Obesity has been associated with an increased risk for cardio-metabolic diseases. The prevalence of obesity among adolescents is increasing worldwide, including Nigeria, but only little data exist on the relationship of nutritional status with cardio-metabolic health among adolescents in Nigeria. This study therefore investigated the relationship of nutrition status, raised blood pressure, glucose intolerance and risk for metabolic diseases among adolescents in southwestern Nigeria.p ≤ 0.05.This was a cross-sectional study conducted among 313 in-school adolescents in Ile-Ife, southwestern Nigeria. The respondents were selected using multi-stage sampling technique, and data were collected using pre-tested structured questionnaires. Anthropometric, blood pressure and random blood glucose measurements were done using standard protocols. Nutritional assessment was done using the World Health Organization (WHO) 2007 reference. Pre-hypertension and hypertension were measured using percentiles for gender, age and height. Analysis was done using IBM SPSS and the level of significance was set at The mean age of the respondents was 14.4 ± 2.0 years. The prevalence of overweight and obesity was 10.2%, and it was significantly higher among females (12.5%) than males (7.0%). The prevalence of systolic and diastolic pre-hypertension was 10.9 and 11.5% respectively, while the prevalence for systolic and diastolic hypertension were 14.4 and 8.6% respectively. Using WHtR to assess cardio-metabolic risk, 7.3% of the respondents were at risk. There were statistically significant relationships between BMI, WHtR and blood pressure levels (< 0.05).The prevalence of overweight/obesity among the adolescents was relatively high, and this was significantly associated with elevated blood pressure and increased risk for cardio-metabolic diseases. There is need for more interest and intervention by stakeholders into the cardio-metabolic health of adolescents in Nigeria.The online version of this article (10.1186/s40795-019-0308-5) contains supplementary material, which is available to authorized users. The prevalence of overweight and obesity among children and adolescents is rising all over the world . The gloThe increasing prevalence of overweight and obesity have been attributed to nutrition transition . AccordiNigeria is experiencing nutrition transition, with rapid urbanization and associated adoption of western diets and reducing energy expenditure among children and adolescents . In the The major challenge with the increasing prevalence of overweight/obesity among adolescents is the morbidity and mortality that has been associated with these nutritional states . OverweiThere are only few studies that have investigated the relationship between the nutritional status and the blood pressure levels of adolescents in Nigeria , 16. No The study was carried out in Ile-Ife, which is an ancient city in Osun State, Southwestern Nigeria. The respondents were adolescents aged 10 to 19 years attending secondary schools in public and private schools in Ile-Ife. Adolescents who were acutely ill or had chronic illnesses like sickle cell disease anaemia that could affect their weight were excluded. Others with disabilities that made them unable to stand were also excluded.The sample size was calculated to get an absolute precision of ±5% using STATCALC on the Epi-Info software. The proportion of expected outcome was taken as 22.2% which was the proportion of in-school adolescents with pre-hypertension in a similar study carried out in eastern Nigeria , with anA self-developed, pre-tested structured questionnaire  was measured with the student in a sitting position, back supported, feet flat on the floor, clothing sleeve rolled back to leave upper arm uncovered, right arm supported and cubital fossa (inner elbow) approximately at heart level, having sat for at least 5 to 10 min to rest before measurement. Two measurements were taken 10 min apart, and the average was taken as the blood pressure. For the blood sugar test, single-use disposable non sterile gloves were used for each participant, as well as single-use disposable lancet device. Tests were carried out as per manufacturer’s instructions. It was challenging to secure the cooperation of the adolescents to fast overnight, so the random blood sugar level was measured in millimole per litre (mmol/L). Respondents were classified such that those with blood glucose level less than 7.8 were normal, those with blood glucose level 7.8 to 11.0 had impaired glucose tolerance, greater than 11.0 had diabetes mellitus .Pre-hypertension was taken as systolic blood pressure (SBP) and diastolic blood pressure (DBP) ≥ 90th percentile, but <95th percentile for gender, age and height, while hypertension was taken as SBP and DBP ≥ 95th percentile for gender, age and height .2. BMI-for-age Z-scores from the WHO reference charts were then used to classify the respondents as underweight (<− 2 SD), normal (≥ − 2 to ≤ + 1), overweight (> + 1 to + 2) and obese (> + 2). Waist hip ratio (WHR) was calculated as waist circumference in centimeters (cm) divided by hip circumference in cm. WHR was classified such that males with ratio equal to or greater than 0.9 and females with ratio equal to or greater than 0.85 were abnormal. Risk for metabolic diseases was assessed using waist-to-height (WHtR) ratio, which has been shown to be the best predictor of cardiovascular risk and mortality [Nutritional status of the respondents were determined using the WHO 2007 reference for children 5–19 years. Body Mass index (BMI) was calculated by dividing the weight in kilograms by the height in meterortality . WHtR wap < 0.05 for this study.The questionnaires were manually sorted out, entered into a computer and the obtained data was analyzed using IBM SPSS version 20. Descriptive analysis of all the variables measured were first done, and the categorical variables were reported as frequencies and proportions/percentages, while the continuous variables were reported as means ± standard deviation. Cross-tabulations were done to test for associations between the different categorical variables (in line with the objective of the study) using the chi-square test. Fisher’s exact test was used when there was an expected value was less than 5. Correlation analysis was done to test the strength and direction of associations between the BMI, SBP, DBP, WHR and WHtR as continuous variables. Binary logistic regression was done to identify the factors associated with elevated blood pressure. The age, sex and other factors that were significantly associated with elevated blood pressure at the bivariate analysis level were entered into the model. Logistics regression was not done for elevated blood sugar level because no factors were significantly associated at bivariate level. Level of significance was set at Ethical clearance was obtained from the Ethical Review Committee, Institute of Public Health, Obafemi Awolowo University, Ile-Ife. Permission was obtained from the heads of the selected schools. The participants’ information sheet and consent was given to the parents and the adolescents who were 18 years or above. Important information on the participants’ information sheet included that the information volunteered will be kept confidential as all questionnaires were coded without names or addresses of respondents. It also emphasized that participants were free to opt-out if they were not comfortable with the information in the questionnaire. Signed consent forms were then obtained from the parents and adolescents who are 18 years and above, while assent was obtained from adolescents who were less than 18 years.The mean age of the respondents was 14.4 ± 2.0 years, more of them were females (58.5%) and 243 (77.6%) lived with both parents. Most of the respondents were from monogamamous family settings (84.0%) with an average of 3.9 ± 1.6 children in their families. Concerning the occupation of the parents, 55.0 and 31.0% of the fathers were skilled  and semi-skilled (artisans) respectively, while 40.9 and 48.9% of the mothers were skilled and semi-skilled respectively. Thirteen (4.2%) of the respondents had ever smoked, but only 4 (1.3%) of them were current smokers. There was a history of taking alcoholic beverages among 65 (20.8%) of them, but 22 (7.0%) were currently taking alcoholic beverages. Only few of the respondents reported the history of hypertension and diabetes mellitus in their fathers  and mothers  respectively, while many of them did not know.p = 0.036) and the mothers’ occupation  had statistically significant associations. This relationship was such that females and children of skilled mothers  were significantly more likely to be overweight/obese. Using random blood sugar (RBS), 6 (3.4%) of the respondents had glucose intolerance but none was in the diabetic range. Cross tabulations of the RBS categories with potential explanatory variables yielded no statistically significant associations.The age and sex distribution of overweight and obesity are shown on Table p < 0.05). Current alcohol drinkers were 3 times  more likely than non-drinkers, females were 2 times more likely than males , overweight/obese adolescents were 6 times  than those underweight and those with high WHtR were 2 times  more likely than those with low WHtR to have elevated blood pressure.The prevalence of systolic and diastolic pre-hypertension was 10.9 and 11.5% respectively, while the prevalence for systolic and diastolic hypertension were 14.4 and 8.6% respectively. Table . Table 3p = 0.045) was the only statistically significant explanatory variable among the socio-demographic characteristics. WHtR had a positive correlation with both systolic blood pressure  and diastolic blood pressure  and BMI  (Table There was the risk for metabolic diseases as measured by the WHtR among 23 (7.3%) of the respondents. Gender


Diabetic nephropathy (DN) is the most prevalent cause of renal disease in type 2 diabetic patients and is usually diagnosed clinically. A kidney biopsy is considered when non-diabetic renal disease (NDRD) is suspected, such as rapid progression in renal function impairment and severe proteinuria. Still, there is yet no consensus on the timing of kidney biopsy in type 2 diabetic patients. This study aims to identify markers that can help differentiate between DN and NDRD and guide the decision of kidney biopsy.We retrospectively reviewed patients with type 2 diabetes who received kidney biopsy from 2008 to 2017 at Taipei Veterans General Hospital. Ophthalmologist consultation and outpatient records, diagnosis of kidney biopsy, laboratory data, and clinical characteristics were collected.P = 0.01), diabetic retinopathy , and urinary RBC  were independent predictors of NDRD. In patients with diabetic retinopathy , the presence of proliferative diabetic retinopathy, pan-retinal photocoagulation, and hematuria were factors predicting NDRD; and in patients without diabetic retinopathy , short DM duration and hematuria were factors predicting NDRD.This study enrolled 160 type 2 diabetic patients, among which 120 (75%) had isolated DN and 40 (25%) had NDRD ± DN . In multivariate logistic regression analysis, DM duration (odds ratio [OR]: 0.907; 95% confidence interval [CI]: 0.842–0.977; Using diabetic retinopathy, DM duration, and hematuria, we developed a 3-step approach to stratify patients into three categories with the different likelihoods of having NDRD. Then different strategies could be taken accordingly. Our stepwise approach is easy to follow and may serve as an appropriate and useful tool to help clinicians in making decisions of kidney biopsy in type 2 DM patients presenting with kidney diseases. Type 2 diabetes mellitus (DM), with its increasing prevalence, is one of the most crucial health problems , 2, and DN is usually diagnosed clinically based on its typical presentations , and absence of clinical or laboratory evidence of other kidney diseases –7. A kidDiabetes-independent factors can cause kidney injury even in patients with DM, resulting in different types of NDRD such as hypertensive nephrosclerosis, atheroembolic disease, genetic kidney disorders, glomerulonephritis, and all kinds of acute kidney injury , 9. TreaThe prevalence of NDRD in DM patients varied widely between previous biopsy-based studies, ranging from 3 to 82.9% , 14, 15.In clinical practice, the value of kidney biopsy in DM patients is to identify NDRD, so proper treatment could be initiated in time. This study aims to explore factors that could help identify the presence of NDRD. We also attempt to propose a practical approach to guide the decision of kidney biopsy in patients with type 2 DM.We retrospectively reviewed patients with type 2 DM who received kidney biopsy at Taipei Veterans General Hospital, a tertiary-care referral center in Taiwan, between 2008 and 2017. Demographic and clinical data were collected from medical records, including age, gender, height, weight, body mass index (BMI), duration of DM before the biopsy, ophthalmic findings , and treatment received for diabetic retinopathy before biopsy . We defined type 2 DM according to diagnoses of inpatient and outpatient medical records. The duration of DM was also defined as accurately as possible according to the medical record. Laboratory data immediately before the biopsy was recorded, including serum creatinine, estimated glomerular filtration rate , level Indications of kidney biopsy were based on clinical features suggesting renal diseases other than DN, including recent onset of heavy proteinuria or nephrotic syndrome, persistent hematuria with dysmorphic RBCs or RBC casts, and unexplained rapidly progressive renal failure. The decision on kidney biopsy was at the discretion of each attending nephrologist.The kidney pathology of each patient was examined by two pathologists who were specialists in kidney diseases. The pathologic criteria for DN included diffuse mesangial expansion with the predominance of an increased mesangial matrix, Kimmelstiel–Wilson nodular lesions, hyaline exudative lesions, and glomerular basement membrane thickening. Based on pathological findings, patients were categorized as isolated DN or NDRD ± DN (isolated NDRD or NDRD superimposed on DN).P-value of less than 0.05 was considered to be statistically significant. Based on the status of the identified NDRD predictors, we divided patients into subgroups; patient distribution in subgroups by pathological diagnosis was examined. After subgroup analysis, we proposed a practical approach to guide kidney biopsy in type 2 DM patients. Data were analyzed using Statistical Package for the Social Sciences (SPSS) for Windows, version 22.0 .Binary variables were expressed in counts and percentages. The chi-square test was used for comparisons of categorical variables. Continuous variables were described as mean ± standard deviation for normally distributed data and as median  for non-normally distributed data. Student’s t-test or one-way analysis of variance (ANOVA) was used for normally distributed data analysis, and the Mann-Whitney U test or Kruskal-Wallis test was used for skewed data analysis. Such variables associated with NDRD in univariate analysis with a significance less than 0.10 were retained for multivariate logistic regression analysis. Independent predictors of NDRD were identified by multivariate logistic regression analysis, with results reported as the odds ratio (OR) and 95% confidence interval (CI). Receiver operating characteristic (ROC) curve analyses were performed to determine the best cut-off value of RBC count and duration of DM for predicting the presence of NDRD. All probabilities were two-tailed, and a n = 25), an inadequate specimen for pathology report (n = 1), lack of ophthalmology evaluation (n = 65), and unavailable urinalysis report (n = 1). A total of 160 patients was included in the analysis , and higher prevalence of diabetic retinopathy  than patients with NDRD ± DN. The urinary RBC count was significantly higher in patients with NDRD ± DN than patients with DN . Patients with NDRD ± DN also had significantly older age  and more male gender . There was no difference in UPCR, urine WBC count, HbA1c, eGFR, and kidney sizes between two groups (Table P = 0.01), diabetic retinopathy , and urinary RBC  were independent predictors of NDRD  patients had isolated DN, 40 (25%) had NDRD ± DN . Patients with isolated DN had a significantly longer duration of DM   Fig. . In patiP = 0.029). In patients without diabetic retinopathy    and PRP  (Table SP < 0.001) and older age at biopsy   Fig. , and subAccording to the presence of NDRD predictors in the whole population and different subgroups, the patient distribution of this study is shown in Figure SP = 0.024) and more IgA nephropathy (P = 0.014) in the NDRD + DN group than in the isolated NDRD group.The pathological diagnoses of NDRD identified in this study were listed in Table Several pathological diagnoses had been identified in patients with NDRD. Membranous nephropathy and IgA nephropathy were the most common two pathological diagnoses in diabetic patients in the Asian population , 19–23. P < 0.001). In predicting NDRD ± DN, the absence of diabetic retinopathy had sensitivity and specificity as 70 and 83.3%, respectively. All patients with diabetic retinopathy had DN, but 12 (10.7%) of them also had NDRD (NDRD+DN). In patients without diabetic retinopathy, 22 (45.8%) had DN, and 20 (41.7%) of them had isolated DN in kidney pathology. Although there was a strong association between DN and diabetic retinopathy, the present study indicated that diabetic retinopathy alone had an imperfect predictive value [We identified a few factors predicting the presence of NDRD, including the absence of diabetic retinopathy, short DM duration, and the presence of hematuria. The definition of hematuria varies in previous studies , and theve value . In addiWe also examined factors reflecting the severity of diabetic retinopathy, including PDR, ME, and specific treatment received . To our best knowledge, there were scarce studies analyzed these issues. A meta-analysis that examined four studies suggested that PDR may be a highly specific indicator for DN  . In our Duration of DM is closely related to the prevalence of DN in type 1 patients. The prevalence rate of microalbuminuria and macroalbuminuria will increase after 10 years . HoweverThe presence of hematuria has been considered as one of the atypical features suggesting the presence of NDRD in the previous guidelines  and repon = 35) and other NDRD (n = 5), there were more urinary RBC in glomerulonephritis than that in isolated DN patients (P = 0.003). In addition, hematuria was not different between glomerulonephritis and other NDRD (P = 1.000), as well as other NDRD vs. isolated DN (P = 0.159) . A kidney biopsy will be suggested once the patient becomes classified into a high likelihood of NDRD in repeated evaluation. Previous studies have identified various predictors of NDRD ; correlaOur study has some limitations. Firstly, this is a biopsy-based study. Kidney biopsies were performed for diagnostic purposes but not for research purposes, and selection bias must exist. All the patients included had been selected by clinicians before biopsy and could not represent the true population of patients with type 2 DM and kidney disease. Besides, the indications of kidney biopsy were not standardized in this retrospective study. Patients presented with typical findings of DN would not receive a biopsy and were therefore excluded from our study. As a single-center study in Taiwan, the results can only be applied in the Asian population. This is a retrospective study with limited population size, and baseline characteristics such as age and gender were not similar between isolated DN group and NDRD ± DN group. For the evaluation of hematuria, the data of dysmorphic RBCs was not available in every patient, so we could not assess the diagnostic value of glomerular hematuria. Our analyses only included data at the time of biopsy. Previous data of renal function, proteinuria, and hematuria were not available, which precluded us from analyzing these variables. Without baseline renal function, we didn’t know whether a patient had acute kidney injury, which is one of the crucial indications of kidney biopsy. The optimal approach for patients with acute kidney injury might be different from other DM patients. Our 3-step approach stratifies patients into 3 categories with varying likelihoods of having NDRD, and there is no standard measure and no standard definition on such risk stratification. Besides, this is a descriptive study that can help hypothesis generation but not to address causal relationships. Further prospective research is warranted to validate this approach.In conclusion, a kidney biopsy is essential for diabetic patients to diagnose NDRD accurately, and outcomes will be improved in NDRD patients once timely treatment is applied. However, loose criteria for performing kidney biopsy will yield unnecessary risks of bleeding complications, especially in patients under high risks, such as having high blood pressure and bleeding diathesis. Even though several clinical factors had been identified as predictors of NDRD, but we still don’t know precisely who should receive a kidney and who should not, and there is no detailed consensus or guideline on this issue. We proposed a 3-step approach to stratify diabetic patients into three categories with different likelihoods of NDRD, by using the presence of diabetic retinopathy, DM duration, and hematuria. Our stepwise approach is easy to follow and may serve as a useful tool to help clinicians in making decisions of kidney biopsy in type 2 DM patients presenting with kidney diseases.Additional file 1:Figure S1. The receiver operating characteristic (ROC) curve of urinary RBC predicting NDRD in patients with diabetic retinopathy. The ROC area under the curve (AUC) = 0.743.Additional file 2:Figure S2. The receiver operating characteristic (ROC) curve of urinary RBC predicting NDRD in patients without diabetic retinopathy. The ROC area under the curve (AUC) = 0.786.Additional file 3:Figure S3. The receiver operating characteristic (ROC) curve of duration of diabetes predicting NDRD in patients without diabetic retinopathy. The ROC area under the curve (AUC) = 0.745.Additional file 4:Figure S4. Patient distribution according to diabetic retinopathy, proliferative diabetic retinopathy, DM duration (≥ 5 or < 5 years), hematuria (urine RBC count > 6 /HPF), and diagnosis of kidney pathology. The prevalence of the non-diabetic renal disease in each subgroup is presented at the bottom. PDR, proliferative diabetic retinopathy; NPDR, non-proliferative diabetic retinopathy; DN, diabetic nephropathy; NDRD, non-diabetic renal disease.Additional file 5:Table S1. Clinical and biochemical characteristics of patients with proliferative diabetic retinopathy. Table S2. Clinical and biochemical characteristics of patients with non-proliferative diabetic retinopathy. Table S3. Clinical and biochemical characteristics of patients without diabetic retinopathy & with DM duration ≥5 years. Table S4. Clinical and biochemical characteristics of patients without diabetic retinopathy & with DM duration < 5 years Table S5. Urinary red blood cells in different pathological diagnosis.


High residual platelet reactivity (RPR) in patients after percutaneous coronary intervention (PCI) receiving antiplatelet agents has been associated with a high risk of developing acute kidney injury (AKI).This study aimed at identification of independent prognostic predictors of AKI risk in patients with acute coronary syndrome (ACS) after PCI.This was a prospective single-center clinical trial that included 155 patients , who underwent PCI with stenting. We prospectively evaluated RPR using optical aggregometry. Development of AKI was the primary endpoint.Acute renal dysfunction was observed in 36 patients (23.2%) after PCI, the risk factors of which according to univariate regression analysis were: age (p = 0.040), low diastolic blood pressure (DBP) (p = 0.001), having severe heart failure (HF) according to Killip (p<0.001), low level of hemoglobin (p = 0.026) and erythrocytes (p = 0.005), increased creatinine (p<0.001), low baseline glomerular filtration rate (GFR) (p<0.001), low left ventricular ejection fraction (LV EF) (p = 0.003), high residual platelet reactivity (RPR) (p<0.001) and platelet aggregation area under the curve (AUC) with 10 μg/mL ADP (p<0.001), as well as dose of X-ray contrast medium (XCM) (p = 0.008). As a result of multivariate regression analysis the following independent predictors of AKI were established with the inclusion of the above factors: baseline creatinine level , RPR with 10 μg/mL ADP , dose of an XCM , diastolic blood pressure (DBP) .ADP-induced high residual platelet reactivity, baseline creatinine level, X-ray contrast medium, low diastolic blood pressure were independent predictors of AKI in patients with ACS after PCI. Cardiovascular disease is the leading cause of death worldwide . Acute cNumerous studies have shown that in patients with ACS, acute renal dysfunction occurs in one of five cases and is one of the leading predictors of cardiovascular complications and mortality in the hospital period and in the long term –5.When performing reperfusion therapy in patients with ACS, mechanical revascularization is the strategy of choice compared to the pharmacological reperfusion method . Dual anThe mechanism of development of AKI of ACS has not yet been fully studied, and the measures for its prevention are not unified. Therefore, prediction of acute kidney injury is critical.To improve outcomes in patients with ACS after PCI performed with XCM, early identification of patients at high risk for acute renal impairment is necessary. The aim of this study was to identify independent predictors of AKI in patients with ACS after myocardial revascularization.2Y12 receptor inhibitor and acetylsalicylic acid (ASA).The present prospective study included 155 patients with ACS, who were hospitalized in the cardiac surgery department of the University Hospital of Semey Medical University (Kazakhstan) from 2018 to 2019. All patients had undergone PCI and were prospectively evaluated for PRP using optical aggregometry induced by adenosine diphosphate (ADP) and epinephrine. Inclusion criteria: patients with ST-elevation acute coronary syndrome (STE-ACS) and non ST-elevation acute coronary syndrome (NSTE-ACS) according to coronaroangiography data, coronary artery disease requiring PCI with stenting; taking DAPT with a PExclusion criteria: terminal renal failure in program hemodialysis patients, incidence of oncological diseases, intolerance to antiplatelet agents, refusal to participate in the study.The study design was approved by the local ethics committee and followed the principles of Helsinki Declaration. Study design was аpproved by Local Ethical Committee of "Medical University Semey" Non-Commercial Joint-Stock Company Protocol 9 dated September 13, 2017. All patients gave written informed consent to participate in the study.All patients received 325 mg of aspirin and a loading dose of 600 mg of clopidogrel or ticagrelor 180 mg, followed by a maintenance dose of 325 mg daily of aspirin and 75 mg daily of clopidogrel or ticagrelor 90 mg daily.Acute kidney injury was the primary endpoint, which was defined according to the recommendation of KDIGO 2012) as an increase in serum creatinine (Cr) level ≥26.5 μmol/L within 48 hours after PCI compared to the initial indicator –12. To d as an in0С by adding one of the agonists , RPR with 10 μg/mL ADP , X-ray-contrast medium dose , diastolic blood pressure (DBP) . The accuracy of the forecast when including the established independent predictors of AKI was 87.1%, sensitivity– 58.3% and specificity– 95.8%.To determine the optimal cut—off points for quantitative variables, a ROC analysis was performed with the construction of ROC curves .The areas under the ROC curves for independent predictors of AKI development are shown in In the study population, the optimal cut—off points for variables with the highest sensitivity and specificity were: creatinine level 119 μmol/L, RPR value 45%, X-ray contrast medium dose 275 ml, diastolic blood pressure 70 mm Hg.—likelihood of AKI, e—the base of the natural logarithm, approximately equal to 2.718; C—creatinine; RPR—residual platelet reactivity induced by ADP; XCM—X-ray contrast medium; DBP—diastolic blood pressure. If the value of P is greater than 0.5, then the onset of the AKI is expected, otherwise the event will not occur.The following multivariate mathematical model was obtained to calculate the probability of the onset of AKI in miltifactorial logistic regression:To assess the quality of the obtained predictive model, we used ROC analysis with the inclusion of predicted values of the probability of AKI development .Given the presence of a multi-factor predictive model, the optimal value of one factor depends on the indicators of other factors that affect the development of the event.Acute renal dysfunction is a common complication that can develop in patients with ACS and reach the rate of 30% –19. In oThe key result of this study was the identification of independent predictors for the development of acute renal dysfunction in patients with ACS after PCI with stenting. The baseline high creatinine level, high RPR (induced by 10 μg/mL ADP), the dose of XCM, low diastolic blood pressure were the main factors for the development of AKI against the background of DAPT, including ASA and clopidogrel/ticagrelor. In binary regression analysis, a multivariate mathematical model of risk was obtained that allows calculating the probability of AKI in patients with ACS after PCI with stenting. The prognostic model we obtained included such factors as ORT, DBP level that can change during therapy, i.e. by optimizing treatment, the likelihood of AKI can be reduced, thereby personalizing the therapy.One of the important evaluation criteria in this study was platelet function testing by optical aggregometry induced by ADP. Currently, many methods are used to determine platelet aggregation activity. However, the effectiveness of antiplatelet therapy is not controlled, since there is still no standardized parameter by which platelet hyperactivity and the degree of its change against the background of antiplatelet therapy could be established , 21.Several studies have established the dominant role of platelet function in the pathogenesis of ACS and the prognostic value of the high residual platelet reactivity associated with DAPT in the development of adverse cardiovascular events in patients undergoing PCI –24. HoweHakan Uçar et al. noted that the medium platelet volume (MPV) may serve as a marker of impaired renal function in patients with stable angina pectoris . In a stIn this work, the role of platelets in the development of acute renal dysfunction was studied by determining the residual platelet reactivity by the ADP inducer. It was found that platelets are involved in the development of AKI since platelet hyperactivity has proven to be one of the important modifiable independent predictors of AKI in patients with ACS after PCI (p = 0.001).One of the factors for the development of AKI with the introduction of XCM is the total amount of contrast used during the procedure. Irfan Sahin et al. found that an increase in the level of XCM (p = 0.01), age (p = 0.05) and the platelet distribution width (PDW) (p = 0.04) were independent predictors of the development of CIN in patients with ACS after coronarography and/or PCI . AccordiNumerous studies have shown that renal failure or chronic kidney disease (CKD) is an independent predictor of AKI in patients with ACS (p<0.001) . The basPatients with cardiogenic shock and initial CKD have a higher risk of developing AKI during PCI . Study bThere is a Cleveland score (2005) risk stratification model for assessing AKI after heart surgery that includes variables such as gender, chronic heart failure, left ventricular ejection fraction, preoperative use of an intra-aortic balloon pump, chronic obstructive pulmonary disease, diabetes mellitus, heart surgery, type of surgery, emergency surgery, baseline creatinine level . The aboUnfortunately, there is still no consensus on a personalized approach to prescribing DAPT. The results of large randomized trials, such as TRIGGER-PCI, GRAVITAS, ARCTIC, did not reveal the advantages of a personalized approach to prescribing DAPT to patients after planned PCI –39. In cThe results of our study indicate the need for a personalized approach in prescription of antiplatelet therapy based on platelet function testing, the correction of which can reduce the likelihood of AKI after PCI.This study has found that independent predictors of the development of acute renal dysfunction in patients with ACS after PCI with stenting against the background of DAPT are: baseline creatinine level (p<0.001), 10 μg/mL ADP-induced high RPR (p = 0.001), dose of XCM (p = 0.014), low DBP (p<0.001). RPR, dose of XCM, BP level are modifiable factors. By optimizing treatment aimed at correcting the obtained variables, it is possible to reduce the likelihood of AKI, thereby personalizing the therapy.Thus, high RPR in patients with ACS 12–48 hours after PCI, detected by optical aggregometry, indicates a high risk of AKI. Given the prognostic significance of platelet function testing, RPR should be determined in this category of patients to identify those at high risk of AKI.A possible association between high platelet activity and progression of renal failure has not been adequately studied. The results of this work show the need for further prospective studies in this area as well as during other angiographic procedures.S1 Data(ZIP)Click here for additional data file.


IntroductionLiving donor kidney transplantation is the best replacement therapy for patients with end-stage renal disease. It offers more benefits than deceased donor transplantation. However, living kidney donors (LKDs) undergo an extensive evaluation to ensure their suitability for donation, and this can result in rejection of many potential donors.AimThe aim of this study was to recognize the reasons for declining LKDs in our Organ Transplant Center at King Abdulaziz Medical City.Settings and DesignThis was a retrospective study to determine the various reasons to reject an LKD at the Organ Transplant Center.Methods and MaterialAll the LKDs from January 2016 to December 2019 were included. Declined donors were reviewed and data were obtained from the electronic database and transplant nephrology shared files.Statistical analysisWe performed data analysis using SPSS version 24.0 . Data for continuous variables were presented as mean ± standard deviation and were compared using t-test. Categorical variables were presented as frequencies and percentages; chi-square test was used to test for main association and then Bonferroni adjustment was used for post-hoc testing. Statistical significance was considered if a two-tailed p-value of <0.05 was achieved.ResultsA total of 410 potential LKDs were evaluated, of whom 241 (58.8%) successfully underwent donor nephrectomy and 169 (41.2%) were unable to proceed for kidney donation. The most common reasons for rejection of LKDs were medical (47.9%) followed by immunological reasons mainly blood group incompatibility (19.5%). Other reasons were donor withdrawal (15.4%), recipient-related reasons (7.1%), surgically unfit to proceed for nephrectomy (4.7%), or psychological reasons (2.3%).ConclusionsA significant proportion of potential LKDs did not complete the kidney donation process due to medical, immunological, and surgical reasons. In addition, a proportion of LKDs decided to withdraw at some point during the evaluation process. Investing in donors’ educational programs and implementing a standardized evaluation process are essential to increase LKDs pool. Renal transplantation is the best treatment option for patients with end-stage renal disease as it significantly improves the patients’ quality of life ,2. KidnePotential living kidney donors (LKDs) undergo an extensive evaluation to ensure the short- and long-term safety before proceeding for donation . All LKDBy the end, accepting or declining LKDs should depend on whether the benefit outweighs the risk in both the donor and recipient or not. However, there are still considerable variabilities between transplant centers regarding acceptance or rejection of LKDs. Living donors' rejections can be due to medical, surgical, immunological, and/or psychological reasons. In this study, we report our experience with potential LKDs at King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. The main goal is to identify the reasons for declining potential LKDs in our Organ Transplant Center.All rejected potential LKDs from January 2016 to December 2019 were reviewed and analyzed at the Organ Transplant Center at KAMC. Demographic data, recipient relation, evaluation process, and outcomes  were collected using electronic database retrospectively.The potential LKDs passed through stages of evaluation before being accepted for donor nephrectomy Figure . In the Data analysis was performed using SPSS version 24.0 . Data for continuous variables were presented as mean ± standard deviation and were compared using t-test. Categorical variables were presented as frequencies and percentages; chi-square test was used to test for main association and then Bonferroni adjustment was used for post-hoc testing. Statistical significance was considered if a two-tailed p-value of <0.05 was achieved.A total of 410 potential LKDs were evaluated at the KAMC Organ Transplant Center from January 2016 to December 2019. Of those, 241 (58.8%) successfully underwent donor nephrectomy, whereas 169 (41.2%) were unable to proceed for kidney donation due to different reasons. There was no specific pattern regarding the annual rate of LKDs rejection during the study period, as shown in Table 2 in both groups, although more patients had a BMI of >30 kg/m2 in the rejected group versus donated candidates (32% vs. 13.7%). Regarding kidney function, similar average glomerular filtration rate (GFR) was found in both accepted (113mL/min/1.73 m2) and rejected donors (111 mL/min/1.73 m2), and similar average creatinine (mg/dL) was found and in accepted (71.6 mg/dL) and rejected donors (73.6 mg/dL). HbA1c was also similar, with 5.1 to 5.3 in both, groups and majority of candidates were non-hypertensive in both groups. However, hypertension was more prevalent among rejected LKDs. Table There was no significant difference in accepted and rejected donors’ demographics in terms of average age (29 years in accepted vs. 31 years in rejected group) and male predominance (79.6% in accepted vs. 86.3% in rejected donors). More than half of the donors were non-smokers in both groups (59.3% of the accepted group and 54.4% of the rejected group). Most of LKDs’ BMI was between 18.5 and 29.9 kg/mTable Living kidney donation contributes to more than 80% of kidney transplantation in Saudi Arabia . The lowIn our study, more than half (58.8%) of the evaluated potential LKDs successfully underwent donor nephrectomy, which was similar to another study conducted in New York in which donor nephrectomy was proceeded in (56%) of their fully evaluated kidney donors . This peThe majority of the potential donors in our study were young with no significant difference in average age between accepted (29 years) and rejected (31 years) donors, which was similar to the KFSH study where the average age of potential LKDs was 32 years . In contOur study also demonstrated that more than half of the donors were non-smokers in both groups (59.3% and 54.4%). In general, we advised our donors to stop smoking and offer medical and psychological support to help them quit smoking but we did not decline a donor who is a smoker. In a risk index lately established for LKDs, a history of smoking was a crucial factor in the living donor in comparison to each other and to deceased donor kidneys . Further2 in both groups, although more patients had a BMI of >30 kg/m2 in the rejected group versus donated candidates (32% vs. 13.7%). In our program, we accept only LKDs with a BMI of <30 kg/m2. Donors with a BMI of >30 kg/m2 are counselled to lose weight and encouraged to contact the transplant coordinators when they reach their target weight. Acceptable BMI cutoffs are variable between transplant centers. A survey was conducted by Mandelbrot et al. in 2007 who reported that 50% of transplant programs use a 35 kg/m2 limit in the body mass index [2 should be taken on a case-by-case basis considering medical conditions and demographic factors [Regarding the reasons for the rejection of potential LKDs, the most common were medical reasons (47.9%). Of these, diabetes or impaired glucose tolerance were the most frequent followed by obesity and hypertension. Similarly, other local and global studies showed that the most common reasons for the rejection of potential LKDs were medical with diabetes and hypertension constituting the majority of the medical reasons ,11,17. Ass index . Guideli factors . Majorit2 or greater should be considered an appropriate degree of kidney function for kidney donation, whereas donor candidates with GFR less than 70 mL/min/1.73 m2 should no longer donate. LKDs with GFR between 70 and 90 mL/min would be individualized based on donor age, comorbidity, and other factors. In our study, we found that both groups had similar renal function estimation with almost similar average GFR (mL/min/1.73 m2) of 113 and 111.06, which was different from an Australian study where 15% of accepted candidates were found to have a GFR of less than 80 mL/min/1.73 m2 [Kidney function evaluation is essential pre-donation. Kidney donors should have normal renal function, without proteinuria or hematuria. In our study, only 5% LKDs were rejected because of low GFR. In our practice, we follow KDIGO 2012 Chronic Kidney Disease (CKD) guidelines for renal function evaluations ,22. GFR /1.73 m2 . This co/1.73 m2 . In our /1.73 m2 . In our /1.73 m2 ,18. At oABO, HLA, and Rh incompatibility were the second most common reasons for rejection in 19.5% of the potential LKDs. This is actually contrary to a study conducted in India that showed that blood group incompatibility was the most common reason for rejection (45.8%) followed by diabetes, renal diseases, and hypertension . In our Declining LKD because of surgical reasons accounted for only 4.7% of declined donors, although reports were varied from transplant centers. Connaughton et al. found that 13% of donors declined due to surgical contraindications . The KFSIn our study, 15.3% of evaluated LKDs withdrew their consent to donate at different stages of work-up. This was considered a high percentage as compared to a study conducted in Italy showing that 6.3% of the reasons of not to proceed for donor nephrectomy were due to donor withdrawal . Almost This study has several limitations. This is a retrospective, single-center study. The data for this study were obtained by chart review and it was difficult to obtain detailed information that might have influenced the decision of accepting or rejecting the donation. However, despite these limitations, this study reflects our current practice and we need to design a better system to recruit and retain LKDs in an efficient and safe way.2 without other cardiovascular risk factors, adopting paired exchange programs at a national level in Saudi Arabia, and expanding desensitization protocols to overcome immunologic barriers are possible pathways to improve the transplantation rates. In addition, providing more education for LKDs who withdraw and give them more time to come back for donation could increase the LKD pool.In conclusion, there is a significant number of potential LKDs that did not proceed for kidney donation. There were different reasons such as medical, immunological, surgical, and consent withdrawal. Working on measures to minimize rejection is essential to meet the transplantation demands. Accepting more marginal donors such as well-controlled hypertension, BMI 30-35 kg/m


Acute inflammation and sepsis are known to induce changes in vascular properties, leading to increased arterial stiffness; at the same time, the autonomic nervous system (ANS) also affects vascular properties by modulating the arterial smooth muscle tone, and it is widely reported that sepsis and septic shock severely impair ANS activity. Currently, clinical guidelines are mainly concerned to resuscitate septic shock patients from hypotension, hypovolemia, and hypoperfusion; however, if the current resuscitation maneuvers have a beneficial effect also on vascular properties and autonomic functionality is still unclear. The objective of this work is to assess the effects of standard resuscitation at vascular level and to verify if there is any association between alterations in vascular properties and ANS activity.Six pigs underwent a protocol of polymicrobial septic shock and resuscitation . The arterial blood pressure (ABP) waveform was recorded in the central aorta and in the peripheral radial and femoral artery. The characteristic arterial time constant was computed at the three arterial sites based on the two-element Windkessel model, to characterize the overall arterial vascular tree. Moreover, independent estimates of total arterial compliance (AC) and total peripheral resistance (TPR) were performed. Baroreflex sensitivity (BRS), low frequency  spectral power of diastolic blood pressure, and indices of heart rate variability (HRV) were computed to assess ANS functionality.Septic shock induced a severe vascular disarray, decoupling the usual pressure wave propagation from central to peripheral sites; this phenomenon appeared as an inversion of the physiological pulse pressure (PP) amplification, with a higher PP in the central aorta than in the peripheral arteries. The time constant was decreased, together with AC and TPR. ANS dysfunction was described by a reduced BRS, decreased LF power, and suppressed HRV. This compromised condition was not resolved by administration of fluids and noradrenaline. Thus, a persistent vascular and autonomic dysfunction were reported also in the resuscitated animals, and they were found to be significantly correlated.Measures of vascular function and ANS activity could add information to standard hemodynamic and clinical markers, and the current resuscitation strategies could benefit from the adjunction of these additional functional indices. Acute inflammation and sepsis are known to impair endothelial functions, leading to an imbalance of vasodilatory and vasoconstrictive mechanisms, which may lead to multi organ failure . Much reSepsis and septic shock were proved to significantly increase the stiffness of the large arteries. For example, LPS injection in rabbits has been shown to induce a dysfunction of the endothelium-mediated vascular relaxation in the aorta , and addAt the same time, the sympathetic autonomic nervous system (ANS) physiologically contributes, mainly through the release of noradrenaline, to the modulation of arterial smooth muscle tone; thereby it interacts with local endothelial mechanisms and it may affect the arterial mechanical properties. A relationship between muscle sympathetic nerve activity—an invasive measure of the peripheral ANS—and PWV was observed in healthy individuals, regardless of any other cofounding factors , and an Current clinical guidelines are mainly concerned to recover septic shock patients from hypotension and hypovolemia and the mean value of arterial pressure is one of the key therapy targets ; howeverGiven these premises, the main objectives of this study are (1) to measure the vascular system properties, at central and peripheral levels, in an experimental model of polymicrobial septic shock with standard resuscitation, i.e., fluids and vasopressors administration; (2) to assess the effects of these therapies at vascular level and to extend the previous observations made on endotoxin shock models . FinallyThis experimental study has been performed in the Experimental Laboratory of Intensive Care (LA1230336), at the Université Libre de Bruxelles, on a large animal model of septic shock induced on young adult swine by a fecal peritonitis. The local animal ethics committee  approved the present study (protocol 641 N) and we followed the EU Directive 2010/63/EU for animal experiments, the ARRIVE guidelines for animal research, and the MQTiPSS recommendations for sepsis translational research .®, Baxter, Belgium) served as the only maintenance perfusion, at a very low rate (1 ml/kg/h) and, as soon as the animal reached a hypotensive state of mean arterial pressure (MAP) < 50 mmHg, it was modestly increased to keep this MAP between 45 and 50 mmHg for one last hour, in order to consolidate the peripheral hypoperfusion and the multiple organ failure onset . At the end of this period, a second time point T2 was defined as reference for non-resuscitated septic shock condition. Immediately after a series of hemodynamic measurements recording, a full fluid resuscitation was initiated with both the same rate of balanced crystalloid perfusion  and colloid perfusion , aiming at reaching an arterial pulse pressure variation (PPV) < 12%. After 120 min of hemodynamic stabilization, defined by the absence of further increase in cardiac output and a stable PPV, additional hemodynamic measurements were recorded again . Finally, a continuous infusion of norepinephrine at a fixed dose of 0.3 μg/kg/min was administered and after 1 h, the last series of hemodynamic measurements were recorded again . Animal were then euthanized with a potassium chloride injection and an overdose of thiopental.Six pigs of both sex  were obtained from a local farm (BE 400108–48). Animals were fasted for 18 h prior to the experiment with free access to water. Details on the instrumentation and experiment preparation can be found in the Supplemental Material of a previous article . BrieflyTwo out of six animals were immediately fully resuscitated with vasopressors because of the severity of the distributive shock, therefore the measurements at time point T3 are missing. For this reason, in the following, we refer only to baseline (T1), shock (T2), and to fully resuscitation (T4) period. We want to underline that the early introduction of vasopressor in two pigs allowed us to keep the animal cohort more homogeneous, by avoiding some animals to suffer from prolonged and irreversible organs hypoperfusion and hypoxia, while others did not. In this way, we ended up at T4 with all the animals receiving exactly the same preload optimization and the same dose of noradrenaline.®, Millar, United States). Radial arterial pressure was measured using a fluid filled catheter  and an external pressure transducer ; potential damping or resonance artifacts were excluded by careful cares and regular fast flush tests . Each arterial pressure signal was exported to an A/D recording station , similarly to the surface ECG signal, with a high temporal resolution (100–500 Hz).Arterial blood pressure (ABP) was continuously recorded during the experiment at three different sites: in the ascending aorta , in the common femoral artery and in the radial artery. Aortic and femoral arterial pressures were measured using high-fidelity pressure transducers on solid tip catheters , diastolic (DAP), mean (MAP) pressures, and pulse pressures (PPs), computed as the difference between SAP and DAP within the same ABP pulse, were obtained from ABP waveform using standard algorithms . The tim–1) monitoring was performed using a pulmonary artery catheter , from which were computed the continuous stroke volume SV (ml).Continuous cardiac output CO  of the measured ABP waveforms by adopting the method proposed by x(t) is created, which consists in an impulse train where each impulse is placed at the time instant of the onset of ABP upstroke and has an area equal to the ensuing PP.First, a cardiac contractions signal x(t) and the ABP waveform named y(t) is characterized by estimating an impulse response function h(t), which is found by minimizing in the least squares sense the convolution with x(t) in order to best fit y(t). By mathematical definition, the estimated h(t) represents the ABP response to a single cardiac contraction .Then, the relationship between the cardiac contractions signal h(t). The time interval for the determination of the time constant τ is updated at each time point based on the exponential decay of h(t). An example of the obtained impulse responses at two different time points is reported in Next, the Windkessel time constant τ is determined over a selected interval after the time of its maximum value based on exponential fitting. This optimization problem is solved via linear least squares estimation by log transforming The total arterial compliance AC was independently estimated with further two different methods: (i) as the ratio between continuous SV and aortic PP; (ii) as proposed in s+Ad)/AdK = /CO, according to the Windkessel model , where tThe cardiac baroreflex, i.e., the ANS control of oscillations in the RR-intervals or HP induced by oscillations in SAP, was estimated via the bivariate model method on the aortic ABP. Details of the method can be found in We assessed the heart rate variability (HRV), as an indicator of the ANS control on HR, by computing the root mean square of successive differences between adjacent HP (RMSSD), the standard deviation of successive differences between adjacent HP (SDSD), and the standard deviation of the overall HP time series (SD) . The anaSpectral indices obtained from power spectra of DAP included the normalized low frequency power (LFu), which represents the relative power in the low frequency  band and it is computed as the LF power divided by the total power without the very LF (VLF) component (0–004 Hz). LF oscillations in DAP values are meant to be mainly associated to the sympathetic ANS control of peripheral resistance.–1), and mixed venous oxygen saturation SvO2 (%).Clinical variables collected at each time point were urine output UO (ml), lactate  were compared at each time point among the different sites  taking the aorta as a reference by means of Mann–Whitney U-test. Parameters values are reported as median .Friedman test was performed to detect differences among the three time points across multiple test attempts. In case of significant Friedman test In order to test for significant associations between changes in vascular characteristics and ANS activity, correlations analyses were performed by using the Spearman correlation test.p-value < 0.05.Significance was considered with a 2 have values within the physiological range. The arterial compliance AC was near the physiological value of 2 ml/mmHg (At baseline (T1), PP was progressively higher from aortic to the more distal arterial sampling sites, reflecting the physiological peripheral PP amplification. The large increase in peripheral PP (∼15 mmHg) was primarily due to a higher value in SAP, since DAP values resulted similar at all sampling sites; MAP was not significantly different at the three sites. HR, CO, SV, and SvO ml/mmHg .2 denote the potential anaerobic cellular metabolism and heterogeneous microcirculatory alterations typical of shock. AC was more than halved in all pigs, hinting a certain degree of arterial stiffness.After development of septic shock (T2), aortic PP slightly increased with no significant changes, whereas both femoral and radial PP progressively decreased and became slightly lower than aortic PP . The dec2 increased becoming higher than baseline values, and all the main hemodynamic indices, e.g., CO, SAP, DAP, showed a positive trend, i.e., the differences between the values at T4 and T2 were positive  are: 7.8 [6.5–8.9] at baseline, 12 [10–15.5] at T2, and normalized at 4.7 [4.4–5.3] at T4.After full resuscitation with fluids and vasopressors T4), the hypoperfusion and hypovolemic condition was restored as MAP increased to >60 mmHg, SV returned to values similar to baseline, SvOpositive . Howeverpositive . The valpositive , 4. Inte, the hypmulation . FinallyIt is important to recall that a decrease in ABP could alter arterial compliance, independently on the sepsis condition, due to the volume–pressure relationship . HoweverThe estimated TPR showed a significant decrease at T4 with respect to un-resuscitated shock condition (T2) .Results of the correlation analysis are reported in In this study, a characterization of the arterial tree changes in mechanical properties, both at central and peripheral arterial sites, was investigated in a population of six pigs undergoing a fecal peritonitis-induced septic shock, including full resuscitation with fluids and noradrenaline. The interaction between the ANS dysfunction and these vascular changes were also assessed.Our study confirms that septic shock induces a decoupling of the arterial pulse wave propagation from central to peripheral sites, without resolution after full resuscitation with fluids and noradrenaline. The ANS-related indices, i.e., indices of BRS, arterial pressure spectral analysis, and HRV, showed that septic shock produces signs of autonomic dysfunction and these are associated to changes in vascular properties, both at central and peripheral arterial sites.An inversion of the physiological PP amplitude propagation from central to peripheral arteries was observed after the development of septic shock, as already reported in a recent study of endotoxin shock . Of inteThe origin of this PP reversal could be related to the different tissue composition of central and peripheral arterial walls and, thus, to a different response to inflammatory vasoactive substances, such as nitric oxide (NO).In large compliant arteries, local endogenous NO generation has been demonstrated to contribute to the regulation of large-artery stiffness at basal condition , and it In peripheral resistance vessels, NO is recognized to be crucial in the modulation of vasomotor tone, and a growing body of evidence indicates that NO plays an important role in the hyporesponsiveness of resistance vessels to vasoactive agents . The celThe differences in structural components between large complaint and peripheral resistance vessels could partly explain the different endothelial response to inflammation: large-artery stiffening is caused by a reduction in NO bioavailability following inflammation and sepsis, and, conversely, the persistent peripheral vasodilation is caused by the large increase in NO at peripheral level occurring in sepsis and shock.Although NO bioavailability was not measured in our experiment, in a previous work , we obseAnother important factor that can contribute to PP reversal and peripheral vascular decoupling observed in these animals may be a modification in the reflection of pressure waves. In Finally, the increased capillary permeability secondary to endothelial dysfunction may also contribute to the general vascular derangements observed in these animals. High capillary leakage may lead to changes in extracellular matrix composition and this, in turn, could have an influence on the contraction and relaxation properties of the vessels.The vascular dysfunction induced by septic shock could also help in explaining the increase in FF gain, which measures the direct influence of heart interval duration on SAP, not mediated by autonomic control, but instead by a perturbation mechanism based on the Starling law and diastolic runoff . The decThe autonomic indices of cardiovascular regulation such as BRS, HRV, and LF normalized power of DAP all showed a depressed value in shock which persisted, or even worsened, after full resuscitation , 3. ThusOn the basis of our data, we cannot say if this autonomic impairment involves the central or peripheral nervous system or both. Sepsis-associated encephalopathy is commonly observed in septic patients, and, although its pathophysiology has not been established yet, several processes are known to contribute to its generation, such as brain ischemia, inflammation, metabolic and mitochondrial dysfunction, altered cerebral blood flow autoregulation, or blood–brain barrier leakage . A centrTypically, a reduced baroreflex FB gain and a depressed HRV, together with an elevated HR, are interpreted as signs of a depressed vagal activity at the heart level. These observations suggest a vagal driver for an effective resuscitation, and this hypothesis is in line with the recent literature on vagus nerve stimulation as an innovative therapeutic strategy, which has been proven to be beneficial also in septic shock .The depressed LFu power of DAP hints a dysfunction of the sympathetic nervous system also in the periphery. Changes in LF oscillations of arterial pressure can be related to changes in the outflow of the sympathetic nervous system, and spectral analysis of arterial pressure has been proven to be a powerful tool for identification of the different cardiovascular control mechanisms that regulate arterial pressure . From thThere are many recent indirect and direct evidences which suggest a very complex link between sympathetic activity and vascular function. Evidence from experimental studies indicates that the sympathetic ANS is influenced, both at central and peripheral level, by the most relevant factors regulating vascular function . For exaThe relationship between autonomic and vascular dysfunction could be causal in both directions, i.e., autonomic impairment generates dysfunction in vascular tone or vice versa, or non-causal, i.e., the two conditions may develop in parallel as inflammatory responses. Sympatho-excitatory maneuvers were found to impair endothelial function and to increase arterial stiffness, and markers of vascular dysfunction were shown to be inversely related to sympathetic discharge . On the Another causal mechanism could be the increase in HR, as a sympathetic-mediated increase in HR per se results in stiffening of the central arteries . FinallyIn conclusion, although this study did not demonstrate a direct causal relationship between vascular dysfunction and ANS activity, our observations clearly proved that both the vascular and the autonomic system are impaired in septic shock and they mutually influence each other. This compromised condition is not resolved by standard therapy, i.e., fluids and noradrenaline administration, and it can be macroscopically appreciated from the changes in morphology of blood pressure waveforms. Few cardiac beats of aortic pressure waveform are shown in The main limitation of this study consists in the small sample size, which may be the source of a high variability in the results so to affect the statistical tests. However, the results showed evident trends that can still be considered important, even if not statistically significant. Further studies with a larger number of subjects will permit to validate the results herein presented.Moreover, direct measures of peripheral arteries compliance and autonomic outflow were not available and this did not permit other than speculation about possible associations. Also, the lack of an invasive local flow measurement at some of the arterial pressure measurement sites impeded us to compute the local characteristic impedance, but it was the price to pay in order to keep a closed chest, closed pericardium model, with intact cardiopulmonary and interventricular interactions and less tissue damages.Finally, it could be worthy to integrate these analyses with molecular mechanism involved by shock and resuscitation, since vasoactive agents released during sepsis, such as NO, have a directly influence on the hemodynamic response to shock, and the responsible mechanisms still remain to be elucidated.The present study proposed an insightful analysis of the changes of vascular properties occurring during a protocol of polymicrobial septic shock and full resuscitation, and suggested a possible relationship with autonomic dysfunction typical of septic shock. In fact, a significant positive correlation between an increase in arterial stiffness and a depressed vagal activity has been reported, together with a decreased TPR and time constant τ and an impaired sympathetic activity at the peripheral sites. Interestingly, this abnormal condition generated by septic shock was not resolved after administration of fluids and noradrenaline. Although global hemodynamic markers were restored by the resuscitation maneuvers, such as MAP, HR, CO, and SV, as shown in The discussed results foster further investigations on the integrative aspects of septic shock-induced cardiovascular dysfunction, and they may suggest that the current resuscitation strategies could benefit from the adjunction of additional functional indices combined to the standard hemodynamic and clinical markers. Moreover, our study suggests that measures of vascular properties should be taken into account in further studies in order to have a more comprehensive picture of the effectiveness of the therapy. The computation of time constant τ is a powerful approach to investigate the vascular behavior in terms of total compliance and resistance, and it could be easily computed by the recorded pressure waveform.Finally, a more effective vasopressor therapy should take into account the different characteristics between central and peripheral arteries and further studies should be performed to understand the right balance in order to restore not only MAP but also a physiological condition of cardiovascular interactions and arterial pressure control.The datasets generated for this study are available on request to the corresponding author.The animal study was reviewed and approved by Comité Ethique du Bien-Être Animal, Experimental Laboratory of Intensive Care (LA1230336), Université Libre de Bruxelles.MF, AH, and GB conceived and designed the research. AH performed the experiments. MC analyzed the data, prepared figures, and drafted the manuscript. MC, MF, and AH interpreted the results and edited and revised the manuscript. MC, MF, AH, GB approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The prevalence of chronic kidney disease (CKD) has been rapidly increasing and has become one of the most concerned global health problems. It is of good importance to improve therapeutic efficiency of CKD and delay disease progression to end stage renal disease (ESRD). Traditional Chinese Medicine (TCM) is a widely used complementary therapy for patients with CKD. The aim of this study is to evaluate whether basic treatment combined with Chinese herbs mixture Qi Gui Yi Shen decoction could achieve better therapeutic effect on CKD patients.To determine whether traditional Chinese medicine Qi Gui Yi Shen decoction could achieve better therapeutic effect, we will conduct a randomized controlled trial. A total of 100 CKD patients that meet the inclusion criteria will be enrolled and divided into 2 groups: Qi Gui Yi Shen group (QGYS group) and placebo group. Each group will receive 6-monthly basic treatment in combination with TCM or placebo 3 times per day. Efficacy of Qi Gui Yi Shen decoction is evaluated by analyzing renal function and TCM symptoms, other efficacy assessments include serum level of PAI-I, expression of transforming growth factor beta1 (TGF-beta1). Routine blood count, plasma albumin (ALB), and alanine transaminase (ALT) are evaluated as side effect and safety profile.The results from the clinical trial will provide evidence for the effectiveness and safety of Qi Gui Yi Shen Decoction as a treatment for CKD patients. Furthermore, this will propose a new theory and method for CKD treatment.www.chictr.org. (Registration number: ChiCTR1900021622) on 1 March 2019.Registered with Chinese Clinical Trials Registry at  CKD is associated with a significantly increased risk of hospital admission, morbidity, and mortality due to cardiovascular disease, and other complications including kidney-disease progression, acute kidney injury, cognitive decline, anemia, mineral and bone disorders, and fractures. Treat or not, a certain number of CKD patients would still progress to the most severe form: end stage renal disease (ESRD). The only therapeutic option for ESRD is renal replacement treatment (RRT): dialysis or transplantation. However, the mortality of patients on dialysis can be as high as 20% per year and transplantation is limited by organ shortage. With people's lifestyle changing, the common risks of CKD nowadays are mainly diabetes, hypertension, old age, and cardiovascular disease. However, no matter what causes CKD, renal fibrosis is the final common consequence and can be hardly reversed. Renal fibrosis now is believed to be a wound healing response to tissue damage and is usually characterized by glomerulosclerosis and tubulointerstitial fibrosis. Glomerulosclerosis manifests as vascular damages and loss of capillaries which will accelerate renal epithelial cells injury for nutrient intake limitation from vessels and finally leads to cell death, epithelial-to-mesenchymal cell transition and inflammatory cytokines release from these cells.,10 Besides, overwhelming inflammatory response, in turn, leads to glomerulus impairment. Interstitial inflammation and renal tubular injury also give rise to excessive extracellular matrix (ECM) accumulation and collagen production, thus finally leads to fibrosis generation.,12Chronic kidney disease (CKD), also called chronic kidney failure, is described as a sustained reduction in glomerular filtration rate or evidence of structural or functional kidney abnormalities. Yet by 2016, the total population of CKD published by National Bureau of Statistic in China reached nearly 147 million. However, the therapeutic options for CKD are very limited, such as protein, salt and lipid intake restriction, blood pressure control and angiotensin II receptor blockers or angiotensin converting enzyme inhibitors administration, and the efficacy is not satisfactory though. Therefore, it is of great importance to find effective and safe approaches to prevent or interfere disease progression from an early stage. Literature have suggested that for a long time Traditional Chinese Medicine (TCM) could postpone CKD progress while alleviate drug toxicity and side effects, thus improving patients’ survival and life quality.In recent years, the prevalence of CKD has been rapidly increasing and has become one of the most concerned global health problems. In high-income countries the prevalence of CKD is about 11%. According to the epidemiologic investigation by Peking University Institute of Nephrology, the prevalence rate of CKD by 2012 in China was 10.8%. Astragalus membranaceus (Huangqi in Chinese), for instance, is reported to be able to reduce proteinuria both in clinical and lab studies, and could also reduce serum cholesterol, improve immune function by regulating T cells and extenuate renal fibrosis. Angelica sinensis (Danggui in Chinese) is another widely studied Chinese herb, it has been shown with the ability of attenuating kidney impairment by suppressing oxidative stress and inflammation. Chinese herbs used for kidney diseases treatment is usually prescribed following different principles such as clearing heat and eliminating dampness and coordinating Yin and Yang in the body and the prescription varies by people of different sexes, ages, natural stamina to their different TCM clinical symptoms.,21With the emerging worldwide interest in Chinese herbs, researchers conduct in vitro and vivo studies which have confirmed the biological activity and therapeutic effects of several Chinese herbs.,23 We also conducted clinical researches on IgA-nephropathy patients and QGYS decoction achieved ideal therapeutic effects. This formula aims to treat Qi deficiency in spleen and kidney, which presents symptoms as sore waist and knee, hard breathing, spontaneous perspiration, pale face and hypodynamia, and so on. This decoction is of independent intellectual property rights and we are still searching its potential mechanisms of renal protection.Based on our years of clinical and experimental works in TCM, we suggest that through reinforcing spleen and kidney function and activating blood circulation, TCM could postpone CKD progress. According to that theory, we invented QGYS and it has been proven to be able to protect renal function and alleviate renal fibrosis in mouse experiments.22.1A randomized, parallel, placebo controlled clinical trial will be conducted Fig. . The pro2.2The aim of this study is to evaluate the efficacy of conventional western medicine treatment combined with or without Qi Gui Yi Shen decoction in patients with CKD.2.3Patients diagnosed of CKD of stage II-III; TCM diagnose is spleen and kidney deficiency with syndromes as follows.2.3.1Diagnostic criteria for CKD and stages: according to NKF-K/DOQI Clinical Practice Guideline by America National Kidney Foundation. Creatinine clearance is calculated according to CG GFR formulas: Ccr = (140−age) × weight × 1.23/Scr  and Ccr = (140−age) × weight × 1.03/Scr  for CKD stage determination.2.3.2 Spleen and kidney deficiency syndromes include primary symptoms as weakness in waist and knees, shortness of breath and spontaneous perspiration, pale complexion, feeling spiritless; secondary symptoms including sallow complexion, heaviness of the head, foot edema, cold limbs, incontinence of urine, nocturia, and diarrhea , and considering a drop-out rate of 20%, the total sample size required is determined to be 98, 49 in each group.Sample size is determined for 2.6Participants is randomly allocated to the controlled and TCM group with random number table. Numbers are generated and kept by a certain researcher who has no direct contact with the study participant. The randomized numbers will be kept in sealed envelopes, and random allocation will be conducted by opening an envelope as the researcher is informed of a participant's registration number. Before the randomization allocation, participants will be informed that they will be assigned to one of the 2 groups.2.7Because TCM syndrome differentiation is needed during the research process, in this trial only participants and the laboratory technicians as well as the biostatisticians responsible for the statistical analysis will be blinded to the assigned treatments.2.8The primary outcome measure for this study is renal function and including estimated glomerular filtrate rate (eGFR), serum creatinine (Scr), blood urea nitrogen (BUN) and urinary protein creatinine ratio. They will be measured every 2 to 4 week.The secondary outcomes include TCM symptoms changes Table , cardiovSafety assessment: blood routine, liver function  and blood coagulation Fig. .2.9t test will be used to analyze within the groups. A P value of less than .05 is considered as significant.Data analysis will be conducted with SPSS 15.0 for windows by professionals. The quantitative data are presented as mean ± standard deviation and analyzed by analysis of variance when normally distributed. Non-parametric data will be analyzed by Wilcoxon test. A paired 2.10In this 6-month clinical trial, participants will take research medication for at least 8-week and 16-week follow-up. They need to pay regular visit to the research center and fill the evaluation questionnaire. The trial schedule is listed in Figure 2.11www.chictr.org, trial identifier ChiCTR1900021622). Written informed consent will be obtained from each participant before enrollment. During the research, participants could withdraw from the trial for any reason at any time. Researchers could remove participants from the trial to ensure their safety or maintain the quality of the trial. Severe adverse event and unexpected adverse event will be reported to the Ethics Committee within 2 days.This study is approved by the Ethics Committee of the First Affiliated Hospital of Soochow University and the trial protocol is registered at ChiCTR (3This protocol aims to evaluate the efficacy and safety of TCM Qi Gui Yi Shen decoction in the treatment of patients with CKD. CKD is now becoming increasingly common and hazardous while the current therapeutic options are limited, like angiotensin receptor blockers or angiotensin converting enzyme inhibitors usage, diary restriction and initiating diseases management. Their therapeutic effect is not satisfactory and the side effects are obvious. With the advances in clinical TCM theory and practice in kidney disease treatment, people tend to recognize TCM as an ideal complementary therapy and conduct extensive researches on the efficacy of TCM and the underlying mechanism, in the hope that better therapeutic effect could be achieved in more CKD patients. And this study will provide another new evidence of integrative therapy strategy for CKD.Yi Xi, Xun Lun, and Like Zhu are responsible for study design and drafting manuscript. Xiaoyi Sun, Yuqin Jiang and Minggang Wei obtain informed consent from potential trial participants. Weiming He supervises the experiment process, Xiaoyi Sun and Yuqin Jiang help to collect data. Weiming He and Minggang Wei contribute to the research design and made critical revisions. All authors have read and approved the final manuscript.


Identifying stroke and other intracranial lesions in patients with a decreased level of consciousness may be challenging in prehospital settings. Our objective was to investigate whether the combination of systolic blood pressure, heart rate and age could be used to identify intracranial lesions.We conducted a retrospective case-control study including patients with a decreased level of consciousness who had their airway secured during prehospital care. Patients with intracranial lesions were identified based on the final diagnoses at the end of hospitalization. We investigated the ability of systolic blood pressure, heart rate and age to identify intracranial lesions and derived a decision instrument.P < 0.0001 for all). A systolic blood pressure ≥ 140 mmHg had an odds ratio (OR) of 3.5 , and > 170 mmHg had an OR of 8.2 (95% CI 4.5–15.32) for an intracranial lesion (reference: < 140 mmHg). A heart rate < 100 beats/min had an OR of 3.4 . Age 50–70 had an OR of 4.1 (95% CI 2.0 to 9.0), and > 70 years had an OR of 10.2 (95% CI 4.8 to 23.2), reference: < 50. Logarithms of ORs were rounded to the nearest integer to create a score with 0–2 points for age and blood pressure and 0–1 for heart rate, with an increasing risk for an intracranial lesion with higher scores. The area under the receiver operating characteristics curve for the instrument was 0.810 (95% CI 0.850–0.890).Of 425 patients, 127 had an intracranial lesion. Patients with a lesion were characterized by higher systolic blood pressure, lower heart rate and higher age (An instrument combining systolic blood pressure, heart rate and age may help identify stroke and other intracranial lesions in patients with a decreased level of consciousness in prehospital settings.Not applicable. Patients with an altered level of consciousness are often encountered by emergency medical services (EMS) in the prehospital setting and by emergency department (ED) personnel in-hospital , 2. CommMany patients with an intracranial lesion are hypertensive , 10. becWe hypothesized that the first blood pressure and pulse measured in the prehospital setting, combined with the age of the patient, could be used to predict if a patient with an altered level of consciousness has an intracranial lesion.We conducted a retrospective case-control study comparing the initial prehospital systolic blood pressure, heart rate and age of patients with and without an intracranial lesion. The study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. The study was retrospective and register-based. The data was de-identified before analysis. Patients were not contacted for study purposes, nor did the study affect their treatment. Thus, approval from an ethics committee was not required by Finnish legislation. The authorities of the Helsinki University Hospital approved the study protocol and provided permission to access the patient data.The study was based on the FinnHEMS database, where all the missions of every helicopter emergency medical services (HEMS) unit in Finland are entered. We included only patients of the busiest HEMS unit of the country, as carefully validated data of intubated patients were available . The datWe analyzed the data of patients with Glasgow Coma Score < 15, having their airway managed by the crew of a single HEMS unit (FinnHEMS 10) and alive upon arrival at the hospital during 2014 and between March 2015 and Dec 2016. Data on patients encountered during Jan 2015 and Feb 2015 were not used because of the changes in the operational models of the HEMS unit during that time, which would have potentially biased the quality of the registry data. The HEMS unit is dispatched as an addition to ground units by emergency dispatchers on predetermined criteria. It is alerted for all missions where an unconscious patient without a pain response is reported by the caller. The only exemptions are suspected hypoglycemia or convulsions, where only a paramedic staffed unit is dispatched. At the time of the study, the HEMS unit was the only EMS unit providing prehospital anesthesia and intubation in its operation area. Thus, the unit covers virtually every unconscious patient in need of airway management.All adult age > 16) patients with their airway managed by the HEMS crew and patients with a recorded GCS < 15, were included. The indications and protocol for prehospital anesthesia in the unit are described in a previous study [ patientsFor the study, we used the first systolic blood pressure and heart rate acquired by the first EMS unit on scene. Blood pressure and heart rate were measured using a monitor-defibrillator with an automatic noninvasive blood pressure monitor . The measurements were automatically transferred via WiFi or Bluetooth to the electronic patient record system, removing the potential of errors in data collection. Patients with either heart rate or blood pressure recorded initially were analyzed for the recorded vital sign. All patients in the area were transported to the public hospitals with the electronic patient record system. The primary diagnoses according to the International Statistical Classification of Diseases (ICD-10) at the end of hospitalization period were searched afterwards from the hospital’s electronic patient record system .Included patients were categorized into two groups according to their final diagnoses at the end of hospitalization: 1) those having an intracranial lesion and 2) those without. In addition to stroke, other diagnoses that may lead to elevation of ICP were included in the former group . A full The two groups were compared by age, heart rate and systolic blood pressure. We divided each variable into categories to derive a scoring system for clinical use. Finally, the diagnostic accuracy of the scoring system to detect an intracranial lesion was tested. Based on our data, we chose convenient cut-off values of 140 and 170 mmHg for systolic blood pressure. The lower cut-off for blood pressure was the cut-off for stage 2 hypertension according to the AHA guidelines . and corIndependent two-sample t-tests for equal variances were used to determine the significance of differences in blood pressure, heart rate and respiratory rate between the groups. For age and peripheral oxygen saturation, independent two-sample t-tests for unequal variances were used. For age, we used the χ2 test.We investigated the predictive ability of systolic blood pressure, age and heart rate to predict whether a patient would have a lesion. We fitted logistic regression models for the variables separately and with all three in the same model. The multivariable model was then used to create a score for the lesions.The discrimination abilities of the models were investigated using receiver operating characteristics curves (ROC) and areas under the ROC (AUROC) . We alsoDuring the study period, 1071 patients had their airway secured by the HEMS crew. After exclusions, 425 patients were analyzed in the study  had a stroke, including 41 with intracerebral hemorrhages (I61), 31 with subarachnoidal hemorrhages (I60) and 21 with cerebral infarctions (I63). A total of 21 (17%) were found to have an intracranial injury (S06.1-S06.9), with 18 traumatic subdural hemorrhages (S06.5). Eight (6%) were found to have other intracranial lesions, of which 5 were inflammatory diseases of the central nervous system (G00–09).Of the patients without an intracranial lesion, 92 (31%) had a diagnosis of poisoning by drugs, medicaments and biological substances (T36-T50), 83 (28%) had a primary diagnosis of epilepsy, status epilepticus or unspecified convulsions , and 123 (41%) had other diagnoses.Patients with an intracranial lesion were characterized by higher systolic blood pressure, lower heart rate and higher age Table .Table 1Distinguishing between patients with and without an intracranial lesion, initial systolic blood pressure had an AUROC of 0.808 (95% CI 0.762 to 0.853). The initial heart rate and age had AUROCs of 0.616 (95% CI 0.558 to 0.675) and 0.769 (95% CI 0.724 to 0.814), respectively.p-value n.s.). The AUROC for the continuous multivariate model was 0.858 (95% CI 0.819 to 0.896) and was 0.852 (95% CI 0.813 to 0.892) for the categorized model.Heart rate was divided into two categories, while age and systolic blood pressure were grouped into three categories Table . The regThe score was created by counting logarithms of odds ratios from the multivariable model Table . These wThe resulting score discriminated well between having and not having an intracranial lesion: the AUROC was 0.810 (95% CI 0.850 to 0.890), Fig. Excluding all patients with a primary diagnosis of epilepsy or other seizures in a separate sensitivity analysis further improved the discrimination capability of the score, resulting in an AUROC of 0.844 (95% CI 0.882–0.920).Our study indicated that a decision instrument combining the initial systolic blood pressure, heart rate and age can provide a useful aid in assessing whether a decrease in the level of consciousness is caused by an intracranial lesion or some other mechanism. To our knowledge, this is the first study investigating this approach in a prehospital patient population. Our findings are consistent with previous studies performed in Japanese EDs , 4. IkedWe did not categorize seizures as intracranial lesions, as the standard of the care does not include measures to control intracranial hypertension, in contrast to the care of patients with intracranial lesions such as a stroke . FurtherThere is a strong rationale underlying the use of blood pressure, heart rate and age to detect intracranial lesions in unconscious patients. As previously stated, an increase in blood pressure and a decrease in heart rate are commonly observed during stroke . as a coIdentifying patients with stroke or other intracranial lesions early is paramount because the focus of prehospital care of these patients is to minimize a secondary insult to the brain tissue and maximize salvageable brain by optimizing brain perfusion and oxygenation while expediently transporting the patients to a stroke unit or neurosurgical center . SeveralWe believe that in the case of these high priority calls, prehospital personnel could use this instrument as guidance when deciding on the receiving hospital and whether to engage in procedures to control ICP. We named the HeSA-score according to the measured attributes: heart rate, systolic blood pressure and age. Using the scoring system is simple, and a score ≥ 2 provides a good sensitivity of over 0.9 for an intracranial lesion, while a score of 3 provides a useful combination of sensitivity (0.802) and specificity (0.788). At higher scores, our tool becomes highly specific. The score could be integrated into the electronic patient record system, providing an automatic warning when detecting a patient at an elevated likelihood for having an intracranial lesion. In some regions, the utilization of mobile stroke units has brought CT capabilities to the prehospital setting , but becThe main limitation of the study is that the categorization was performed using the diagnoses acquired from patient records, and the validity and uniformity of the diagnosis processes were not controlled by any study protocol. Not all the diagnoses were confirmed by advanced imaging of the brain; thus, some patients categorized as not having an intracranial lesion might have had a lesion that remained undiagnosed. However, all the hospitals to which the studied patients were transported had resources to perform instant computer tomography imaging, and most also had magnetic resonance imaging scans available at least during the daytime. Thus, the reason not to confirm the diagnosis by advanced imaging has not been the non-availability of the imaging but a clinical decision instead. All hospitals receiving and treating intubated patients at the time of the study were also part of the public health care system, funded by municipalities and the state. Thus, the social status or health insurance of the patient did not have any effect on the investigations or treatments. The diagnoses used in the study were set at the end of hospitalization. Thus, we assume that cases where an underlying lesion remained unrecognized were rare in the study population.The study population consisted of patients requiring airway management; therefore, further study is needed to investigate whether the score could be applied to more well-appearing patients. The score was developed based on the patients treated by a single HEMS-unit, the busiest base in the country, creating a possible source of bias. Therefore, validation in other patient populations is necessary. We are planning further studies including data from all six Finnish HEMS units. However, the strength of the study is that it included data from virtually all unconscious patients in need of intubation in the study area. The HEMS unit does not have strict criteria on the decision-making process if the patient needs intubation, and the final conclusion is made by the anesthesiologist on the scene. Thus, selection bias is possible but unlikely.Patients with altered level of consciousness caused by stroke and other intracranial lesion can be identified by the combination of systolic blood pressure, heart rate and age. This approach complements the current scoring systems that require co-operation of the patient to neurological examination.Additional file 1. Diagnoses categorized as intracranial lesionsAdditional file 2. Regression analysis results