <30 mm Hg) alone is also reported unreliable. Ho found high compartment pressures are frequently seen in patients with tibial shaft fractures, but in most cases, it does not equate to the presence of compartment syndrome, and unnecessary fasciotomy should be avoided. Prayson et al followed blood pressure and compartment pressure in 19 patients with lower extremity fractures, and also did not found compartment syndrome with the perfusion pressure threshold (<30 mm Hg). Janzing and Broos reported that 45.4% of patients would have undergone fasciotomies using ΔP under 30 mm Hg, leading to a number of unnecessary operations and complications.Besides pressure methods, the threshold of pressure identifying ACS was also controversial. It was identified a compartment pressure of 30 mm Hg was resistant to infusion of fluid and recommended as indication of surgical fasciotomy. In earthquake, fasciotomy was always carried out without pressure measurement.The overtreatment based on intracompartmental pressure measurements alone was still existed in a sizeable number of patients, and not all hospitals have the technical equipment to do this. In a war, the clinical practice guidelines for treating patients do not support the use of pressure measurements due to time limited, the early and liberal use of prophylactic fasciotomies was advocated. Although early, fasciotomy has reduced the incidence of ACS among soldiers, it comes at a cost in terms of associated morbidities such as infection, nerve injury, and sensory, following surgery for delayed wound closure with high cost. The incidence of complications associated with fasciotomy has been reported to be as high as 87% following battlefield trauma.Above all, when the clinical observations are inconclusive, pressure measurement can be helpful to confirm or exclude the diagnosis, not as a screening tool for those with an increased risk of developing compartment syndrome. However, there was no standard criterion even when clinical indication and pressure threshold combined that enable a successful prediction of the need for surgery treatment. And after considering the confusion about ACS, we begin to doubt the accuracy of ACS, and the existence of ACS.3,31 Labbe et al reported that when the ischemia was 3, 4, and 5 hours, the necrosis of leg muscles was up to 20%, 30%, and 90%, respectively. On the contrary, Sheridan and Matsen found that 68% of 22 patients treated within 12 hours recovered normal lower extremity function compared to only 8% treated after 12 hours. There was not only damage to muscles but also to the associated nerves traversing the compartment if compartment syndrome is not diagnosed and treated early. It was reported that if compartmental release was performed within 4 hours, the nerve conduction velocity returned to normal regardless of the amount of pressure or time of the pressure applied. However, nerve conduction velocity will not return to normal if the release was performed after 12 hours. The late diagnosis may result in the possibility of irreversible nerve, muscle damage, amputation, and even death.As we mentioned earlier, in traditional view, immediate surgical fasciotomy was important to prevent severe suquelae of the ACS. However, there was still controversy about the right time that fasciotomy should be done to avoid irreversible ischemic changes. The ischemic necrosis of muscle can be observed as early as 3 hours, 5% may be injured after 4 hours, and become permanent in 8 hours. In contrast, others suggested that 8 hours of ischemia can result in permanent myonecrosis, so traditional fasciotomies should be restricted as fasciotomies can no longer reverse the nerve damage and muscle necrosis, and the procedure may potentially lead to wound problems and infection. Reis and Michaelson suggested that the skin serves an important role as a barrier to infection, and patients with closed crush injuries treated by late fasciotomy (≥24 hours) had worse outcomes than those treated nonoperatively. Finkelstein et al also reported that infection after delayed fasciotomy has greater morbidity than the muscle contractures occurred from myonecrosis. Ritenour et al reported that wounded soldiers that had delayed fasciotomies, had higher rates of muscle excision, amputation, and mortality. Therefore, prophylactic fasciotomy can also induce major complications, and the risk–benefit ratio should be weighed heavily.Despite there is obvious evidence that delay in treatment leads to poorer outcomes, it is difficult to determine the exact time of performance for fasciotomy. For delayed compartment syndrome in adults, someone propose that routine fasciotomy should be conducted to prevent more morbidity and complication. After a system review, Lin and Balch Samora reported that pediatric patients could still achieve functional recovery in 24 hours. Kanj et al found that although ACS of the upper extremity in children is often associated with a long delay between injury and fasciotomy, most children still achieve excellent outcomes. Above all, increased intracompartmental pressure can be tolerated for longer time compared with adults before tissue necrosis becomes irreversible. There was more time allowed to diagnose pediatric ACS after identifying the exact mechanism of injury.However, functional outcomes were different and controversial in different aged patients. Livingston et al reported the time from symptom onset or initial injury to ACS diagnosis in nonfracture pediatric patients to be over 48 hours.4 Furthermore, the most important thing to treat ACS was comprehension to the true injury mechanism, but a systemic classification about traumatic mechanism in most literature was not clear. Patients in most articles can be classified into soft-tissue injury related, vascular injury related, fracture related according to the injured anatomical structure.The consequences of missed diagnosis are severe for both patients and surgeons. It is important to be cognizant that there is no universal pressure measurement that serves as the threshold for fasciotomy. The main etiologies of ACS was traumatic injuries such as fracture and crush-type injury, while other injuries such as limb ischemia (ischemia-reperfusion injury after revascularization), tourniquet, tight splint, shock trousers, drug injection, or snake bites could also induce ACS.,42,43 On the other hand, the fasciotomy convert a closed wound into an open one which increases the rate of infection. Despite high or increasing intracompartmental pressure, conservative treatment was advocated unless open wound existed or the limb circulation is decreased.,44–46 For those patients with the necrotic muscle, Huang et al suggested that fasciotomy offers no benefit but increases the rate of infection and amputation.Soft-tissue injury can be considered as crush syndrome. Patients with crush syndrome are induced by continuous prolonged pressure on muscle tissues, and character with massively swollen limbs, shock, myoglobinuria, and renal failure. Although fasciotomy is considered as the gold standard for ACS, but the role of fasciotomy in the treatment of crush syndrome is still controversial. The most debate was that in one hand, early fasciotomy prevents further muscle damage, and there were researches recommend fasciotomy for patients with crush syndrome.The ACS was always found to be mixed with the concept of crushing syndrome and Volkmann contracture. Crush syndrome is a medical condition that can be caused by a “crush injury,” and skeletal muscle becomes damaged under the heavy weight. The injury mechanism includes earthquakes, traffic accident, and war conflict and so on. The saved entrapped victims without immediate medical treatment caused the damage to the structure of compartment and lead muscle necrotic or damaged, and induce acute kidney injury that requires rapid and special treatment. The early debridement (not fasciotomy) should only be considered in patients with crushing injuries. Vascular injury associated with orthopedic trauma is also a potentially limb- and life-threatening, if the diagnosis of an associated vascular injury is missed or delayed, Volkmann contracture presented in late status Table . On the other hand, infection associated with open fasciotomy incisions has been concerned. Although the reperfusion in patients with vascular injury was existed, but with an intact structure, nerve and function may recover later with some extents. Anecdotal indicated that infections after fasciotomy may result in leg amputation.,50 Rollins et al also considered that the concept of fasciotomy for revascularization syndrome is rarely indicated. Abouezzi et al concluded that the presence of combined vascular injury especially the ones above the knee did not necessitate routine fasciotomy. Furthermore, the fasciotomy was also harmful to the function of limb in long term even there was no evidence of venous obstruction or reflux. In patients with persistent absent pulses or other sign of vascular injury, immediate vascular surgery consultation should be obtained.Reperfusion was one reason reported for the development of ACS, and different from complete ischemia, ACS causes myonecrosis in the face of patent vessels 68. Furthermore, there are also debates regarding the role of early fasciotomy in vascular-injury-related patients. On one hand, the proponents argue that the morbility and amputation rates were unacceptable if the fasciotomy was delayed, so early fasciotomy has been cited as a major factor contributing to limb salvage and preservation of function, especially in vascular trauma patients. It was recommended as routine procedure along with vascular repair especially when popliteal arterial injury is associated with concomitant venous injury. Fracture is considered as a major contributing factor for ACS (approximately 75%).,54–56 In patients with fracture, the structure in compartment was actually not disturbed which is different from crushing injury. In patients with crushing, cellular death or cell membrane lysis releases osmotically active cellular contents into the interstitial space, causing further accumulation of fluid and further increase in intracompartment pressure. In fracture-related patients, the cellular death or cell membrane lysis may be not common. The obvious differences of pressure increase among fracture, and crushing injury was that the former can be released though some mechanism surrounding intact fascia. If the patients was classified as fracture related, it stands a good chance that blister on the skin which reflects a release mechanism of pressure was observed, then the microcirculation of the tissues in that compartment is recovered soon or later .Although some authors reported that tibial fracture with segmental tibia fracture, medial knee fracture-dislocation had a high rate of ACS, the patients diagnosed intraoperatively by objective compartment measurements may have never developed clinical ACS, and the mechanism classification should be reviewed carefully especially for severe tibial plateau fractures. Halawi also found that the blister which may induce infection can be observed after primary total knee arthroplasty, and the etiology of blister was multifactorial. The structure of skin was actually intact and without dermal–epidermal injuries excluding incision after arthroplasty, and we propose that the blister was more than just skin injury, and might be an efficient mechanism to release pressure. To be accordant with our hypothesis, Varela et al also reported that it is one of the mechanisms to relieve abnormally high pressure in compartment. Although there was no enough laboratory results to support our hypothesis, it can still be considered as an absolute mechanism to release pressure after tibial or ankle fracture from clinical observation, and the necessary of fasciotomy to fracture-related patients should be deliberate. Following experiment will be conducted soon to verify the hypothesis.Fracture blisters were reported as a relatively uncommon complication of high-energy fractures (2.9%), but most tibial fracture can be observed with clear fluid or blood filled blister as early as 6 hours postfracture. It was considered that the factor in development of blister is injury to the dermal–epidermal junction resulting from high shear in the skin. The retention of some degree of epidermal cells in the clear-filled blisters contributed to a faster reepithelializaiton compared with blood-filled blister. However, the theory cannot explain the blister remote from the fracture deformity.5The ACS is considered as an orthopedic emergency which can lead to limb and life-threatening outcome if there is delay in diagnosis and treatment. Surgeons that involved in dealing with such emergencies should be vigilant, and the indication for fasciotomy should be strictly controlled following with injury mechanism especially for patients without severe soft-tissue injury. For those crushing and soft-tissue injuries, the current evidence-based strategies for managing patients were useful, but for those fracture-related injury, more examination was necessary to avoid overtreatment especially for those patients with blister observed. In facing patients’ medical history, injured mechanism should be paid special attention, and rigorous classification about traumatic etiology was the key for the treatment of these patients.Zhiyong Hou designed the study. Jialiang and Yingchao Yin conducted the procedure and collected the data of the study. Jialiang Guo, Lin Jin and Ruipeng Zhang drafted the manuscript. Zhiyong Hou and Yingze Zhang revised and approved the final manuscript.Conceptualization: Zhiyong Hou.Data curation: Yingchao Yin.Supervision: Zhiyong Hou, Yingze Zhang.Validation: Zhiyong Hou.Visualization: Zhiyong Hou.Writing – original draft: Jialiang Guo, Lin Jin, Ruipeng Zhang.Writing – review & editing: Yingze Zhang.


Uromodulin is specifically synthesized and secreted by kidney tubular epithelial cells. Studies on the association of serum uromodulin and outcomes of chronic kidney disease (CKD) are lacking. This study aimed to evaluate whether serum uromodulin was associated with outcomes of patients with CKD.We measured serum uromodulin concentrations by ELISA in 2652 CKD patients from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) and investigated the association of serum uromodulin with outcomes of CKD patients, including end-stage kidney disease (ESKD) receiving kidney replacement therapy, cardiovascular events and mortality by Cox proportional hazards regression model.2, of whom 58.4% were male. The median level of urinary albumin/creatinine ratio and serum uromodulin was 473.7 mg/g (IQR 134.1–1046.6 mg/g) and 77.2 ng/mL (IQR 48.3–125.9 ng/mL), respectively. Altogether, 404 ESKD, 189 cardiovascular events, and 69 deaths occurred during the median follow-up of 53.6 (IQR 44.0–64.0) months. Lower levels of serum uromodulin were independently associated with higher risk of incident ESKD after adjusting for traditional cardiovascular risk factors, with the hazard ratios (HRs) of 3.23  for the middle tertile and 7.47 (95% CI 5.06–11.03) for the bottom tertile, compared with top tertile and 0.31 (95% CI 0.25–0.38) per every standard deviation increase. After further adjustment for the baseline eGFR, the association was greatly attenuated, but still significant, with HRs of 1.92 (95% CI 1.26–2.90) for the bottom tertile compared with top tertile and 0.69 (95% CI 0.55–0.86) per every standard deviation increase.A total of 2652 CKD patients were enrolled in this study, with an age of 48.7 ± 13.8 years and the baseline eGFR of 49.6 ± 29.4 mL/min/1.73 mSerum uromodulin is independently associated with an increased risk of incident ESKD in CKD patients.The online version of this article (10.1186/s12967-018-1693-2) contains supplementary material, which is available to authorized users. Chronic kidney disease (CKD), with a high prevalence of over 10%, is one of the leading global public health problems . It is tUMOD gene have been described as a cause of hereditary autosomal-dominant tubulointerstitial diseases /88.4) × 0.79) . All eGF2 (m2). Blood pressure was measured three times at 5-min intervals by a sphygmomanometer. The mean value of the three readings was calculated. The use of anti-hypertensive medications in the past 2 weeks before baseline examination was recorded. Diabetes was defined as the fasting plasma glucose of 7.0 mmol/L or more, or the use of hypoglycemic agents or a self-reported history of diabetes.Body mass index was calculated by using the following formula: weight (kg)/height2. All the ESKD events included in the current study have initiated hemodialysis, or peritoneal dialysis, or kidney transplantation. Cardiovascular events included acute myocardial infarction, unstable angina, hospitalization for congestive heart failure, cerebrovascular events , and peripheral vascular diseases. Echocardiogram and electrocardiogram examination were requested in the validation of cardiovascular events; however, cardio-angiography was not routinely performed. Only one event per patient was included in the current analysis. Finally, we separately evaluated the associations of baseline serum uromodulin with different clinical outcomes of CKD patients, including ESKD, cardiovascular events and all-cause mortality.The pre-specified end-point events of the CKD patients included ESKD, cardiovascular event, and all-cause mortality. ESKD is defined as the initiation of chronic dialysis or renal kidney transplantation or irreversible development of eGFR < 15 mL/min/1.73 mThe end-point events were collected at 3- to 6-month intervals until 30 June 2017 in the current analysis. The director at each clinical center asked for end-point events according to the new-onset events registration form either by phone calls or routine clinical visits. Once the end-point events occurred, the director at the clinical center filled out the new-onset events registration form and submitted the related clinical data to the Renal Institute of Peking University via email within 1 month. The suspected clinical outcomes were then adjudicated by an independent committee consisting of specialist physicians.All CKD patients were stratified according to tertiles of baseline serum uromodulin levels. Continuous variables are presented as the means and standard deviations, except for highly skewed variables that are shown as median and interquartile ranges (IQR), and categorical variables are presented as proportions. One-way ANOVA was used to compare continuous variables, and Chi squared tests were used to compare categorical variables.The incidence rates of end-point events  were calculated as number of events per 100 person-years. We depicted cumulative hazard function for the three events separately according to uromodulin levels by using a Kaplan–Meier curve and compared the event rates by using log-rank test.P < 0.05 (two-sided) was considered statistically significant.To investigate the association between serum uromodulin and outcomes, Cox proportional hazards regression models were used to estimate hazards ratios (HRs) and 95% confidence intervals (CIs). We found that the risk of ESKD was linearly increased through the decline of uromodulin as shown in the linear spline analysis  participants had an eGFR greater than 60 mL/min/1.73 m2 at baseline. Altogether, 1053 (39.7%) and 811 (30.6%) patients were in CKD stages 3 and 4, respectively.Among the 2652 CKD patients included in our study, 1548 (58.4%) were male, and 1104 (41.6%) were female, with an age of 48.7 ± 13.8 years. The baseline eGFR was 49.6 ± 29.4 mL/min/1.73 mP < 0.001). The baseline characteristics of CKD patients according to tertiles of the serum uromodulin levels are presented in Table P < 0.001). In addition, we found a positive correlation between serum uromodulin and eGFR in multivariable linear correlation analysis .The median level of serum uromodulin was 77.2 ng/mL (IQR 48.3–125.9 ng/mL) in 2652 CKD patients. The levels in the three etiologic types of CKD were 100.4 ± 65.6 ng/mL in glomerular diseases, 69.0 ± 40.6 ng/mL in tubulointerstitial diseases and 73.4 ± 51.4 ng/mL in other or unknown causes, respectively  and 0.8601 (95% CI 0.8413–0.8789), respectively. The difference of the AUCs was 0.0023 (95% CI − 0.0007 to 0.0052) .In the current study, we described the association of serum uromodulin and ESKD, cardiovascular events, all-cause mortality in the context of CKD. We found that the baseline lower levels of serum uromodulin were associated with an increased risk of incident ESKD independent of the traditional risk factors for progression of CKD.UMOD gene were found to be associated with a decline in the occurrence of CKD and a lower urinary uromodulin level [Uromodulin is a glycosyl phosphatidylinositol (GPI) linked glycoprotein exclusively synthesized in renal tubular epithelial cells . Most ofin level , 13. Prein level , 25, 27,in level . Thus, wTo the best of our knowledge, the current study is the first prospective one assessing the association between serum uromodulin and kidney disease progression in CKD population. Our results were, to some extent, in line with several recent studies , 29. A rUromodulin is specifically secreted by renal tubular epithelial cells. Experimental data from Trudu  showed tAlthough the physiological role of circulating uromodulin remains largely unknown, the present data strengthens the notion that serum uromodulin represents a marker of kidney health independent of markers of the glomerular function and might help to distinguish high-risk CKD patients with rapid progress on kidney function. With regard to the ESKD events, our results only found a trend of improvement in the discriminating ability after inclusion of serum uromodulin in the model with traditional markers for kidney function and kidney damage. With regard to the cardiovascular complications, Leiherer et al. and Delgado et al. reported that serum uromodulin could predict the risk of cardiovascular events and all-cause mortality among people with coronary disease , 16. HowThere are some limitations of the current study. First, the cohort has a relatively short duration of follow-up and a limited number of cardiovascular events and death, which limited our power to investigate the association between the levels of uromodulin and cardiovascular disease. Furthermore, some laboratory tests for cardiovascular disease, including NT-proBNP, hs-Troponin and Galectin-binding protein, were not included in our study. Second, although most well-established risk factors of CKD progression were included in the multivariable regression models, the possibility of residual confounding still exists. Finally, considering the baseline characteristics of our study, these results will be primarily applicable to patients seen by nephrologists rather than the large population with CKD in the general population who have lower levels of proteinuria and older age.This study represents the first prospective cohort study with a large sample size investigating the association between serum uromodulin and outcomes in CKD population. Serum uromodulin levels are independently associated with incident ESKD.Additional file 1. Additional figure and tables.


Intraocular pressure (IOP) is known to have a definite circadian rhythm and its fluctuation correlates well with glaucoma progression. Twenty-four hour monitoring of IOP is an important indicator intraocular pressure fluctuation, as well as its peaks and spikes. However, Diurnal variation in IOP is well recognized but many decisions in glaucoma management are taken after one or two IOP measurements.Patient directed self-tonometry can be preformed through the twenty-four cycle, and has been the subject of an ongoing debate. In this review, we studied the history of self-tonometry devices and the present technologies for future. The results of various techniques studied revealed that a standardized method of conducting diurnal variation is yet to be ascertained, and for this, a proper research method is required. Defined as chronic progressive optic neuropathy, glaucoma blindness continues to maintain its reign as the second leading cause of irreversible blindness worldwide. Global measurements of disease prevalence estimate that, by 2020, the number of people with glaucoma will be around eighty million, while as many as 11.2 million will have been blinded due to glaucoma [32]. Various research studies have proven that the decrease of intraocular pressure subdues glaucoma progression, thereby preventing blindness and maintaining IOP as a modifiable risk factor.Primary glaucoma can be divided into two main categories based on angle morphology: primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG). Intraocular pressure (IOP) elevation is known to be one of the most important risk factors for both the onset and the progression of the disease in both open and angle closure glaucoma. Emerging research shows the impact of other potential modifiable risk factors, aside from IOP, that contribute to glaucoma, including socioeconomic status, nutritional intake, body mass index, obesity, exercise, smoking, and sleep apnea; many of these studies having significant limitations [3-5]. In fact, IOP recorded during office hours is significantly less, approximately 5 mmHg, than when recorded at night [4]. This difference between real life conditions and the clinical setting may be more exaggerated in angle closure glaucoma eyes due to the effect that ambient lighting has on the size or dilatation of the pupil, and thus IOP [5-8]. IOP has been proven to have a definite circadian rhythm, and its fluctuation, both short term and long term, have been indicative of glaucoma progression. In fact, both peak intraocular pressure and IOP fluctuations are known independent risk factors for disease progression. Similarly, there is evidence to suggest that large diurnal intraocular pressure fluctuations may be considered as an independent risk factor for the disease [10-14]. Recent research has shifted its aim toward exploring diurnal variation of IOP in angle closure disease due to the importance of diurnal IOP behavior for disease management in glaucoma patients. For diurnal variation records, most of these studies have to either focus on IOP measurements during the working hours or rely on self-tonometry. There has also been some interest in 24-hour continuous measurement of IOP in angle closure glaucoma before and after iridotomy [5] was performed to find publications on the above subject and the 24-hour intraocular pressure monitoring devices in angle closure, to determine the various methods of studying intraocular pressure fluctuations. Cross references were also hand searched along with the expert consultation to enlarge the reference data.Given that angle closure disease constitutes a serious global burden of disease and blindness, this review aimed to collate the current available knowledge about diurnal variation of IOP in patients with angle closure and encourage clinicians to remember the pertinence of managing this subgroup of glaucoma patients. Keeping this in mind, an extensive search [12]. The diurnal intraocular pressure measurements in angle closure, especially in the less controlled non-clinic environment, have been intermittently documented. Few studies compared diurnal IOP fluctuation of PACG to POAG eyes, while some have looked at the IOP fluctuation through the day and correlated it with the stage of angle closure. Recently, there has been considerable interest in 24-hour continuous IOP monitoring and its relation to angle closure patients . To better understand the physiology of IOP variations in angle closure patients, one additional diurnal IOP recording is necessary following laser peripheral iridotomy [9-14].Some studies have shown that the risk of glaucoma progression may be higher in patients with larger fluctuations in their IOP during certain periods [33]. In a study conducted by Bhartiya, it was found that in angle closure patients, the peak IOP was greater than office hour IOP recordings for 25% of the patients [34]. The many barriers to 24-hour IOP monitoring are both economically and logistically prohibitive. The cost of a sleep lab study or a continuous IOP monitor can be exorbitant and, since multiple IOP recording would be required throughout the night, normal sleep patterns would be drastically disrupted. Both researchers and clinicians have struggled to circumvent these problems .The barriers for recording diurnal variation of IOP in angle closure disease are similar to those for open angle glaucoma. One of the problems with 24-hour continuous intraocular pressure monitoring is the reproducibility of the IOP recording. Predictive values of first diurnal IOP have been proven to retain low long-term reproducibility in POAG patients when evaluating the risk of IOP fluctuations. Moreover, the association of a single diurnal IOP and future IOP fluctuations is so poor that it holds limited value in clinical settings, as even between-visit agreement of IOP was poor  reported a significantly higher diurnal fluctuation in eyes with open angle and angle closure glaucoma as compared to normal controls; they excluded eyes with peripheral anterior synechiae in less than three quadrants compared to normal patients, diurnal control being higher in POAG eyes treated with laser iridotomy.Sihota et al. [6].Baskaran et al. found that, compared to PACS and normal patients, both PACG and PAC subjects have 2.38 times the chance of developing more than 3 mmHg of fluctuations in IOP. The study enrolled all the PACG subjects after having LPI done but before having any medical treatment [17] conducted a study on 100 patients with primary adult onset glaucoma (50 patients of POAG and 50 of PACG) to compare the difference between mean office hour IOP (9am to 5 pm) and diurnal IOP using GAT. The study concluded that two thirds of the patients had significant peak IOP measurements outside of office hours rather than during (p<0.003). There was a significant correlation between baseline IOP and fluctuation in IOP . They also found that there was no difference doing IOP between 7 a.m. to 10 p.m. as compared to doing 24-hour diurnal variation. Bhartiya et al. [15] studied 24-hour DV in primary angle closure subjects using GAT in 77 eyes with a peripheral iridectomy done a minimum of 3 weeks prior . IOP fluctuation was reported to be significantly higher in the PACG subjects (4.4 ± 1.5 mmHg) and the PAC (5.5± 2.3 mmHg) group than the PACS subjects (4.4± 1.5mmHg). They reported a peak IOP during early morning hours at around 4 a.m. in all except for 2 eyes. Peak IOP was higher than office hour IOP in 25% of the overall subjects and in 40% of PAC/ PACG subjects. Arora et al. [18-27]. Of them, one of the very important studies is IMPACT study conducted by Bourne et al. [27], which measured DV using GAT, and compared the effect of Argon Laser peripheral trabeculoplasty (ALPI) or no ALPI in post Laser Peripheral Iridoplasty (LPI) in PACS/ PAC patients in 22 eyes. In their study, DV was done pre-ALPI and 3 months after ALPI. They concluded that diurnal IOP at 3 months was significantly reduced (5.04 mmHg ± 1.61 mmHg). Maximum IOP was significantly higher in patients without ALPI . They inferred that ALPI achieved a widening of even those parts of the angle that had remained occludable after the LPI.There are numerous studies related to Laser Iridoplasty and their effect on diurnal variation [28] conducted a RCT in 90 patients on diurnal variation using GAT to determine the effect of timolol versus placebo in untreated high IOP patients. They reported significant risk in mean IOP only and not with IOP fluctuations (p=0.49). The main limitation in their study was that they only measured three readings during office hours, whereas more readings would have led to increased accuracy. In a retrospective study that reviewed charts of 113 eyes of patients with normal tension glaucoma, Choi et al. [29] investigated the risk factors for optic nerve damage. None of these patients had used, or were using any anti glaucoma drugs. They evaluated the intraocular pressure over 24 hours in a hospital setting, every 2 hours from 12 p.m. to 10 a.m. the next day. During 12 a.m. and 6 a.m., IOP was measured at an interval of 3 hours. They defined fluctuation to be the difference between the highest and lowest recorded eye pressures over the duration under evaluation. They also performed a multivariate regression, and reported that neither the mean peak nor the fluctuation of intraocular pressures had a significant association with glaucomatous damage to the visual fields, or the optic nerve head. The major limitation of this study was that the authors studied the charts of the patients retrospectively. In their Malmo Ocular Hypertension Study, Bengtsson et al. [Sleep Labs30].Liu et al. conducted a 24-hour sleep lab study on 33 healthy adults, to monitor the effects of posture on IOP. They regulated the lab environment, ensuring light for sixteen hours, and a dark environment for eight hours. They used a pneumotonometer to measure the eye pressures once every two hours. They divided their patients into two groups. For the first group, the eye pressure was measured with the subjects sitting in the light environment, and supine in the darkness (simulating nighttime records). For the other group, all eye pressure records were in the supine position. To maintain the environment and minimize exposure to light, the researchers wore special goggles designed for use in darkness. When measuring eye pressures during the period of darkness, the authors reported that the intraocular pressure was significantly higher during the darkness, as compared to the light period. For group one, the difference between the peak and trough IOP was 8.2+/ -1.4mm Hg. The trough was noted in the last light wake recording while the peak was recorded during the last recording in darkness. For group two, this pressure difference was found to be less, 3.8+/ -0.9mm Hg. In addition, the higher IOP recording was found in the light wake measurement. IOP measurements coincided with circadian rhythms, with the highest IOP during the end of the dark period. This indicated that the nighttime eye pressure elevation might be independent of body posture, and its changes. Moreover, even though these recordings were made in young adults without glaucoma, the trends may still be indicative of the effects of body posture in angle closure patients [31]. Liu et al. also evaluated the 24-hour IOP profile in 16 subjects, measuring their IOP at two hours, when sitting, and lying down in the supine position. They reported an elevation of IOP during nighttime, with daytime mean IOPs being significantly less. They also found that the IOP peaks were noted towards the end of the nighttime IOP measurements, and troughs appeared at the end of the diurnal period. The difference between the highest and the lowest eye pressures recorded was 3.8+/ -0.6mm Hg in the sitting position, and 3.4+/ -0.6 in supine position. Therefore, they concluded that there is an IOP elevation at night, in both sitting and supine positions [32]. Kida et al. evaluated the relationship between eye pressure and central corneal thickness. Fifteen young adults were evaluated during a 24-hour monitoring in a sleep lab. The eye pressure and ultrasonic pachymetry were recorded after every two hours. The highest CCT was recorded between 1:30 to 5:50 a.m., while the highest IOP was recorded at 5:30 a.m. The authors also noted that the nocturnal means were higher than the diurnal means. However, because of the difference in the time of the nighttime peaks, they did not report consistent evidence that IOP was related to CCT thickness or corneal biomechanical properties after cosine fits of the data [Self-Tonometry33].Takagi et al. conducted a study that compared eye pressure measurements using the ICare HOME Rebound Self-Tonometer with measurements from the Goldmann applanation tonometer (GAT). One hundred twenty-eight outpatient subjects diagnosed with glaucoma had their IOP measured using an ICare HOME unit by both themselves and an ophthalmologist and a GAT measurement by an ophthalmologist only. The mean GAT IOP was 12.2+/ -2.8, mean IOP using ICare by the patient (HOMEp) at home was 12.8+/ -3.7, while the mean IOP recorded by the ophthalmologist using the ICare (HOMEo) was 13.1 +/ -3.8 mm Hg, respectively. The mean difference between the HOMEp and HOMEo was found to be 0.21mm Hg . Likewise, HOMEp and GAT measurement had a mean different of 0.70 mm Hg , and between the HOMEo and GAT measurements the mean differed by 1.00 mm Hg . Their study concluded that the ICare HOME tonometer might have a practical use for patients who wish to monitor their IOP. However, it was noted that, at times, the ICare HOME measurements were overestimated when compared to applanation tonometry. Thus, patients should use the ICare HOME tonometer for monitoring [34]. Asrani et al. also conducted a similar study to investigate the accuracy of the ICare IOP measurements when used by patients and trained technicians in comparison with Goldmann tonometry performed by a trained technician. They also wanted to establish if the IOP records, so obtained, were reproducible. One hundred patients had their IOP taken in the right eye by a trained technician and were then given instructions on how to take their own IOP. A different technician measured the eye pressure using GAT and was then asked to compare with the ICare IOPs previously taken by the patient and the technician. 82 patients had intraocular pressure recordings within 3 mm Hg of that recorded by the trained technician, while 75% of the recordings were within 3 mm Hg of the applanation results. Thus, authors reported that ICare rebound tonometer could be used reliably even by untrained patients. As it is generally easy to learn, this device could allow patients to self-administer and monitor their eye pressures within the comfort of their home [35]. Halkiadakis et al. also compared Icare ONE rebound self tonometer (ICRBT) with GAT. In their study, 60 patients took two readings of their eye pressure using the rebound tonometer. A trained examiner took their eye pressure using the ICRBT, and a different masked, trained examiner used the GAT. The mean difference between the rebound tonometer and GAT readings was 2.3 mm Hg (p=0.001). The IOP difference was within 3 mm for 63% of the subjects. They also found that the difference in eye pressure measurements correlated with the central corneal thickness. The IOP difference (ICRBT − GAT) was within ± 3 mm Hg for 63% of the cases. They also found that the difference in IOP measurement of ICRBT and GAT was positively correlated with CCT , suggesting that a greater thickness might be associated with a larger difference in IOP when using the two different appliances. Similar to the other studies, they found that the ICRBT was reliable enough in patient hands, allowing it to be used for IOP self-monitoring. They also found that ICRBT overestimated GAT measurements . The Triggerfish 24-hour Contact Lens Sensor is a sensor that is embedded within a soft contact lens that records the IOP fluctuations in a subject’s eye by measuring the variations in limbal diameter. Its use has been validated in several clinical studies, and data from Triggerfish monitoring of angle closure patients has shown significant diurnal variation in eye pressures [37]. Tan et al. evaluated the differences in intraocular pressure fluctuations and their association with disease progression in 25 patients with PACG. The patients were analyzed as either glaucoma by measuring the mean deviation, classified as either having “progressive” or stable glaucoma, based on mean deviation, visual field index, and retinal nerve fiber layer thickness changes, as measured at every 6 months. They found that, in comparison with stable patients, the ones with documented progression (as ascertained by a significant change in mean deviation), had significantly different gradients (first derivative) of the intraocular pressure curves during ten to eleven p.m. and from seven to eight a.m. They also reported a significant difference in the second derivative of the intraocular pressure curve from eleven to twelve a.m., and from eight to nine a.m. Therefore, the authors concluded that 24-hour IOP data using the contact lens monitor indicated that the IOP fluctuation in patients with progressive disease is more than that observed in patients with stable glaucoma  .Bhartiya et al.  evaluated the diurnal IOP curves in 12 newly diagnosed patients of PAC and PACG before and after LPI. They found that the amplitude of the acrophase was not significantly different before and after LPI. They also reported that the CLS amplitude (maximum CLS minus minimum CLS) was not significantly different when compared Pre and Post LPI. However, the difference in the mean nighttime amplitude seemed lower than the mean diurnal amplitude . In their study, they noted that the intraocular pressure after cataract surgery in the anterior chamber anatomic parameters following cataract extraction [40]. De Moraes et al. tested if the twenty-four hour reading of IOP measured from the CLS could correlate to the rate of visual progression of glaucoma, as evidenced from visual field loss. Forty patients who had undergone at least eight visual field tests had their mean deviation of parameters assessed through the CLS, including number of large peeks, mean peak ratio, wake to sleep slope, amplitude, and area under the cosine curve, and variability from mean. The 24-hour IOP related parameters recordings showed that the CLS was able to provide the rate of visual field progression offering a better measure of goodness of fit than Goldman parameters. Number of peaks along with mean peak ratio was their best predictor of faster progression when patients were awake. Their study also helped identify that this technology may be critical in detecting which eyes are at a higher rate of progression, during waking hours [41-43]. To help decrease the worldwide burden of glaucoma, future studies need to focus on the mechanisms that are currently understudied or explore unknown factors other than IOP. Future research should also incorporate broader behavioral and social factors that may affect glaucoma, such as exercise, sleep apnea and the role of nutritional factors [44-46].Currently, patients should be made aware of the options they have, to accurately monitor their IOP to help maintain disease progressions [