Recent studies have reported the epidemiological link between Metabolic Syndrome (MS) and asthma, but it has rarely been studied in Egypt. The study aimed to investigate the prevalence of MS and its predictors among asthma patients in Egypt.In total, 320 patients with bronchial asthma were included. The following were assessed: spirometric evaluation, anthropometric indices, blood pressure, fasting blood sugar and serum lipid profile. We analyzed the correlation between metabolic scores and patient characteristics. Predictors of MS were identified using logistic regression analysis.The prevalence of MS was 57.5% in asthma patients. For asthma patients, low High-Density Lipoprotein (HDL) and abdominal obesity were the commonest metabolic abnormality. Waist circumference, Fasting Blood Sugar (FBS) and triglyceride correlated significantly with asthma (P ‹ 0.05). FBS and DBP were the best predictors of MS.MS is frequent in asthma patients in Egypt. Obesity and lipid abnormalities were the commonest metabolic abnormality. Screening of these patients for components of metabolic syndrome should be a part of routine workup. ReversiA quarter of the world’s population is estimated to have MS and increased cardiovascular risk compared with people without it . DiabeteTo date, the prevalence of metabolic syndrome in asthma subjects has not been studied before in Upper Egypt. Therefore, we aimed to investigate the prevalence and predictors of metabolic syndrome in asthma patients.22.1A cross-sectional study on 320 asthma patients was performed. The patients admitted to the Department of Pulmonology, Sohag University Hospital were selected. The protocol of the study was reviewed and approved by the Ethical Committee, Sohag university hospital.2.22), and waist circumference were measured in all patients [Clinical and laboratory findings including history taking, clinical examination, spirometry, blood picture, ESR, liver and kidney functions, lipid profile , and CRP level were analyzed. Bodyweight, height, BMI (wt in kg/ht in meterpatients .2.3The definition of Diabetes Federation (IDF) of metabolic syndrome was used to diagnose MS . MS was 2.4Data was collected and analyzed using SPSS v.17.0 . The ANOVA test was used to assess the differences between the groups; Spearman’s correlation coefficient was used to assess the strength of correlations between variables. To identify independent predictors of MS presence, multivariate logistic regression analysis was conducted. A P value of < 0.05 was considered significant.33.11. Using IDF definition, MS was diagnosed in 184 (57.5%) patients with asthma.All the biochemical and anthropometric parameters pertaining to the diagnosis of MS are depicted in Table 1).The percent of each component of the MS was estimated in asthma patients. Abdominal obesity was represented in 40%, low HDL-C levels in 40%, elevated fasting glucose levels in 27.5%, elevated triglyceride levels in 15%, and raised blood pressure in 12.50%. So, in asthma patients, the highest percentage was low HDL and abdominal obesity, then FBS  respectively, but TG and hypertension were of the lowest incidence . The most prevalent component in participants with asthma was waist circumference (40%) and Low HDL (40%) .Asthma patients who did not meet the criteria for MS (n-136), 24 (7.5%) patients had no features of metabolic syndrome while 56 (17.5%) had at least one parameter of metabolic syndrome and 56 (17.5%) had 2 parameters of metabolic syndrome .Comparing asthma group who did not have MS and asthma group with MS, there were significant differences between the 2 groups regarding waist circumference , CRP , DBP , triglycerides , and fasting blood glucose  , SBP, DBP  and FBS  were positively associated with MS.The correlations between clinical parameters and MS observed in subjects affected by MS are shown in Table 3.43 and 4. The best predictors of MS in asthma were FBS , and DBP  (Table 4).In order to predict the presence of a MS in patients with asthma, logistic regression analysis was done to identify predictors of MS. The independent variables which predict the presence of MS are presented in Tables 4Ours is the first study in Upper Egypt to evaluate the prevalence of MS in patients with bronchial asthma and to examine the correlations between MS with comorbidities and asthma characteristics.et al., studied the prevalence of metabolic syndrome in asthma patients which was 36.7%, being lower than our study [.) may partly explain the differences in the prevalence of metabolic syndrome.The main findings of the current study were (57.5%) patients with asthma had MS. The prevalence of metabolic syndrome varies worldwide; its prevalence is not uniform. It has been reported to be 18–46% in different local studies . 0ur finur study . Diverseet al., found that the prevalence of obesity in asthma patients was 49.4% which is higher than our own study [In our study, the most prevalent component in participants with asthma was waist circumference (40%) and low HDL (40%). A previous study reported that type 2 diabetes mellitus, dyslipidaemia and hypertension, tend to occur more in asthma patients. The prevalence of obesity in asthma patients and the use of steroid therapy by asthmatics may be the cause. Adeyeye wn study .Obesity and asthma are both characterized by inflammation. Obesity leads to a proinflammatory milieu characterized by increased levels of TNF-α, plasminogen activation inhibitor-1, angio-tensinogen, plasminogen activation inhibitor-1, IL-6, leptin, and decreased adiponectin levels which enhance endothelial functions. The TNF-α is also included in the initiation of allergic airway responses in asthma. Meta-analysis has shown the association between obesity and the development of asthma . Asthma etal., it was reported that the pulmonary function test was not affected by the presence of MS. This because that our asthma patients were already diagnosed and were on treatment for asthma [We found a statistically significant difference between patients with MS and patients without MS regarding metabolic parameters but no statistical significance regarding functional parameters. So, the incidence of MS is not related to the severity of the disease. In our study, we did not find any significant association between the presence of MS in asthmatic patients and pulmonary function tests. In a similar study by Adeyeye r asthma . In contr asthma .et al., showed that the MS -asthma association was substantially mediated by insulin resistance and systemic inflammation. MS and each MS component were significantly associated with insulin resistance and systemic inflammation [An interesting observation was that patients with MS in asthma had significantly higher CRP compared with those without MS. Park ammation . This obammation .Another objective of the study was to explore the association of individual components of MS with asthma patients. The association with individual components was further explored using the logistic regression models. In a patient of asthma, the data showed a significant positive association with FEV1, SBP, DBP and FBS. These findings suggest that MS-related factors could contribute to the relationship between MS, and asthma. MS components such as abdominal obesity, hyperglycemia , dyslipiThe last objective of the study was to explore the determinants of association between the individual components of MS and asthma. Among the components of MS; FBS, DBP is the best predictor of MS.The prevalence of metabolic syndrome is high in patients with BA. It shows the importance of the development of comprehensive strategies aimed at the prevention and treatment of co-morbidities. Correction of the risk factors of MS may have a significant role in the prevention of complications and improvement of quality of life of patients with BA.


Background and objectivesDelayed graft function (DGF) may increase the risk for kidney graft dysfunction. Renal resistive index (RRI) in Doppler ultrasonography is useful in measuring blood flow changes in kidneys which is indicative of tubulointerstitial damage. Most of the diseases in DGF etiology are related to tubulointerstitium and arteries of the kidneys. In this study, we investigated whether there is a relationship between delayed graft function and renal resistive index in kidney transplant recipients (KTR).Materials and methodsPatients who underwent kidney transplantation were included in this retrospective study. KTR were divided into two groups as DGF (+) and DGF (−). Comparison of RRI values of DGF (+) and DGF (−) groups according to the measurements at different times.ResultsThe findings showed that both RRI measurements (post-transplant in the first week and the end of the first year) of the DGF (+) group were higher than DGF (−) group . The interaction of measurements and DGF did not have an effect on RRI (p>0.05).ConclusionThe value of RRI in the DGF (−) group was lower than DGF (+) group in the first week after kidney transplantation. Delayed graft function (DGF) is defined as the need for dialysis within the first week after kidney transplantation. The etiology of DGF includes acute tubular necrosis, accelerated/acute rejection, thrombotic microangiopathy, vascular and surgical complications  ,2. The eRenal resistive index (RRI) in Doppler ultrasonography is useful in measuring blood flow changes in kidneys and showing damage to the tubulointerstitium . The decOur study was designed retrospectively. Patients who underwent renal transplantation in the organ transplant unit of our hospital between October 2015 and March 2020 were included in this study. DGF was defined as the need for dialysis within the first week after kidney transplantation [RRI value was determined by examining the interlobar artery in the upper, middle, and lower zones of the kidney and by the average of three different measurements. Toshiba Aplio XG Doppler ultrasonography device was used together with a convex transducer PVT-375BT). RRI was calculated using the formula ‘‘peak systolic velocity − end-diastolic velocity/peak systolic velocity’’ [5BT. RRI Blood was drawn from each patient in the early morning following at least eight hours of fasting. All blood samples were studied in our hospital’s biochemistry laboratory. Serum creatinine and urea analyses of the patients were examined using the colorimetric method on the Roche Cobas 6000 device 501 modules. Biochemistry markers of each patient were recorded on the first day of kidney transplantation, the third month, and at the end of the first year.The data collected from the patients in this study were transferred to the Statistical Package for the Social Sciences (SPSS) 19.0 program . The demographic data of the patients, such as age and gender, were determined by descriptive statistics. Comparison of DGF (+) and DGF (−) groups on the age variable were performed using the Mann-Whitney U test since they did not show normal distribution. The relationship of the patient groups concerning gender was examined by chi-square analysis. Comparison of the groups concerning RRI at post-transplant in the first week was performed by Student’s t-test because it conformed to normal distribution. As the number of patients decreased, the comparison of RRI values of the groups at the end of the first post-transplant year was performed using the Mann-Whitney U test. Bonferroni, a multiple comparison test, was conducted to investigate that there were significant differences between groups. Comparison of RRI, serum urea, and creatinine values of DGF (+) and DGF (−) groups according to the measurements at different times was made using a two-factor analysis of variance (ANOVA) test.Eighty-six kidney transplant recipients  were included in this study. The average age of the patients was 52±13.07. Of the kidney transplant recipients, 45 (from 44 cadaveric and one living donor) were DGF (+) and 41 (from 37 cadaveric and four living donors) were DGF (−). When evaluated according to chronic kidney disease, 17 patients had diabetes mellitus, 32 had hypertension, 12 had chronic glomerulopathy, four had autosomal dominant polycystic kidney disease, three had urological causes, and 18 had an unknown etiology. Antithymocyte globulin  was administered to each renal transplant recipient as induction therapy. Triple immunosuppressive therapy  was given to each patient after transplantation.No statistically significant difference was found between the groups regarding age (p=0.792). The findings obtained in this study showed that there was no statistically significant difference in the diagnosis of DGF according to gender (p=0.937). Cold ischemia time was higher in DGF (+) group than in DGF (−) group. The result was statistically significant (p=0.002). The groups were found similar concerning human leukocyte antigen (HLA) mismatch (p=0.081).RRI measurements of DGF (+) and DGF (−) patients in the first week after kidney transplantation and at the end of the first year were compared with each other. The estimated marginal means of RRI in both groups are shown in Figure RRI values were statistically significantly different according to the measurement . RRI values were statistically significantly different according to DGF groups  but it was seen that the interaction of measurements and DGF did not have a statistically significant effect on RRI . The comparison of the RRI values of DGF groups according to the measurement at different times is shown in Table Serum creatinine levels were not statistically significantly different according to the measurement . Creatinine levels were statistically significantly different according to DGF groups , but it was seen that the interaction of measurements and DGF did not have a statistically significant effect on serum creatinine levels .Serum urea levels were statistically significantly different according to the measurement . Urea levels were statistically significantly different according to DGF groups , but it was seen that the interaction of measurements and DGF did not have a statistically significant effect on serum urea levels . Serum mean urea and creatinine levels and standard deviation values of the groups after kidney transplantation are given in Table The risk of developing DGF after kidney transplantation from a donation after brain death (DBD) was reported to be between 24% and 70% . In our Delayed graft function is defined as the need for dialysis within the first week after kidney transplantation . During In addition to measuring blood flow changes in the kidneys, RRI also reflects damage to the tubulointerstitium . Many diOur study has some limitations. This study was planned retrospectively. Most of the patients in our center had a deceased kidney donor, and the number of patients transplanted from a living donor was low. Thus, subgroups of patients who underwent kidney transplantation from living and deceased donors could not be compared with each other. RRI values of a small number of patients could be measured due to lack of clinical indication and patient incompatibility. Recipient dialysis status, panel reactive antibodies, the detailed information of the donor's kidney, the kidney donor profile index, and warm ischemia time (donor and recipient) could not be determined.The value of RRI in the DGF (−) group was lower than the DGF (+) group in the first week after kidney transplantation. The elevated RRI may be linked to a higher risk of DGF within the first week after transplantation. Prospective studies defining the optimal cut-off value and timing measurement of RRI should be designed in this area.


Objective: The aim of this study was to evaluate non-hyperemic resting pressure ratios (NHPRs), especially the novel “resting full-cycle ratio” , compared to the gold standard fractional flow reserve (FFR) in a “real-world” setting.Methods: The study included patients undergoing coronary pressure wire studies at one German University Hospital. No patients were excluded based on any baseline or procedural characteristics, except for insufficient quality of traces. The diagnostic performance of four NHPRs vs. FFR ≤ 0.80 was tested. Morphological characteristics of stenoses were analyzed by quantitative coronary angiography.Results: 617 patients with 712 coronary lesions were included. RFR showed a significant correlation with FFR . Diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of RFR were 78% , 72% , 81% , 63% , and 86% . Relevant predictors for discordance of RFR ≤ 0.89/FFR > 0.8 were LAD lesions, peripheral artery disease, age, female sex and non-focal stenoses. Predictors for discordance of RFR > 0.89/FFR ≤ 0.8 included non-LCX lesions, percent diameter stenosis and previous percutaneous coronary intervention in the target vessel. RFR and all other NHPRs were highly correlated with each other.Conclusion: All NHPRs have a similar correlation with the gold standard FFR and may facilitate the acceptance and implementation of physiological assessments of lesion severity. However, we found ~20% discordant results between NHPRs and FFR in our “all-comers” German cohort. Despite great advances in the prevention and treatment of cardiovascular diseases, ischemic heart disease remains one of the main causes of morbidity and mortality worldwide . FractioThe development of resting indices, referred to as non-hyperemic pressure ratio (NHPR), is therefore of great importance. Two large randomized clinical trials among patients with stable angina or acute coronary syndrome revealed that instantaneous wave-free ratio (iFR), which is calculated during the diastolic wave-free period and used by one of the leading manufacturers of pressure wires, is clinically non-inferior to FFR with regard to serious adverse events at one year , 12. MorIn the present retrospective, single-center study, we sought to investigate the diagnostic accuracy of FFR and NHPRs and the clinical utility of NHPRs and especially the relatively new non-hyperemic index RFR in a German “all-comers” population with intermediate coronary stenoses. The objective of this study is to assess the correlation of FFR and NHPRs in a real-world setting and evaluate predictors of discrepancies.From 9th of March 2015 until 15th of February 2019, a total of 696 adult patients underwent 869 pressure wire recordings of at least one intermediate coronary lesion  for standard clinical indications at the Heart Center of the University of Cologne. Pressure wire recordings were not performed in the following settings: (1) contraindication for adenosine, (2) cardiogenic shock (3), ST-segment elevation myocardial infarction, (4) culprit vessels in the setting of myocardial infarction (5), stenosis technically not suitable for analysis and (6) lesions without myocardial viability. All patients with FFR recordings in this period were included in this study, i.e., no patients were excluded from the analysis based on any baseline or procedural characteristics, except for insufficient quality of recorded traces, which impeded a reliable retrospective analysis (see pressure wire assessment). All collected patient data were anonymized before the analysis. The study design was approved by the local ethics committee and complied with the Declaration of Helsinki.Coronary angiography was executed according to current guidelines and institutional standards by a femoral or radial approach, using a diagnostic or guiding catheter and low-osmolar contrast agents. Angiographic views were obtained in multiple standard projections. Diameter stenosis percentage, minimal and reference lumen diameter, and lesion length were assessed retrospectively by quantitative coronary angiography with validated software .® ) was calibrated, equalized, and advanced distal to the target lesion, and intracoronary nitrate was administered. Then continuous intravenous adenosine (140 μg/kg per min) was applied through a peripheral vein to induce hyperemia in the target vessel for FFR measurement. In the majority of cases, a pullback recording was made to exclude pressure drift.Interventional procedures and application of medication were performed according to current guidelines and manufacturer's and institutional standards. A pressure guidewire  and aortic pressure (Pa) traces at baseline, i.e., before application of adenosine, were used to determine NHPRs. FFR was calculated using the lowest Pd/Pa under hyperemic conditions. FFR, RFR, diastolic pressure ratio during wave-free period (dPR[WFP]), diastolic pressure ratio during entire diastole (dPR[entire]), and Pd/Pa values  stenoses was performed using a dedicated software for calculation of quantitative flow ratio (QFR) based on coronary angiography  .t-test or Mann-Whitney-U test for continuous variables, depending on their distribution. Kruskal–Wallis test was used to test for differences among >2 groups followed by post-hoc Mann-Whitney U tests with Bonferroni correction. Pearson's correlation coefficient was used to assess the relationship between several indices.Continuous variables are presented as mean ± standard deviation or median with interquartile range (IQR), while categorical variables are reported as frequencies and percentages. The differences were evaluated using Chi-square test or Fisher's exact test for categorical variables and Student's To assess the diagnostic value of NHPRs in comparison to FFR (≤0.80), the area under the curve (AUC) of the receiver-operating characteristic (ROC), as well as the accuracy metric were used. Diagnostic accuracy, sensitivity, specificity, negative, and positive predictive value, likelihood positive and negative ratio were calculated. Diagnostic agreement between the different indices was assessed by Bland-Altman plots with corresponding 95% limits of agreement.p-value < 0.05 by forward selection in univariate analysis were included in the multivariable model after testing for multicollinearity. Backward stepwise selection was performed using a binary logistic model . A two-tailed p-value of < 0.05 was regarded as statistically significant. Statistical analysis was conducted in SPSS Statistics, version 28  and R programming language version 4.1.2 .Predictors of discordance between FFR and NHPRs were determined using a logistic regression model. The associated covariates with a Clinical and angiographic characteristics are displayed in The lesions were located most often in the left anterior descending coronary artery . The reference diameter showed sufficient size for PCI (2.98 ± 0.57 mm). The lesions had a minimum diameter of 1.42 ± 0.42 mm, the mean percent diameter stenosis (%DS) was 52.9 ± 8.7 %, and the mean lesion length 15.6 ± 9.54 mm. Two hundred and ninety (40.7%) lesions were non-focal.p = 0.43). FFR was correlated with NHPRs  for FFR, 0.91 (IQR: 0.88 to 0.96) for RFR, 0.92 (IQR: 0.88 to 0.96) for dPR[entire], 0.92 (IQR: 0.88 to 0.96) for dPR[WFP] and 0.94 (IQR: 0.90 to 0.97) for Pd/Pa, respectively. Ischemia defined as FFR ≤ 0.80 was detected in 222 of 712 lesions . Nineteen (3%) minor side effects [chest discomfort/dyspnea (1.4%) and transient atrioventricular block (0.5%)] occurred during adenosine infusion, but no serious adverse events were observed. Resting indices suggested ischemia in 253 lesions (35.5%) for RFR, 222 (31.2%) for dPR[entire], 238 (33.4%) for dPR[WFP], and 280 (39.3%) for Pd/Pa. The prevalence of ischemia, regarding the cut-off value of 0.89, between dPR[WFP] and RFR were not statistically significant . Increasing the per-lesion threshold to RFR ≤ 0.93 resulted in higher sensitivity of 90% to predict FFR ≤ 0.80, RFR ≤ 0.97 had 100% sensitivity. ROC curve analysis was performed to examine diagnostic performance of NHPRs using FFR ≤ 0.80 as the reference standard  pressure tracings; in 80 (2.2%) pressure tracings the lowest ratio of Pd/Pa was located within systole in all analyzed cycles. The RFR was more frequently located within systole, when left circumflex artery (LCX) and right coronary artery (RCA) were examined .Concordant and discordant findings of FFR and NHPRs are summarized in p < 0.01), female sex (p = 0.01), peripheral artery disease (p = 0.01), LAD lesion (p < 0.01) und non-focal lesion (p = 0.02) were associated with discordance of RFR ≤ 0.89/FFR > 0.8 (p = 0.01), % DS (p < 0.01) and non-LCX lesions (p < 0.01) were associated with discordance of RFR > 0.89/FFR ≤ 0.8 (p = 0.01), non-focal stenoses , female sex , peripheral artery disease  and LAD lesion  as predictors of RFR ≤ 0.89/FFR > 0.8 (p = 0.02), % DS  and non-LCX lesion  were confirmed as predictors of RFR > 0.89/FFR ≤ 0.8 in the multivariate analysis  in the present study, although most previous studies reported slightly higher rates of ischemia determination by FFR , 26. BotPredictors of RFR > 0.89 /FFR ≤ 0.8 discordance, i.e., revascularization would be performed based on FFR but deferred based on an NHPR, were %DS, history of percutaneous coronary intervention in the target vessel, and non-LCX lesions in the multivariate analysis. The relevance of %DS was small with an odds ratio of 1.14. %DS was also a predictor of iFR > 0.90 /FFR ≤ 0.8 discordance in the work by Lee et al. . Other sLesion location  and multivessel disease had no significant effect on the concordance or discordance of indices. Due to the relatively high number of patients with ACS in our study, we could analyze the interaction between the presence of an ACS and the concordance or discordance of indices, which was not significant. This is an interesting finding, since microvascular function may be altered in patients with ACS, which may diminish the effect of adenosine and lead to false negative FFR values . MoreoveA subgroup analysis of patients with and without prior myocardial infarction (irrespective of the location) revealed no interaction with the discordance of indices, too. However, we cannot exclude that an analysis of prior myocardial infarction in the territory of the examined vessel may have led to different findings. Unfortunately, information on the exact location of prior myocardial infarction was not available for our population.It was speculated that coronary stenoses with iFR > 0.90 /FFR ≤ 0.75 show similar coronary flow properties as angiographically unobstructed vessels and, in cases with normal or high CFR and FFR ≤ 0.75, the low FFR may reflect high flow states in response to adenosine rather than significant stenoses, which would be associated with a good prognosis , 40. In In our study, all parameters of diagnostic performance were similar for all analyzed NHPRs, increasing the body of evidence that NHPRs are largely comparable among one another, as suggested by one previous trial . Thus, aSince iFR is the only NHPR with evidence from randomized controlled trials, differences between iFR and other NHPRs are of particular interest. Van't Veer et al. reported that available diastolic resting indices calculated in the “wave-free period” are identical to iFR despite minor differences in algorithms , so we cAccordingly, only 2.2% of RFR measurements detected the lowest Pd/Pa in systole. This is much lower than reported in most previous studies with a range from 11.4–12.2% , 14. FloOur trial has several limitations. It was an observational retrospective cohort study conducted at a single center. Revascularization of the target lesion was based on FFR values and operators' decision, and not on NHPRs. Patient selection for pressure-wire assessment was also within the discretion of the treating physician, which may have led to bias. However, we intended to study pressure wire-derived indices under real-life conditions. Another limitation is that we did not investigate clinical outcomes after revascularization. Thus, the clinical impact of discrepancies between FFR and NHPRs could not be assessed.Our cohort comprised patients with diabetes, CABG, and intake of beta-blockers. On the other side, we consider the broad “all-comers” population as one strength of the present study, since it probably better reflects the realities of care than previous studies with more extensive exclusion criteria.No assessment of microvascular function or coronary flow was performed. A better understanding of microcirculation and coronary flow under baseline and hyperemic conditions would have improved the interpretation of discrepant findings of NHPRs and FFR.A total of 157 out of 869 (18.1%) pressure tracings could not be analyzed. Previous studies have shown that even in the context of a prospective clinical trial, physiological assessments of stenosis severity may be limited by pressure tracings being unanalyzable due to artifacts and failure in up to 30% , 25. PatThe external analysis of pressure curves by an expert core lab is not fully representative for the real-life situation, however it reduces inter-observer variability and ensures reliability of the calculations. Moreover, due to the retrospective nature of our study and the incapability of commercially available systems to calculate all investigated resting indices online in the catheterization laboratory, an offline analysis was necessary.All NHPRs have a similar correlation with the gold standard FFR and may facilitate the acceptance and implementation of physiological assessments of lesion severity. However, we found ~20% discordant results between NHPRs and FFR in our “all-comers” German cohort. Most relevant predictors for discordance of RFR ≤ 0.89 /FFR > 0.8 were LAD lesions, PAD, female sex and non-focal stenoses. Strong predictors for discordance of RFR > 0.89/FFR ≤ 0.8 were non-LCX lesions and previous percutaneous coronary intervention in the target vessel. The impact of discrepant findings on outcome and the optimal treatment strategy needs to be further elucidated by future prospective trials.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee Medical Faculty, University of Cologne. The Ethics Committee waived the requirement of written informed consent for participation.HW, MH, and SB: study concept and design. HW, AM, VM, and TB: acquisition and analysis or interpretation of data. HW: writing and original draft preparation of the manuscript. HW, VM, MA, SB, and MH: discussion or critical revision of the interpretation for important intellectual content. MH: study supervision. All authors reviewed the manuscript.The corelab analysis at Coroventis Research AB was supported by Abbott Vascular.SB and MH received institutional grant support and speakers' honoraria from Abbott Vascular. HW received institutional grant support from Abbott Vascular. Abbott Vascular had no influence on the design of the study, data analysis or interpretation of findings. The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Urine albumin/creatinine ratio (UACR) is an important marker of early renal damage (ERD) caused by hypertension. Recent studies showed that blood pressure was a significant inverse association with temperature and climate. The purposes of our study were sought to explore the association of common medical comorbidities with ERD, and find independent risk factors to ERD in Chinese tropics with essential hypertension.2) test. We calculated correlations between UACR and age, hypertension duration (HD), systolic blood pressure (SBP), and diastolic blood pressure (DBP) using the Spearman’s rho test. To determine the odds ratio (OR), we evaluated binary logistic regression models.From January 2018 to December 2019, we assessed UACR in a total of 599 hypertensive Chinese Hainan patients. We defined ERD as a UACR between 30 mg/g and 300 mg/g. We analysed differences between qualitative variables using the chi-squared . In multivariate analysis using stepwise regression, age (OR = 1.468), DBP (OR = 1.853), and diabetes (OR = 2.031) were significant independent predictors of ERD. The area under the receiver operating characteristic (ROC) curve was 0.677, and the sensitivity and specificity of the optimal cut-off value were 44.5 and 81.1%, respectively.Among the 599 patients, 281 (46.9%) were found to have ERD. ERD and factors related to sex, body mass index (BMI), and SBP did not differ significantly . Our main findings showed that age, HD, and DBP were associated with ERD . Furthermore, age ≥ 65 years, HD ≥10 years, DBP ≥ 90 mmHg, SBP ≥ 160 mmHg, and diabetes differed significantly according to ERD status (Common medical comorbidities are associated with ERD; age, DBP, and diabetes are independent risk factors for ERD in patients with essential hypertension who live in the Chinese tropics. Early monitoring of the UACR, as well as control of blood glucose and DBP, can effectively delay ERD. Hypertension is a risk factor for cardiovascular disease and chronic kidney disease (CKD) . AccordiFor a long time, uncontrolled hypertension could lead to renal failure, a marker of ERD through UACR testing , 6. MoreFrom January 2018 to December 2019, we selected 599 hypertensive patients at both outpatient and inpatient department based on inclusion and exclusion criteria in the First/Second Affiliated Hospital of Hainan Medical University. We included patients if they had newly diagnosed hypertension by measured systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg three times on different days, or had suffered from hypertension and were taking blood pressure medication. We excluded patients who took high doses of vitamin C in the previous 10 h; engaged in intense exercise in the previous 24 h period; stood for a prolonged period over 6 h; had a fever or infection ; were menstruating or pregnant; had a history of primary/secondary renal disease, blood system diseases, malignant tumours, connective tissue disease, severe hepatic insufficiency, hyperthyroidism, or chronic heart failure; or had significant proteinuria (>150 m/24 h), which can be induced by all kinds of diseases.All patients who met the diagnostic criteria for hypertension had an SBP ≥ 140 mmHg or a DBP ≥ 90 mmHg in the sitting position after 5 min of rest, as determined by the general practitioner in triplicate; we also included those taking antihypertensive drugs.n = 318) with a UACR of 0–29 mg/g, and ERD (n = 281) with a UACR of 30–300 mg/g.To monitor the UACR, all urine specimens were supplied in the morning. We gauged urine albumin concentration and urinary creatinine with Clinitek Strips . The colour appeared after letting the Clinitek Strips stand for 60 s, and we read the values of microalbuminuria and creatinine via a visual method as compared to the chromatogram Figs.  and 2. FWe measured body mass index (BMI), daytime SBP, and daytime DBP. We recorded sex, age, hypertension duration (HD), diabetes, CHD, and stroke. We diagnosed diabetes using medical history if the patient was under antidiabetic treatment, or based on two or more fasting or 2-h post-meal plasma glucose determinations of ≥7.0 mmol/L (126 mg/dL) and ≥ 11.1 mmol/L (200 mg/dL), respectively. BMI < 24 is represented as the normal range.2) test. Since the UACR is an ordinal scale, we calculated correlations between UACR and various factors  with Spearman’s rho test. To determine the odds ratio (OR) of ERD, we evaluated binary logistic regression models. We performed a binary logistic regression analysis using SPSS software, version 19.0 . We considered p < 0.05 to be statistically significant. The OR indicates the ERD risk of subjects with higher values compared to those with lower values; 95% confidence intervals (CIs) were reported in the multivariate logistic regression models. For the detailed analysis process, we referenced the work of Lavanderos [Continuous variables are presented as the means ± standard deviations (SD); categorical variables are shown as percentages. We performed statistical analysis of quantitative variables using an independent t-test, and we analysed the differences between qualitative variables via the chi-squared (χvanderos . To furtvanderos .p > 0.05). Clearly, the age of onset was higher in the ERD group than in the non-ERD group , and the same as in the DBP . Moreover, the ERD had a longer HD   had ERD. There were no differences in male sex, BMI, SBP, or antihypertensive drug , HD , and DBP . The Spearman correlation between ERD and SBP was not significant.We used Spearman’s rho test to analyse correlations between ERD and related variables Fig. . There w2 test. Compared with no ERD, ERD was associated with age , HD , DBP , SBP  and diabetes status , which were significantly different according to the presence of ERD. There was no significant difference between ERD and sex, BMI, CHD, or stroke (p > 0.05) —we employed the χ2 test, they could not become independent predictors of ERD with binary logistic regression model analysis. Therefore, age, DBP, and diabetes were independent risk factors for essential hypertension in patients who suffered from ERD.To evaluate the weight of the dependent variable and to correct the interaction effect among the above variables, we used a binary logistic regression model for analysis. As outlined in Table p < 0.001). We chose the optimal cut-off value of ≥0.551; the sensitivity and specificity of the optimal cut-off value were 44.5 and 81.1%, respectively . The area under the ROC curve was 0.677 . The Framingham heart study signalled that DBP tends to decline from midlife as a consequence of arterial stiffening , and in The latest research has shown that there is a significant inverse association between BP and temperature; tighter BP control is more necessary in winter than in summer, especially in a colder climate . The ChiAnti-hypertensive drugs were not covered in this article.Our findings imply that common medical comorbidities are associated with ERD in patients with essential hypertension in the Chinese tropics. Age, DBP, and diabetes are independent risk factors of ERD. Early monitoring of UACR, as well as control of blood glucose and DBP, can effectively delay EDR in patients with essential hypertension in the Chinese tropics.


The use of awake prone position concomitant to non-invasive mechanical ventilation in acute respiratory distress syndrome (ARDS) secondary to COVID-19 has shown to improve gas exchange, whereas its effect on the work of breathing remain unclear. The objective of this study was to evaluate the effects of awake prone position during helmet continuous positive airway pressure (CPAP) ventilation on inspiratory effort, gas exchange and comfort of breathing.Forty consecutive patients presenting with ARDS due to COVID-19 were prospectively enrolled. Gas exchange, esophageal pressure swing (ΔPes), dynamic transpulmonary pressure (dTPP), modified pressure time product (mPTP), work of breathing (WOB) and comfort of breathing, were recorded on supine position and after 3 h on prone position.2O. The PaO2/FiO2 was higher in prone compared to supine position . Respiratory rate and minute ventilation decreased from supine to prone position from 20 [17–24] to 17 [15–19] b/min (p < 0.001) and from 8.6 [7.3–10.6] to 7.7 [6.6–8.6] L/min (p < 0.001), respectively. Prone position did not reduce ΔPes  and dTPP . Conversely, mPTP and WOB decreased from 152 [104–197] to 118 [90–150] cmH2O/min (p < 0.001) and from 146 [120–185] to 114 [95–151] cmH2O L/min (p < 0.001), respectively. Twenty-six (65%) patients experienced a reduction in WOB of more than 10%. The overall sensation of dyspnea was lower in prone position (p = 0.005).The median applied PEEP with helmet CPAP was 10 [8–10] cmHAwake prone position with helmet CPAP enables a reduction in the work of breathing and an improvement in oxygenation in COVID-19-associated ARDS.The online version contains supplementary material available at 10.1186/s13613-021-00967-6. The SARS-CoV-2 infection can result in coronavirus 2019 disease (COVID-19). The clinical spectrum of COVID-19 can range from mild to critical forms of acute respiratory distress syndrome  with an associated in-hospital mortality of up to 84% .In the early phase of the pandemic, based on previous, positive studies on the use of prone position in ARDS , 7, inteIn addition to severe hypoxemia, CARDS suffering patients are characterized by an increased respiratory rate and inspiratory effort that in turn can promote patient self-inflicted lung injury (PSILI) . Non-invIn light of the scarcity of data regarding the benefits of awake prone position concomitant to non-invasive respiratory support in CARDS, we aimed to evaluate the effect of awake prone position in helmet CPAP ventilated patients by comparing it to supine position regarding the reduction of inspiratory effort, the improvement in gas exchange and comfort of breathing.2/FiO2 ratio < 300 mmHg under application of a PEEP ≥ 5cmH2O by means of helmet CPAP, displaying bilateral ground glass opacities on chest X-ray or computed tomography (CT) of the lung, admitted to the high dependency unit of the ASST Santi Paolo e Carlo Hospital, Milan, Italy from February to April 2021 were enrolled. Patients were excluded in case they required immediate endotracheal intubation, presented unstable hemodynamics or had a Glasgow Coma Scale < 15.All adults (> 18 years), presenting with a laboratory-confirmed SARS-CoV-2 infection and suffering acute hypoxemic respiratory failure with a PaOThe study was approved by the institutional review board of the ASST Santi Paolo e Carlo Hospital (protocol number 0008332) and informed consent was obtained according to Italian regulations. The study has been registered on ClinicalTrials.gov.At hospital admission every patient received a CT of the lung at atmospheric pressure Fig. .Fig. 1Lu2O through an adjustable mechanical valve and FiO2 was titrated to maintain a SpO2 > 94%.CPAP was delivered through a high flow generator , using a helmet . PEEP within the helmet was maintained between 7.5 and 10 cmHWhen required to improve collaboration, patients received light sedation/analgesia with continuous infusion of morphine titrated between 10 and 20 mg/24 h and/or hydroxyzine titrated between 50 and 100 mg three times a day (150–300 mg/24 h), and haloperidol, in case of delirium, titrated between 0.5 mg four times a day and 2 mg six times a day (2–12 mg/24 h). The sedation was already started at study enrollment in supine position and the level of sedation  was not changed throughout the study, among supine and prone position.At enrollment, a standard balloon catheter was positioned to measure the esophageal pressure  and a single-use padset sensor was placed on chest to measure respiratory volumes . On supine position and after 3 h from the initiation of prone position, arterial blood gas analysis, hemodynamics and esophageal pressure swings were assessed. The tidal volume, respiratory rate and minute ventilation were measured and breathing comfort was evaluated.Patient’s demographic data and the most relevant clinical characteristics were recorded at study entry. HACOR and Charlson score were also computed , 25.To measure the esophageal pressure a standard balloon catheter, consisting of a 108 cm long tube with a 10 cm long walled balloon, was positioned in the lower section of the esophagus. The esophageal catheter was emptied of air and introduced transorally into the esophagus to reach a depth of between 45 and 55 cm measured from the mouth. Subsequently the balloon was inflated with 4 ml of air . The amoThe tidal volume, respiratory rate and minute ventilation were measured by the ExSpiron 1Xi system. This system employs a bioelectrical impedance technique and consists of a single-use PadSet sensor placed on the chest .The presence of dyspnea was evaluated on the basis of the “Borg perceived dyspnea” scale . PatientThe non-invasive work of breathing was objectively evaluated by an independent physician according to a dedicated scale for COVID-19 patients, ranging from 1 to 7, considering the respiratory rate, the presence of nasal flaring and the use of sternocleidomastoid as well as abdominal muscles .Patients were followed until hospital discharge, the occurrence of intubation and/or death were recorded.A quantitative CT scan analysis was performed. The total lung gas volume, weight, and the proportions of the respective inflation compartment  were computed as previously described .Breath patterns were continuously recorded for 3–5 min, then analyzed and the results averaged for each study period.As surrogate measure for the inspiratory effort the esophageal pressure swing (ΔPes), that is the maximal negative inspiratory deflection of esophageal pressure during the inspiration, was used. In addition, the dynamic transpulmonary pressure (dTPP) during the inspiration, that is the maximal difference between the airway pressure and esophageal pressure, the modified pressure time product (mPTP), computed as the product of ΔPes and respiratory rate, and the work of breathing (WOB), calculated as the product of tidal volume, respiratory rate and the dynamic transpulmonary pressure, were used as inspiratory effort surrogate measures , 22. ForThe ventilatory ratio and the estimated dead space fraction were computed according to previously described equations .A sample size of 40 patients was chosen given the mechanistic design of this study, in accordance to similar investigations having studied non-invasively mechanically ventilated patients , 22, 32.2 and had a median of 2 [1–3] comorbidities, of which arterial hypertension was the most prominent (40%). They were admitted to the hospital 6 [5–10] days after symptom onset. Helmet CPAP and prone position were started after 2 [2–4] days from hospital admission. All patients received the first pronation at the time of enrollment and were able to maintain the prone position consecutively for 3 h.Forty patients suffering from CARDS and supported with helmet CPAP were enrolled in the study. The main baseline characteristics are shown in Table 2O with a PaO2/FiO2 ratio of 166 [136–224] mmHg. At admission the quantitative lung CT scan showed a median lung weight and gas volume of 1112 [903–1291] g and 3282 [2698–3721] ml, respectively. The amount of non-aerated lung tissue corresponded to 11 [8–17] %, while the well-aerated tissue was 52 [43–62] % of the total lung tissue . Thirty-four (85%) patients had an improvement in PaO2/FiO2 higher than 20%, corresponding to a mean rise of 138 [95% CI 108–169] mmHg, from supine to prone position. The change in oxygenation from supine to prone position was not related to the oxygenation in supine  and dTPP (p = 0.34)     and sensation of dyspnea, in supine position, did not reveal any subgroups with a higher benefit from proning  required endotracheal intubation and invasive mechanical ventilation, and 4 of these (53%) died within the 28 days ensuing study inclusion.This study, evaluating the effect of awake prone position in CARDS patients treated with helmet CPAP showed that prone position was associated with: (1) a reduction in the work of breathing, (2) an improvement in oxygenation in 85% of the patients, and (3) a reduced sensation of dyspnea in all patients.COVID-19 pneumonia is characterized by the presence of hypoxemia, bilateral lung infiltrates and microvascular thrombosis within the lung vasculature, contributing to a profound ventilation–perfusion mismatch , 34. ThuIn addition to prone position, non-invasive respiratory support, such as HFNC, helmet CPAP and pressure support have been applied both to ameliorate gas exchange and to reduce the inspiratory effort. The combination of prone position and non-invasive respiratory support has been reported to ameliorate the oxygenation in the majority of the studies , 14, 16.Several beneficial mechanisms associated with prone position previously described both in acute respiratory failure and in ARDS, could be also found in patients suffering CARDS . In lineIn addition to hypoxemia, CARDS is characterized by vigorous breathing efforts and a high respiratory rate . The strTo date, no data exists on the effects of awake prone position with helmet CPAP on the work of breathing in CARDS. In the present study the inspiratory effort exerted by the respiratory muscles assessed by means of the changes in esophageal pressure and dynamic transpulmonary pressure did not vary between supine and prone position, while the modified pressure time product and work of breathing significantly decreased. These beneficial effects were related mainly to a reduction in respiratory rate, while the tidal volume did not change, thus arguing against a significant change in pulmonary viscoelastic properties, or alveolar recruitment, and diaphragm position and function, between supine and prone position. Furthermore, the reduction in work of breathing was correlated to the amount of work of breathing in supine position, suggesting a higher utility of prone position in patients presenting elevated inspiratory efforts .It has been reported that between 15 and 31% of spontaneously breathing and non-invasively respiratory supported patients suffering COVID-19 subjectively perceive dyspnea , 44. In Prone position delivered concomitantly to helmet CPAP thus presents unique advantages regarding improvements in gas exchange and a reduction in the work of breathing, while its impact on endotracheal intubation and invasive mechanical ventilation requirements nevertheless remain unclear , 23.Possible limitations of this study are: (1) long term effects of prone position and persistency of effects after returning to supine position are unclear, (2) trans-diaphragmatic pressure was not measured, thus the possible effect of expiratory muscle activity on the measured pressure cannot be assessed, (3) due to the study design, effects of prone position on clinically relevant outcomes could not be evaluated, (4) prone position was not randomized.In conclusion, awake prone position in addition to helmet CPAP may be offered to CARDS patients to improve oxygenation and reduce WOB. However, a strict clinical evaluation should prevail, to prevent delays in endotracheal intubation and provision of invasive mechanical ventilation.Additional file 1. Tables S1–S6, Annex S1 and Figures S1–S15.


Renal dysfunctions are associated with increased morbidity and mortality in sickle cell disease (SCD). Early detection and subsequent management of SCD patients at risk for renal failure and dysfunctions are essential, however, predictors that can identify patients at risk of developing renal dysfunction are not fully understood.In this study, we have investigated the association of 31 known kidney dysfunctions-related variants detected in African Americans from multi-ethnic genome wide studies (GWAS) meta-analysis, to kidney-dysfunctions in a group of 413 Cameroonian patients with SCD. Systems level bioinformatics analyses were performed, employing protein-protein interaction networks to further interrogate the putative associations.A1CF-rs10994860 (P = 0.02020), SYPL2-rs12136063 (P = 0.04208), and APOL1 (G1)-rs73885319 (P = 0.04610) are associated with eGFR; and WNT7A-rs6795744 (P = 0.03730), TMEM60-rs6465825 (P = 0.02340), and APOL1 (G2)-rs71785313 (P = 0.03803) observed to be protective against micro-albuminuria. We identified a protein-protein interaction sub-network containing three of these gene variants: APOL1, SYPL2, and WNT7A, connected to the Nuclear factor NF-kappa-B p105 subunit (NFKB1), revealed to be essential and might indirectly influence extreme phenotypes. Interestingly, clinical variables, including body mass index (BMI), systolic blood pressure, vaso-occlusive crisis (VOC), and haemoglobin (Hb), explain better the kidney phenotypic variations in this SCD population.Up to 61% of these patients had micro-albuminuria, 2.4% proteinuria, 71% glomerular hyperfiltration, and 5.9% had renal failure. Six variants are significantly associated with the two quantifiable phenotypes of kidney dysfunction : This study highlights a strong contribution of haematological indices (Hb level), anthropometric variables , and clinical events  to kidney dysfunctions in SCD, rather than known genetic factors. Only 6/31 characterised gene-variants are associated with kidney dysfunction phenotypes in SCD samples from Cameroon. The data reveal and emphasise the urgent need to extend GWAS studies in populations of African ancestries living in Africa, and particularly for kidney dysfunctions in SCD. Sickle Cell Disease (SCD) is a monogenic disease with high prevalence and high mortality rates in Africa. Globally, SCD is estimated to affect more than 300,000 births per year, with nearly two-thirds occurring in sub-Sahara Africa . CamerooApolipoprotein L1 (APOL1) and Heme oxygenase 1 (HMOX1) genes have been associated to chronic kidney disease  for rs60910145, rs73885319 and rs71785313, and HMOX1 for rs3074372 and rs743811, relevant to populations of African ancestry  have been conducted in many non SCD-affected populations . Furtherancestry , e.g., SSeveral studies, including a previous study from our group , have shThe study was performed following the Declaration of Helsinki. This study was approved by the Faculty of Health Sciences Human Research Ethics Committee of the University of Cape Town, South Africa (HREC REF: 661/2015), and the National Ethics Committee of the Ministry of Public Health, Yaoundé, Republic of Cameroon (No. 193/CNE/SG/10). Patients older than 18 years self-consented into the study and informed consent was given by the parents or guardians for participants younger than 18 years old with a requirement for children older than 7 years to also sign assent forms.hydroxycarbamide treatment. Community-based recruitments were also conducted through two SCD patients’ associations who were engaged for collaboration. Additional patients were subsequently recruited during the SCD patient associations’ monthly meetings. No incentive was provided for participation in the study. Socio-demographic and clinical events were collected by means of a structured questionnaire administered to parents/guardians or adult patients. Body mass index (BMI) and blood pressure (BP) were also measured. Patients’ clinical records were extracted from their medical records covering the past 3 years. These clinical records include blood transfusion history, the occurrence of vaso-occlusive crisis (VOC) and hospitalisation rates per year.Cameroonians living with SCD were prospectively recruited at the Yaoundé Central Hospital and Laquintinie Hospital in Douala, between January 2010 and December 2012. Only patients older than 2 years of age who had not received a blood transfusion in the past 6 months were included. None of the patients were receiving Complete blood counts and foetal haemoglobin (HbF) quantifications were conducted during hospital visits. Two methods of HbF detection were employed in this study for patients: initially using the alkali denaturation test in 55% of the cohort and subsequently High-Performance Liquid Chromatography when it became available at the haematological laboratory of the Centre Pasteur of Cameroon (CPC).2, renal hyperfiltration as an eGFR > 130 ml/min/1.73 m2 for women and >140 ml/min/1.73 m2 for men, and normal filtration as an eGFR between 90 ml/min/1.73 m2 and 130/140 ml/min/1.73 m2  at CPC, and Genotype analyses were performed at the Division of Human Genetics, University of Cape Town, South Africa.HBB, followed by a digestion with DdeI restriction enzyme on the PCR product  to amplify a 770 bp segment of  product .HBB cluster were amplified using published primers and methods to analyse the HBB haplotype background (Five restriction fragment length polymorphism (RFLP) sites in the ckground .HBA1/HBA2 deletion was successfully screened using the expand-long template PCR as previously published -rs60910145, APOL1 (G1)-rs73885319, APOL1 (G2)-rs71 785313, HMOX1-rs3074372, HMOX1-rs743811, were genotyped with the iPLEX Gold Sequenom Mass Genotyping Array. Thereafter, the validation of the genotyping results was done by Sanger sequencing using BigDye terminator mix in 10% subset of sample (Twenty-six African American specific kidney dysfunction-related gene variants were genotyped in this SCD cohort after being mapped to 53 single nucleotide polymorphisms (SNPs) identified in a GWAS meta-analysis of kidney diseases . Five adnsidered . Thus, af sample .p-values (P) for Bonferroni multiple corrections and gene functional annotations were retrieved from the Ensembl database , socio-demographic and clinical variables, and 31 known kidney dysfunction-related variants among this group of SCD patients. First, to ensure genotypic quality of the data, we ran PLINK 1.9 , performdatabase .n = 168) of patients had (3 VOC per year and 28.1% (n (=114) had 2 hospitalizations hospitalisations per year. All participants were homozygous HbSS, Benin being the most prevalent . It is worth noting that, in this study, we used the modified annotation protocol suggested by HBA1/HBA2 deletion, respectively.A total of 413 SCD steady state Cameroonian patients were included in the study. The participants’ characteristics are described in For the genotype dataset and two renal phenotypes under consideration, a prior QC and value adjustment processes were performed, respectively. Only 18 out the 31 genetic variants . Isolated hyperfiltration was present in 25.8% (n = 105) of patients, while 41.5% (n = 169) and 2.2% (n = 9) were experiencing glomerular hyperfiltration with micro- and macro-albuminuria, respectively. Haemoglobin, HbF, MCV, platelet, lymphocytes, and granulocytes presented highly significant p-values and positive correlation with eGFR, explaining some proportion of eGFR variations (P = 0.04674) and VOC frequencies (P = 0.02802), explaining 40.55 and 21.73% of the eGFR variation, respectively , APOBEC1 complementation factor (A1CF-rs10994860) and Apolipoprotein L1 (APOL1 (G1)-rs73885319) are significantly associated with eGFR with respective P-values of 0.04208, 0.02020, and 0.04610. A1CF-rs10994860 is protective against renal dysfunction -rs73885319 to prevalent hyperfiltration and ultimately to the renal dysfunction .Three genetic variants: function . On the Protein Wnt-7a (WNT7A-rs6795744), Transmembrane protein 60 (TMEM60-rs6465825), APOL1 (G2)-rs71785313 with P-values of 0.03730, 0.02340, and 0.03803, respectively. With knowledge of the crude-albuminuria distribution as shown in APOL1 provides a protective effect against prevalent micro-albuminuria  deletions decrease crude-albuminuria value by 0.12686 and 0.24732 ml/min/1.73/m2, respectively. Though this phenotype level change is negligible due to the effect size, it can be essential for crude-albuminuria extreme values .Three genetic variants were also identified to be significantly associated with crude-albuminuria: uminuria . These rP = 0.0813e–2 and 0.0203, respectively, accepting the alternative hypothesis that the HbF level median is greater than 9.3%, the lower bound of the HbF level confidence interval (P = 0.01007) under the null hypothesis that odds ratio is equal to 1.HbF is a major SCD modifier, which is known to modulate the SCD phenotype , to amelinterval , which iinterval . FurtherUsing the eGFR- and crude-albuminuria-based logistic regression model, we compute areas under the receiver operating characteristic (ROC) and Precision-Recall (PR) curves, as well as accuracy to identify the best phenotype proxy for predicting kidney dysfunction in Cameroonian SCD patients. Different areas are shown in APOL1, SYPL2, WNT7A, IGFBP5, UNCX, NFKB1, UMOD, and SKIL. Three gene variants within this sub-network, namely APOL1 (G1)-rs73885319, as well as APOL1 (G2)-rs71785313, WNT7A-rs6795744, and SYPL2-rs12136063, have been identified to influence variation in renal dysfunction phenotypes in SCD patients. These variant genes are connected to NFKB1, identified to be essential or a hub based on the network centrality measures within the sub-network via some specific intermediate genes  in which WNT7A, revealed to be likely implicated in SCD patient renal dysfunction, is involved. This process is possibly involved in the development of VOC complications, resulting in proteinuria and glomerular hyperfiltration, and ultimately in kidney damage.We analysed how interactive genes from knowledge-based Protein-Protein Interaction (PPI) interacted with the 18 genes used in different analyses, focusing specifically on six genes identified to be associated with kidney dysfunction phenotypes. Mapping these 18 genes to a comprehensive human Protein-Protein Interaction (PPI) network , we idente genes , followite genes . This NFThis is the first study to investigate the relevance of kidney dysfunction-related variants identified through a GWAS meta-analysis as well as functional enrichment and protein-protein interaction network analyses in SCD patients. The results highlighted the high prevalence of micro-albuminuria as presented in a previous study in Cameroon by Geard in 2017 . This prThe prevalence of glomerular hyperfiltration was similar to the 76% found among SCD children in the United States , but higA1CF-rs10994860 with reduced risk of renal dysfunction for two allele changes and a protective effect against prevalent glomerular hyperfiltration; It confers about 2 times more protection to SCD individuals with one allele change or heterozygous genotype as compared to a patient with no copy, and explaining only 0.18% of status change to the glomerular hyperfiltration or renal dysfunction. However, SYPL2-rs12136063 as well as APOL1 (G1)-rs73885319 conferred increased risk of progressing to the renal dysfunction or to prevalent glomerular hyperfiltration, explaining 11.04 and 0.97% of status changes, respectively. Like eGFR, three gene variants are also identified for crude-albuminuria: WNT7A-rs6795744, TMEM60-rs6465825, and APOL1 (G2)-rs71785313 providing a protective effect against prevalent micro-albuminuria , which is eliminated exclusively by glomerular filtration . HoweverAPOL1 gene variants: (G1)-rs73885319 and (G2)-rs71785313, shown to be strongly associated with renal dysfunction in SCD patients, as well as A1CF-rs10994860, SYPL2-rs12136063, WNT7A-rs6795744, and TMEM60-rs6465825 in Cameroonian SCD patients. Though the protein-protein interaction network and enrichment analyses have revealed the sub-network, which may influence extreme phenotype levels, enriched with the cartilage condensation process, which likely contributes to the development of VOC complications and possibly to the renal dysfunction, these gene variants only explain a small proportion of status changes. The results also suggest that haematological indices, clinical events, anthropometric and socio-demographic variables, are major contributors to the pathophysiology of kidney dysfunction in SCD. This elicits the need for further research to investigate new genetic biomarkers which account for kidney dysfunction risk factors in SCD patients in the African setting.This study has replicated The data supporting the findings of this study are available from the corresponding author upon reasonable request.The studies involving human participants were reviewed and the study was performed following the Declaration of Helsinki. This study was approved by the Faculty of Health Sciences Human Research Ethics Committee of the University of Cape Town, South Africa (HREC REF: 661/2015), and the National Ethics Committee of the Ministry of Public Health, Yaoundé, Republic of Cameroon (No. 193/CNE/SG/10). Patients older than 18 years self-consented into the study and informed consent was given by the parents or guardians for participants younger than 18 years old with a requirement for children older than 7 years to also sign assent forms. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.AW, VN-B, KM, TM, and GA conceived and designed the experiments. VN-B, SB, KM, and TM performed the experiments. VN-B, SB, RE, FN-S, TM, KM, and AW needed patient recruitment, samples, and clinical data collection. GM, VN-B, VN, KM, and AW processed and analysed the data. AW, GA, GM, and VN contributed to reagents, materials, and analysis tools. VN-B, KM, GM, and AW wrote the manuscript. GM, VN-B, SB, KM, TM, RE, VN, FN-S, GA, and AW revised and approved the manuscript. All the authors approved the manuscript and agreed to be accountable for all aspects of the presented work.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.


Considering the Kazakh-Chinese people have the highest prevalence of hypertension in Xinjiang, and the High Blood Pressure-Health Literacy (HBP-HL) has not been included in the study of HRQoL. The synergistic effects and the potential mechanism HBP-HL, self-management behavior, therapeutic adherence, self-efficacy, social support on HRQoL remain unclear. This study aimed to introduce the HBP-HL, and develop a structural equation model (SEM) to identify the factors influencing of the HRQoL among Kazakh hypertensive patients.Health-Related Quality of Life (HRQoL) of hypertensive patients is not only affected by the disease itself but also by some subjective factors. Low health literacy is prevalent among ethnic minoritiesp ≤ 0.05 was taken as significant.The data was obtained by questionnaire survey and physical examination in 2015. Patients with hypertension were recruited through random cluster sampling in Kazakh settlements in Xinjiang. Firstly, the blood pressure was measured. Then the one-for-one household interviews were conducted by Kazakh investigators. The questionnaires regarding HBP-HL, HRQoL, self-management behavior, therapeutic adherence, self-efficacy, and social support were used to collect data. Finally, SEM was constructed, and 2/df = 2.078, AGFI = 0.944, GFI = 0.968, CFI = 0.947, IFI = 0.949, RMSEA = 0.046). The model indicated that the HBP-HL has the highest correlation with HRQoL, following with self-management behavior, social support, and self-efficacy.The data was analysed by SPSS18.0 and AMOS18.0 software. 516 Kazakh hypertension patients were recruited, and 94.4% of them had a relatively low HBP-HL score. The mean standardized scores of HRQoL, self-management, therapeutic adherence were poor; they were 63.5, 66.2, and 64.4, respectively. But 96.1% and 98.3% of the participants had high levels of self-efficacy and social support. The SEM of the HRQoL had a good overall fit (χLow HBP-HL is a major influenced factor of HRQoL among Kazakh hypertensive patients. Future programs should consider HBP-HL as the breakthrough point when designing targeting intervention strategies. Hypertension is the most significant risk factor for cardiovascular disability and death that affect a high proportion of people worldwide. Especially in low- and middle- income countries, for example China, Brazil, India and Mexico, the economic burden of cardiovascular disease (CVD) and hypertension contributed together 50% of the total number of economic estimates identified . The ChiHealth-related Quality of Life (HRQoL) refers to how well a person functions in their life and his or her perceived wellbeing in physical, mental, and social domains of health . HRQoL hHRQoL of hypertensive patients is not only affected by the disease itself but also by some subjective factors such as health literacy, self-management and psychological factors.High Blood Pressure-Health Literacy (HBP-HL) refers to the ability of hypertensive patients to acquire, understand, and deal with hypertension-related knowledge as well as the medical services needed to control diseases . PreviouSelf-management is a dynamic process in which individuals actively apply cognitive and behavioral strategies to manage their own thoughts, emotions and behaviors . EffectiTherapeutic adherence refers to patients’ compliance with medical conventions and active adoption of health-promoting behaviors . StudiesSelf-efficacy is an important determinant of intention and behavior. On the one hand, self-efficacy can predict HRQoL, and low self-efficacy usually leads to low HRQoL . On the An increasing number of studies demonstrate that social support is significantly related to self-efficacy, the interaction between the two factor can predict the HRQoL, and is one of the important mediating factors in determining the level of HL and self-management behavior , 38. ForBased on the above mentioned existing literatures, HBP-HL, self-management behavior, therapeutic adherence, self-efficacy, social support and HRQoL are related and have complex relationships. However, their synergistic effects on HRQoL and the potential mechanism remain unclear. Only one article using the structural equation model (SEM) explored the relation between health literacy and HRQoL in hypertension patients and found that enhancing the level of health literacy and self-management might improve the HRQoL of patients with hypertension, but the health literacy is universal and lack of pertinence . TherefoThe Kazakh hypertension patients in the rural area of Xinjiang were recruited through random cluster sampling in 2015. First, based on the census data of Xinjiang, a list of the main Kazakh residence areas in Xinjiang was generated; one research site (from Urumqi counties) was randomly selected from this list. Second, five towns/town ships were randomly selected from the selected Urumqi counties. In the selected towns, only Kazakh residents who were diagnosed with hypertension at the age of 18 years or older were eligible for this study. Finally, hypertensive patients diagnosed in Kazakh settlements in Baiyanggou, Toli Ranch, Gangou Township, Xiaoquzi, and Sardanban Townships in Urumqi County, Xinjiang who met the following inclusion criteria were recruited: (1)18 years old or older; (2) Meeting the criteria for the diagnosis of essential hypertension, systolic blood pressure (SBP) ≥140 mmHg, and / or diastolic blood pressure (DBP) ≥90 mmHg ; (3) BloA general rule of thumb is that models with 5 or more items were analysed, at least 500 observations sample were needed . Then adThe one-for-one household interviews were conducted by Kazakh investigators. The questionnaires were further checked for missing data. If any missing information was identified, further information was collected via phone call to the numbers provided by the participants or one more visit to the participants’ house. However, a group of participants have missing data; they were unreachable later on.The survey collected general information  from the participants. HBP-HL, HRQoL, self-management behavior, therapeutic adherence, self-efficacy, and social support were also measured. All these scales were assembled into one questionnaire.consists of 15 items in 5 dimensions , which was developed and validated by Kim MT, et al. in 2012 . AccordiThe QLICD-HY includes 30 items, it was divided 4 dimensions , and was used to evaluate HRQoL for patients with hypertension, which was developed and validated by Wan C, et al. in 2012 . The scoThe scale includes 33 items, which was developed and validated by F Zhao, Q, et al. in 2012 . The hig. Cronbach’s α of the overall scale was 0.86, and the test-retest reliability was 0.96.consists of 25 items, which was developed and validated by Tang H, et al. in 2011, and was used to assess the compliance of hypertension patients in recent months. A higher scores mean better therapeutic adherenceSelf-efficacy for managing chronic disease was assessed by the Stanford 6-item Scale, which was developed and validated by Lorig KR, et al. in 2001 . The sca10 items with 3 dimensions and the total scores are the sum of each item, which was developed and validated by Xiao SY, et al. in 1994 . It has All original scale scores were standardized to make the comparable standardized scores =  × 100, with the exception of QLICD-HY.The AU-621  electronic sphygmomanometer  was used to measure the blood pressure of the right upper limb of the patient. The AU-621 was calibrated every 6 months. Before the measurement, the participants were asked to rest for at least 5 min. The sphygmomanometer’s cuff was placed on the right upper limb elbow of the patient two consecutive times, at least 30 s apart, and averaged.P ≤ 0.05 indicates statistical significance. The following indexes were used to evaluate the goodness-of-fit of hypothesized models:χ2 /df < 3, Root Mean Square Error of Approximation (RMSEA < 0.08), Goodness-of-fit Index (GFI > 0.90), Adjusted Goodness-of-fit Index (AGFI> 0.90), Incremental fit Index (IFI > 0.90), Comparative fit Index (CFI > 0.90) [All statistical analysis was performed using SPSS18.0 and AMOS18.0 software. The continuous variables  were reported as mean ± standard deviation. The categorical variables  were reported in percentage or composition ratio. The path analysis model was used to create the structural equation model (SEM) for predicting the HRQoL of Kazakh hypertension patients with hypertension .  > 0.90) .The study was conducted in 2015. Overall, 550 patients who met the eligibility criteria, in the selected townships from the rural area of Xinjiang. Among them, 24 invalid questionnaires (with incomplete data) were excluded; 516 questionnaires were valid, with a return rate of 93.82%.Among the 516 included Kazakh hypertension patients in the rural area, 239 were male (46.3%), and 277 were female (53.7%). The mean age of the participants was 58.14 ± 12.05 years old. The majority of the participants were farmers and herdsmen (87.60%). In addition, around 70% participants only attended junior high school or below, and about two-thirds of the participants have an annual family income of less than RMB 10,000 yuan (75.6%).The average SBP was 156.26 ± 24.40 mmHg, and the average DBP was 87.55 ± 14.73 mmHg for the participants , the social function (66.1 points), the hypertension specific module (61.5 points), and the physical function 57.2 points). The standardized HBP-HL score was 24.2 points. Overall, 487 patients (94.4%) lacked HBP-HL, 7 patients (1.4%) had a medium level of HBP-HL, and only 22 patients (4.2%) were considered to be sufficient in HBP-HL. The standardized scores of self-management behavior and therapeutic adherence were 66.2 points and 64.4 points, respectively. The standardized score of self-efficacy was 64.0 points, including 20 cases (3.9%) with low self-efficacy, 422 cases (81.8%) with medium self-efficacy, and 74 cases with high self-efficacy (14.3%). The standardized social support score was 76.0 points, including 1 case (0.2%) with low social support, 8 cases (1.6%) with medium social support, 172 cases (33.3%) with high social support, and 335 cases (64.9%) with very high social support (see Table  points. P < 0.001). Based on the results mentioned above, and the literature, the initial hypothesis model (M1) of HRQoL, HBP-HL, self-management behavior, therapeutic adherence, self-efficacy, and social support of Kazakh hypertension patients in rural areas were constructed  and literature data, the paths that did not reach a significant level and were unreasonable, were deleted. Thus, the paths between social support and self-management behavior, social support and self-efficacy, HBP-HL and self-management behavior, self-management behavior and therapeutic adherence, HBP-HL and therapeutic adherence, and therapeutic adherence and HRQoL, were deleted. After optimization, the HRQoL impact factor model M2) had a better fitting index than the hypothesis model (M1). The optimized model is shown in Fig.  had a beWe further evaluated the fitting effect of the path analysis model for HRQoL. When a sample size of 500 was amassed, the model reached the standard, and the fitting indicators met the requirements; this means the model fits well  and meaningful  [ points [Our results showed that the majority of the patients, up to 94% of them, lack HBP-HL. They are unable to read or understand the instructions of the prescription drugs, or can’t communicate effectively with doctors. Research discussed that patients with high HBP-HL have better hypertension control and better HRQoL. The low health literacy causes a 10-year increased risk of cardiovascular disease . FurtherThe standardized score of self-management behavior among the Kazakh hypertension patients was at a medium-low level (66.23 points), and it was much lower than the score among hypertension patients in Guangdong, China (86.01points) . PotentiExtensive research indicates that health literacy plays an important role in promoting the HRQoL , 62, 63.. Recent studies strongly suggested that the higher the level of health literacy, the better the HRQoL [Our study that introduced hypertension-specific health literacy (HBP-HL) instrument, further explored the direct and indirect effect of factors affecting HRQoL, which might lead to better interventions aimed at ameliorating HRQoL of Kazakh hypertension patients. The indexes of the model reached the adaptation criteria, and the fitting was good. The effects of HBP-HL, social support, self-efficacy, and self-management behavior on HRQoL are positive and statistically significant. HBP-HL has the biggest direct effect on HRQoL. The results of this study are consistent with worldwide results. For example, Tartavoulle study showed that social support had a positive effect on the path of HRQoL . The stuhe HRQoL . These sThere is a positive correlation between therapeutic adherence and HRQoL, however, the path of therapeutic adherence and HRQoL is not statistically significant in SEM. This result is not accordance with the study by Mollaoğlu M, et al. , but it Some possible limitations of this study should be noted. First, a cross-sectional design limits the causal conclusions that we can draw, and the causal relationship should be confirmed in further prospective studies. Second, Kazakh hypertensive patients were recruited from the same region, which might have limited the generalizability of the study results. Thus, further efforts should be made using multiple strategies to make the sample more comprehensive in future.HRQoL, HBP-HL, and self-management behavior of Kazakh hypertension patients in rural areas are poor. The structural equation model of HRQoL works well. HBP-HL has the largest impact on the HRQoL in the model. The results highlight that researchers should give a priority to evaluate patient’s HBP-HL before intervention. Next, tailored interventions are implemented for patients, and ultimately it will contribute to control blood pressure and improve patients’ HRQoL.


Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development.To identify genetic variants associated with kidney injury in patients with obstructive uropathy.We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase.2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues.Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 mCDH12 gene was the most clear (p = 7.5 × 10–7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization.Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 as a candidate gene for kidney injury in PUV.This study identified CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra . This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.We found that variants of the  CDH12 increase the risk of kidney injury in patients with posterior urethral valves. This is the first time that this gene has been reported on in this context. Our study provides interesting new information about pathways involved in obstructive uropathies and important leads for further research.We found that variants of  PUV affects only boys and occurs in one in 4000 live male births Knowledge about the molecular pathways involved in the pathophysiology of kidney injury in congenital obstructive uropathy has mainly been derived from neonatal rats and mice with induced complete unilateral ureteral obstruction (UUO). Kidney response to experimental UUO involves oxidative stress, monocyte infiltration, uncontrolled apoptosis of tubular cells, fibroblast accumulation, and increased deposition of extracellular matrix Most of the genetic studies described above focused on candidate genes, but a hypothesis-generating approach, such as a genome-wide association study (GWAS), may shed new light on pathways involved in the development of kidney injury in obstructive uropathy. In addition, genetic variants associated with kidney function decline could be used in prognostic modeling approaches to better predict long-term kidney function. As no such studies have been conducted so far, the aim of this study was to perform a GWAS for kidney injury in obstructive uropathy. We included patients with PUV and UPJO under the assumption that similar genetic variants are associated with kidney function decline in both obstructive uropathies.22.12.1.1AGORA  is a database and biobank in the Radboudumc  collecting questionnaire data, blood/saliva samples, and phenotypic information from patients with congenital malformations and their parents 2.1.2For replication purposes, we included patients treated in the Isala clinics, Zwolle or University Medical Center (UMC), Groningen, The Netherlands. Owing to registration issues, we were only able to identify patients treated in 2002 or later.2.1.32) was enrolled between 2010 and 2012 and followed until 2018 at 39 pediatric nephrology centers in eight European countries. We selected children with PUV as the underlying diagnosis for whom genotype data, longitudinal eGFR measurements, and information on treatment changes were available.The European replication sample was derived from the 4C study 2.22, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. In the European replication sample, the primary endpoint was kidney injury defined as a composite of 50% loss of eGFR, eGFR <10 ml/min/1.73 m², or kidney replacement therapy .The medical files for the Dutch patients were scrutinized for information about kidney function and for clinical descriptions. Patients were defined as having signs of kidney injury in case of dialysis, nephrectomy, kidney transplantation, eGFR <60 ml/min/1.73 m2.3The Dutch samples were genotyped by deCODE Genetics  using Infinium OmniExpress bead chips or Global Screening arrays . European replication samples were genotyped using Illumina Infinium 2.5M-8 microarrays. Quality control and imputation are described in the Supplementary material.2.4www.cog-genomics.org/plink/1.9/). Analyses were adjusted for the first four principal components to account for population stratification. We repeated the analyses with imputed genotypes for the area showing an association signal and visualized the results in LocusZoom (http://locuszoom.org/). For single-nucleotide polymorphisms (SNPs) passing the threshold of p = 1 × 10–5, we examined the associations separately for PUV and UPJO patients to verify the assumption of similar genetic variants associated with kidney function decline in these phenotypes, performed Kaplan-Meier and Cox regression analyses to include 130 patients with <5 yr of follow-up, and checked results in the replication samples. In additional analyses, we adjusted the Cox regression analysis for the most significant SNP in the PUV subgroup of the discovery sample for the possible prognostic factors from https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman/revman-5-download) using the inverse-variance method and a random-effects model.We excluded patients with <5 yr of follow-up from our discovery sample and compared patients with and without signs of kidney injury within 5 yr after surgery using the PLINK whole-genome data analysis toolset (2.5www.ebi.ac.uk/gxa/home) in February 2019 to see which tissues CDH12 is expressed in We used the Expression Atlas (www.proteinatlas.org/) in February 2019 We used the Protein Atlas  in February 2019 to see whether the SNPs that we identified are expression quantitative trait loci (eQTL) influencing expression of CDH12.Finally, we checked the GTEx portal  participated . We excluded 40 patients who did not have their first surgery (pyeloplasty or PUV resection) in the Radboudumc, four patients with end-stage kidney disease before surgery, and five patients without follow-up information. Of the remaining 535 samples, 12 failed genotyping and 36 failed sample quality control . Genotyping information for 487 patients was available for the discovery analyses .3.1.2For replication purposes, we identified 131 patients treated in the Isala clinics and 270 in UMC Groningen. Of these patients, 87 (66%) and 164 (61%), respectively, participated. We excluded three patients without follow-up information and 26 samples that failed quality control . We used genotyping information for 222 patients in the replication analyses.3.1.3The European replication sample was derived from a study including 704 children 3.2–5; p = 7.5 × 10–7). The other signals were from chromosomes 8  and 13 . Genotype frequencies were in Hardy-Weinberg equilibrium in controls , except for rs2957086 (p = 0.04). After imputation, rs6874819 remained the SNP with the strongest signal.We excluded 130 patients with <5 yr of follow-up and compared 141 patients with and 216 patients without signs of kidney injury within 5 yr after surgery. Six SNPs in three loci reached suggestive genome-wide significance (p < 1 × 10n = 235) and UPJO (n = 122) groups separately showed that the signals on chromosomes 5 and 13 were stronger in the PUV group, while the signal on chromosome 8 was stronger in the UPJO group (Supplementary Table 2).Subgroup analyses for the six SNPs in the PUV .In an additional analysis, we adjusted the Cox regression analyses for rs6874819 among the discovery PUV patients for the possible prognostic factors from 3.3GA 1.8, p = 0.11; HRGG 2.4, p = 0.40; GA 1.8, p = 0.11; HRGG 3.1, p = 0.04; Of the 222 Dutch replication samples, 78 were genotyped on the same platform as the discovery samples, while 144 were genotyped on the Global Screening array. Only two of the six suggestive SNPs (rs6874819 and rs2148707) were directly genotyped with the latter, so we used imputed genotypes for the others. We performed Kaplan-Meier and Cox regression analyses for 102 PUV and 120 UPJO patients, of whom 34 and 65, respectively, developed signs of kidney injury within 10 yr after surgery. Although not statistically significant, the associations of the SNPs on chromosome 5 were in the same direction as in the discovery sample for PUV patients . All studies in the Expression Atlas CDH12 shows the highest expression in human adult brain, whereas it is not expressed in adult kidney. The NIH Epigenomics Roadmap (http://www.roadmapepigenomics.org/) showed that CDH12 is expressed in human fetal kidneys CDH12 expression, whereas adult brain tissue does. Fetal kidneys showed expression levels comparable to those in adult brain. Transcriptomic analyses of 15 human embryonic tissues and organs 33–55 d after conception revealed that CDH12 is widely expressed in embryonic tissues, with highest levels in retinal pigmented epithelium, followed by the kidneys Visualization of the association results using imputed genotypes for the discovery sample in LocusZoom Immunohistochemical staining confirmed CDH12 expression in the fetal retina and kidney. At approximately 12 wk after conception, CDH12 was expressed in the ureteric bud, the precursor of the collecting duct, and in early condensates, where the ureteric bud induces mesenchymal cells to condense and start to form epithelia. In addition, CDH12 expression was localized to proximal tubules within the developing human kidney at 12 and 15 wk after conception .Fig. 3ImCDH12 in the adrenal gland. Several SNPs in the associated area resulted in higher expression of CDH12 . Two of these SNPs were directly genotyped in our samples. The CC genotypes resulted in statistically significantly higher expression of CDH12 in the adrenal gland according to the GTEx portal, and were associated with time to the development of signs of kidney injury in our data (Supplementary Table 3).The GTEx portal showed that the associated area was an eQTL for 4CHD12 as a gene potentially involved in the development of kidney injury in patients with obstructive uropathies. This result was seen among PUV patients, but not clearly among UPJO patients, possibly because of the different timing of PUV and UPJO development, or because both kidneys are exposed to high urinary pressure in PUV, whereas generally only one kidney is in UPJO.We identified for the first time CDH12 despite our small and nonhomogeneous sample suggests that it may be an important factor. This was confirmed by detection of the signal in the European PUV replication sample, which was a very different patient group. Although the primary results for rs6874819 were not statistically significant at a genome-wide level, the result for the allelic meta-analysis among PUV patients was. In addition, all results show the same direction of effect. The fact that our association signal is located in an eQTL and that CDH12 is expressed in fetal kidneys further enhances the reliability of our finding.The association signal on chromosome 5 among PUV patients was the most clear and the other suggested SNPs were not associated with kidney injury in the Dutch replication sample. Detection of the signal for In an additional analysis, we adjusted our analyses in the European replication sample for eGFR at study entry, which changed the effect of rs6874819 only slightly. Since eGFR at study entry correlates with GFR at birth, this finding suggests that the effect of rs6874819 on kidney injury we observed is not sufficiently explained by effects of CHD12 on fetal kidney development. Our hypothesis is that the damage arises in the period when affected kidneys are exposed to elevated pressure, which is from early fetal development up to the postnatal period preceding surgery. The damage may not be severe enough to display signs of kidney injury at that point in time, but as the patients grow and need greater filtration capacity, the affected kidneys may fall short and the previously acquired damage begins to show.CDH12 is a member of the neural cadherin (N-cadherin) gene family, which encode transmembrane calcium-dependent homophilic adhesion receptors that play an important role in cell recognition and sorting during development CDH12 has not been described in relation to kidney development before, but it is involved in the progression of several cancers MCP1 gene expression in these kidney tissues, which is in line with the suggestion by Diamond et al CDH12 is a target of MCPIP A drawback of our study is the relatively small sample size. We may have missed less strong but still important associations because our discovery analyses only had enough power (80%) to detect variants with an allele frequency of 30% and genotype relative risk of 2.7 or higher under a multiplicative disease model. In addition, use of a more homogeneous cohort of, for example, only prenatally detected PUV, or a more homogeneous endpoint, such as the eGFR decrease in the first yr of life, may have been better. Instead, we used any sign of kidney injury as the outcome to achieve larger numbers, but did not have enough patients with specific signs to perform separate analyses for subgroups. Nevertheless, when we performed additional analyses that excluded one kidney functioning at <45% from the definition of signs of kidney injury (the diagnosis that explains why more UPJO than PUV patients have signs of kidney injury), results for PUV patients in the discovery sample were very comparable to the initial results. Using a more homogeneous cohort would result in patients being more comparable for other factors that could influence the prognosis of PUV 5CDH12 variant, which facilitates monocyte infiltration and the development of progressive kidney fibrosis and exacerbates kidney injury. This hypothesis is in line with the importance of monocyte infiltration in the development of kidney injury in obstructive uropathy and provides leads for further research. The role of CDH12 in monocyte infiltration and the development of kidney injury in PUV, and the predictive value of rs6874819 for the prognosis of individual PUV patients are important future research topics, as is the generalizability of our findings to other forms of obstructive uropathy.We hypothesize that MCP1 pathway upregulation due to an increase in urinary tract pressure in PUV patients is augmented in carriers of the Author contributions: Loes F.M. van der Zanden had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: van der Zanden, van Rooij, Renkema, Schreuder, Roeleveld, Feitz.Acquisition of data: van der Zanden, van Rooij, de Wall, Bongers, Renkema, Schreuder, Roeleveld, Feitz, Quaedackers, Nijman, Steffens, Schaefer, Kirchner, Behnisch, Bayazit, Caliskan, Obrycki, Montini, Duzova.Analysis and interpretation of data: van der Zanden, van Rooij, Renkema, Schreuder, Roeleveld, Feitz, Schaefer, Kirchner, Behnisch, Wuttke, Jennings, Hanley, Milmoe, Winyard.Drafting of the manuscript: van der Zanden.Critical revision of the manuscript for important intellectual content: van Rooij, Quaedackers, Nijman, Steffens, de Wall, Bongers, Schaefer, Kirchner, Behnisch, Bayazit, Caliskan, Obrycki, Montini, Duzova, Wuttke, Jennings, Hanley, Milmoe, Winyard, Renkema, Schreuder, Roeleveld, Feitz.Statistical analysis: van der Zanden, Behnisch, Hanley.Obtaining funding: van der Zanden.Administrative, technical, or material support: None.Supervision: Feitz, Roeleveld, Schreuder.Other: None.Financial disclosures: Loes F.M. van der Zanden certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript , are the following: Rien J.M. Nijman has received lecture fees from AstraZeneca, Giovanni Montini has received consultancy fees from Merck, and Neil A. Hanley has received consultancy fees from APIS Assay Technologies, all outside the scope of the current manuscript. The remaining authors have nothing to disclose.Funding/Support and role of the sponsor: This research was supported by a Kolff junior postdoctoral grant from the 10.13039/501100002997Dutch Kidney Foundation (13OKJ36) and a ZonMW-VENI grant from The 10.13039/501100003246Netherlands Organisation for Scientific Research (91618036). The sponsors played a role in the design and conduct of the study.Acknowledgments: We would like to thank all those involved in data collection, all patients and parents for their cooperation in this study, and deCODE Genetics  for performing the microarray experiments. Part of the collaboration was supported by the European Reference Networks (ERNs) for rare urogenital diseases and complex condition (ERN eUROGEN) and for Rare Kidney Diseases (ERKNet). Fetal tissue was provided at the UCL GOS Institute of Child Health by the MRC-Wellcome Trust Human Developmental Biology Resource.Ethics considerations: This study was approved by the Regional Committee on Research Involving Human Subjects Arnhem-Nijmegen and by the board of directors of the Isala Clinics and University Medical Center, Groningen. The 4C study was approved by the central ethics committee of Heidelberg University Medical Faculty and by each local institutional review board. All participants and/or their parents provided written informed consent. The collection, storage, and use of human embryonic and fetal material were approved by the North West Research Ethics Committee or via the Human Developmental Biology Resource, under the codes of practice issued by the Human Tissue Authority and legislation of the UK Human Tissue Act 2008.