Peripheral vascular disease (PVD) and coronary artery disease (CAD) are, in many cases, asymptomatic and not usually diagnosed. The timely diagnosis of peripheral vascular diseases can act as an indicator or practical evidence of CAD. Therefore, this study was conducted to determine the relationship between interarm systolic blood pressure difference (IASBPD) and severity and number of coronary artery stenosis.  The samples in this cross-sectional study consisted of 578 patients who were candidates for coronary angiography, with an average age of 57.5 ± 10.5 years. Patients were classified according to CAD and number and severity of coronary artery stenosis. The relationship between IASBPD and presence or lack of CAD as well as the number and severity of coronary artery stenosis was studied. The sensitivity, specificity, and positive predictive value of IASBPD index were calculated for the detection of CAD using the Kappa coefficient.  There was no statistically significant relationship between IASBPD, CAD, and severity and number of coronary artery stenosis. This index had low sensitivity and predictive value in the diagnosis of CAD and stenosis in coronary arteries in comparison with angiography.  The results showed that the IASBPD index cannot be a valid criterion for the diagnosis of CAD as well as the number and severity of coronary artery stenosis. More studies with larger sample sizes and different designs are needed in this regard to achieve more conclusive results. Peripheral vascular disease (PVD) and coronary artery disease (CAD) are two major problems of modern medicine –4. By thConsidering the high prevalence of CVD, presenting and introducing a criterion is very valuable and effective in the screening and diagnosis of PVD and consequently CAD in asymptomatic patients and those who are at the early stages of the disease , 6, 7. IThe frequency of IASBPD ≥10 mmHg varies from 1–4.0% up to 38.0% depending on the person's individual characteristics –11. TokiIn this regard, Clark et al. (2016) showed that the overall mortality and CVD mortality rate were higher in patients with IASBPD ≥10 mmHg than in patients with IASBPD of ≤10 mmHg . YamamotThe study population in this descriptive-analytical and cross-sectional study consisted of all patients attending the catheter section of Imam Ali Hospital. This hospital is a subspecialty cardiology center in western Iran, Kermanshah, where usually 500 angiographies are performed monthly. For sampling, about 30% of patients who underwent angiography were enrolled in the study monthly. Patients who are candidates for angiography are admitted to the CCU ward one day before angiography. Sampling was done by convenience sampling method. For this purpose, the researcher referred to the CCU ward on a daily basis and included samples with inclusion criteria. Patients were included if undergoing elective CAG, if it was possible to measure blood pressure from both arms, having systolic blood pressure of 90–200 mmHg, and absence of a history of coronary artery bypass graft, congestive heart failure (based on ejection fraction of less than 30.0%), severe heart valve disease (based on echocardiography), congenital heart disease (based on echocardiography), atrial fibrillation rhythm (based on electrocardiogram), kidney failure , systemic inflammatory diseases (fever or evidence of the diseases), systemic thromboembolism (according to patient's history), and pregnancy in female patients. Cancellation of CAG for any reason led to the withdrawal of the sample from the study and its replacement with another patient.The sample size was calculated based on the study of Tak et al. (2013) . For thiData collection tools included a demographic information questionnaire and a data sheet for recording blood pressure and CAG results. To measure blood pressure, the Microlife blood pressure measuring device , which was capable of simultaneously measuring blood pressure from both arms, was used. This device has a precision of about ± 3 mmHg, which requires calibration every two years according to the manufacturer's recommendations. In this study, a brand new device with accurate calibration was used.For data gathering, the researcher attended the angiography department of the hospital and selected the patients who met the inclusion criteria. These patients had been admitted a day earlier to undergo angiography. First, the personal information form was completed by the researcher, and then the blood pressure of both left and right arms was measured by a digital device.Based on the guidelines, a standard tourniquet (arm) with a width of 12-13 cm and a length of 35 cm was used. A larger and a smaller size tourniquet were also available if needed. The patient's blood pressure was measured and recorded by the researcher the night before the CAG. Patients were positioned in a comfortable position for at least five minutes before measuring their blood pressure, and their arms were placed at the same level as their heart in the center of a bed with a height-adjustable table. Patients were asked not to take stimulants such as tea or coffee half an hour before the blood pressure measurement. The device automatically measured the blood pressure at intervals of up to three times per minute and calculated the blood pressure and its mean, which was based on the calculation of the interarm difference (IAD) in the current study. According to the method of Tokitsu et al. (2015) and Weinberg et al. (2014), blood pressure was measured from both arms, and IASBPD ≥10 mmHg was considered the cut-off point , 13. BasCAG was performed by an angiographic specialist using a fluoroscope and X-ray device  with the injection of contrast agent. During the CAG, the number and severity of coronary artery stenosis were determined. After CAG, the severity of the stenosis (in terms of stenosis of the diameter of the vessel) and the number of narrowed vessels (according to the doctor's report) were recorded in the data sheet. Based on the CAG results, the patients were divided into two groups of without CAD  and with CAD (with moderate stenosis of 51.0–70.0% and severe stenosis of more than 71.0%). Patients with CAD were divided into three groups according to the number of narrowed vessels, including one, two, and three narrowed vessels. Each of these groups was divided into two subgroups, which included moderate stenosis (stenosis of 51.0–70.0% of the diameter of the vessel) and severe stenosis (stenosis of more than 71.0% of the diameter of the vessel). This process is shown in P-value of less than 0.05 was considered significant.Data were analyzed by 16th version of the Statistical Package for Social Sciences  using descriptive statistics (mean and frequency percentage) and inferential statistics . The Chi-Square test was used to determine the relationship between IASBPD and the number and severity of coronary artery stenosis. To determine the predictive power of IASBPD index in diagnosing CAD (based on stenosis of more than 50.0% in at least one major coronary artery), kappa coefficient was used. The KUMS' Ethics Committee approved the study. The goals of the study were explained to the participants and written informed consent was obtained from all of them. The participants were assured about the confidentiality of their personal information and their profile.n = 27) of women, 9.6% (n = 43) of patients aged >50 years, and 6.3% (n = 9) of smokers had IASBPD ≥10 mmHg. Finally, 14.1% (n = 28) of subjects with LASBP ≥140 mmHg (left arm systolic blood pressure) and 10.8% (n = 20) of them with RASBP ≥10 mmHg (right arm systolic blood pressure) had IASBPD ≥10 mmHg  were male. The mean age of the subjects was 57.5 ± 10.5 years, and they had an average body mass index of 27.55. About half of the samples (47.9%) had a history of HTN and 135 patients (23.4%) had diabetes. Moreover, 186 of them (32.0%) had HLP and 144 (25.0%) were smokers. The mean left ventricular ejection fraction was 49.0 ± 8.0%. The results showed that 11.0% (≥10 mmHg .n = 14). The Chi-Square test did not show a statistically significant relationship of IASBPD in patients with and without CAD (The mean systolic blood pressure (SBP) levels of the right and left arms were 133.3 ± 20.4 and 131.8 ± 20.0 mmHg, respectively. The lowest and highest SBP levels were 90 and 199 mmHg, respectively. The SBP level in the left arm in 198 (34.0%) of the samples was equal to or greater than 140 mmHg, and SBP level in the right arm in 185 (32.0%) of them was equal to or greater than 140 mmHg. A total of 367 patients (63.5%) had at least one narrowed vessel with the stenosis level of ≥50.0%, who were considered to have CAD. In addition, 211 (36.5%) of the samples had no significant stenosis in their coronary arteries. The frequency of IASBPD ≥10 mmHg in patients with three narrowed vessels (with any level of stenosis) was 10.1% (hout CAD .n = 29) of the samples with IASBPD ≥10 mmHg had CAD and 43.0% (n = 22) of them did not have CAD. However, in samples with IASBPD ≤10 mmHg, about 64.0% (n = 338) had CAD and 36.0% (n = 189) did not have CAD. The Kappa coefficient did not show any correlation between the IASBPD index and the existence of CAD , the samples were divided into two groups of patients with CAD and without CAD based on the severity of coronary artery stenosis of at least 75.0% of the vein diameter. The results showed that the frequencies of onset in people with and without CAD were 62.0% and 38.0%, respectively . HoweverWe did not find a statistically significant relationship between IASBPD ≥10 mmHg and the number and severity of coronary artery stenosis. In fact, IASBPD ≥10 mmHg as an indicator does not have a diagnostic value in predicting CAD. This result can be due to the different effects of atherosclerosis on coronary arteries compared to subclavian arteries or could be due to the weak ability of IASBPD index in identifying stenosis in the subclavian artery. The types of stenosis cause a difference in blood pressure between the two arms that have one-way flow and involve more than 60.0% of the diameter of the artery . In thisWe did not find a statistically significant relationship between the frequencies of IASBPD and CAD and the severity and number of coronary artery stenosis, which are not consistent with the results of Tokitsu et al. (2015) . This diIn the present study, IASBPD ≥10 mmHg had very low sensitivity and high specificity for the prediction of CAD, indicating the low predictive value of this index for the diagnosis of CAD. Despite extensive searches on credible databases, we did not find any study to determine the sensitivity, specificity, and positive predictive value of the IASBPD index to predict the existence of CAD. English et al. (2001) also used IASBPD index to predict the presence of subclavian artery stenosis. The results showed that IASBPD ≥10 mmHg had low sensitivity (65.0%) and high specificity (85.0%) in the diagnosis of subclavian artery stenosis, with a positive predictive value of 13.0% and a negative predictive value of 99.0%.English also indicated that IASBPD index can be considered for the prediction of CAD as the subclavian arterial stenosis is accompanied by CAD . The resOur study had some limitations. Several factors affect the accuracy of blood pressure measurements by digital devices, including the low accuracy of device sensors in high or low blood pressures. In our study, people with high blood pressure (greater than 200 mmHg) and very low blood pressure (less than 80 mmHg) were excluded from the study, which could have affected the results. Another limitation was the fact that we could not measure blood pressure from the arms during angiography. We measured the blood pressure of both arms the night before angiography. The last limitation is related to the nature of the convenience sampling method. In this method, because the samples are underrepresentation of subgroups, the probability of selection bias is high, which makes the generalizability of the results limited.In our study, there was no statistically significant relationship between IASBPD and the severity and number of coronary artery stenosis. The IASBPD index had lower sensitivity and negative predictive value in detecting the severity and number of coronary artery stenosis than the gold standard of angiography index. Therefore, based on our results, the IASBPD index cannot be used to predict the presence or absence of the coronary artery disease. Given the contradiction between our findings and the results of other existing studies, further studies with larger sample sizes and different designs are necessary.


This study is to assess the diagnostic value of noninvasive regional myocardial work (MW) by echocardiography for detecting the functional status of coronary stenosis using fractional flow reserve (FFR) as a standard criterion.A total of 84 consecutive patients were included in this study, among which 92 vessels were identified with ≥50% stenosis confirmed by invasive coronary angiography. Patients were investigated by invasive FFR and transthoracic echocardiography. Regional MW indices including myocardial work index (MWI), myocardial constructive work (MCW), myocardial wasted work, and myocardial work efficiency were calculated.p < 0.01). There were significant positive associations between MWI and MCW with FFR. In total group, MWI <1,623.7 mmHg%  and MCW <1,962.4 mmHg% , and in single-vessel subgroup, MWI <1,412.1 mmHg%  and MCW <1,943.3 mmHg%  were optimal to detect left ventricular segments with an FFR ≤ 0.75. MWI and MCW significantly increased after percutaneous coronary intervention in 13 cases.MWI and MCW were significantly impaired in the FFR ≤ 0.75 group compared with the FFR > 0.75 group (both In patients with coronary artery disease, especially those with single-vessel stenosis, the regional MW measured by echocardiography exhibited a good diagnostic value in detecting significant myocardial ischemia compared to the standard FFR approach. For patients with coronary artery disease (CAD), assessment of the functional significance of intermediate coronary atherosclerotic plaques remains challenging. Fractional flow reserve (FFR) is the gold standard for the evaluation of coronary lesion-related ischemia. However, FFR may not be a method of preference for patients who do not need coronary intervention. Therefore, non-invasive imaging techniques for functional assessment of coronary arterial stenosis have been developed . AlthougThis study retrospectively analyzed the data of 84 consecutive patients with clinically suspected CAD who visited Beijing Hospital  between November 2018 and December 2021. From the coronary angiography, we identified 92 vessels with lumen stenosis. Intermediate stenosis was defined as 40–75% lumen stenosis , 14. FFRAll patients underwent an invasive coronary angiography with FFR. Coronary pressure measurements were routinely collected during heart catheterization to assess the functional severity of the intermediate coronary stenosis. During the procedure, a 6F angiography catheter was inserted through the radial artery or femoral artery for selective left and right coronary angiography. The baseline coronary angiogram was acquired in multiple projections.After the angiography, a guiding catheter of more than 6F was inserted to the target vessel. A pressure–temperature sensor-tipped 0.014-inch guidewire , previously flushed and calibrated to zero pressure, was advanced to the tip of the guiding catheter where an equalization was performed to ensure identical pressures between the guiding catheter and the pressure guidewire . The FFRBaseline echocardiography was performed before the coronary angiography when patients were admitted to hospital. The echocardiographic studies were conducted by experienced sonographers using a Vivid E95 ultrasound system equipped with a M5S transducer . Images were acquired and stored in cine loop format for offline analysis using the EchoPac software . All measurements were performed according to the American Society of Echocardiography guidelines , 22. LVEIn the Echopac software, MW indices were obtained using a pressure-strain loop (PSL) area module, which was constructed from non-invasively estimated LV pressure curves and LV strain. Peak systolic LV pressure was assumed to be equal to the peak brachial cuff systolic blood pressure that was measured simultaneously at the echocardiography examination. This method has been validated in many studies , 24–27. t-test. Among LV segments perfused by vessels with an FFR ≤ 0.75, 0.76–0.80, and >0.80, MW parameters were compared using One-way ANOVA followed by Tukey's HSD post-hoc test. Comparison of non-normally distributed variables was performed using a Mann-Whitney U test. A paired t-test was used to compare the MW parameters before and after PCI. A χ2 or Fisher exact-test was used for categorical data. Pearson's correlation was used to test the correlation between FFR and MW parameters. To test the diagnostic accuracy and determine the cut-off values of MW in detecting LV segments perfused by vessels with FFR ≤ 0.75 and FFR ≤ 0.80, receiver operator characteristics (ROC) analysis was performed. Intra and inter-observer variabilities were calculated using intraclass correlation coefficients (ICCs). A p < 0.05 was considered statistically significant. Statistical analyses were performed using the SPSS version 23.0 software .Continuous variables were expressed as mean ± SD and categorical variables as numbers and percentages. The normality of the distribution was tested using the Kolmogorov–Smirnov test. The comparison of normally distributed variables between two groups was performed using an independent-sample p = 0.034). Between the two FFR subgroups, there were no significant differences regarding systolic blood pressure (BP) , diastolic BP , and heart rate . No significant differences were observed in other clinical  or echocardiographic characteristics  between the two FFR subgroups (FFR ≤ 0.75 vs. > 0.75), in both total-vessel and single-vessel groups. 67.9% of the patients had a single vessel involved, 23.8% had two vessels involved, and the rest (8.3%) had three vessels involved. The left anterior descending (LAD) vessel was the most frequently involved vessel. A typical MW pattern of a patient with LAD stenosis is shown in The baseline clinical, angiographic, and echocardiographic characteristics are displayed in p = 0.011).The single-vessel stenosis subgroup was comprised of 57 subjects. 91.2, 5.3, and 3.5% of the patients had LAD stenosis, left circumflex (LCX) stenosis, and right coronary artery (RCA) stenosis, respectively. The mean invasive FFR value was 0.82 ± 0.08, and the mean percentage of stenosis was 53.0 ± 9.2%. In the single-vessel stenosis subgroup, the percentage of stenosis in patients with FFR ≤ 0.75 was increased compared to those in patients with FFR > 0.75 .For both the total-vessel and single-vessel stenosis groups, the MWI and MCW in patients with FFR ≤ 0.75 were significantly lower than those in patients with FFR > 0.75 . There wIntra- and inter-observer variabilities were measured in 15 randomly selected patients. The intra-class correlation coefficient (ICC) for intra-observer variability was 0.95 (95% CI: 0.86–0.98) for MWI and 0.90 (95% CI: 0.73–0.97) for MCW. The inter-observer ICC was 0.83 (95% CI: 0.56–0.94) for MWI and 0.89 (95% CI: 0.71–0.96) for MCW.r = 0.394, p = 0.000; r = 0.410, p = 0.000) and the single-vessel stenosis groups . Other MW indices were not significantly correlated with FFR values. GLS showed a significant negative correlation with FFR values in both total-vessel group  and single-vessel stenosis group .As shown in p < 0.01]. The optimal cutoff values of MWI and MCW were 1,623.7 mmHg%  and 1,962.4 mmHg%  in the total-vessel group and 1,412.1 mmHg%  and 1,943.3 mmHg%  in the single-vessel group , MCW  and GLS  increased significantly at a median of 3 days (range 1–7 days) after intervention. There were no significant differences in MWE and MWW when comparing before and after PCI (p > 0.05).There were 18 vessels with FFR ≤ 0.75. In those patients who received PCI, echocardiography was repeated after PCI in 13 of the 18 vessels (72.2%). In total, 72.2% of the patients had both preoperative and postoperative images. MWI . Our study is a post-hoc analysis of data from an IRB-approved prospective clinical trial (NCT03905200). The patients/participants provided their written informed consent to participate in this study.YG, CY, and FW are the major contributors in writing the manuscript. YG and HZ analyzed the echocardiograms. XW, ZZ, and XM collected the patient information. ZP, XL, and SN revised the manuscript carefully. FW conceived the study and supervised the project. All authors read and approved the final manuscript.This work was supported by grants from the National Key R&D Program of China (2020YFC2008100/2020YFC2008106) and the Beijing Hospital Research Project (No. BJ-2019-133).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.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.


Butyricicoccus, a genus with butyrate-generating properties, was decreased in abundance in advanced stages of CKD compared to the earlier stages (p = 0.043). In conclusion, in this cross-sectional study no gradual differences in the gut microbial profile over the different stages of CKD were observed. However, the decrease in the abundance of Butyricicoccus genus with loss of kidney function stresses the need for more in-depth functional exploration of the gut microbiome in CKD patients not on dialysis.Chronic kidney disease (CKD) is characterized by the accumulation of uremic toxins which exert deleterious effects on various organ systems. Several of these uremic toxins originate from the bacterial metabolization of aromatic amino acids in the colon. This study assessed whether the gut microbial composition varies among patients in different stages of CKD. Uremic metabolites were quantified by UPLC/fluorescence detection and microbial profiling by 16S rRNA amplicon sequencing. Gut microbial profiles of CKD patients were compared among stages 1–2, stage 3 and stages 4–5. Although a substantial inter-individual difference in abundance of the top 15 genera was observed, no significant difference was observed between groups. Bristol stool scale (BSS) correlated negatively with  Aromatic amino acids  are predominantly metabolized in the distal colon by gut bacteria into p-cresol, indole and IAA  were included. The ‘Chronic kidney disease epidemiology collaboration (CKD-EPI)’-creatinine equation was used to determine the estimated glomerular filtration rate (eGFR) of each patient. Based on their eGFR, the total group of patients with CKD was divided into three groups: (i) eGFR above 60 mL/min/1.73 m2 corresponding to CKD stages 1 and 2 (n = 36), (ii) eGFR between 30 and 60 mL/min/1.73 m2 corresponding to CKD stage 3 (n = 44), and (iii) eGFR below 30 mL/min/1.73 m2 corresponding to CKD stages 4 and 5 (n = 31). From each patient of the CKD population, a single blood and fecal sample was collected in parallel. Bristol Stool Scale (BSS), a visual scale of the aspect of stool, from hard (1) to liquid (7) , creatinine 133 Da), phosphorus (31 Da) and total protein content were measured with standard laboratory methods in the routine laboratory of the Ghent University Hospital, Belgium. In plasma, total concentrations of the PBUTs escribed ,33. Da, phos®  and Illumina-based microbial profiling were performed as described previously . A significant negative correlation was found between BSS and plasma HA in the total CKD cohort and in stages 1–2; and between BSS and ages 4–5 .pCSG points in the opposite direction as BSS. Because part of the samples were taken from participants on laxatives and to avoid distortion due to laxative usage, analyses were also repeated excluding the samples of patients on laxatives (n = 101). Similar significant correlations between BSS and pCS and HA were found (On the triplot in re found .Butyricicoccus was found in latest stages (CKD 4–5) of the disease compared to the earliest stages (CKD 1–2)  data showing that the abundance of Butyricicoccus spp. but also of other gut bacteria such as Roseburia spp., Faecalibacterium prausnitzii, and Bifidobacterium spp. declined with advancing stages of CKD [Roseburia spp. and Faecalibacterium prausnitzii [Roseburia inulinivorans, Ruminococcus torques and Ruminococcus lactaris were already less abundant in early CKD compared to the control group and this in the absence of clear gut microbiome changes [Faecalibacterium prausnitzii is also associated with inflammatory bowel disease (IBD) and irritable bowel syndrome [In this study, the gut microbial composition was assessed among patients at different stages of CKD not on dialysis, i.e., CKD stages 1 to 5, taking their plasma levels of PBUTs into account. No specific microbial profile was linked to different degrees of kidney function decline, as was also observed in ESKD patients compared to the control group in our previous study . Howevers of CKD  and confusnitzii . In addi changes . Moreove changes ,36,38,39syndrome ,41,42. Tsyndrome .pCS and pCG (p-cresyl conjugates) [p-cresyl conjugates (pCS and pCG)  . Similarand pCG) . Interesdialysis  and in idialysis .The lack of overt difference in gut microbiota composition between the different stages of CKD observed in the present study and in a previous study on HD patients by our group points to potential limitations of 16S rDNA-based approaches, and calls for more in-depth studies focusing on functional characteristics of gut microbiota. This is exemplified by the recent finding that dietary intake of sulfide donors can tune microbiota function via post-translational modification without altering microbial community composition . ShotgunThe major strength of this study is that it covers the whole range of pre-dialysis CKD, while most studies focus on patients with ESKD. To follow up this cross-sectional approach, however, longitudinal sampling is preferred to also allow other covariates to be included in data analysis. In addition, given the high inter-individual variation observed, expansion of the cohort’s sample size could provide more power to reveal potential microbiota differences between subsequent CKD stages.Butyricicoccus with loss of kidney function. Additional in-depth studies taking into account the functional capacity of the gut microbiome will be required to identify potential targets to tackle chronic inflammation and to decrease levels of intestinally generated uremic toxins and their precursors.In this cross-sectional study we observed no gradual differences in the gut microbial composition in patients at different stages of CKD. However, a non-supervised comparison of CKD stage 1–2 with CKD 4–5 revealed a decrease in the abundance of the butyrate-producing genus


Hypertension, especially if poorly controlled, is a key determinant of chronic kidney disease (CKD) development and progression to end stage renal disease (ESRD).To assess hypertension and risk factor management, and determinants of systolic blood pressure control in individuals with CKD and hypertension.Cross-sectional survey using primary care electronic health records from 47/49 general practice clinics in South London.Known effective interventions, management of hypertension and cardiovascular disease (CVD) risk in patients with CKD Stages 3–5 were investigated. Multivariable logistic regression analysis examined the association of demographic factors, comorbidities, deprivation, and CKD coding, with systolic blood pressure control status as outcome. Individuals with diabetes were excluded.Adults with CKD Stages 3–5 and hypertension represented 4131/286,162 (1.4%) of the total population; 1984 (48%) of these individuals had undiagnosed CKD without a recorded CKD clinical code. Hypertension was undiagnosed in 25% of the total Lambeth population, and in patients with CKD without diagnosed hypertension, 23.0% had systolic blood pressure > 140 mmHg compared with 39.8% hypertensives, p < 0.001. Multivariable logistic regression revealed that factors associated with improved systolic blood pressure control in CKD included diastolic blood pressure control, serious mental illness, history of cardiovascular co-morbidities, CKD diagnostic coding, and age < 60 years. African ethnicity and obesity were associated with poorer systolic blood pressure control.We found both underdiagnosed CKD and underdiagnosed hypertension in patients with CKD. The poor systolic blood pressure control in older age groups ≥ 60 years and in Black African or obese individuals is clinically important as these groups are at increased risk of mortality for cardiovascular diseases.The online version contains supplementary material available at 10.1007/s40620-021-01149-0. HoweverHypertension, especially if poorly controlled , 11 is aKnown markers of CKD progression (measured by eGFR decline) include proteinuria –18, and Patients with CKD and hypertension alone are managed and captured differently under Quality Outcome Framework, compared to those with CKD and diabetes. The NCKDA report has previously published differences in management by diabetes status. To our knowledge, there has been limited focus on the management of CKD in the UK by hypertension status. This study aimed to assess hypertension and risk factor management, and determinants of systolic blood pressure (SBP) control in individuals with CKD and hypertension HT.Cross-sectional study of non-diabetic individuals with CKD.We used a dataset derived from general practice electronic health records (EHRs), Lambeth DataNet (LDN), south London, extracted from patient records from 1990 until October 2013. LDN contains clinical data, prescription data, laboratory data, and demographic information, such as age, sex, and ethnicity, based on categories of the UK 2001 census, CVD risk factors and co-morbidities. We investigated demographic factors, comorbidities, and other interventions considered as potentially effective, in a population identified as having CKD Stage 3–5, with and without hypertension.Individuals with CKD Stage 3–5 (defined based on the criteria reported below). Patients with diabetes were excluded, as they have different profiles of proteinuria and cardiovascular risk . The stu2 calculated from serum creatinine using the modified four-variable Modification of Diet in Renal Disease (MDRD) equation adjusted for sex and, when appropriate, Black African or Black-Caribbean ethnicity [2. Hypertensive CKD is defined as individuals with CKD and hypertension.Our CKD Stage 3–5 cohort comprised diagnosed and undiagnosed cases. Diagnosed CKD status was determined using QOF incentive scheme CKD descriptive codes, plus codes for dialysis or renal transplantation (Appendix Table S1). Non-diagnosed CKD was defined, in the absence of the previous codes, based on the latest two readings ≥ 90 days apart of eGFR levels < 60 ml/min/1.73mthnicity . We exclIndividuals were defined as hypertensive if they were included In the hypertension Quality Outcome Framework (QOF) register.Risk factor management and CKD prevalence by stage was investigated. Appropriate systolic blood pressure control was defined as below 140/90 based on the mean of the two latest readings, in individuals with CKD, according to NICE guidelines . As we wWe examined the following factors: age, gender, ethnicity, deprivation (Index of Multiple Deprivation 2015), and selected comorbidities likely to influence SBP control including coronary heart disease (CHD), heart failure (HF), stroke and serious mental illness, (SMI). Other measured factors were: diastolic blood pressure (DBP) control, prescribed ACEIs or ARBs, calcium channel blockers (CCBs), statins, NSAIDs and COX-2 inhibitors, (COXIBs) and lifestyle factors smoking and obesity. High alcohol intake was defined as > 14 units/week. BMI was determined according to the World Health Organization (WHO) classification . EthniciThe primary outcome was systolic blood pressure control; the secondary outcome was CVD risk factor control in patients with CKD.A cross-sectional study design was used to describe demographic factors, comorbidities, and other interventions considered as being potentially effective  associated with hypertension status. Analysis was stratified by CKD Stage. Differences between categorical variables were assessed using Pearson’s chi-squared test  and fully adjusted , both in patients with hypertensive without acknowledged and coded hypertension.Table S3 shows CKD Stage and measured eGFR according to demographic variables. The prevalence of hypertensive CKD in stage 3 was higher in females than males , but prevalence of hypertensive CKD in stage 5 was higher in males than females The proportion of patients who achieved the SBP target was similar in pateints younger or older than 75 years (61.3% versus 59.1%). Achievement of the systolic blood pressure target (< 140 mmHg) was lower in CKD 3–5 in patients of Black African ethnicity compared with patients of White ethnicity , but was not different when compared with Black Caribbean patients  (Table S2).Three hundred nine/4,131 (7.4%) individuals with diagnosed HT and CKD were not taking any of the anti-hypertensive medications considered in our study. Statins were under-prescribed, and this was more marked in hypertensive vs. non hypertensive CKD patients, receiving statins respectively in 54.9% vs 23.3% of the cases (P < 0.001)  and underdiagnosed hypertension (23%) in patients with CKD. Furthermore, systolic blood pressure control was below target in a relevant percentage of cases. Multivariable logistic regression revealed that factors associated with improved systolic blood pressure control in CKD included diastolic blood pressure control, and the presence of comorbidities that are probably associated with a more strict patient control; these include serious mental illness, history of cardiovascular co-morbidities, CKD diagnostic coding, and age < 60 years. African ethnicity and obesity were conversely associated with poorer systolic blood pressure control. The finding of a better blood pressure control in patients with serious mental illness is important as this group is at increased risk of cardiovascular mortality .This is a study of a well characterized ethnically and socially diverse population in 47 GP practices in Lambeth SE London, with extensive recording of clinical data, medication, and patients' characteristics. Our large database allowed us to undertake a detailed exploration of risks in individuals with CKD and hypertension, sorting them by ethnicity, and adding important information on CKD prevalence and management in Black African and Black Caribbean sub-groups.The study has however several limitations and these limitations are mostly shared by observational real life studies; these include diagnostic misclassifications, lack of data on medication adherence and patients' choices, missing data  and unmeasured confounders. We tried to correct some misclassifications by revising CKD codes, using MDRD ethnicity-adjusted eGFR values. Furthermore, blood pressure readings were based on the mean of the last two recorded measurements after CKD diagnosis, and BP trajectories may provide better longer-term estimates of BP control in future studies. Currently, smoking cessation services are provided by an external provider, and are poorly coded in our database, and so this information was not included in this study.Although prescriptions were well captured, we did not have estimates of adherence to the prescribed treatments, which may be modulated by ethnicity and CKD status. Lastly, we were also unable to look at longitudinal outcomes, including morbidity and mortality and start of renal replacement therapy.We found that the overall prevalence of CKD ≥ 3 (both diagnosed and undiagnosed) amongst adults was 3.3%, which is lower than the national average of 4.3% . As the 2 [Obesity and poor blood pressure control are key risk factors for CKD development , 23. How2 . The lat2 , althougRaising awareness of the importance of risk factor management in primary care includes more rigorous management of systolic blood pressure, together with a series of potentialy beneficial actions on CKD progression, including smoking cessation, which however was not analysed in our study, and correction of overweight and obesity tailoring pharmacotherapy  is also an important tool to prevent CKD development and slow progression. Public health strategies, and education about CKD are important to minimise preventable morbidity and mortality . SubsequThe main result of this study was to find a high prevalence of underdiagnosed CKD and underdiagnosed hypertension in patients with CKD. In CKD patients with hypertension, poorly controlled blood pressure may contribute to CKD progression and increase the risk of heart failure. Our study shows that there is an unmet need to improve CKD detection and management (relative underdiagnosis of CKD Stage 3) in high-risk groups . In our study, management of modifiable risk factors was found to be sub-optimal, particularly in younger patients. This applies also to pharmacotherapy , which was found to be under prescribed. Improving risk factor management and establishing public health educational strategies should be a priority, as these interventions may help prevent CKD diagnosis or delay disease progression.Supplementary file1 (DOCX 115 KB)Below is the link to the electronic supplementary material.


N = 2,402), to investigate the relationship between the dietary data of nutrient intake in the breakfast, lunch, and dinner and blood pressure. Daily total intake of various nutrients such as sodium, sodium-to-potassium ratio, total energy, lipid, carbohydrate, and saturated fat showed a significant association with blood pressure depending on the meal timing. From multiple regression analysis, eliminating the confounding factors, lunch sodium-to-potassium ratio, dinner energy, lipid, cholesterol, saturated fat, and alcohol intake were positively associated with blood pressure, whereas breakfast protein and lunch fiber intake showed a negative association with blood pressure. Our results suggest that nutrient intake timing is also an important factor in the prevention of high blood pressure. Our study provides possibilities to prevent hypertension by changing the timing of nutrient intake, especially sodium, together with potassium and lipids. However, because our research was limited to food-log app users, broader research regarding the general population needs to be conducted.Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide, and one of the most significant risk factors for CVDs is high blood pressure. Blood pressure is associated with various nutrients, such as sodium, potassium, and cholesterol. However, research focusing on the timing of intake of these nutrients and blood pressure has not been conducted. In this study, we used dietary data and a questionnaire asking about the sleep, physical activity, and blood pressure, collected from the food-log app “Asken” (total  Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide, and one of the most significant risk factors for CVD is high blood pressure , 2. BlooThe blood pressure is well-controlled by urine and sodium excretion through the Na/K reuptake mechanism located in the renal tubule . Excess From transcriptome and metabolome analyses of human blood and tissue samples, it has been reported that circadian rhythms also exist in food digestion, absorption, and metabolism , 19. “ChAs previously stated, the association between blood pressure and the circadian clock has been suggested in various studies. Furthermore, the metabolism and excretion of nutrients associated with blood pressure exhibit a circadian rhythm. The excretion of sodium and potassium by the kidneys is controlled by the circadian timing system . CholestAccording to the National Nutrition Survey in Japan (NNSJ) in 2019, compared to the estimated average requirement, the average intake of sodium and saturated fat is excessive, while that of potassium and dietary fiber is insufficient . ProposiDietary data and questionnaire answers were collected through a popular food log and food coaching app, “Asken.” Based on the Dietary Intake Standards for Japanese determined by the Ministry of Health, Labor and Welfare, the app provides feedback on the dietary content of the meal, showing the excess and deficiency of nutrients.The validity of Asken has been confirmed in previous studies. When comparing weighed dietary records with records from Asken, the energy and nutrient intakes were correlated, suggesting the validity of Asken . Paper-bIn addition to these dietary records, an online survey was conducted in January 2021. This experiment was approved by the Ethics Review Committee on Research with Human Subjects at Waseda University (No. 2020-046) and followed the guidelines laid down in the Declaration of Helsinki. A total of 2491 participants responded at first, and by excluding data missing the reports of all three meals a day or missing basic characteristics such as body mass index (BMI) and sleep, physical activities, and subjects taking medicine, the final data were 707 for males and 1,695 for females.From an online survey, the basic characteristics of the participants  and other lifestyle-related factors  were obtained.Sleep factors such as morningness was assessed by MSFsc (sleep—corrected midpoint of sleep on free days). The computation was as follows: MSFsc = MSF—[(sleep duration on free days)—(sleep duration in workdays)]/2. This assessment is widely used and established .From an online survey, physical activity was determined by the number of days and hours spent on the three types of activities . We calculated weekly metabolic equivalents (MET) based on the International Physical Activity Questionnaire (IPAQ) analysis guidelines for each activity intensity for total physical activity . The IPAParticipants answered the question; “Please answer the most recent record of maximum blood pressure (systolic blood pressure) by upper arm sphygmomanometer through medical checkup and/or at home.” Participants answered their systolic blood pressure by a score of 1–6 . Blood pressure is usually recorded in the morning. We also asked if they were taking medication for high blood pressure, and the answers of those who answered yes were excluded.The dietary data were analyzed using ~1-month average dietary records of the application. Energy content , protein, fat, carbohydrate, sodium, potassium, cholesterol, dietary fiber, saturated fat, and alcohol intake were measured for each of the three meals and snack. The intake timings of snacks might be different among participants, because of no check of snack time. From previous research, the validity of the dietary record of this app was high . The Na/p-value of <0.05 was considered statistically significant. To investigate the relationship between dietary patterns and blood pressure, Spearman's rank correlation analysis was conducted. To clarify the relationship excluding other factors, multiple regression analysis among the three meals for each nutrient was conducted. Data are expressed as mean and standard error.Statistical analysis of the obtained data was performed using a predictive analytics software for Windows , and a p < 0.001), and males exhibited higher blood pressure than females  age was 45.95 (0.237) years, BMI was 23.12 (0.0778), total PA MET min/week was 32.05 (0.818), and MSFsc was 3.36 (0.0254) . All val females . There w females  and betw females . However females . Althoug females .Next, the intake volumes of each nutrient were compared among breakfast, lunch, and dinner in male and female participants . Intake Correlation analysis of the intake of various nutrients and blood pressure was applied for each meal  and snack. In addition to the amount of intake for each nutrient, the mean energy ratios of protein, fat, and carbohydrate were compared for each meal and snack. Spearman's correlation analysis showed that blood pressure had a strong positive association with the Na/K ratio for every meal in both males and females . NutrienMultiple regression analysis showed that even when eliminating the effects of confounding factors, such as sex, age, BMI, MSFsc, and PA MET min/week, various nutrients showed different associations with blood pressure depending on their intake timing . FocusinIn this study, we investigated the association between blood pressure and different nutrient intake timing among mobile health app “Asken” male and female users. Our findings confirm previous findings that high Na/K ratio, high lipid intake, high alcohol intake, and low dietary fiber are associated with high blood pressure , 17, 18.From previous studies, dietary records collected by Asken have been reported to be an effective method for estimating the energy and nutrient intakes of Japanese women . As statOur results showed that blood pressure had a strong positive association with the Na/K ratio, especially the lunch and snack Na/K ratio. In addition, the negative correlation of lunch potassium shows that promoting excretion of sodium is important for lowering blood pressure at lunch time. Sodium and potassium urine excretion has been previously reported to exhibit circadian rhythm, which is explained by the rhythm of aldosterone . AldostePotassium and dietary fiber are both rich in vegetables. Lunch fiber and potassium intake showed a negative correlation with blood pressure in the current experiment, suggesting the intake of more vegetables at lunch and snack time to protect higher blood pressure. Higher blood pressure has been reported to be associated with lower gut microbiota alpha diversity in many human cross-sectional studies . A low iFurthermore, breakfast protein was negatively correlated with blood pressure. The beneficial effect of proteins on blood pressure is small, according to previous studies . HoweverDinner cholesterol and saturated fatty acids were positively correlated with blood pressure. A high dinner energy also showed a positive correlation. It is well-known that a high intake of cholesterol and saturated fatty acids causes progression of arteriosclerosis and higher blood pressure , 53. HowHigh energy intake and lipid intake at dinner are reported to lead to obesity, which is known to be strongly associated with blood pressure . In the There are some limitations to our study. First, the dietary data were collected through self-reports by the subjects, and this self-reporting may have resulted in self-efficacy. Previous studies have discussed that self-monitoring results in behavioral changes . The secWe analyzed the relationship between the intake timing of nutrients and blood pressure. In both males and females, a positive association between meals and blood pressure was observed in the Na/K ratio (lunch), energy (dinner), lipid (dinner), and saturated fatty acids (dinner). Moreover, a meal-specific negative association with blood pressure was seen in protein (breakfast), potassium (lunch), and dietary fiber (lunch). Our study provides possibilities to prevent hypertension by changing the timing of various nutrient intakes, especially sodium together with potassium and lipids. However, an intervention study to investigate the effect of the timing of each nutrient on blood pressure needs to be conducted in the future.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This experiment was approved by the Ethics Review Committee on Research with Human Subjects at Waseda University (No. 2020-046) and followed the guidelines laid down in the Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.MI, HS, YT, TS, SM, MK, AT, NA, MM, and SS designed the research and analyzed the data. MI and SS wrote the manuscript. All authors contributed to the article and approved the submitted version.This research was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Kiban A) and the JST-Mirai Program (Grant Number: JMPJM120D5) by SS.MM is a corporate officer in Asken Inc. AT and NA are employees of Asken Inc. 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.


OBJECTIVES/GOALS: High blood-pressure (BP) is a common adverse effect of erythropoietin (EPO) therapy among patients with chronic kidney disease on hemodialysis, and even among otherwise healthy individuals who receive EPO. In human genetics, EPO is associated with not only red blood cell traits, but hypertension (HTN) as well. Currently, there is no vascular gene expression data available in the setting of EPO-induced HTN that may explain precise role of key cellular players in its hypertensive etiology. Our aim is to characterize vascular transcriptome to identify key cellular players in EPO-induced HTN. METHODS/STUDY POPULATION: 10-12 week C57BL/6 male and female mice were randomly divided into two groups 1. Vehicle , 2. EPO, (N = 4). VEH and EPO were intraperitoneal administered  for 20 days. Blood-pressure was measured non-invasively via tail-cuff plethysmography. We characterized in-vivo transcriptome response of mouse descending aorta to EPO-HTN and vehicle control group by high-throughput RNA-sequencing. RESULTS/ANTICIPATED RESULTS: Systolic blood pressure (SBP) was significantly higher in EPO treatment, compared to vehicle . Comparison of in-vivo transcriptional differences between vehicle and EPO-treated reveal statistically significant changes in cellular pathways consistent with hypertension such as upregulation of RAS signaling pathway and oxidative stress. In-vitro mouse aortic smooth muscle cells, EPO markedly increased phosphorylated-ERK activity, suggesting increased RAS activity. DISCUSSION/SIGNIFICANCE OF IMPACT: This study highlights the importance of previously unknown vascular key players and advances our understanding of the transcriptional events associated with EPO-induced hypertension.


The autoregulation of cerebral blood flow protects against brain injury from transient fluctuations in arterial blood pressure. Impaired autoregulation may contribute to hypoperfusion injury in neonates and infants. Monitoring cerebral autoregulation in neonatal cardiac surgery as a guide for arterial blood pressure management may reduce neurodevelopmental morbidity. Cerebral autoregulation monitoring has been validated in animal models and in an adult trial autoregulation monitoring during bypass improved postoperative delirium scores. The nuances of pediatric cardiac disease and congenital heart surgery make simply applying adult trial findings to this unique population inappropriate. Therefore, dedicated pediatric clinical trials of cerebral autoregulation monitoring are indicated. Highly sensitive oligodendrocytes occupy a watershed region in the neonatal brain, and this is thought to contribute to the high incidence of white matter injury reminiscent of preterm periventricular leukomalacia  . MRI stuomalacia . The duromalacia , 5. The omalacia  ImprovedNeonates, especially preterm neonates, lack the robust, redundant cerebral vasculature that is present in infants and adults. Poor vascular redundancy in the deep white matter may enhance the risk of watershed injury during cerebral dysautoregulation. Fragile vascular overgrowth in the germinal matrix is a risk factor for hemorrhage for the preterm neonate, but germinal matrix hemorrhage is a less common injury after CPB than watershed WMI.  CongenitThe goal of autoregulation monitoring in neonates with congenital heart disease is to delineate the lower limit of autoregulation (LLA), providing a target for ABP management.  MaintainIn principle the maintenance of ABP above LLA during neonatal cardiac surgery may prevent neurological injury and improve neurodevelopmental outcomes. This remains as an only partially tested hypothesis which requires further study . CerebraThe concept of autoregulation pre-dates the technical ability to measure autoregulation in real time. Conceptually, a real time autoregulation monitor requires a measure of arterial blood pressure (ABP) or cerebral perfusion pressure (CPP), a measure of cerebral blood flow (CBF) or a proxy, and a mathematical approach to determine if cerebral blood flow is passive to blood pressure .The first modern attempts to monitor autoregulation in real time are typified by Czosnyka et al. in 2 seminal papers , 21. TheThe feasibility of less invasive monitors of cerebral pressure autoregulation using reflectance near infrared spectroscopy (NIRS) was established in a series of experiments in neonatal piglets , 23. In Two relevant observations came from these experiments. First, rTHb showed high coherence (relatedness in the frequency domain) with ICP at the slow wave frequency. This observation inadvertently validated the assumption that ICP slow waves are the result of fluctuating CBV, which is an assumption inherent to the PRx. Second, non-invasive measures of autoregulation (COx) and cerebral vasoreactivity (HVx) effectively differentiate periods of cerebral autoregulation from dysregulation with similar performance to invasive measures . For example, the area under the curve (AUC) of the ROC for HVx was 0.85, compared to an AUC of 0.88 for the invasive measure PRx. HVx had a sensitivity of 77% and specificity of 84%. COx had an AUC of 0.89, sensitivity of 83%, and specificity of 75%.In their pioneering work, Czosnyka et al. discussed the importance of examining the correct frequency of waveform when monitoring cerebral autoregulation. ABP fluctuates over each second due to cardiac systole/diastole, every few seconds due to respirations, and over minutes to hours due to changes in clinical status. In addition, ABP fluctuates every 30 seconds to few minutes in a phenomenon termed slow waves. These waves were first described in the ICP pressure tracing and were termed B waves  . Slow waThe number of proposed measures of autoregulation and vasoreactivity has increased in the last decade, with varying levels of evidence to support their utilization. All metrics share 3 fundamental components :Changes in ABP must occur and be measured. Measurement of ABP is straight forward using intra-arterial catheters which are standard practice in intensive care units. Most attempts to measure autoregulation have focused on the slow wave oscillations in ABP described above.1) Changes in CBF or CBV must be measured. A number of different non-invasive monitors of CBF or CBV have been proposed, most of which rely on measuring blood flow by doppler effect, or oximetry and blood volume based on the light absorption of hemoglobin.2) The relationship between ABP and CBF/CBV must be quantified to identify periods when CBF/CBV are passive to changes in ABP. Of the three components this is the least intuitive to most clinicians. Conceptually all measures of relatedness can be divided into time-domain and frequency-domain measures. Time domain measures of relatedness determine if and to what extent two variables “move together” over time. The Pearson correlation coefficient is the most commonly used time-domain metric. Alternatively, complex biologic signals such as ABP or cerebral tissue oxygenation can be broken down into combinations of waves of different frequencies and magnitudes. In an oversimplification, frequency domain measures determine if and to what degree the component waves that make up more complex signals are shared between different signals .3) Although the NIRS based measures utilizing correlation or phase shift have performed well in animal validation, there are several other potential measures of CBF/CBV and mathematical approaches to assessing passivity to blood pressure. This leads to an essentially endless list of possible combinations. With so many measures of autoregulation (and more likely to be developed), it is important to consider the evidence burden needed to compare and optimize these potential tools. The following three requirements have been proposed :1) Validate the candidate index against an accepted gold standard measure of autoregulation . Given that gold standard measures of cerebral blood flow are invasive, this criterium is likely to require animal study.2) Show strong relatedness of a candidate index to outcome reproducibly in prospective studies of humans.3) Demonstrate feasibility of using actionable data from a candidate index, such that clinicians can optimize clinical care and minimize morbidity.Utilizing the piglet experimental construct described above, a large number of candidate indices were compared with each other and to the gold standard LLA . The avaHVx and COx are candidate indices that meet the requirements of being hands-free and non-invasive. Both performed well in the animal validation study. However, neither has been studied adequately in the clinical environment to demonstrate feasibility or efficacy to prevent neurologic injury in the neonatal cardiac population. As a start to this effort, the feasibility NIRS-based methods to measure autoregulation during cardiac surgery in children was demonstrated in a prospective observational pilot study of 54 children . The LLAAs described above, function of the neonatal heart is negatively impacted by afterload in the perioperative window. Raising ABP to exceed LLA is an expected intervention from showing LLA to care providers with autoregulation monitoring. Options include increasing pump flow rates, contractility, preload, and systemic vascular resistance. Each of these has the potential for harm. Does optimizing perfusion of the brain also optimize cardiac performance and perfusion of the visceral organs? It seems unlikely given that the brain is dependent on ABP for perfusion while the viscera are dependent on cardiac output , 28. If 2 via internal jugular oximetric measurements, decreased arteriovenous O2 content differences, and improved systemic blood flow (Neonates undergoing cardiac surgery are at risk of a distinct low cardiac output state/syndrome (LCOS) about 6–18 h post-operatively. When LCOS is accompanied by high SVR cardiovascular collapse can result. This was noted in the Norwood procedure for hypoplastic left heart syndrome which historically had perioperative morbidity of 50% within the first 48 h of surgery . The iniood flow , 31. Stuood flow . The PRIood flow . The neep = 0.04)  , 18.The outcomes of adult studies cannot serve as a template for neonatal studies. MRI findings in adults are largely embolic while MRI findings in neonates after cardiopulmonary bypass are primarily watershed white matter injuries (WMI) , 4. It iOvert neurologic injury is uncommonly seen in neonates, even with substantial MRI injury. Therefore, neurologic exam is likely too insensitive to use as an outcome. Delirium cannot be measured with the same precision in neonatal populations as in adult populations, so it is unlikely that a neonatal study could replicate the adult finding of reduced delirium.Seizure activity occurs in nearly 10% of neonates after cardiac surgery, is most often clinically silent, and is strongly associated with developmental outcome , 34. SeiThe gold standard neurologic outcome for neonates with neurologic risk is the developmental exam. Any study that collects data for 5 yr and then requires a 5 yr follow up developmental exam becomes a 10-yr study. The most impactful developmental study of neonates with cardiac disease is the Boston circulatory arrest trial, which followed serial developmental exams into the late teen years . Even ifTeams that care for neonates with cardiac disease have made substantial progress in achieving survival for complex and delicate surgical disease with very little room for error. The current frontier is the unacceptably high rate of neurologic injury in the survivors of neonatal heart surgery. Given the multifactorial vulnerabilities of the neonatal brain perfused by a malformed circulation, it is not likely that any single intervention will eliminate brain injury. Autoregulation monitoring stands at the front of the line with these interventions because low ABP is needed for survival of neonatal heart surgery, and we do not currently know how low we can lower ABP and still perfuse the brain. The most logical way to answer this question is to measure LLA with autoregulation monitoring.Dynamic autoregulation monitoring has been developed with adequate validity to reliably delineate optimal perfusion pressure for patients with traumatic brain injury. These concepts have been applied to develop non-invasive methods using reflectance NIRS, and the NIRS-based measures have been validated against gold standard measures of LLA in animal models. What remains is clinical translation specific to the neonatal population, demonstrating feasibility, safety, and efficacy. We have outlined challenges peculiar to neonates with heart disease for each of these clinical research steps.If feasibility cannot be demonstrated with current methods to measure autoregulation, one can ask if this is inability to modulate blood pressure in the setting of cardiac surgery, or if the autoregulation data is coming to slow to delineate LLA in a practical way. In the latter case, the challenge to making autoregulation monitoring faster has been the fundamental frequency of the autoregulation mechanism which acts as a high pass filter for ABP waves having a period of 30 seconds or longer . One proSafety was not only demonstrated in the adult data, but major morbidity including AKI (acute kidney injury) was lower in patients when ABP was above LLA. It is not clear that the same pattern will hold true in neonates. If SVR crisis, renal or bowel injury, respiratory failure, heart failure, arrhythmia or death are higher in study groups where ABP is kept above LLA, then the specific interventions used to manage ABP will have to be examined. Any method to raise ABP in this population has the potential to cause some combination of these complications. Autoregulation monitoring will only prove beneficial and safe if the intervention can maintain ABP above LLA without causing complication related to low cardiac output.Once feasibility and safety are demonstrated, sample size required to document efficacy can be calculated. It is anticipated that such a trial will be multi-center, and that the outcomes will be a combination of MRI, seizure activity, and developmental follow-up. The stamina required to complete such a study is non-trivial and would likely span two decades of work. Although this study is the optimal pathway to apply evidence-based medicine to clinical practice, there is very little precedent for successful randomized trials of monitoring technologies. Most standard monitoring was adopted despite a failure of trials to demonstrate outcome benefit . PerhapsAll authors contributed to the article and approved the submitted version.This research was supported by grant from Additional Ventures: Single Ventricle Research Fund 2020.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.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.


Escherichia coli is still the most common pathogen in UTI. A wide variety of other pathogens may be involved in UTI. Urological interventions, catheterization, as well as repeated courses of antibiotics contribute to an increased challenge of antimicrobial resistance. The diagnosis of UTI in CKD is based on standard clinical and laboratory criteria. Pyuria (≥10 leucocytes/µl) is more often observed in patients with oligoanuria and low bacterial colony counts. The treatment strategies for this population are based on the same principles as in patients with normal renal function. However, drugs cleared by the kidney or by dialysis membranes need dose adjustment. Antimicrobials with potential systemic toxicity and nephrotoxicity should be administered with caution.Epidemiological studies show an increasing number of patients worldwide suffering from chronic kidney diseases (CKD), which are associated with a risk for progression to end-stage kidney disease (ESKD). CKD patients stage 2–5, patients with regular chronic dialysis treatment , and patients suffering from kidney allograft dysfunction are at high risk to develop infections, e.g. urinary tract infections (UTI) and/or sepsis (urosepsis). These groups show metabolic disturbance, chronic inflammation, and impaired immunocompetence.  Chronic kidney disease (CKD) is a very common problem especially in elderly patients. Approximately 11% of the US adult population (20 million people from 1988 to 1994) are suffering from CKD at various stages. The CKD stages are defined in Table 1 2) for more than 3 months, often combined with proteinuria. Beside morphological alterations and tissue remodelling within the kidney , various other serious alterations are involved in these processes, e.g. alterations of calcium-phosphate and vitamin-D metabolism , electrolyte and water imbalance , metabolic acidosis, microinflammation, dysregulation and instability of blood pressure  or endothelial dysfunction, increased risk of cardiovascular events, mediasclerosis, stroke, maldigestion, sarkopenia, frailty, and immunodysfunction.The typical sign of kidney injury is loss of renal function, as indicated by a reduced estimated glomerular filtration rate (eGFR). CKD is defined as a clinical condition where eGFR persists abnormally Other malformationsUrological  surgery & instrumenting and devicesFrequent admission to hospital, e.g. ICUPresence of indwelling cathetersNephrostomaImpaired glucose tolerance, Diabetes mellitusChronic prostatitis; recto-ano-genital syndromeNephrolithiasis, renal tubular acidosis, nephrocalcinosisUrolithiasis Autosomal dominant polycystic kidney disease (ADPKD)Diverticulae of the bladder, urethraInborn metabolic syndromes Medullary cystic kidney diseaseReflux Female pelvic floor dysfunctionNeurological disorders, bladder incontinence, fecal incontinenceSenile brain syndrome; low fluid intake, malnutritionComorbidities: lymphoma, myloma, cancer, etc.Urethral stenoses; endoluminal valvesCancer of the urothelInterstitial nephritisPhagocytosis capacity, recruitment of immunocompetent cellsHypoproteinaemia, anaemia, uremiaInnate immunity  Immunoglobulin subclass deficiencyBlood group B, AB, and non-secretor of blood group componentComplement activity, -activation UMOD gene (low to very low biosynthesis of Uromodulin)Mutations of RANTES polymorphism (deficiency)Immunosuppressive and cytotoxic drugsDrugs/toxins altering the urothelial mucosal barrierDisturbed microbioma of the intestine and the urinary tractParenteral iron supplementation (peaking levels), iron overloadSodium-glucose-cotransporter-2 inhibitors (SGLT2 inhibitors)Only little data exist on how many of these patients are suffering from urinary tract infections (UTI). The incidence of infections associated with CKD is less than 1 per 5,000 people per year , 4], , . ClinicaA literature search was performed in various data bases, e.g. Medline, the Cochrane Database, as well as Embase; and publications of Karger, Elsevier, Klywer, Springer, Thieme, Urban & Fischer, and Dustri were studied. The following keywords were used: urinary tract infection/UTI, renal insufficiency, kidney insufficiency, end-stage renal disease/end-stage kidney disease, diseases of the kidneys, dialysis , microbiome, microorganisms of the urinary tract, obstruction, antibiotic treatment, prophylaxis in recurrent UTI, evaluation of renal function, and bacteriuria. Only publications with published abstracts were evaluated.Apart from the impaired immune defence associated with CKD, the risk for developing UTI also depends on the underlying kidney disease. High-risk groups are patients suffering from diabetic nephropathy, nephrotic syndrome, and hypoproteinaemia, patients with analgesic nephropathy, autosomal dominant polycystic kidney disease, Randall plaques , and renal stone formers. Among them, one may also find those with congenital errors of the metabolism: cystinosis, oxalosis, chloride channel mutations, Fabry’s disease, Dent’s disease, Bartter syndromes (e.g. Bartter type V), renal tubular acidosis, idiopathic hypercalciuria, hypocitraturia, familiar hypomagnesiaemia, nephrolithiasis, genetic defects of the calcium-sensing receptor, etc. Obstructive nephropathy associated with an increased risk for UTI may arise from papillary necrosis and/or exfoliation of tissue debris into the tubular lumen, most commonly in ischaemia as well as diabetic and analgesic nephropathy. A variety of primary kidney diseases , membranous GN, focal sclerosing glomerulopathy) are treated with immunosuppressive agents. Early diagnosis of UTI may be missed easily in those patients with no or only minor clinical symptoms. In a similar manner, CKD patients suffering from systemic vasculitis, autoimmune disease, and renal allograft dysfunction should be closely monitored for UTI. Typical signs of an infection are often completely missing in these cases.In patients with mild and moderate CKD , vancomycin-resistant enterococci (VRE), Acinetobacter spp., Klebsiella spp., Morganella morganii, and E. coli, often resistant also to carbapenemes. Unfortunately, there are no detailed studies characterizing the properties of virulence factors in uropathogens. In selected febrile patients, also rare uropathogens, e.g. Leptospira bacteria, should be excluded . T. T20]. TE. coli, Bacteroides fragilis and/or Chlamydia, and Bartonella henselae.Another unsolved issue is the urinary presence of ultra-small bacteria, so-called ‘nanobacteria’. These are about 200 nm in diameter, exhibit densly packed spirals and few ribosomes; some show hairlike appendages of the cell surface. Hjelle et al.  found naNumerous data demonstrate that the immunological profile of patients with CKD or ESKD is more or less compromised with regard to their humoral and cellular adaptive and innate immunity , 24], , , 26], , , 28], , , 30], , , 32], , , 34]..34].CKD and HD patients show elevated endotoxin serum levels and a chronic microinflammatory status, mainly due to an increased translocation of bacteria and microbial material from the intestine. In addition, endotoxins from the dialysate fluid may enter the blood compartment and contribute to chronic inflammation and a risk for infectious diseases , 35], , .Even under immunosuppression, patients with a renal transplant disclose an increase of proinflammatory blood monocytes . In patiThe importance of toll-like receptors (TLR) (pattern recognition receptors) and the role of defensins in the pathogenesis of UTI, especially TLR2 and TLR4, and alterations in the expression of TLR in CKD patients were repeatedly confirmed , 46], , . The chrUMOD gene ..UMOD genImmunological factors contributing to UTI are summarized in Table 3 Uromodulin, a 85–95 kDa glycoprotein, exclusively synthesized by cells of the thick ascending limb of Henle’s loop, is the major urinary inhibitor of renal stone formation and acts as a potent antimicrobial kidney-specific defensin , 56]. D. D56]. DUMOD gene, reveal low to very low uromodulin concentrations even before the decline in eGFR, progressive renal papillary calcification, and urolithiasis, and are at risk to develop UTI and ESKD. Furthermore, low uromodulin levels are associated with a worse metabolic profile, higher prevalence of diabetes mellitus, arterial hypertension, heart failure, and overall mortality   may also be pathologically relevant, particularly in cases where a single microbe is cultured and leucocytes  are present in high numbers.Diluted urine in polyuric patients with CKD may reduce the bacterial counts and reveal a negative nitrite reaction on the dipstick test, thus presenting misleading data. In patients with symptoms suggestive of UTI, one should not rely on dipstick testing if urinary culture is recommended. Although ‘significant’ bacteriuria is usually defined as colony forming units (cfu) of ≥10A minor part of CKD patients with transient ‘significant’ bacteriuria may not suffer from ‘true’ invasive UTI, whereas others exhibiting lower bacterial counts with pyuria, fever, elevated C-reactive protein, leucocytosis may represent ‘active’ tissue-invasive bacterial interstitial nephritis . TherefoThe risk that pathogens cross the mucosal urothelial barrier depends on the host defence mechanisms, which may be altered in patients with renal failure .Apart from bacterial uropathogens, interstitial nephritis may involve nephrotropic viruses mimicking pyelonephritis, but lacking positive urine cultures and mass pyuria. Kidney pathohistology typically reveals granulomatous interstitial nephritis including epithelial necrosis of tubuli, associated with intranuclear inclusions, interstitial inflammation, giant cells, and epithelioid macrophages. Human herpes virus 6 (HHV6) involves tubular epithelial cells of the distal nephron and lymphocytic interstitial infiltrations. Interstitial nephritis due to polyoma virus infection shows positive SV-40 large-T antigen staining of nuclei of infected tubular cells, tubular atrophy, and urinary excretion of so-called ‘decoy cells’. In addition, infections with adenovirus (e.g. type 11) are usually accompanied by hemorrhagic cystitis. In all cases, elevated urinary α-1-microglobulin (>15 mg/g creatinine) indicates decreased epithelial reuptake of the biomarker due to tubular epithelial injury.Staphylococcus aureus (MRSA) . U. U71]. UA majority of patients with early CKD show normal or increased urine volumes (KDIGO stage-1 and CKD2). Oliguria is characteristic in patients treated over years by dialysis, where the residual urine volume declines progressively until (oligo-)anuria. In this context, however, oliguria is combined with reduced ability to concentrate urine, which is also seen in polyuric acute renal failure . Patients on dialysis even with residual urine output will not reach effective concentrations of antibiotics . There aThe dosage of those drugs that are preferentially cleared by the kidney needs to be adjusted according to the eGFR , 78]  and the intrinsic characteristics of the dialyzer . In a similar manner, treatment modalities in patients on peritoneal dialysis  also influence drug levels. Furthermore, the cell viability of the peritoneal membrane governs uptake (i.p. administration of antibiotics) and clearance of i.v. antibiotics, and severely alters in cases with encapsulated peritoneal sclerosis associated with high membrane transport.The antibiotic for treatment should be chosen according to the severity of symptoms, the susceptibility of the causative microorganisms, the level of CKD, and whether or not additional comorbid factors have to be taken into account. Substances with nephrotoxic potential, e.g. aminoglycosides, should be used with great caution. Antibiotics without cumulative effects, and a wide therapeutic range index should be preferred. Broad-spectrum cephalosporins and fluoroquinolones may be effective and are the drugs of choice in this setting , 81], b, b81], bOther antibiotics cause (secondary) elevation of serum creatinine by mechanisms other than direct nephrotoxicity, e.g. trimethoprim inhibits tubular secretion of creatinine . OxytetrAsymptomatic bacteriuria, ranging from 27% to 44%, has frequently been reported in CKD patients and HD patients , 43], , , 93]. I. I93]. IThere are no valid published data from randomized trials determining the optimal duration of treatment of UTI in patients with CKD and in dialysis patients. It is customary to treat even uncomplicated cystitis for at least 7 days and to continue for 21 days or more, depending on clinical severity , 70]. H. H70]. HRecurrent UTI presumably occur due to bacterial regrowth from colonies of non-planktonic bacteria residing in a protected biofilm environment. Persistent microbial niches may develop and colonize deeply within damaged renal parenchymal or urothelial tissue. Furthermore, antibiotic therapy may select highly resistant intracellular, ecologically stable bacterial communities living temporarily as commensals, so-called ‘small colony variants’ (SCV).Ultimately, the available option is surgical excision of diseased tissues. Nephrectomy is only very occasionally performed in patients with incurable relapsing destructive pyelonephritis and signs of rapidly progressive CKD. Here, the majority of patients shows resistance to any further antimicrobial treatment, and suffers from a malignant form of nephrolithiasis, heavily scarred kidneys, abscess formation, severe congenital obstruction, as well as severe recurrent UTI in polycystic kidney disease.Importantly, recent studies have confirmed again that any infection irrespective of severity is an independent risk factor for increased adverse events in the CKD population .There is no sufficient evidence that UTI  or asymptomatic bacteriuria generally worsens kidney function (eGFR). Leukocyturia and inflammation markers are important signs of UTI. Recurrent episodes of UTI increase the risk of ESKD in CKD patients. Any severe infection, such as acute episodes of pyelonephritis, recurrent UTI, urosepsis, or any UTI in symptomatic patients with ESKD and on dialysis with comorbidities should be adequately treated with antibiotics according to the recommendations of ‘antimicrobial stewardship’ in order to lower the rates of bacterial resistance. Unfortunately, no prospective clinical trials are available to assess the optimal management of UTI in patients with CKD stage 4–5 and in dialysis populations, respectively.AKI: acute kidney injuryCAKUT: congenital abnormalities of the kidney and urinary tractCKD: chronic kidney disease CKD-EPI: chronic kidney diseases epidemiology collaborationCM: contrast mediumCMS: colistimethateCT: computed tomographyeGFR: estimated glomerular filtration rateeGFR-EPI: estimated glomerular filtration rate – epidemiology collaborationESKD: end-stage kidney diseaseFGF23: fibroblast growth factor 23GN: glomerulopathy, glomerulonephritisHD: hemodialysisHHV6: human herpes virus 6HLA-DR: human leukocyte antigen – DR isotypeICU: intensive care unitIgG: immune globulin GKDIGO: Kidney Disease: Improving Global Outcomes (organization)MDR: multidrug-resistant microbesStaphylococcus aureusMRSA: methicillin-resistant MRI: magnetic resonance imagingPCR: protein chain reactionPPI-Inhibitor: proton secretion inhibitorSCV: small colony variantsSLE: systemic lupus erythematosusTLR: toll-like receptorUT: urinary tractUTI: urinary tract infectionVRE: vancomycin-resistant enterococciThis article will also be published as a chapter of the Living Handbook “Urogenital Infections and Inflammations” .JS declares that he has no competing interests.RF reports consulting fees within the last two years  from Novartis Pharma GmbH and Boehringer.KN reports personal consulting fees within the last two years  from Adamed, Biomerieux, Bionorica, Eumedica, Hermes, Immunotek, Janssen, Klosterfrau, Medice, OM Pharma.


IgA nephropathy (IgAN) is still one of the most prevalent forms of primary glomerulonephritis globally. However, no guidelines have clearly indicated which kinds of renin angiotensin system blockade therapies (ACEIs or ARBs or their combination) in patients with IgAN result in a greater reduction in proteinuria and a better preservation of kidney function. Thus, we conducted a Bayesian network analysis to evaluate the relative effects of these three therapy regimens in patients with IgAN.The protocol was registered in PROSPERO with ID CRD42017073726. We comprehensively searched the PubMed, the Cochrane Library, Embase, China Biology Medicine disc, WanFang and CNKI databases for studies published since 1993 as well as some grey literature according to PICOS strategies. Pairwise meta-analysis and Bayesian network analysis were conducted to evaluate the effect of different regimens.Seventeen randomized controlled trials (RCTs) involving 1,006 patients were analyzed. Co-administration of ACEIs and ARBs had the highest probability (92%) of being the most effective therapy for reducing proteinuria and blood pressure, but ACEIs would be the most appropriate choice for protecting kidney function in IgAN.The combination of ACEIs and ARBs seems to have a significantly better antiproteinuric effect and a greater reduction of blood pressure than ACEI or ARB monotherapy in IgAN. ACEIs appear to be a more renoprotective therapy regimen among three therapies. IgA nephropathy (IgAN) is the most prevalent form of primary glomerulonephritis globally, and remains a leading cause of chronic kidney disease (CKD) and kidney failure . Among pCurrently, the common treatments for IgAN include renin angiotensin system blockades, immunosuppressive agents, other antihypertensive agents, fish oils, anticoagulants and surgical tonsillectomy. Although there is a lack of consensus about treatment protocols due to the different clinical and pathological manifestations of IgAN, the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines in 2012  pointed Previous clinical studies and meta-analyses have shown that patients with IgAN can experience a reduction in proteinuria in response to treatment with ACEIs/ ARBs alone or a combination of ACEIs and ARBs . HoweverThe protocol of this study was registered in PROSPERO, an International prospective register of systematic reviews, which is available under ID CRD42017073726.PRISMA  guidelines  were useThe PICOS was as follows:Population: patients with IgA nephropathy.Intervention: angiotensin-receptor-blockers, ARBs, angiotensin-converting enzyme inhibitors, ACEIs, the names of currently available ARBs or ACEIs .Comparator: angiotensin-receptor-blockers, ARBs, angiotensin-converting enzyme inhibitor, ACEIs, placebo, other antihypertensive agents.OutcomesPrimary outcomesUrinary protein excretion: urinary total proteinuria.Secondary outcomesEstimated glomerular filtration rate (eGFR)/blood pressure (BP).Study design: RCTs.Studies meeting the following criteria were included: (1) randomized controlled trials (RCTs); (2) participants aged 12 years or older; and (3) participants with IgA nephropathy who reported urinary total proteinuria. Patients undergoing dialysis or kidney transplantation were excluded.Two reviewers (Zhihao Huo and Huizhen Ye) independently extracted information according to the registered protocol. The following data were extracted from each study: first author, year of publication, geographic region, and study participant characteristics . Any disagreement was resolved by a third researcher (Yaozhong Kong) after a discussion.In our study, the primary outcome was proteinuria reduction. Decreases in blood pressure and eGFR were the secondary outcomes.We used the CASP Checklist 2 statistic, and Bayesian network analysis was conducted by using ADDIS 1.16.5 software in a Bayesian Markov chain Monte Carlo framework with a consistency model or an inconsistency model. For the ranking of the interventions, stochastic multicriteria acceptability analysis (SMAA)-based models were used  . It showWe performed sample size assessment via the method called “effective sample size from an indirect comparison” recommended by A total of 682 records met the initial search criteria. A total of 642 articles were excluded after the title and abstract were reviewed, and 40 articles were found to be eligible for PICOS analysis. The remaining 40 articles were reviewed at the full-text level. Of these, 23 studies were excluded for various reasons, as shown in In this network study, 5 therapy regimens were considered for analysis: (1) combination therapy of ACEIs plus ARBs; (2) ACEI monotherapy; (3) ARB monotherapy; (4) other antihypertensive agents; and (5) placebo. In addition, the network map is shown in In our analysis, 528 patients were males (52.5%). Among the 17 trials, the longest follow-up period was 38 months, and 3 trials were reported to be multicenter studies.P values > 0.05, suggested data consistency. Hence, we conducted Bayesian network analysis with consistency random-effect models , suggesting no evidence of inconsistency. Additionally, we conducted node-splitting analysis via direct and indirect effects as presented in t models  using ADProteinuria reduction was reported in all 17 trials . The priAmong the 17 included trials, systolic blood pressure reduction was reported in 9 trials . The ranIn addition, a total of 14 studies  were inc2, and the other was due to not reporting the eGFR before treatment. Finally, the remaining 15 studies were included in the sensitivity analysis. No change was observed in the ranking of the antiproteinuric effects. For kidney function protection, the study of Shen PC et al. was excluded in the sensitivity analysis for low eGFR baseline (To assess any impact of study quality on the effect estimates, a sensitivity analysis was also conducted. Of these 17 studies, considering that different stages of chronic kidney disease may reduce the accuracy of the results, 2 studies were excluded. One was because of eGFR < 60 ml/min/1.73 mbaseline , while fTo explore the effective sample size, we performed sample size assessment according to “Sample size and power considerations in network” . The resThis Bayesian network analysis showed that combination therapy of ACEIs plus ARBs significantly seemed to have the best antiproteinuric effect and a greater reduction of blood pressure in patients with IgA nephropathy compared with single drug regimens. In addition, ACEIs appeared to be the best therapeutic approach for kidney repair, although ARBs were more likely to reduce proteinuria than ACEI therapy.β1 (β1 means slowing down the natural course of ESRD for IgAN patients.Proteinuria, an indispensable risk factor for the progression of IgAN, could be reduced by renin angiotensin system blockades, and its remission could improve the prognosis of patients with IgAN . Our stuβ1 , which iβ1 . Thus, rCollectively, co-administration of ACEIs and ARBs have greater inhibition of the adverse effects made of Ang II. Admittedly, reducing blood pressure and proteinuria to a certain extent can preserve kidney function. However, it does not mean that this can translate into a better outcome with eGFR in the long run because the decline in eGFR is also related to many factors, such as hyperglycemia, hypoproteinemia, anemia, smoking, hyperlipidemia, hyperhomocysteinemia, advanced age, malnutrition, and uremic toxin. Additionally, it is noteworthy that combining the ACEIs and ARBs would magnify side effects such as hyperkalemia and acute kidney injury . Joint Nβ1. Therefore, long-term treatment with ACEI therapy shows beneficial effects in protecting kidney function. Zhang GH and Hou FFs study (In the present network study, the second major finding was that ACEIs seemed to be a more appropriate choice to restore kidney function than dual therapy or ARB monotherapy in IgAN. The results of this study are consistent with those of others . First, Fs study  also rev2 were the primary endpoints of the STOP-IgAN trial, while urinary total proteinuria was our primary outcome.Recently, Lennartz et al. based on the results of the 3-year trial STOP-IgAN, found no obvious difference in blood pressure between treatment groups, but patients on dual RAS blockade had a slightly higher level of proteinuria. In addition, there was no significant difference between groups regarding the loss of kidney function during the trial . The resHowever, some limitations in the present network analysis should be considered. First, the inclusion criteria regarding blood pressure in the trials were different. Current therapeutic guidelines  recommenThis network meta-analysis indicates that a combination of ACEIs and ARBs seems to have a significantly better antiproteinuric effect and a greater reduction of blood pressure than ACEI or ARB monotherapy for IgA nephropathy. However, we recommend that the levels of serum creatinine, potassium and blood pressure should be closely monitored during combination drug use because of the potential harms. Our findings also imply that ACEIs would have the highest probability of protecting kidney function among all three therapies. Additional large, well-designed RCTs with longer follow-up periods are warranted to confirm these findings.10.7717/peerj.11661/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.11661/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.11661/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.11661/supp-4Supplemental Information 4Click here for additional data file.10.7717/peerj.11661/supp-5Supplemental Information 5This document explains the position of network meta-analysis. Bayesian network analysis is an extension of traditional meta-analysis. It has allowed the estimation of metrics for all possible comparisons in the same model, simultaneously gathering direct and indirect evidence, while traditional systematic reviews and pairwise meta-analyses usually compares only two interventions at the time. How to choose suitable therapeutic strategies is a common clinical problem, but no clinical studies have focused on all of these therapies. Thus, here, we tried to offer a reference to clinical practitioners.Click here for additional data file.