Appetite loss is one complication of chronic heart failure (CHF), and its association with pancreatic exocrine insufficiency (PEI) is not well investigated in CHF.We attempted to detect the association between PEI and CHF-induced appetite.Patients with CHF were enrolled, and body mass index (BMI), left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) cardiac function grading, B-type natriuretic peptide (BNP), serum albumin, pro-albumin and hemoglobin were evaluated. The pancreatic exocrine function was measured by fecal elastase-1 (FE-1) levels in the enrolled patients. Appetite assessment was tested by completing the simplified nutritional appetite questionnaire (SNAQ). The improvement of appetite loss by supplemented pancreatic enzymes was also researched in this study.The decrease of FE-1 levels was found in patients with CHF, as well as SNAQ scores. A positive correlation was observed between SNAQ scores and FE-1 levels . Pancreatic enzymes supplement could attenuate the decrease of SNAQ scores in CHF patients with FE-1 levels <200 μg/g stool and SNAQ < 14.Appetite loss is commonly seen in CHF, and is partially associated with pancreatic exocrine insufficiency. Oral pancreatic enzyme replacement therapy attenuates the chronic heart failure-induced appetite loss. These results suggest a possible pancreatic-cardiac relationship in chronic heart failure, and further experiment is needed for clarifying the possible mechanisms. Often caused by myocardial infarction, hypertension, valvular heart diseases, cardiomyopathy and other forms of chronic artery diseases, chronic heart failure (CHF) isa progressive and irreversible disease, which is commonly seen in the department of cardiology , 2. The Appetite loss is one complication of CHF and induces a lack of intake in energy, protein and other nutrients, leading to malnutrition . MalnutrIn this study, the pancreatic exocrine function was measured by FE-1 levels in the enrolled patients of CHF. Appetite assessment was tested by the simplified nutritional appetite questionnaire (SNAQ). The association between FE-1 and CHF-induced appetite loss was also investigated. The improvement of appetite loss by supplemented pancreatic enzymes was researched at the same time in this study.In this study, patients with CHF were enrolled, who were hospitalized and followed up in the Department of Cardiology of the First Affiliated Hospital of Soochow University, between August 2013 and December 2014. The diagnosis of CHF was based on the presence of current or previous symptoms, characteristic clinical signs, and evidence of ventricular dysfunction, according to the criteria of the American College of Cardiology/American Heart Association 2005 Guideline Update for the Diagnosis and Management of heart failure [The healthy persons in the control group had no systemic diseases or symptoms, and were drawn from outside the hospital. Written informed consent was given to all the patients before participation and the study was approved by the ethics committee of the First Affiliated Hospital of Soochow University and complied with the Declaration of Helsinki.®, 2#, po, t.i.d.) (N = 30).In experiment 1, blood and feces samples were collected in the enrolled patients (N = 104) with CHF. Blood samples were used for analyzing heart failure-related parameters. Feces were used for the measurement of FE-1 levels. Appetite assessment was tested by SNAQ. In experiment 2, the effect of pancreatin on the appetite loss was evaluated in CHF patients with FE-1 levels <200 μg/g stool and SNAQ < 14 (N = 60). Pancreatin is also known as pancreatic enzymes , which are used to treat malabsorption syndrome due to pancreatic problems. In this randomized controlled trial, patients were randomly allocated to one of two groups (placebo group and treatment group) using a computer-generated table . PatientFollowing an overnight fast (8 hours), blood samples were collected. Venous blood was drawn and sera were then collected after centrifugation at 3000×g for 15 min after coagulation. Serum was stored in the refrigerator at 4°C in aliquots until analysis. All laboratory variables were measured by a central laboratory that undergoes regular internal and external quality audits. A fully automatic biochemical analyzer  was used to determine the serum parameters. N-terminal pro-B type natriuretic peptide (NT-proBNP) was measured by using an immunoassay based on electrochemiluminescence with the Elecsys 1010/2010 System .serum, a commercially available ELISA kit was applied according to the manufacturer’s instructions . This assay kits employ the quantitative sandwich enzyme immunoassay technique and antibodies specific for TNF-α, IL-1β, IL-6 and leptin have been pre-coated onto a microplate with the high sensitivity and excellent specificity for detection. No significant cross-reactivity or interference between human TNF-α, IL-1β, IL-6 and leptin and analogues was observed.For quantitative determination of human TNF-α, IL-1β, IL-6 and leptin in Pancreatic exocrine function was evaluated by FE-1 levels as mentioned previously. FE-1 levels were measured by a commercially available Enzyme-Linked Immunosorbent Assay kit  according to manufacturer’s instructions. FE-1 level ≥200 μg/g stool indicated normal pancreatic function, whereas the concentration of 100 to 200 μg/g stool indicated mild to moderate PEI, and FE-1 <100 μg/g stool were qualified as severe PEI.When at admission, all enrolled patients were asked to complete the simplified nutritional appetite questionnaire (SNAQ) . Subject2 test or Fisher’s exact test was used for comparison of categorical variables. Spearman coefficient was used for measuring linear correlation between variables. Values of P< 0.05 were considered statistically significant.Statistical analysis was performed using SPSS software version 18.0 . The data are expressed as means ± SD. One-way ANONA was used for comparing data with a normal distribution and a Kruskal-Wallis test was used for non-parametric data. Pearson’s χA hundred and four patients with CHF were enrolled in experiment 1, with 20 healthy persons served as control . PatientPEI was found in patients with CHF by FE-1evaluation and the results of FE-1 levels in all groups were given in The effect of pancreatin on the appetite loss was evaluated in CHF patients (FE-1 levels <200 μg/g stool and SNAQ < 14) in experiment 2 . 60 patiDefined as the alteration of pancreatic function, pancreatic exocrine insufficiency (PEI) will lead to maldigestion resulting from the reduction of exocrine secretion in the pancreas, which is caused by diseases of the exocrine pancreas and the endocrine pancreas  . AnatomiCommonly occurred in chronic diseases, decreased appetite and involuntary weight loss have a negative impact on both quality of life and eventual mortality . AppetitThe pancreas is the first organ that decreases its quality of exocrine excretion when there is inflammation and malnutrition. While, in other inflamed organs, such as the heart, many inflammatory mediators are overproduced, inducing anorexia directly on the hypothalamus. In our study, the obvious changes of TNF-α, IL-1β, IL-6 and leptin were found, which are reported to be involved in diseases-induced appetite loss –34. Seru®) is a commercial mixture of several digestive enzymes produced by the exocrine cells of the pancreas, which is composed of amylase, lipase and protease. Taken by mouth, it is clinically used to treat PEI [Oral pancreatic enzyme replacement therapy (PERT) is the treatment of choice for PEI, together with nutritional management and specific nutritional supplementation if required .Pancreatreat PEI . For furIn conclusion, appetite loss is commonly found in chronic heart failure, and is partially associated with pancreatic exocrine insufficiency. Oral pancreatic enzyme replacement therapy attenuates the chronic heart failure-induced appetite loss. These results suggest a potential pancreatic-cardiac relationship in chronic heart failure, and further experiment is needed for clarifying the possible mechanisms.S1 Table(DOCX)Click here for additional data file.


Diabetes is one of the most common metabolic disorders, with a high prevalence of patients with poor metabolic control. Worldwide, evidence highlights the importance of developing and implementing educational interventions that can reduce this burden. The main objective of this study was to analyse the impact of a lifestyle centred intervention on glycaemic control of poorly controlled type 2 diabetic patients, followed in a Community Care Centre.A type 2 experimental design was conducted over 6 months, including 122 adults with HbA1c ≥ 7.5%, randomly allocated into Experimental group (EG) or Control Group (CG). EG patients attended a specific Educational Program while CG patients frequented usual care. Personal and health characterization variables, clinical metrics and self-care activities were measured before and after the implementation of the intervention. Analysis was done by comparing gains between groups (CG vs EG) through differential calculations (post minus pre-test results) and Longitudinal analysis.p < .001) and 4% more (effect-size r2 = .04) in BMI (p < .05). When controlling for socioeconomic characteristics and comorbidities that showed to be associated to each parameter in pre-test, from pre to post-test only EG participants significantly decreased HbA1c ; BMI values ; systolic Blood pressure  and diastolic Blood pressure .Statistical differences were obtained between groups for HbA1c and BMI: EG had a decrease in 11% more (effect-size r2 = .11) than CG for HbA1c . Diabetes, one of the most common metabolic disorders, is a public health concern rising with a widespread significance all over the world, with a clear tendency to increase in the next decades –4.1c) in Nacional Health Service (NHS), 21.8% have values over 8% . By analysing the outcomes of this procedure, new contributions regarding the effects of a structured educational intervention program on metabolic control among Portuguese poorly controlled people with type 2 diabetes are highlighted. More specifically, we intend to ascertain whether a multicomponent educational program focused on lifestyle management strategies: (a) is significantly associated with metabolic control; (b) is effective on improving metabolic control; and (c) whether metabolic control is maintained after controlling for socioeconomic and health individual variables (comorbidities).After a piloting procedure , 17, the1c ≥ 7.5%/58.5 mmol/mol), followed in a Community Health Centre of the Portuguese NHS, using age and HbA1c as relevant control selection variables.The sample is composed of two groups of adult/middle age patients with type 2 poorly controlled diabetes (HbAn = 151) were invited during a routine consultation to participate in our study. From those, 136 agreed to do so, and were randomly allocated by the researcher into EG or CG in series of 2 patients for each group . The researcher was the only one in possession of the process number of the patient, without no further information  and q   with HbA1c between 7.5% (58.5 mmol/mol) and 14% (129.5 mmol/mol)  and 58 in CG, between 35 and 67 year-old ; with HbA1c between 7.5% (58.5 mmol/mol) and 12.4% (112 mmol/mol) .Of the 136 participants, 122 concluded all the phases of the procedure : 64 in EG, between 35 and 67 year-old , apart from personal and health characterization variables. Self-care activities were assessed using the Summary of Diabetes Self-care Activities Scale .As for BP as dependent variables, when we control covariates associated with diastolic and systolic blood pressure, the interactions between within-subjects variables and the between-subjects factors were significant, due to a decreased in both groups from pre to post-test,  as for CG we obtained: BPs within-subjects variables: Wilks’ ʎ = .954; F = 2.67; p = .108; ηp2 = .046; observed power = .362 and BPd within-subjects variables: Wilks’ ʎ = .918; F = 4.72; p = .34; ηp2 = .082; observed power = 569 . The same applies to BMI variation, another cornerstone for diabetes health related outcomes, although this variation has a minor estimated decrease and its clinical value may be of lower significance. Blood pressure was the other clinical metric analysed in this study, due to the well-known relation between hypertension and diabetes, a condition that often affects people with type 2 diabetes. Results show both systolic and diastolic values have decreased from pre to post test, although without statistical significance.Impact of the educational program by itself is supported in the Longitudinal analysis, when variables statistically associated with clinical metrics in pre-test measures were controlled. Notwithstanding the statistical removal of the effect of the covariates, a significant interaction between within-subjects variables and the between-subjects factor remains, leading to the conclusion that only in experimental group participants a significantly decreased in clinical metrics can be verified, as identified in other studies .1c values with an effect size of 11%; of BMI, although effect size is lower (3%) and of BP . CG participants didn’t have a significant decrease in HbA1c values (p = .550), in BPs (p = .108) or in BPd (p = .34) and BMI increased from pre to post-test, although it didn’t have statistical significance (p = .782). These outcomes also are in line with the ones from other studies [With distinct effect sizes, we confirmed experimental group participants reduced significantly clinical parameters from pre to post-test. EG participants registered a statistical significant decrease of HbA studies , 39–41.Furthermore, our results sustain the impact of a structured multicomponent educational intervention on improving clinical metrics, beyond standard educational approach alone , 43–45, [ [It is known that often health expected outcomes fail to meet guidelines, patients’ expectations and needs, due to multiple known barriers to health professionals’ intervention and patients’ outcomes achievement[ , 36–38.Education and lifestyle modification are identified as critical components for metabolic and clinical control in diabetic patients. Evidence-based reports have emphasized the importance of education for type 2 diabetic patients and educational programmes have confirmed their role in glycaemic control and decreasing diabetes associated complications ., were identified and taken into account in the definition of the Complex Intervention.The accuracy and innovative contribution of the present study is intended to be the assessment of the effectiveness of a specific educational program, designed upon an exploratory trial, where detailed educational needs of a group of Portuguese people with type 2 diabetes1c with statistical evidence between groups (CG vs EG), result reinforced when correlated variables were controlled.The multicomponent educational program, structured on the principle of Therapeutic Education, has proven its effectiveness, especially with regard to metabolic control, by lowering HbA1c levels between groups (EG and CG). There was even an aleatory patient distribution into groups, which leads us to suggest more research with Portuguese patients, analysing the impact of these programs in health gains, especially if randomization can be achieved.Nevertheless, these results should be interpreted with some consideration due to the limitations of the study, mainly related to the baseline difference in HbA


The motive of this study was to investigate the interaction between polymorphisms in the MDR1 gene and anesthetic effects following pediatric tonsillectomy. In total, 240 children undergoing tonsillectomy with preoperative propofol-remifentanil anesthesia were selected. Genomic DNA was extracted from the peripheral blood of children after operation, and the MDR1 gene polymorphisms of 2677 G>T/A, 1236 C>T and 3435 C>T were detected by direct sequencing. We tested mean arterial pressure, diastolic blood pressure, systolic blood pressure, and heart rate at several time-points: T0 (5 mins after the repose), T1 , T2 , T3 (0 min after the tonsillectomy), T4  and T5 (5 min after the extubation). The visual analog scale, the face, legs, activity, cry, and consolability pain assessment, and the Ramsay sedation score were recorded after the patients regained consciousness. Adverse reactions were also recorded. The time of induction, respiration recovery, eye-opening, and extubation of children with the CC genotype were found to be shorter compared to the CT + TT genotype of MDR1 1236C > T . The mean arterial pressure, diastolic blood pressure, systolic blood pressure, and heart rate were significantly reduced at T5 in children with the CC genotype . The visual analog scale at 1, 2, 4, and 8 hours post-operation, and the Ramsay sedation score at 5, 10, and 30 min after the extubation were decreased, while the face, legs, activity, cry, and consolability pain assessment score increased . There was no statistically significant difference in the adverse reaction of MDR1 mutations (P> 0.05). It could be concluded that anesthetic effect following pediatric tonsillectomy in patients with the MDR1 1236C > T CC genotype was stronger than in those carrying the CT + TT genotype. Tonsillectomy is known to be one of the most common and severely painful surgeries that children undergo1 . In addiA total of 240 subjects were recruited for this study. According to the sequencing results, the number of wild-type heterozygote patients for MDR1 2677G>T/A with TG, GA, and TA was 101, 31, and 30 respectively, and the number of mutant homozygote patients with TT, GG and AA was 30, 42, and 6 respectively. The number of patients with MDR1 1236C > T wild homozygote CC, heterozygote CT, and the mutational homozygote TT was 25, 118, and 91, respectively. The number of patients with MDR1 3435 C > T wild homozygote CC, heterozygote CT, and mutant homozygote TT was 92, 18, and 40, respectively.The MDR1 gene distribution for 3435C > T, 1236C > T, and 2677G > T/A was consistent with Hardy–Weinberg equilibrium , which indicated that the gene distribution of MDR1 3435C > T, 1236C > T, and 2677G > T/A achieved genetic equilibrium. It was then recorded and represented in Table P >0.05). No significant difference was revealed between MDR1 3435C > T CC and CT + TT genotypes that increased the time of induction, respiration recovery, eye-opening, and extubation . Compared to the MDR1 1236C > T CC genotype, children bearing the CT + TT genotype exhibited longer times of induction, respiration recovery, eye-opening, and extubation , as demonstrated in Table No significant differences were found between different genotypes on MDR1 2677G > T/A concerning the time of induction, respiration recovery, eye-opening, and extubation . There was no significant difference revealed between the MDR1 3435C > T CC and CT + TT genotypes i MAP, SBP, DBP, and HR at T0, T1, T2, T3, T4, and T5 . This was also applicable for the different genotypes on MDR1 2677G > T/A . Compared to the MDR1 1236C > T CT + TT genotype, the children with the CC genotype exhibited significantly reduced MAP, SBP, DBP, and HR at T5  and nonsignificant differences during other time points , as demonstrated in Table The MAP, SBP, DBP, and HR of patients with different genotypes at T1, T2, T3, T4, and T5 were found to be lower than those at T0 . Additionally, there was no significant difference observed among the different genotypes on MDR1 2677G > T/A . Compared to the MDR1 1236C > T CC genotype, a significantly higher VAS was indicated in children who had the CT + TT genotype at 1, 2, 4, and 8 hours post-operation , as demonstrated in Table Compared to VAS at 1 hour post-operation, all the mutations of the genotype of children with post-operative VAS showed a downward trend. There was no significant difference revealed between MDR1 3435C > T CC and CT + TT genotypes in terms of VAS at each time point . No significant differences were observed among different genotypes on MDR1 2677G > T/A . Compared to the MDR1 1236C > T CT + TT genotype, Ramsay scores at the 3 time points were reduced in children with the CC genotype, while FLACC scores were found to be higher , as demonstrated in Table As shown in Table P >0.05).There were 8 cases of adverse reactions to anesthesia that occurred in this study. These included 2 cases of nausea and vomiting found in patients with the 2677 G>T/A CC genotype, 3 cases in patients with the 1236 C>TCT + TT genotype, and 2 cases in patients with the 3435 C>TCC genotype; 1 case of agitation in the recovery period was found with the 1236 C>T CC genotype. The comparisons of adverse reaction rate among different genotypes on MDR1 mutations were found to be nonsignificant  and propofol  initial doses were set at 2.5 μg / L and 2.5 mg / L, respectively, after imputing parameters such as the child’s weight, age and others. Intravenous infusion of 0.1 mg / kg vecuronium by endotracheal intubation then followed. The bispectral index was maintained at 45-55 during surgery. The propofol concentration was adjusted at any time to maintain the mean arterial pressure (MAP) at 60 ∼ 90 mmHg and the heart rate at 80 ∼ 120 beats / min. The remifentanil concentration was adjusted to maintain the stability of anesthesia, and vecuronium was used as appropriate. Remifentanil infusion was ceased at the end of the surgery and propofol infusion stopped 5 minutes after the surgery. The ventilator was cleared when children began to breathe, cough, and swallow normally. The patient was transferred to the observation room at 5 minutes after the oxygen supply stopped, and the percutaneous oxygen saturation (SPO2) stabilized at approximately 95%.Hemodynamics after anesthesia: The times taken for the following activities were recorded: time of anesthesia induction, eye-opening, respiration recovery, and extubation. Mean arterial pressure (MAP), diastolic blood pressure (DBP), systolic blood pressure (SBP), and HR of different genotypes were recorded and compared at 5 minutes after repose (T0), 0 minutes after tracheal intubation (T1), 5 minutes after tracheal intubation (T2), 0 minutes after tonsillectomy (T3), 0 minutes after removal of mouth-gag (T4) and 5 minutes after extubation (T5).Analgesia and adverse reaction observation: At 1, 2, 4, and 8 hours post-operation, the visual analog scale (VAS) was recorded . The RamPeripheral blood sampling and DNA extraction: Fasting venous blood (3 mL) was sampled and placed into a sodium citrate anticoagulation tube labeled with the subject number and name. Using a DNA extraction kit , the blood was centrifuged at 3000 rpm/min for 10 minutes to extract whole blood DNA from the peripheral blood. Fasting venous blood (3 mL) was sampled and placed into the sodium citrate anticoagulation tube labeled with the subject number and name. Using a DNA extraction kit , the blood was centrifuged at 3000 rpm/min for 10 minutes to extract whole blood DNA from the peripheral blood and stored at −80°. We detected 2677 G>T/A, 1236 C>T and 3435 C>T mutations in the MDR1 gene based on extracted genomic DNA. The sequencing primers are shown in Table Statistical analysis was performed using SPSS 19.0 . Measurement data were expressed as the mean ± standard deviation (± s), and comparisons between two groups using were tested using the t test. Counting data was expressed as [n (%)], and the χ2 test was used for statistical analysis with a significance level of 0.05. P <0.05 was statistically significant.


The role of EMPs in arterial hypertension is not well understood and EMPs are increased both in arterial hypertension and coronary artery disease (CAD). The data presented here show EMPs as defined by CD31 Hemodynamics and endothelial function of the brachial artery were assessed as flow-mediated dilatation (FMD). Pulse wave analyses including central blood pressure, pulse wave velocity (PWV), and aortic augmentation index (AIX) were performed by tonometry. Exclusion criteria were manifest peripheral artery, or cerebrovascular disease, acute inflammation (CRP > 0.6 mg/dl), kidney failure (eGFR < 30 ml/min), malignancies, and arrhythmias (heart rhythm other than sinus).We investigated circulating EMPs along with functional and mechanical characteristics of the arterial system in 41 consecutive male subjects, 20 subjects without arterial hypertension and 21 subjects with arterial hypertension as defined by blood pressure > 140/90 mmHg or ongoing antihypertensive medication. The patients were recruited from the outpatient clinic. As the presence of CAD might also affect circulating EMP values, we aimed at including 50% patients with stable CAD. In all subjects, EMP subpopulations . Microbead standards (1.0 mμ) were used to define MPs as < 1 μm in diameter. The EMP subpopulations were defined as CD31+/CD41−, CD62e+, or CD144+ events. The total number of EMPs was quantified using flow-count calibrator beads (20 l).Citrated blood (6 ml) was drawn from the cubital vein and processed within 2 h. Platelet-rich plasma was obtained by centrifugation of whole blood at 300 2.3®, AtCor-Medical, Australia).The Task Force Monitor  was used for continuous beat-to-beat assessment of cardiovascular variables, including stroke volume, BP, heart rate, and total peripheral resistance by impedance cardiography, which included ECG, phonocardiography, Finapres , and BP monitoring system  at the upper arm. We determined 24 h ambulatory BP measurements on the day before study days. Central BP was derived from peripheral pulse wave analysis  and pulse wave velocity (PWV) were measured by radial applanation tonometry using the SphygmoCor2.5max − diameterbaseline)/diameterbaseline. Endothelium-independent nitroglycerin-mediated dilation (NMD) was measured at 4 min after 400 mg nitroglycerin  in the brachial artery at the site of FMD measurements and calculated identically.Brachial artery (BA) FMD was measured by ultrasound  in combination with an automated analysis system  in a 21 °C temperature-controlled room after 15 min of supine rest 2.62.WSS was assessed based on maximal brachial artery diameter and flow velocity measurements obtained during FMD measurements and was calculated as 8 * µ * mean flow velocity/mean diameter, where blood viscosity (µ) was assumed to be constant at 0.035 dyn/s cm2.72  on the volar site of the forearm. Microvascular reactivity was assessed during post-occlusive reactive hyperemia PORH. Following the baseline perfusion , a blood pressure cuff located at the distal upper arm was inflated to suprasystolic pressure over 5 min. After the cuff release, the microvascular response on reactive hyperemia was recorded. Data acquisition and analysis were performed by LDPI Win Software  processing the perfusion as numerical values and color-coded-images All investigations were performed using a scanning laser Doppler perfusion imager . The arm selected for measurements was immobilized to avoid moving artifacts using a vacuum pillow containing polyurethane beads, which molds to the shape of the arm . The laser beam was positioned 15 cm above the forearm scanning a field of 200 mm2.8Baseline characteristics of study subjects and results are described as average and standard deviation. Subgroup analyses between the 4 groups of patients were performed with one way ANOVA and Tukey post-hoc test. Normal distribution was confirmed by Kolmogorov–Smirnov test for all parameters except for subgroups of EMP data. As a conservative approach, we performed decadic logarithmic transformation of all EMPs concentrations. P values of less than 0.05 were regarded as statistically significant. All Analyses were performed with SPSS 23 (IBM Corp.).


The effect of heart rate (HR) and body surface area (BSA) on pulmonary RC time and right ventricular (RV) load is unknown.To determine the association of HR and BSA with the pulmonary RC time and measures of RV load, we studied three large patient cohorts including subjects with 1) known or suspected pulmonary arterial hypertension (PAH) (n = 1008), 2) pulmonary hypertension due to left heart disease (n = 468), and 3) end-stage heart failure with reduced ejection fraction (n = 150). To corroborate these associations on an individual patient level, we performed an additional analysis using high-fidelity catheters in 22 patients with PAH undergoing right atrial pacing.A faster HR inversely correlated with RC time , suggesting augmented RV pulsatile loading. Lower BSA directly correlated with RC time (p<0.05) although the magnitude of this effect was smaller than for HR. With incremental atrial pacing, cardiac output increased and total pulmonary resistance (TPR) fell. However, effective arterial elastance, its mean resistive component , and its pulsatile component  all increased at faster HR.Heart rate and BSA are associated with pulmonary RC time. As heart rate increases, the pulsatile and total load on the RV also increase. This relationship supports a hemodynamic mechanism for adverse effects of tachycardia on the RV. The product of pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC), or RC Time, is the diastolic decay constant of pulmonary artery pressure. For any given resistance, a shorter time constant translates to faster diastolic pressure decay and a higher pulse pressure. Unlike the systemic circulation, prior studies have found that PVR and PAC, the two major components of right ventricular (RV) afterload, depend upon each other and follow an inverse relationship. This coupled relationship results in a constant RC time. Two reasons have been proposed for their relative tight dependence in the pulmonary circulation: 1) most of the vascular compliance is distributed at the lung periphery and therefore the vessels responsible for resistance also account for a significant proportion of the vascular compliance; and 2) elevations in PVR increase pressure within the vascular lumen such that mean pulmonary artery pressure (mPAP) becomes the most important determinant of PAC ) have been associated with shorter RC times , 13. HowWe studied four independent and clinically distinct patient cohorts. For cohort A-C, approval for a retrospective analysis of clinically collected data was obtained from the Johns Hopkins and University of Pennsylvania Institutional Review Boards (IRB). For cohort D, after IRB approval for a prospective study, subjects signed written consent to participate.To determine the association of HR and BSA with the RC time as well as resistive and pulsatile components of RV afterload, we analyzed three patient cohorts comprised of patients from two institutions.Cohort A included all subjects (N = 1008) at Johns Hopkins undergoing right heart catheterization between 2000 and 2010 to evaluate for pulmonary hypertension. Patients with a PAWP>15 mmHg were excluded .Cohort B included patients with unexplained cardiomyopathy undergoing endomyocardial biopsy and hemodynamic assessment at Johns Hopkins between 1982 and 1997. Subjects with mPAP≥ 25 mmHg and pulmonary artery wedge pressure (PAWP)>15 mmHg consistent with pulmonary hypertension due to left heart disease (N = 468) were included .Cohort C included patients (N = 150) with end-stage systolic heart failure undergoing RHC prior to implantation of a continuous-flow left ventricular assist device at the Hospital of the University of Pennsylvania between 2008 and 2014.Next, to assess the influence of increasing heart rate on resistive and pulsatile components as well as total RV afterload at the individual patient level, we performed incremental atrial pacing experiments in a fourth Cohort (D). This cohort was was comprised of 22 prospectively enrolled subjects with pulmonary arterial hypertension (mPAP ≥ 25mmHg and PAWP ≤ 15mmHg) referred for a right heart catheterization (RHC). After consent and standard RHC, the initial right internal jugular sheath was exchanged for a dual-lumen 9F sheath . This enabled simultaneous placement of a 5F pressure-volume catheter  into the RV and either a 2.4F bipolar pacing wire or 4F quadripolar pacing catheter  into the right atrium. The RV volume signal was calibrated based on same day cardiac MRI volume measurements. Pes points were determined from a set of pressure volume loops with varying preload volumes during phase 2 of the Valsalva maneuver, and fit by perpendicular regression to derive the slope of the end-systolic pressure-volume relationship (ESPVR) as previously described [-1 (slightly above the baseline HR), was then increased in 20 min-1 increments until either a peak of 140–150 min-1 or the HR at which 2nd degree atrioventricular block was observed, whichever came first. Hemodynamic values at rest and during peak pacing HR were compared. Cardiac output (CO) before pacing and during peak pacing were calculated as HRxSV (from the PV loop). Mean pulmonary artery pressure was estimated as right ventricular systolic pressure (RVSP)x0.61+2 as described by Chemla et al [Atrial pacing, starting at ~80–90 minla et al . Total pAll subjects underwent a clinically indicated right heart catheterization (RHC) and had hemodynamic assessment by a heart failure or pulmonary hypertension specialist using a balloon-tipped pulmonary artery catheter. Pressure measurements were recorded at end-expiration. Cardiac output was estimated by the thermodilution method for cohorts A, B and D, and indirect Fick method for cohort C. PAC was calculated as stroke volume divided by pulmonary pulse pressure. Effective arterial elastance (Ea), a lumped measure of afterload that incorporates both resistive and pulsatile components, was determined by dividing end-systolic pressure (Pes) by stroke volume (SV). In the setting of pulmonary hypertension and increased impedance, RV pressure rises throughout ejection peaks near end-systole. Therefore, Pes in cohort A-C was estimated by right ventricular systolic pressure (RVSP) . Pes wasAs described previously in studies of the left ventricle , 20, Ea Ea = (mPAP/SV) + (Pes-mPAP)/SV; where the former represents resistive load (mPAP/SV) and the latter represents pulsatile load (Pes-mPAP)/SVFurthermore, mPAP/SV can be re-written as TPR  x HR or TPR/T (with T representing the heart period in seconds). TPR/T shares the same units as Ea (mmHg/mL)Therefore, (Pes-mPAP)/SV = Ea − TPR/TData are presented as mean (standard deviation). Comparison of continuous variables between quintiles of HR and BSA was performed via T-test or Mann Whitney Rank Sum test as appropriate. The Shapiro-Wilk test was used to test for normality. Comparison of proportions was performed using chi square test. Multiple linear regression analyses and non-linear regressions to fit RC curves were performed using Stata SE 14.0, and are presenting with Beta coefficient (standard error). RC curves were compared by performing log-log transformation and then by ANCOVA. Hemodynamic variables at baseline and at peak-paced heart rate in Cohort D were compared using paired T test or Wilcoxon signed-rank test as appropriate. There was no significant collinearity among the variables assessed by the VIF command. A p-value<0.05 was considered statistically significant.Baseline characteristics for the 4 independent cohorts are displayed in In order to control for the effects of other known determinants of the RC time, we next performed multiple linear regression modeling in Cohorts A-C forcing HR, mPAP, PAWP, BSA, and age, race and sex into the model as covariates. In order to test the effects of increasing HR within an individual patient, we performed incremental right atrial pacing. We demonstrate across clinically distinct patient cohorts that HR and BSA are both associated with the pulmonary RC time and may account for some of the “scatter” previously reported. Thus, the notion of a “fixed” RC time in the pulmonary circulation should be modified by at least two additional factors. The magnitude of effect of HR on the RC time is substantial and comparable to the effects of mPAP and PAWP. We also show heart rate is increased, total RV load increases, including at the individual patient level. The increase in RV load at faster heart rates is mediated not only via the HR effect on resistive load (TPR/T) but also through absolute increases in pulsatile RV afterload.When RC time is calculated as PVR x PAC, it can be simplified to (mPAP—PAWP)/(HR x pulmonary pulse pressure) because stroke volume cancels out. Therefore, as HR increases and the diastolic time shortens, the pulmonary pulse pressure must decrease and/or mPAP rise in a proportional manner if the RC time is to remain constant. However, in our cohorts, the changes in pulse pressure and mPAP do not fully offset the increase in HR, and the RC time declined. A lower RC time would suggest that at similar levels of resistive load, tachycardia leads to increased pulsatile loading of the right ventricle, and this may have important clinical implications for patients with pulmonary hypertension. Resting HR is an independent predictor of adverse outcome in PAH, likely in part as a reflection of underlying RV function . AlthougThe mechanism of increasing heart rate leading to a lower RC time is less clear. One possibility is that as the diastolic period decreases (with increasing heart rate), the pulmonary circuit is unable to completely discharge the prior stroke volume (incomplete Windkessel function), and compliance decreases. Indeed, in cohorts A-C, we found an increase in diastolic pulmonary pressure without significant changes in PAWP or pulmonary pulse pressure, the latter of which should fall as stroke volume decreases. MRI studies demonstrating that MRI-measured pulmonary artery distensibility- an index incorporating the difference between systolic and diastolic pulmonary artery diameter- is correlated with response to inhaled vasodilators, outcome, and functional class in pulmonary hypertension , 27. MRIWe also found that a lower body surface area was associated with a lower pulmonary RC time. The systemic RC time has been shown to increase with increasing body size across mammals . Lung siLimitations of our study include the fact that, in cohorts A through C, heart rate was not an independently controlled variable, but an observational variable made in each patient. This could introduce confounding factors, for example, subjects with higher HR tend to have stiffer pulmonary vasculatures. The cohorts consist of patients with varied clinical characteristics, making comparison of magnitude of effect challenging. It is also possible that faster HR resulted in some overestimation of PA pulse pressures due to fluid filled catheter underdamping. This is unlikely given the frequency range we are describing, but cannot be ruled out. Further, in Cohort D, HR was a true independent variable in each patients, and high fidelity catheters were used, yet a similar result was obtained. In this cohort, only RV pressures were available, so that mPAP had to be estimated and pulse pressure (and hence PAC) could not be determined. Therefore, calculated mPAP may underestimate the pulsatile loading in cohort D and while we witnessed absolute increases in resistive and pulsatile load, it is not possible to truly assess the relative contributions of each. Finally, PAC is clearly a lumped simplification for compliance, and while it has been validated against 3-element Windkessel model calculations, some of this theory has been debated .In conclusion, we demonstrate that HR and BSA are both associated with the pulmonary RC time. As heart rate is increased, pulsatile and total load on the right ventricle also increases. This relationship may suggest a pathophysiologic mechanism for adverse effects of tachycardia on right ventricular afterload.S1 FigEstimating Pes as mPAP leads to significant underestimation in these subjects with pulmonary arterial hypertension.(TIF)Click here for additional data file.S1 TableData shown as mean (SD) and N (%). PA = Pulmonary Artery.(DOCX)Click here for additional data file.S2 TableData shown as mean (SD) and N (%). PA = Pulmonary Artery.(DOCX)Click here for additional data file.S3 TableData shown as mean (SD) and N (%). PA = Pulmonary Artery.(DOCX)Click here for additional data file.


Evaluation of patient’s dry weight remains challenging in chronic hemodialysis (HD) especially in children. Inferior Vena Cava (IVC) measurement was reported useful to assess fluid overload both in adults and children.We performed a monocentric prospective study to evaluate the relation between predialytic IVC diameter measurements and hydration status evaluated by physicians and bioimpedance spectroscopy (BIS) and between IVC measurements and persistent hypertension.p = 0.20). Patients whose blood pressure normalized after HD had a more dilated maximal IVC diameter before dialysis session than patients with persistent hypertension ) with an optimal cut-off of −0.5 SD.Forty-eight HD sessions in 16 patients were analyzed. According to physicians, patients were overhydrated in 84.5% of dialysis sessions, 20.8% according to BIS, and 0%, 4.1% and 20.8% according to IVC inspiratory, expiratory and collapsibility index reference curves respectively. There was no correlation between relative overhydration evaluated by BIS and IVC measurements z-scores  contains supplementary material, which is available to authorized users. Hydration status evaluation is one of the major issues in children on chronic hemodialysis (HD). Acute overhydration can lead to acute pulmonary oedema and hypertension while chronic overhydration is a well-known factor of cardiovascular morbidity and mortality both in adults and children , 2. IntrMany methods exist to complete the clinical evaluation of the hydration status: cardiothoracic index based on chest X-ray evaluation, Inferior Vena Cava (IVC) diameter evaluated by ultrasound, biomarkers like Brain Natriuretic Peptide, Bioimpedance Spectroscopy (BIS), plasmatic volume variation monitoring  and rece2 is associated to a low CVP less than 3 mmHg and a minimal IVC diameter superior to 11.5 mm/m2 is associated to a high CVP above 7 mmHg . Five patients were treated for hypertension, four required one anti-hypertensive drug and one required three. Five patients had bilateral nephrectomy before the study period and only three patients had urine output greater than 0.5 ml.kg−1.h-1. Most of the patients had three dialysis sessions a week and only three patients had four sessions a week. Vascular access was central venous catheter in six patients and A-V fistula in 10. The median urea Kt/V was 1.34 [1.2–1.9].Sixteen patients were included (13 boys and three girls). The median age was 14.3 years old [9.9–15.5]. The median time from the start of hemodialysis was 19 months [9.5–21.8]. The median Body Mass Index was 17.8 kg/mIn our cohort, patients were considered overhydrated in 84.5% of dialysis sessions by clinical assessment before dialysis session. The median ultrafiltration volume was 35.4 ml/kg/session [15.6–51.4] with a loss of 3,4% of predialysis body weight by session [1.3–4.3].p = 0.0004)), and the maximal ) IVC diameter. We also found a median IVCCI increase of 0,10 mm  . There was a good correlation between IVC maximal and minimal diameter measurement (Pearson correlation coefficient = 0.77). Measurements were reported on the reference curves . Considering BIS evaluation as reliable, 46% of the sessions were correctly classified for hydration status based on IVC diameters and 48% based on predialysis IVCCI . Mean rel.OH was −3.4% (range − 7.25 to +2.52) and 52.1% of patients were found to be normohydrated (rel.OH -7 to +7%) whereas 25% were found dehydrated (rel.OH < −7%), 10.4% moderately overhydrated (7% < rel.OH < 15%) and 10.4% severely overhydrated (rel.OH >15%). There was no statistically significant correlation between overhydration estimated by clinical evaluation and BIS evaluation  were associated with symptoms of intolerance. Two patients (4%) had abdominal pain, nine (19%) had sudden drop of blood pressure with associated tachycardia. There was a decrease of 30% of systolic blood pressure (range 23 to 35%) and 33.4% of diastolic blood pressure (range 23.4 to 38.4%). Nine patients had tachycardia with a median increase of 17.2% of heart rate (range 12.9 to 20.5%). When intolerance symptoms occurred, all patients underwent passive leg rising and ultrafiltration stop. Three received volume expansion of isotonic saline solution.p = 0, 08).Patients’ age, blood pressure at start of dialysis, hydration status evaluated by BIS and echocardiographic measurements were not found to be associated with the tolerance of dialysis sessions Table . There wp = 0,28), and between patients with persistent hypertension and patients who normalized their blood pressure after the session . None of the patients with persistent high blood pressure had bilateral nephrectomy. Two of the twelve patients had predialytic high blood pressure despite antihypertensive therapy. None of these patients had postdialytic hypertension. Ultrafiltration during the session was significantly higher for patients with persistent high blood pressure than for those whose blood pressure normalized ). Patients whose blood pressure normalized after HD had a more dilated maximal IVC diameter before dialysis than those with persistent hypertension ) . After seven sessions, some patients had remaining high blood pressure . We found no difference of hydration status assessed by BIS before hemodialysis between patient presenting high blood pressure and those with normal pressure  among critically ill and healthy adult patient , 11. TheIn our study, we found significant modifications of IVC diameter between pre and postdialysis measurements, which is consistent with previous studies. Indeed, three studies demonstrated a decrease of IVC diameter after dialysis session in children –19. HaciIn 2000, Dietel et al. published referent curves for IVC maximal diameter  based onHowever, we found no correlation between hydration status evaluated by IVC measurement based on the reference curves from Kutty et al. and the hydration status assessed by BIS. Thus, the dilatation or the collapsus of IVC does not seem to be a good reflection of hydration status. Allinovi et al. found similar results when comparing 22 IVC measurements in 13 patients on peritoneal and hemodialysis to the hydration status evaluated by BIS . These mOur second objective was to assess whether IVC measurements could help predict dialysis tolerance. The only factor in our study which seems to be associated with perdialytic complications is a high ultrafiltration rate. That is consistent with previous pediatric studies , 30. We We determined ultrafiltration volume on the clinical parameters and per dialytic complications during previous sessions. The underestimation of dry weight by clinical assessment found in our study might be due to the use of high blood pressure as a marker of overhydration although dialysis patients are known to frequently present fluid independent hypertension . That miTo our knowledge, the present study is the first one to compare hydration status assessment by echographic measures of IVC reported on referent curves to BIS evaluation in a cohort of children on hemodialysis. Our study has several limitations. First, the small population size due to the scarcity of ESRD in children and the monocentric design of the study. The second is the lack of “gold standard” evaluation of hydration status. Indeed deuterium dilution is not available in clinical practice. Although BIS measurements and measurements by dilution techniques correlates, BIS have been reported to be less precise than dilution techniques . The thiOur study indicates that predialityc measurement of IVC diameter is not sufficient to assess hydration status but can predict volume-dependant high blood pressure in children on chronic HD. Thus, other methods are needed and the impact of the use of BIS on acute and chronic haemodialysis complications has to be evaluated in future studies.


N-acetyl-β-D-glucosaminidase (NAG) were correlated with the stages of CKD, and the association of these biomarkers with CKD progression and adverse outcomes was determined. A total of 250 patients, including 111 on hemodialysis, were studied. Urinary KIM-1, NGAL, and NAG were measured at baseline. Patients not on dialysis at baseline who progressed to a worse CKD stage were compared with those who did not progress. The association of each biomarker and selected covariates with progression to more advanced stages of CKD, end-stage kidney disease, or death was evaluated by Poisson regression. NGAL was moderately correlated  with the five stages of CKD; KIM-1 and NAG were also correlated, but weakly. Sixty-four patients (46%) progressed to a more advanced stage of CKD. Compared to non-progressors, those patients exhibited a trend to higher levels of KIM-1 (P=0.064) and NGAL (P=0.065). In patients not on dialysis at baseline, NGAL was independently associated with progression of CKD, ESKD, or death . In patients on dialysis, for each 300-ng/mL increase in urinary NGAL, there was a 1.3% increase in the risk of death (P=0.039). In conclusion, urinary NGAL was associated with adverse renal outcomes and increased risk of death in this cohort. If baseline urinary KIM-1 and NGAL predict progression to worse stages of CKD is something yet to be explored.Urinary biomarkers can predict the progression of chronic kidney disease (CKD). In this study, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and  Although mortality due to advanced chronic kidney disease (CKD) has decreased in the last few years in the USA  and EuroTraditional blood markers (creatinine) and urinary markers  of kidney injury have been used for decades in clinical studies for diagnostic and prognostic purposes. For prevalent nephropathies such as diabetic kidney disease, they remain as useful clinical markers of renal injury and even of CKD progression. However, considering the variety of causes that lead to kidney damage, these markers seem to be neither sensitive nor specific, mainly in the early disease stages . AdditioDistinct molecules are being investigated in the search for an ideal biomarker that could provide a window for intervention between cell disruption, renal damage, and clinical manifestations. Markers of inflammation , glomerular filtration rate (cystatin C), proximal tubular response , and tubular enzymes [N-acetyl-β-D glucosaminidase (NAG)] in serum and/or urine have all emerged as predictors of AKI before renal function decline can be detected clinically –19. TNotably, KIM-1, NGAL, and NAG are urinary biomarkers that reflect tubular damage and AKI, and are earlier and more sensitive markers than plasma creatinine in acute renal failure . UrinaryThe aim of this study was to ascertain whether urinary levels of KIM-1, NGAL, and NAG correlate with the five stages of CKD, including patients on dialysis, and to determine the association of these biomarkers with the adverse outcomes of CKD progression, ESKD , and death.Between April 2014 and October 2014, 250 patients were selected among individuals representing the five stages of CKD as defined by estimated glomerular filtration rate (eGFR) calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (creatinine based). This cohort was followed prospectively at Hospital de Clínicas de Porto Alegre (HCPA) and at an external private hemodialysis clinic in Southern Brazil, the two units from where the patients were recruited. Patients with ESKD on hemodialysis, except those with no residual renal function (anuria) and those scheduled for a kidney transplant, were also included. This study was approved by the HCPA Research Ethics Committee and performed in accordance with the 1975 Declaration of Helsinki. All participants provided written informed consent prior to enrollment. The Research Ethics Committee is registered with the Human Research Protection Committee of the Brazilian Ministry of Health under Institutional Review Board No. 00000921.Demographics and baseline clinical characteristics were assessed. Clinical data included age, gender, ethnicity, etiology of CKD, comorbidities such as hypertension (defined as current antihypertensive therapy), diabetes mellitus , and tobacco use. Data on etiology of CKD, comorbidities and tobacco use were extracted from medical reports. Patients with ongoing immunosuppression for active glomerulonephritis, evidence of acute kidney injury associated with active infection, under use of drugs or other nephrotoxic agents, or with conditions that could influence the evolution of CKD such as surgical interventions for obstructive uropathy were excluded.-1·(1.73 m2)-1; stage 2: 60–89 mL·min-1·(1.73 m2)-1; stage 3a: 45–59 mL·min-1·(1.73 m2)-1; stage 3b: 30–44 mL·min-1·(1.73 m2)-1; stage 4: 15–29 mL·min-1·(1.73 m2)-1; stage 5nd : 10–14 mL·min-1·(1.73 m2)-1; stage 5d : <10 mL·min-1·(1.73 m2)-1. CKD was established in the presence of structural or functional renal damage (eGFR <60 mL·min-1·(1.73 m2)-1) lasting for more than 3 months.CKD stages were defined according to KDIGO guidelines and based on eGFR levels as: stage 1: >90 mL·minPatients were followed from April 2014 to November 2015, for a median of 15 months. The patients were scheduled for planned follow-up visits at periodic intervals, according to CKD stage. The primary outcome measure was progression to a more advanced stage of CKD, and the secondary endpoints were development of ESKD  and death.g for 10 min at 20–25°C to remove the cellular components and the supernatant was aliquoted in 1.8 mL Eppendorf tubes and frozen within 2 h of collection at −80°C. At the time of assay, samples were thawed, vortexed, and centrifuged at 21,952 g for 5 min at 4°C, and assays performed in duplicate for biomarker measurement.First morning void spot urine samples were collected into sterile cups for measurement of KIM-1, NGAL, NAG, total protein, albumin, and creatinine. These measurements were performed at the Renal Division Laboratory of Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Urine was subsequently centrifuged at 400 Urinary KIM-1 and NGAL were measured by a microbead-based sandwich ELISA , and NAG by an enzyme-substrate-based colorimetry assay , according to the manufacturer's instructions. The intra-assay and inter-assay coefficients of variation and assay range were respectively: a) KIM-1: 4.2%, 6.7%; 0.097–40 ng/mL; b) NGAL: 3.7%, 6.5%; 0.49–1,000 ng/mL; c) NAG: <2%; <2%; 0.2–52.9 mU/mL.Urine albumin was measured by an immunoturbidimetric assay and urine creatinine by a kinetic colorimetric assay in an automated analyzer. Urinary albumin, KIM-1, NGAL, and NAG were always related to urinary creatinine. Serum creatinine was measured by the Jaffe reaction  at HCPA.Sample size was calculated using WinPEPI version 11.43  software, based on the study of Fufaa et al. . For a 5t-test or analysis of variance (ANOVA) was used. In case of asymmetry, the Mann-Whitney U and Kruskal-Wallis tests were used, respectively. Progression of CKD stage in patients not on dialysis at study entry was determined by the last measured eGFR, resulting in reclassification to a more advanced stage or maintenance of the baseline CKD stage. We searched for an association between the underlying disease (CKD etiology) and the levels of urinary biomarkers in subjects not on dialysis at study entry.Normally distributed data are reported as means±SD, and asymmetrically distributed variables as medians and interquartile ranges (IQRs). The association between continuous variables was assessed using Spearman correlation coefficients. To compare means between groups, the Student The association of urinary biomarker tertiles with CKD progression and the ESKD or death outcomes in patients not on dialysis at baseline was examined. Additionally, to evaluate the independent effect of age, gender, ethnicity, smoking, CKD etiology, baseline eGFR, and urinary biomarkers on the adverse outcomes CKD progression, development of ESKD , or death, a Poisson regression model was used to control for confounding factors. Variables with P<0.20 on bivariate analysis were entered into the multivariate model. Data were analyzed using the SPSS Statistics Version 22 software package .Clinical characteristics of the study patients are reported in Urinary levels of KIM-1, NGAL, and NAG stratified by CKD stage are reported in Sixty-four patients (46%) progressed to worse CKD stages (progressors). Baseline eGFR, last eGFR and urinary KIM-1, NGAL, and NAG concentrations of progressors compared to non-progressors are reported in The association of urinary biomarker tertiles with CKD progression and ESKD or death outcomes in patients not on dialysis at baseline is reported in vs diabetes, hypertension vs chronic glomerulonephritis, and diabetes vs chronic glomerulonephritis), there was no statistical difference for KIM-1, NGAL, or NAG.We also searched for a potential association between underlying disease and urinary biomarkers in subjects not on dialysis at study entry. Patients with a diagnosis of conditions not related to arterial hypertension, diabetes mellitus, or chronic glomerulonephritis as the etiology of CKD had significantly lower levels of urinary KIM-1 (P=0.011), NGAL (P=0.011), and NAG P=0.033; . CompariTo control for factors independently associated with the adverse CKD progression outcomes, ESKD , or death in patients not on dialysis at baseline, univariate and multivariate Poisson regression analyses were performed . After aIncreasing age and urinary NGAL were associated with risk of death in patients who were on dialysis at study entry. For each 1-year increase in age, the risk of death increased by 4.7% (P=0.007), and each 300-ng/mL increase in urinary levels of NGAL resulted in an average increase of 1.3% in the risk of death . KIM-1 aThere is concern in the nephrology community about strategies for early identification of kidney damage in patients at risk of developing CKD. CKD affects more than 10% of the general population in the U.S. alone and is associated with high rates of all-cause and cardiovascular mortality . In other etiologies, which were predominantly tubulointerstitial  but were underrepresented in our cohort, levels of these biomarkers were significantly lower. This warrants further investigation in a larger sample.An important limitation of this study is the short follow-up time. Even though we could detect a significant association of increasing NGAL and KIM-1 levels with CKD progression, a longer follow-up would be needed to demonstrate more robust correlations between these urinary biomarkers and poor renal and cardiovascular outcomes. Of equal importance, reference values of urinary biomarkers above which kidney damage must be ongoing need to be established for routine use in clinical practice, particularly in the early stages of CKD, when therapeutic interventions are most effective. Another relevant limitation of the study is related to the number of CKD patients not on dialysis (n=139), which is inferior to the calculated sample size; this increases the chance of type II error regarding the outcome ESKD, although not in relation to the combined outcome ESKD or death. Further, a potential limitation is the prolonged sample storage time until biomarker measurement. However, as demonstrated previously ,36, the In conclusion, this study detected a trend toward increased baseline levels of KIM-1 and NGAL in patients with renal impairment who progressed to more advanced stages of CKD. Urinary NGAL was predictive of CKD progression, ESKD, and death in non-dialyzed patients, and was associated with increased risk of death in patients on dialysis patients. The clinical implications of these findings should be explored further in a longer follow-up.


The recent publication of the American Hypertension Society (ASH) position paper on combination therapy in the treatment of hypertension is essential reading for all physicians and for South African medical aid funders.1As all agree that the goal of antihypertensive therapy is to reduce the risk of vascular events, it is essential that effective and easy-to-use antihypertensives with outcomes data be used early in therapy. Available data from clinical trials and meta-analyses have shown that at least 75% of patients will require combination therapy to achieve contemporary targets. The increasing prevalence of obesity, the metabolic syndrome and type 2 diabetes is likely to increase this percentage even higher, the position paper notes.When choosing combination therapy, the position paper points to the physician making a deliberate choice as to which combination for which patient. The physician needs to consider efficacy, tolerability and adherence aspects when prescribing combination therapy.In efficacy terms, rational combination therapy is based on evidence that the combination lowers blood pressure more significantly than its individual components. The blood pressure reduction should be smooth and continuous, meeting pharmacokinetic criteria for once-a-day usage. Dose-dependent effects of the combination should be less than those induced by higher dosage of the monotherapy.Funders need to take note that co-payment by the medical aid member will reduce compliance and reduce the protective effect of the antihypertensive medication on future vascular events.The ASH position paper identifies twodrug combinations that meet the three criteria outlined above (a single pill with three or more drugs were not reviewed) and these are regarded as preferred combinations. Others that have less evidence to support efficacy, safety or tolerance are also identified.This combination is classified as preferred, whether an ACE inhibitor or an angiotensin receptor blocker (ARB), is used with a low-dose diuretic. Most combinations contain hydrochlorothiazide, but chlorthalidone is also identified as the most-used diuretics in US outcomes trials, although combinations with this diuretic are not currently available.The combination of an ACE inhibitor or ARB with a calcium channel blocker (CCB) results in fully additive blood pressure reduction and improves tolerability. The ACCOMPLISH trialThis combination, although without outcome data, has achieved partially additive blood pressure reduction and is well tolerated. In a study of maximum approved doses of valsartan and aliskiren,This combination also results in partially additive blood pressure reduction and performed well in outcome studies.The position paper notes that there is evidence, mainly with the first-generation β-blocker, atenolol, that β-blockers are less effective than diuretics, ACE inhibitors, ARBs and CCBs. β-blockers attenuate the RAAS activation that accompanies the use of thiazide diuretics, and their combination results in fully additive blood pressure reduction.Addition of the diuretic improves the efficacy of β-blockers in black patientsand others with low-renin hypertension.5 These combinations are classed as acceptable with known side effects, such as increased risk of glucose intolerance, fatigue and sexual dysfunction.The use of spironolactone/HCTZ in obese patients is especially noted, as is the fact that the combination should be used only in people with relatively well-preserved kidney function (eGFR > 50 ml/min).The pharmacological effects of these two drug classes are complementary and result in additive blood-pressure reduction. The combination should be with a dihydropyridine CCB and not a non-dihydropyridine CCB such as verapamil or diltiazen because of their additive effects on heart rate and A–V conduction.This position paper places ACE inhibitors and ARBs, RAAS inhibitors and β-blockers, and the combination of β-blockers and centrally acting agents in the category of lower efficacy. It concludes that early use of a combination reduces counter-regulatory responses of monotherapy and brings blood pressure to target in a shorter period of time.


Objectives. The primary objective of this study is to evaluate the use of cinacalcet in the management of hyperparathyroidism in kidney transplant recipients. The secondary objective is to identify baseline factors that predict cinacalcet use after transplantation. Methods. In this single-center retrospective study, we conducted a chart review of all patients having been transplanted from 2003 to 2012 and having received cinacalcet up to kidney transplantation and/or thereafter. Results. Twenty-seven patients were included with a mean follow-up of 2.9 ± 2.4 years. Twenty-one were already taking cinacalcet at the time of transplantation. Cinacalcet was stopped within the first month in 12 of these patients of which 7 had to restart therapy. The main reason for restarting cinacalcet was hypercalcemia. Length of treatment was 23 ± 26 months. There were only 3 cases of mild hypocalcemia. There was no statistically significant association between baseline factors and cinacalcet status a year later. Conclusions. Discontinuing cinacalcet within the first month of kidney transplantation often leads to hypercalcemia. Cinacalcet appears to be an effective treatment of hypercalcemic hyperparathyroidism in kidney transplant recipients. Further studies are needed to evaluate safety and long-term benefits.  Successful kidney transplantation corrects many abnormalities of bone and mineral metabolism associated with end stage renal disease (ESRD). Nevertheless, hyperparathyroidism does not completely resolve in a significant number of patients even after several years of restored renal function . The sevResidual hyperparathyroidism in kidney transplant recipients is commonly associated with hypercalcemia which generally manifests 3 to 6 months after transplantation . FurtherThe primary objective of this study is to evaluate the patterns of use of cinacalcet in the management of hyperparathyroidism in a transplant setting. We will report our local experience and compare the different management options that were attempted. The secondary objective is to identify baseline factors that predict cinacalcet use 1 year after transplantation. This would help clinicians determine which patients are more likely to profit from early parathyroidectomy versus medical management until spontaneous resolution.This retrospective study was carried out in a large academic hospital in Montreal, Quebec, Canada. The study protocol was approved by our institution's research ethics committee. All patients receiving cinacalcet up to kidney transplantation and/or thereafter were included. Patients were identified using electronic health records. Data were collected from the time of transplantation up to January 1, 2013, by reviewing medical charts and laboratory results. Laboratory results were available the day of transplantation, every 3 months in the first 2 years, and every 6 months thereafter. Presumptive cause of ESRD was extracted from patients' pretransplant assessment notes. It was not always specified whether the diagnosis was biopsy proven or not.p values < 0.2 were considered in univariate and multivariate logistic regression models.Collected data were analyzed using commercially available statistical software. Continuous variables were expressed as mean ± standard deviation. Fisher's exact test was used to compare categorical variables and the Mann-Whitney-Wilcoxon test was used for continuous variables. Baseline variables with 2. Six patients initiated cinacalcet only after transplantation. The remaining 21 were already taking cinacalcet prior to transplantation. Cinacalcet was stopped within the first month in 12 of these patients of which 7 had to restart therapy . There were no reports of adverse events and all attempts to stop cinacalcet or reduce dose aimed to lighten the patient's “pill burden.” Average length of follow-up was 2.9 ± 2.4 years. At the end of the study, only 8 patients had stopped cinacalcet. Attempts to reduce dose or to stop cinacalcet altogether were carried out in over 80% of patients . One patAmong the 21 patients already taking cinacalcet, follow-up of at least 12 months was available in 17 . Using lTypical maintenance immunosuppression included prednisone, mycophenolate, and a calcineurin inhibitor . Most paThese results bring to light existing challenges in the management of hyperparathyroidism in kidney transplant recipients. In the majority of patients, efforts were made to either stop cinacalcet or reduce the dose. These attempts were predominantly unsuccessful owing to recurrent hypercalcemia. Consistent with previous studies, laboratory results revealed a transient increase in calcemia within the first 3 months after transplantation. This is likely due to restored calcitriol production and PTH-induced calcium release from bone , 12. HypFor our secondary objective, we could not identify any baseline factors predictive of cinacalcet status one year after kidney transplantation. This is certainly due to insufficient statistical power because of limited sample size.Inherent to the study's retrospective design, selection and information biases could not be excluded. Additionally, this was a single-center study and there was no control group for comparison. Sample size was rather small but similar to other published observational studies. However, the length of follow-up and the duration of cinacalcet use after kidney transplantation were longer than previous studies.Spontaneous resolution of hyperparathyroidism after transplantation is uncommon despite lengthy follow-up and satisfactory graft function. Discontinuing cinacalcet within the first month of kidney transplantation often leads to hypercalcemia. Cinacalcet appears to be an effective treatment of persistent hyperparathyroidism and may serve as a bridge to parathyroidectomy or as an alternative. Further studies are needed to evaluate safety and long-term benefits. No baseline factors could be identified as predictors of cinacalcet use 1 year after transplantation.


This study evaluated the effects of inhalation of Lavender essential oil on vital signs in open heart surgery ICU. The main complaint of patients after open-heart surgery is dysrhythmia, tachycardia, and hypertension due to stress and pain. Due to the side effects of chemical drugs, such as opioids, use of non-invasive methods such as aromatherapy for relieving stress and pain parallel to chemical agents could be an important way to decrease the dose and side effects of analgesics. In a multicenter, single-blind trial, 40 patients who had open-heart surgery were recruited. Inclusion criteria were full consciousness, lack of hemorrhage, heart rate >60 beats/min, systolic blood pressure > 100 mmHg, and diastolic blood pressure > 60 mmHg, not using beta blockers in the operating room or ICU, no history of addiction to opioids or use of analgesics in regular, spontaneous breathing ability and not receiving synthetic opioids within 2 h before extubation. Ten minutes after extubation, the patients› vital signs  were measured. Then, a cotton swab, which was impregnated with 2 drops of Lavender essential oil 2%, was placed in patients’ oxygen mask and patients breathed for 10 min. Thirty minutes after aromatherapy, the vital signs were measured again. Main objective of this study was the change in vital sign before and after aromatherapy. Statistical significance was accepted for P < 0.05. There was a significant difference in systolic blood pressure (p > 0.001), diastolic blood pressure (p = 0.001), and heart rate (p = 0.03) before and after the intervention using paired t-test. Although, the results did not show any significant difference in respiratory rate (p = 0.1), SpO2 (p = 0.5) and CVP (p = 0.2) before and after inhaling Lavender essential oil. Therefore, the aromatherapy could effectively reduce blood pressure and heart rate in patients admitted to the open heart surgery ICU and can be used as an independent nursing intervention in stabilizing mentioned vital signs. The limitations of our study were sample size and lack of control group. Randomized clinical trials with larger sample size are recommended. Nowadays, heart surgery is one of the most common surgeries and the development of cardiac surgery and cardiopulmonary bypass techniques has reduced the mortality rates of these surgeries but it has its own side effects . The proet al. also wrote that although the pain of incision was inevitable, it was controllable and in the absence of rapid and appropriate controls, it could become severe and lead to chronic pain  from Labiatae family with many therapeutic properties is vastly used in the variety of aromatherapy methods  collected from botanical garden of School of Pharmacy in Jan. 2012, and was identified  in Pharmacognosy Lab. in School of Pharmacy, 2% solution was prepared by sesame oil (Saman Co. Iran).. Characteristic subjects of patients under investigation included: full Consciousness and being aware of time and place, not using beta blockers in the operating room or ICU for any reason, extubated and having spontaneous breathing and no history of addiction to opioids or use of analgesics in regular . Exclusion criteria were hemorrhage, heart rate <60 beats/min and hypotension (systolic blood pressure < 100 mmHg and diastolic blood pressure ˂ 60 mmHg), receiving analgesics within 2 h before intervention, having asthma, allergies, chronic obstructive pulmonary and other lung diseases and contact dermatitis to aromatic substances. The patients that needed medical intervention during the inhalation, or in case of allergies, respiratory problems and emergencies, were excluded from this research.This study is a single-blind clinical trial, which has the ethical approval from Ethics Committee of Islamic Azad University of Tehran Medical Branch and registered with code IRCT2013061813711N1 in Iranian registry of clinical trials, and was conducted on 40 patients who had undergone open-heart surgery, cardiac ICU departments in Moheb Hospital and Tehran Heart Center. The Lavender oil was prepared by hydrodistillation from A two-part questionnaire was used in this study for the data collection. The first part included demographic characteristics subjects under investigation  and the second part was used a Japanese analog barometer in order to measure the blood pressure, The respiratory rate, pulse, SpO2, and central venous pressure (CVP).All patients, who were enrolled to the study after Filling out the informed consent form, received a lavender oil patch test, preoperatively. In order to reduce inhalation and skin absorption of the lavender, One drop of lavender oil was dropped to their ankle, the test patch was immediately covered with an occlusive dressing and removed after a two-minute exposure. Then, on the day of surgery, ten minutes after extubation, the vital signs were measured by a nurse. Then a cotton swab, which was impregnated with 2 drops of Lavender 2%, was placed in patients’ oxygen mask, and patients breathed for 10 min. After thirty minutes, the vital signs were measured again . SPSS 18Demographic data from participants showed that 57.5% of samples were males, patients’ age was in the range of 18-65 and majority of samples (47.5%) were 50 to 59 years and average age was 50 years old (SD = 15.16). 37.5% Of patients had hypertension, 30% had hyperlipidemia and 20% had diabetes. 57.5% had an experience of previous surgery and only 10% had an experience of aromatherapy. None of the subjects had previously experience of using Lavender essential oil.The statistical paired t-test before and after aromatherapy showed that there were significant differences in systolic blood pressure (p > 0.001), diastolic blood pressure (p = 0.001), and heart rate (p = 0.03). Although, the results did not show any significant differences in respiratory rate (p = 0.1), SpO2 rate (p = 0.5) and Central venous pressure (CVP) (p = 0.2) before and after inhaling Lavender essential oil. Therefore, the aromatherapy effectively reduced blood pressure and heart rate in patients admitted to the Open heart surgery ICU and can be used as an independent nursing intervention for reducing BP and HR.  and 2.Chi-square statistical test is used to investigate the relationship between demographic characteristics and vital signs but there were not significant effects between demographic variables and physiological variables. The results of our investigation showed that there were significant differences in systolic blood pressure, diastolic blood pressure, and heart rate before and after aromatherapy, but these differences in respiratory rate, SpO2 rate and central venous pressure were not statistically significant. et al., studied on the «Effect of lavender aromatherapy on vital signs and perceived quality of sleep in the Intermediate Care Unit (In 2014, Lytle are Unit . In thisare Unit .et al., studied on the «Effects of aromatherapy on the anxiety, vital signs, and sleep quality of percutaneous coronary intervention patients in intensive care units» their results showed systolic and diastolic blood pressure did not have any significant differences and their results were quite different from ours, although outcome measures patients› state anxiety, sleeping quality significantly low anxiety and improving sleep quality compared with conventional nursing intervention (But in 2013, Cho rvention .Essential oils have both physiological and psychological effects . When la


Neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) were promising biomarkers used to predict diagnosis and prognosis in various inflammatory responses diseases and cancers. However, there have been no reports regarding these biomarkers in kidney stone patients. This study aimed to evaluate the predictive value of inflammatory biomarkers for metabolic syndrome (MetS) and post-PCNL SIRS in nephrolithiasis patients. We retrospectively enrolled 513 patients with nephrolithiasis and 204 healthy controls. NLR, dNLR, LMR and PLR in nephrolithiasis patients were significantly higher than control group. Patients with renal stone have higher NLR, dNLR, LMR and PLR than those without. ROC curve analysis indicated NLR, dNLR, LMR and PLR for predicting patients with nephrolithiasis and MetS, displayed AUC of 0.730, 0.717, 0.627 and 0.606. Additionally, ROC curves, using post-PCNL SIRS as the end-point for NLR, dNLR, LMR and PLR with AUC of 0.831, 0.813, 0.723 and 0.685. Multivariate analysis revealed that NLR, dNLR represented independent factors for predicting post-PCNL SIRS. While LMR independently associated with MetS. These resluts demonstrate preoperative NLR, dNLR and LMR appears to be effective predictors of post-PCNL SIRS and LMR of MetS in nephrolithiasis patients. Nephrolithiasis is an increasingly common condition in the Asia with a prevalence of 10.6% and 7.1% in men and women, respectively, , 0.625 (0.58–0.67), 0.662 (0.621–0.703) respectively . We found that the patients with kidney stones had higher NLR, dNLR and PLR than healthy controls ( P < 0.001) Table &4, whileIn Spearman correlation analysis, there were statistically significant positive correlations between NLR, dNLR, LMR, PLR and MetS and post-PCNL SIRS (All P < 0.05) Table .In Spearman correlation analysis, there were statistically significant positive correlations between MetS and NLR, dNLR, LMR, PLR, BMI, hypertension, Killip level, diabetes, ASA score, neutrophil, lymphocyte counts, total cholesterol, FBG and operative time Table .In addition, by spearman correlation analysis there were statistically significant positive correlations between post-PCNL SIRS and NLR, dNLR, LMR, PLR, gender, white blood cell, neutrophil, lymphocyte, monocyte counts, hemoglobin, total cholesterol, FBG, calcium, bicarbonate, serum creatinine, BUN, GFR, stone burden, operative time, stay length, multiple nephrolith, staghorn nephrolith and hydronephrosis Table .ROC curves, utilizing MetS as the end-point for NLR, dNLR, LMR and PLR, are depicted in Figure In addition, ROC curves, using post-PCNL SIRS as the end-point for NLR, dNLR, LMR and PLR, are shown in Figure Table Additionally, via univariate Cox proportional hazards analysis factors associated with post-PCNL SIRS included the NLR, dNLR, LMR, PLR, gender, hypertension, Killip level, white blood cell, neutrophil, lymphocyte, monocyte counts, hemoglobin, total cholesterol, bicarbonate, GFR, stone burden, operative time, stay length, multiple nephrolith, staghorn nephrolith and hydronephrosis . After extensive univariate analysis, these significant variables were included in the multivariable Cox proportional hazards models, which showed that the level of NLR , dNLR , White blood cell , Neutrophil , Lymphocyt , Albumin , Bicarbonat , Stay length , Multiple nephrolith  and Hydronephrosis  were significant predictors of post-PCNL SIRS.Nephrolithiasis is a common disease whose recurrence rates are up to 50% and 80% within the first five and ten years, respectively, after an initial stone episode. To our knowledge, this is the first research to evaluate NLR, dNLR, LMR and PLR as the predictors of kidney stone. Our study indicates, a significant correlation between inflammation biomarkers and kidney stones. Patients with kidney stone have higher NLR, dNLR, LMR and PLR levels than healthy controls. Additionally, patients with MetS, post-PCNL SIRS have higher NLR, dNLR, LMR and PLR levels than those without. We also demonstrated that increased pre-operation NLR, dNLR, LMR and PLR positively correlated with MetS comorbidities and post-PCNL SIRS in patients with kidney stones. The Cox regression multivariate analyses indicated that NLR appeared to be potentially independent useful inflammatory biomarker of in patients with kidney stone, and could serve as a new inflammatory markers for monitoring disease activity, especially for patients with kidney stones in critical care following PCNL. Although dNLR, PLR and LMR were significantly associated with survival in univariate analysis, they were not maintained as independent indicators in the multivariate model. These results were supported by several mechanisms of inflammatory reactions to kidney stones.MetS has been recognized as one of the most relevant clinical components associated with kidney stone. It is known that MetS is associated with systemic inflammation and in patients with MetS, the risk for development of kidney stone increases. In patients with kidney stones and metabolic syndrome who had PCNL. Also, MetS was associated with deterioration of renal function in the long-term follow-up,  The estiPrevious researches have reported that even with careful preparation before operation, SIRS occurs in 11%-35% of patients following PCNL and progress to sepsis in 2.5% of patients , 30. In The relationship between elevated pre-operative NLR, dNLR, LMR and PLR and kidney stones is yet to be elucidated. Firstly, neutrophil was triggered by stone-stimulated inflammatory factors, including the granulocyte colony stimulating factor, tumor necrosis factor-alpha, interleukin-6, and myeloid growth factors. Moreover, elevated circulating neutrophils have been reported prompt secretion of inflammatory mediators and therefore accelerate stone formation. Thus elevated neutrophils may aid in the formation of kidney stone by providing an adequate environment. Secondly, decreased lymphocyte count may also play an important roles in inflammatory reaction to stones. Known as an inflammatory response, neutrophil suppresses the immune response by inhibiting the cytolytic activity of immune cells such as lymphocytes, activated T cells, and natural killer cells .There is an intimate relationship between kidney stone and inflammatory cytokines. Extrapolating this to the microenvironment of the kidney, some investigators of pro-inflammatory state have found in the presence of molecules generally involved in inflammatory pathways, such as osteopontin, heavy chain of inter-alpha-inhibitor, collagen, and the zinc in the nephron, specifically in interstitial plaques of the renal papillae in stone formers , 34. Reaet al. reveal a novel mechanism that neutrophils and T cells cooperate to generate a metastasis-supporting immune suppression, and Wculek et al. found that neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis [Finally, neutrophils play an important role both in pro- and anti-tumor functions in cancer and immune-related disease progression. In two recent publications in Nature, Coffelt igenesis . These fThe possible advantage of this study was that it focused on the clinical utility of this type of laboratory biomarkers. For the kidney stone patients with higher risk of post-PCNL after evaluating preoperative NLR, careful preparation peri-operation and post-operative standard-of-care were recommended. It also raised the cost-effectiveness of routine blood test.The current study has several limitations that should to be taken in account. Firstly, our results were from a retrospective design, single-center study and thus the predicative significance of systematic inflammatory biomarkers in patient’s with kidney stones remains to be confirmed by prospective and clinical validation studies. Although we demonstrated the initial evidence that NLR, dNLR, LMR and PLR were increased in patients with kidney stone which were associated with post-PCNL SIRS and MS comorbidities, the NLR, dNLR, LMR and PLR were not predictors of kidney stone formation. Besides further basic studies will be carried out to identify the detailed mechanisms by which kidney stones mediate inflammatory cells responses and inflammatory mediators stimulated kidney stone formation and accumulation. Finally, since CRP and PCT are not routinely tested in our clinical practice, therefore CRP and PCT were not included in our analyses. Further researches should compare the predictive role between NLR, dNLR and CRP, PCT as well as clinicopathological parameters.In conclusion, we demonstrate for the first time that NLR, dNLR, LMR and PLR are all increased in kidney stone patients, and positively correlated with MetS comorbidities and post-PCNL SIRS. In multivariate analysis, NLR appears to be potentially useful inflammatory biomarkers of systemic inflammation in patients with kidney stone, which suggests that increased NLR level before surgery was independent and adverse predictor of MS comorbidities and post-PCNL SIRS. We suggest that clinicians should consider the level of NLR before surgery to help select the most appropriate therapy plan for their patients with kidney stone, especially for operational evaluation in MetS comorbidities patients and monitoring the SIRS following PCNL.Retrospective investigation and analysis were carried out in patients with kidney stones who had PCNL at Tongji Hospital between January 2015 and December 2015. The inclusion criteria were as follows: 1) A CT and stone composition analysis was performed for all patients with a kidney stone; 2) Treated with PCNL; 3) No history of previous therapies or other malignancies; 4) No perioperative mortality; 5) No antibiotic treatment before surgery, infection and hyperpyrexia; 6) Preoperative blood parameter data available; 7) Informed consents were obtained from eligible patients. Exclusion criteria included: a previous placement of stent, nephrostomy tube or indwelling catheter, history of renal failure, fever prior to surgery, presence of infectious diseases on admission, previous interventional treatment, concomitant bladder stone or tumor, concomitant therapy with other antibiotics, the presence of contra-lateral renal or ureteral stone, and complicated with cyst and malignancy. Through this approach we successfully recruited 513 patients with kidney stones and 204 healthy controls in our study.For each patient and healthy control, we collected the following clinical and pathological information: age, gender, BMI, residence, hypertension, Killip level, diabetes, ASA score, stone characteristics  and perioperative variables (operation time and stay length and post-PCNL SIRS rates). All patients were performed routine blood tests  and imaging test , renal ultrasonography, ntravenous urography (IVU) or computed tomography (CT). Clinical parameters such as hydronephrosis were found by physical examination and confirmed by ultrasonography, CT or magnetic resonance imaging (MRI). Stone characteristics included the number of stones (detected via CT or MRI scan), staghorn (yes/no), stone location and stone burden. Stone surface area (stone burden) was calculated by the following formula: length × width × π × 0.25 . In case9/L, (5) A systolic blood pressure below 90 mmHg or decrease of 40 mmHg below baseline in the presence of SIRS was defied as septic shock [Hematological parameters were obtained 1 week prior to kidney stone treatment. Preoperative NLR, dNLR, LMR and PLR were measured by peripheral blood cell count, and were described as follows: NLR = neutrophil to lymphocyte ratio; dNLR = neutrophil to (white cell count- neutrophil count) ratio; LMR = lymphocyte to monocyte ratio; and PLR = platelet count to lymphocyte ratio. MetS was defined as: individuals with 3 out of the 5 criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) were met, modified for pre-diabetes (fasting glucose 100-125 mg/dL) . In the This study was approved by the Medical Ethics Committee of Huazhong University of Science and Technology. Written informed consent was obtained from all participants.http://www.r-project.org/). The optimal cut-off levels of NLR, dNLR, LMR, and PLR were determined by receiver operating curve (ROC) analysis. Associations of NLR, dNLR, PLR, and LMR with other clinicopathological factors were determined using student’s t-test, chi-square test and linear-regression analysis. Univariate and multivariate analyses were determined by the Cox regression model. Variables that reached a level of statistical significance in the univariate analysis were included into the multivariable analysis. All statistical tests were two sided and p-values less than 0.05 (p < 0.05) were considered statistically significant unless otherwise specified.Statistical analyses was performed using GraphPad Prism version 5.013 , SPSS 2.0  and R software version 3.2.0 (