Previous studies suggested blood pressure variability (BPV) might help reveal interactions between blood pressure fluctuation and white matter lesions, and the impact of elevated BPV on white matter hyperintensity (WMH) or cerebral arterial dilation is unclear.This retrospective observational study involved 2634 stroke-free individuals , who underwent magnetic resonance imaging and magnetic resonance angiography scans, from a single center in Shanghai, China. Measurements for variability of blood pressure were made based on 7 days blood pressure recordings. WMHs were quantified from T2-FLAIR images and further classified as periventricular WMH or deep WMH. M1 segment of middle cerebral artery dilation was assessed from magnetic resonance angiography images. General linear model was used to examine the associations.β=0.02 , P=0.01; diastolic: β=0.05 , P<0.001). Only periventricular WMH was associated with BPV . MCA dilation was found in 125 individuals (4.75%). Systolic BPV was associated with MCA dilation only in the hypertensive individuals . Increased WMH volume was found associated with dilated MCA .Both increased systolic and diastolic BPV were associated with increased WMH volume (systolic: Increased BPV might be one of the pathophysiological phenomena involving in the small vessel disease independent of hypertension. Increased BPV might independently contribute to intracranial arterial dilation. Management of BPV might be a target to preserve cerebrovascular wellness. High blood pressure variability is linked to white matter hyperintensity and intracranial arterial dilation independent of hypertension.Even in nonhypertensive individuals, diastolic blood pressure variability was associated with increased white matter lesion volume. Moreover, excessive variability in systolic blood pressure was associated with intracranial arterial dilation only in the hypertensive individuals.Besides hypertension, management of blood pressure variability might be a target to preserve cerebrovascular wellness.1 Being a leading cerebrovascular risk, hypertension has been reported to have deleterious effects on the cerebral vessels, resulting in cerebrovascular morbidities including stroke and cerebral small vessel disease (CSVD).3 Episodic hypertension, based on the average of blood pressure (BP) measurements upon hospital admission, is commonly used to define hypertension.4 Yet, such definition may, very often, not reliably reflect the real BP of the patients.5 Not to mention it also disregards fluctuations in the BP levels.6Hypertension affects around one-third of adults worldwide.7 Excessive fluctuations in BP would affect vessels supplying the deep white matter or periventricular regions due to their anatomic features.8 Previous studies have suggested that extreme BP variability (BPV) over time could lead to higher risks of dementia and stroke.10 Moreover, extreme BPV was reported to impact large vessels, increasing arterial stiffness which predisposes risks for future stroke.11 Intracranial arterial dolichoectasia (IADE), distinct from intracranial atherosclerotic stenosis and characterized as an excessive increase in length or diameter of at least one intracranial artery, is a dilative arteriopathy.13 IADE has a different pathophysiological changes of arterial walls compared with intracranial atherosclerotic stenosis and, therefore, may be influenced by different risk factors commonly reported to contribute to intracranial atherosclerotic stenosis.13 However, only aging was consistently found to be correlated with increased cerebral arterial diameters in previous studies.15 The association between BPV and IADE has less been reported.However, as an organ with high blood flow, the brain is vulnerable, not only to elevated BP, but also to rapid changes in BP.17 As the most commonly observed clinical feature of CSVD, WMHs have been under extensive investigation, and their relationship with hypertension has frequently been reported.19 The relationship between WMHs and BPV, however, has been largely debated.20Increased BPV, meanwhile, could also affect vessels of smaller sizes. CSVD, characterized by several neuroimaging features, including recent small subcortical infarcts, cerebral microbleeds, lacunes, and white matter hyperintensities (WMHs), results in significantly increased risk of stroke and is found involved in approximately half of the dementia cases.21 We hypothesize that increased BPV would result in lesions of the both large and small cerebral vessels, manifested as larger WMH lesion volume and more severe IADE. WMHs were classified as the periventricular WMH (PWMH) or deep WMH (DWMH) to further study the differential effects of BPV on anatomically distinctive vessels, and the impact of BPV on WMH spatial distribution was reported.To investigate the complex nature of lesions of both large and small cerebral vessels and their relations with extreme BP fluctuations, we monitored the BP of subjects for 7 consecutive days and analyzed the day-to-day BPV in a large group of patients free of stroke.The data that support the findings of this study are available from the corresponding author upon reasonable request.22 The subjects involved in this study were mostly elderly individuals with traditional cerebrovascular risk factors. The main reasons for their visits were due to headache, dizziness, sleep disorders, palpitation, gait disturbances, memory loss, or concentration problems. Patients with CT-confirmed signs of CSVD were admitted for hospitalization, and conventional BP and heart rate monitoring and brain MRI were performed for further evaluation of CSVD. Neuropsychological test, sleep monitoring, and gait analysis were performed only for part of the subjects. The study uses only previously collected data, with no additional tests or interventions undertaken on any participants and thus would inflict no impact on patient care or the outcome. The Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine approved the current study (Number: 2020-060).This retrospective, observational study involves data from the Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China. Patients hospitalized in the department of neurology and underwent brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) between January 2017 and June 2021 were included as the candidates. Subjects with acute stroke, dementia, carotid, or cerebral artery stenosis were excluded. Cerebral artery stenosis was defined as any degree stenosis in at least one of the following arteries: intracranial carotid artery, middle cerebral artery (MCA), anterior artery, intracranial segment of vertebral artery, basilar artery, and posterior cerebral artery.am and 8 am after overnight fasting and used for the determination of lipid profile , creatinine, glucose, and glycated hemoglobin.Demographic characteristics, personal and family medical history, and lifestyle risk factors were collected in the clinic. Cigarette use, alcohol consumption, hypertension, diabetes, hyperlipidemia, history of cardiovascular disease  were assessed. Hypertension was defined as self-reported hypertension, treatment with antihypertensive agents, systolic BP ≥140 mm Hg, or diastolic BP ≥90 mm Hg. Venous blood samples were taken by certified nurses between 7 p and multiplied the average value of SBP in the cohort to the power p, which is obtained by fitting a curve of SD against the within-individual mean SBP.11BP was measured after the subject rested at least 5 minutes in a seated position. An appropriately sized cuff was placed on the dominant forearm arranged at the horizontal level of the fourth intercostal space at the sternum and BP was measured using a validated digital electronic tensiometer OMRON . In the following days, BP was taken from the same arm, at a similar time. BPV was calculated based on first 7 consecutive measurements after admission. Three commonly used BPV parameters were assessed including within-individual SD (mm Hg), coefficient of variation  and variation independent of mean . VIM was calculated as the SD divided by the within-individual mean to the power Supplemental Material.Individuals underwent brain MRI and MRA scan on one 3.0T MR scanner . The MRI protocol included T1-weighted structural imaging, T2 FLAIR, and time-of-flight MRA with more protocol details in the 23 The presence of WMH in the basal ganglia region was defined as at least 0.01 mL of WMH in this region. Voxel-wise regressions were performed to investigate the impact of BPV on WMH spatial distributions,24 with more details in the Supplemental Material.WMH lesions were automatically segmented from the T2 FLAIR images. The total WMH, PWMH, and DWMH lesion volume were obtained after registration of T2 FLAIR images to the Montreal Neurological Institute brain template.Figure S1). The mean diameter of each vascular segment was assessed. The sum of mean diameter of left and right M1 segment was used. Presence of MCA dilation was defined as the within-individual diameter ≥ mean diameter in the cohort + 2 SD in the cohort.13 The internal carotid artery and basilar artery were not included in the analysis as their origin could not be clearly defined in the MRA images. For more detailed information for the MRI analysis, please see Methods in the Supplemental Material.The M1 segment of the MCA was manually quantified from the vascular segmentation on MRA images .Multivariable linear regression analysis was used to assess the association of BPV with cerebral artery dilation and WMH. Due to the skewed distribution of WMH lesion volume, logarithmic transformation was applied. General linear model with logistic link function and binomial distribution was used for the binary response variable. The results of normally distributed continuous variables were presented as mean and SD or as median and interquartile range. For categorical variables, frequencies and proportions were presented. Two-sample The individual characteristics are presented in Table Table S1). In multivariable models, age remained associated with both systolic and diastolic BPV, and sex was associated with systolic BPV.Age, sex, and hypertension were found to be associated with BPV in bivariable models  and diastolic BPV , as shown in the Table P=0.02; diastolic SD: β=0.04 , P=0.01), and the association remained for diastolic SD after adjusted for risk factors .In general, higher SD, CoV, and VIM were found to be associated with increased total WMH volume, after adjusting for age, sex, and risk factors for both systolic . In the hypertensive individuals, these associations remained, whereas in the nonhypertensive individuals, only diastolic BPV was associated with WMH volume. Nevertheless, no significant interaction between BPV and hypertension status on WMH volume was observed (Table S4).These associations were further examined in hypertensive and nonhypertensive individuals . After adjusted for age, sex and risk factors, higher systolic SD  was still associated with increased MCA diameter. Meanwhile, presence of MCA dilation was associated with only three systolic BPV measures , and such associations remained after adjusted for age, sex and risk factors . In the subgroup with BMI information, after adjusted for BMI and all risk factors, presence of MCA dilation still associated with elevated BPV, while no significant association between MCA diameter and BPV was found as shown in the Table S5.Association between BPV and cerebral arterial dilation was presented in Table Table S6, in hypertensive individuals, increased systolic VIM was associated with increased diameter of MCA  after adjusted for age, sex, and risk factors. No significant association between BPV measures and cerebral arterial dilation was found in nonhypertensive individuals (Table S7), and no significant interactions were observed (Table S8).As shown in the P<0.001) and after adjusted for age, sex, and risk factors . Higher total WMH volume was also found in individuals with dilated MCA . Such patterns were similarly observed for PWMH, but not DWMH.. Only MCA diameter was associated with DWMH volume after adjusted for age, sex and risk factors . In a more focal view, the presence of WMH in the basal ganglia region was significantly associated with increased MCA diameter  and MCA dilation .The relationships between cerebral arterial dilation and WMH were further examined as shown in Table In this study, BPV indices including CoV, SD, and VIM were calculated based on consecutive measurements of BP over 7 days. CoV allows us to see how great the dispersion is around the mean, as larger CoV values indicate greater variability in BP. VIM, however, was used to help assess the associations of BPV with WMH and arterial dilation irrespect of the mean BP levels. Consequently, significant associations of VIM with several indices of vascular lesions identified in this study suggest large fluctuations in BP alone would increase the liability of the cerebrovasculature to damages. The current study provides preliminary data for future prospective studies investigating the driving forces for spatially distinct clusters of WM lesions and also suggests more active investigations on stabilizing BP for hypertensive individuals as a possible means to preserve the soundness of the cerebrovasculature should be carried out.26 To date, the association between high BP and CSVD in elderly individuals has been well established in cross-sectional and longitudinal studies.28 In addition to higher BP, large variations in BP from consecutive measures may also contribute to CSVD.31 Nonetheless, such relationship between BPV and WMH is still largely debated. Zhou et al20 suggested that long-term or short-term SD of BP are not associated with WMH features measured, and similarly, others reported no association between 24-hour SD of BP and the presence of WMH.32 In this study, increases in all three short-term measurements of BPV in systolic or diastolic BP were found to be associated with increased WMH lesion volume independent of hypertension status, and the results are the most pronounced in hypertensive patients. Such results may suggest that increased mean BP may increase the vulnerability of the vascular system to large fluctuations in BP.High BP during mid-life is widely recognized as a modifiable risk for late-life cerebrovascular disease.20 used SD based on seven days home BP measurements, while Filomena et al30 used several BPV features including SD, CoV, and weighted-SD based on 24 hours BP monitoring. Another possible reason for these inconsistent results was the differences in the measurement of WMH. In this study, after dividing the WMHs into PWMHs and DWMHs, elevated BPV, as indicated by all 3 BPV indices used, was only found associated with higher PWMH volume. Moreover, the spatial distribution pattern of WMH associated with elevated BPV is distinct from that associated with hypertension, suggesting the spatial distinct clusters of WMHs might be implicated in different pathological processes. PWMH was associated with mean arterial pressure, since the periventricular region were supplied by long straight arteries with very few branches, resulting in greater pressure transmitted directly to the small resistance vessels.33 On the contrary, the small arterioles of the cortex usually branch off long arteries with numerous branches, which resulted in a drop in BP.8 Variations in BP would, thus, expected to have diminished effects on the white matter. The heterogeneous nature of WMHs could probably underpin the discrepancies found in previous studies. Future studies should be cautious in evaluating WMH, while more attention is needed to explore other mechanisms associated with DWMH.Various BPV measurements have been used in previous studies which might be the reason for the inconsistencies found in the reported association between BPV and cerebral lesions. For example, Zhou et al13 The prevalence of MCA dilation in the current study was nearly 5%, similar to the prevalence reported in the stroke-free population (5.4%) and lower than that in patients with stroke (12%).35The cerebral artery dilation discussed in the current study is the one of the common used imaging diagnostic criteria of IADE.13 Aging, hypertension, and a history of myocardial infarction have been associated with IADE.34 In a stroke-free cohort study, only aging was found to be associated with IADE.35 Nevertheless, BPV has been associated with the functions of vessel wall, including endothelial function and smooth muscle function,36 which may be one of the reasons for the link between BPV and IADE. Furthermore, BPV was found to be associated with the prevalence of MCA dilation only in hypertensive individuals. This result suggested that elevated BPV might be more likely to induce intracranial vasodilation in hypertensive individuals. Since the arterial stiffness is associated with hypertension,37 fragile vessels walls might be more vulnerable to elevated BPV, leading to the development of excessive arterial dilation. However, the mechanism of MCA dilation in normotensive individuals remains unclear.In this study, systolic BPV was associated with intracranial arterial dilation. In previous studies, risk factors for IADE have been mainly investigated in patient with stroke.39 In this study, except for carotid dilation, intracranial arterial diameters were assessed. Increasement of MCA diameter was associated with increased WMH lesion volume, adding the additional knowledge that intracranial arterial dilation was associated not only with the presence of WMH but also with the severity of WMH. There were at least 2 possible explanations for this finding.Previous studies have reported the association between carotid dilation and CSVD.40 The association of increased diameter of the carotid artery with CSVD is also thought to be a compensatory mechanism to counteract the increase in stiffness and thickness of the arterial wall to maintain normal arterial compliance.38First, proximal vessels might undergo compensatory dilation when distal small vessel disease happened. In the experimental study, cerebral hypoperfusion due to unilateral common carotid artery occlusion is gradually restored over several months by an increase in diameter of the contralateral internal carotid artery.41 According to the Poiseuille’s law, the pressure drop is inversely proportional to the fourth power of the lumen radius. As a result, the dilated proximal vessels inevitably have a reduced partial pressure capacity, and thus elevating the BP in the distal vessels would lead to the disruption of small vessels. Moreover, it has been suggested that elevated BP may affect CSVD by reshape the large intracranial arteries.42Second, proximal vascular dilatation might lead to increased distal BP, which results in the fragile distal vessels being more vulnerable to the impact of BP. The cerebral circulation is thought to be susceptible to pressure damage, since the torrential circulation receives less vascular resistance.43 Future longitudinal studies could help to distinguish the sequence of these two processes, and thus allowing for different interventions to reduce damage to the cerebrovascular system.Nevertheless, it is more likely that the above 2 processes interact with each other, forming a vicious circle, which promotes the growth of WMH. A similar vicious cycle related to morphological modifications between large and small arteries caused by hypertension has been reported previously.There are several limitations to be addressed. First, day-to-day BPV measures can only be obtained from hospitalized subjects in this current study, since home BP measuring requires training of the subjects and the quality/credibility of data cannot be gauranteed. Further investigations are needed to determine the relationships of BPV over longer periods or 24-hour BPV with WMH and IADE. Second, the assessments of cerebral arterial dilation were based on internal diameter of the vessels. It is not yet available to direct assess modifications in the vessel wall from our current MRA scans. The use of additional imaging modalities and techniques will facilitate direct analysis of the intracranial vascular wall. Third, the configuration of the circle of Willis was not included in the analysis. The effect of the circle of Willis on the cerebral arterial dilation still needs further studies. Fourth, causal relationships between BPV and the vasculopathies could not be established in this study due to the retrospective design and observational nature. Since increased BPV might be a result of disturbed cerebral autoregulation caused by damaged vascular services. Further longitudinal studies will help distinguish the sequence of these 2 pathological alterations, and thus allowing for different interventions to reduce damage to the cerebrovascular system. Although a large sample was drawn (2634), most of them were elder Chinese residing in Shanghai, with two-thirds of them being hypertensive. As a result, our findings were not pronounced in the normotensive subpopulation and should also be interpreted with caution. Future studies involving more normotensive individuals are required to establish the association between BPV and cerebral vasculopathy.This study contributes to elucidating the impact of BPV on the cerebral vasculature. Currently, higher BP have been associated with increased CSVD. This study indicated that variation in BP, independent with BP level, was associated with both large cerebral arterial modification and small vessel disease, suggesting that elevated BPV might be one of the common pathophysiological phenomena involving in these cerebral vasculopathy. Cautions, though, were warranted since our study, limited by the retrospective design, was incable of establishing a causal relationship between excessive BPV and cerebral vasculopathy. Future longitudinal studies investigating the temporal sequence of cerebral vascular lesions and BPV changes would be required for better clinical relevance.We are greatly thankful to all the members in our research group at Fudan University and Yueyang Hospital who helped to accomplish the study.This work was supported by the National Key R&D Program of China (No. 2018YFC1312900), National Natural Science Foundation of China (No. 81971583), Shanghai Natural Science Foundation (No. 20ZR1406400), Shanghai Municipal Science and Technology Major Project  and ZJLab.None.Detailed MethodsTables S1–S8Figures S1 and S2References 42


Biologics that target Type 2 inflammation are effective in reducing exacerbations of severe asthma. We conducted a systematic review and integrated analysis of the efficacy and safety of these biologics in chronic obstructive pulmonary disease (COPD) patients with increased peripheral blood eosinophils.ClinicalTrials.gov. We analyzed the clinical efficacy of anti-IL-5-targeted therapy at approved  and high  doses.Clinical trials of biologics that target Type 2 inflammation in COPD were found using PubMed, the Cochrane Library, and p = 0.05], but did not reduce exacerbations requiring emergency department visits or hospitalization. High-dose benralizumab and mepolizumab reduced moderate-to-severe exacerbations by 12%  and exacerbations requiring emergency department visits or hospitalization by 33% . Neither dose improved St. George's Respiratory Questionnaire or COPD Assessment Test scores. The safety of benralizumab and mepolizumab was comparable to placebo.Approved benralizumab and mepolizumab doses tended to reduce moderate-to-severe exacerbations by 9% , Benralizumab and mepolizumab have limited efficacy in reducing moderate-to-severe exacerbations in COPD patients with increased peripheral blood eosinophils and requires at least high doses. •This integrated analysis shows limited efficacy of anti-IL-5 therapy in COPD.•High doses of anti-IL-5 therapy are required to reduce moderate-to-severe exacerbations. Benralizumab; Chronic obstructive pulmonary disease; Eosinophil; Exacerbation; Mepolizumab COPD is caused by airway and/or alveolar abnormalities following exposure to noxious particles such as tobacco smoke . COPD exType 2 airway inflammation induced by antigen-specific immunoglobulin E (IgE), interleukin-4 (IL-4), IL-5, IL-13, and thymic stromal lymphopoietin is associated with increased exacerbations and airway remodeling in patients with asthma. Omalizumab, dupilumab, benralizumab, and mepolizumab are monoclonal antibodies (mAbs) against IgE, IL-4/IL-13 signaling, the anti-IL-5 receptor α, and anti-IL-5, respectively. In phase III clinical trials, these four mAbs reduced moderate-to-severe exacerbations in severe asthma patients with Type 2 airway inflammation  and are 22.1ClinicalTrials.gov databases on 1 December, 2021.This systematic review and integrated analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) Statement . We sear2.2Double-blind, placebo-controlled trials of these mAbs in study subjects with COPD were included. Subjects with asthma COPD overlap (ACO) were excluded. Two reviewers independently validated the relevant studies from the literature searches. The eligible studies were selected by PRISMA criteria and the disagreements regarding eligibility were resolved by consensus. The quality of a body of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system .2.3The following outcome measures were included to evaluate clinical efficacy and safety: moderate-to-severe exacerbations, time to the first moderate-to-severe exacerbation, exacerbations leading to an emergency department (ED) visit or hospitalization, the St. George's Respiratory Questionnaire (SGRQ) score, COPD Assessment Test (CAT) score, pre-bronchodilator forced expiratory volume in one second (FEV1), rescue inhaler use, the proportion of nights awoken, all adverse events, serious adverse events, and death. The effect measures used in the outcome synthesis are as follows. The risk ratio (RR) was used for moderate-to-severe exacerbations and exacerbations leading to an ED visit or hospitalization. The hazard ratio (HR) was used for time to first moderate-to-severe exacerbation. The mean difference (MD) was used for the SGRQ score, the CAT score, FEV1, rescue inhaler use, and the proportion of nights awoken. The odds ratio (OR) was used for all adverse events, serious adverse events, and death.2.4p-value less than 0.05 was considered statistically significant. Statistical heterogeneity among the trials was assessed using the standard I2 value of 0–25%, 25–50%, 50–75%, and 75–100%, which indicated no, low, moderate, and high heterogeneity, respectively. A fixed-effect model (the inverse variance method for MD and HR as well as the Mantel-Haenszel method for RR and OR) was used when heterogeneity was absent. Otherwise, a random-effect model (the Der Simonian and Laird method) was used. We did not consider publication bias because of the low number of publications included in the study.The integrated analysis was conducted with the "meta" package of R version 4.1.1. A 33.1A PRISMA flow diagram to select studies for the integrated analysis of biologics that treat COPD with increased peripheral blood eosinophils is shown in 3.2To analyze COPD patients with increased peripheral blood eosinophils, all cases reported by Dasgupta, et al.   and high  doses were included in the integrated analysis of COPD patients with increased peripheral blood eosinophils. In the TERRANOVA, benralizumab 10 mg was administered subcutaneously, but these subjects were not included in the integrated analysis because it was not shown to be effective, it was a lower dose than approved, and was subject to being double counted in the placebo. The pilot study  was not 3.3p = 0.003]. An integrated analysis of approved benralizumab and mepolizumab doses showed a trend of 9% reduction in moderate-to-severe exacerbations    and 23% , respectively (p = 0.0004) but high doses of mepolizumab did not. An integrated analysis of high benralizumab and mepolizumab doses showed a 33% reduction in exacerbations leading to an ED visit or hospitalization  , 2,230 patients received benralizumab, but only 1,581 were COPD patients with increased peripheral blood eosinophils , 10, 11.dence C) A. At higdence B) A. Approvectively B. An intectively C. High ddence B) C.Figure 3.4p = 0.02), which was less than the minimal clinically important difference (MCID) of two points [An integrated analysis of either approved or high doses of benralizumab and mepolizumab did not improve SGRQ scores (level of evidence C) A. The apo points . An intep = 0.03, level of evidence B) and 0.49 puffs/day , respectively . There was a trend for high-dose benralizumab to reduce the proportion of nights awoken   B.Figure 3.5In both approved and high doses of benralizumab and mepolizumab, the incidence of all adverse events, serious adverse events, and death was comparable to placebo in patients with COPD  A–C.Figur4In the present systematic review and integrated analysis, we showed statistically significant but limited benralizumab and mepolizumab efficacy at reducing moderate-to-severe exacerbations in COPD patients with increased peripheral blood eosinophils.Approved doses of benralizumab and mepolizumab tended to reduce moderate-to-severe exacerbations by 9% but did not reduce exacerbations requiring ED visits or hospitalization or improve SGRQ or CAT scores. High doses of benralizumab and mepolizumab reduced moderate-to-severe exacerbations by 12% and exacerbations leading to an ED visit or hospitalization by 33% but did not improve SGRQ or CAT scores. These data clearly demonstrate that high doses are required for anti-IL-5-targeting therapy to alleviate moderate-to-severe exacerbations in COPD patients with increased peripheral blood eosinophils. When discussing clinical efficacy, it should be noted that study subjects were not only COPD patients with increased peripheral blood eosinophils, but also those with frequent exacerbation mostly taking inhaled corticosteroids and about 30% of patients were current smokers .ClinicalTrial.gov, which raises questions about the accuracy of the analyses [Five meta-analyses for biologics in patients with COPD were published to-date. Rogliani et al. conducted a meta-analysis of biologics with differing mechanisms of action, including anti-IL-5, anti-IL-5 receptor α, ant-IL-1β, anti-IL-1 receptor 1, anti-IL-8, and anti-tumor necrosis factor-α mAbs . Unfortuanalyses . Pavord analyses . Zhang, analyses . Some pranalyses , but thiCrinicalTrials.gov, the high-dose benralizumab or mepolizumab group had a 33% reduction in exacerbations leading to an ED visit or hospitalization. Third, previous meta-analyses concluded that anti-IL-5-targeted therapy significantly reduced moderate-to-severe exacerbations in COPD, but our integrated analysis of two doses demonstrated that the doses approved for severe asthma were not sufficient. In our analysis, high doses, at a minimum, were required to reduce moderate-to-severe exacerbations in COPD patients with increased peripheral blood eosinophils. Finally, drug costs for these biologics are extremely expensive. Approved doses of 100 mg mepolizumab costs about $1,550 every 4 weeks, and 30 mg benralizumab costs about $3,100 three times a month and $1,550 every 8 weeks. Therefore, the clinical benefits of biologics do not appear to be worth their cost for COPD patients with increased peripheral blood eosinophils.The major differences between previous meta-analyses and the present study are described below. First, we conducted an integrated analysis of approved doses, those approved for severe asthma, and high doses in COPD patients with increased peripheral blood eosinophils. High doses of benralizumab and mepolizumab did not prevent the primary endpoint of moderate-to-severe exacerbations, in their respective clinical trials, but when the two drugs were integrated for the analysis, moderate-to-severe exacerbations decreased by 12%. Second, the data for benralizumab, which was not included in the original paper, was included as a secondary endpoint in the integrated analysis for exacerbations leading to an ED visit or hospitalization. By combining the detailed data reported in the There are several limitations to our study. First, multiple cutoff values for peripheral blood eosinophils were used to define COPD patients with increased peripheral blood eosinophils, as mentioned in the results. Second, we did not evaluate publication bias with a funnel plot analysis because of the few studies used for the integrated analysis.5The anti-IL-5-targeting biologics benralizumab and mepolizumab have limited efficacy in reducing moderate-to-severe exacerbations in COPD patients with increased peripheral blood eosinophils. Given their high costs, we do not recommend prescribing benralizumab or mepolizumab for COPD patients with increased peripheral blood eosinophils that do not have asthma complications.Hiroshi Ohnishi: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the paper.Masamitsu Eitoku: Analyzed and interpreted the data; Wrote the paper.Akihito Yokoyama: Conceived and designed the experiments; Wrote the paper.The authors declare the following conflict of interests: Hiroshi Ohnishi and Akihito Yokoyama receive lecture fees from pharmaceutical companies including AstraZeneca K.K., Japan, GlaxsoSmithKline plc, Japan, Novartis Pharma, Japan, and Sanofi K.K., Japan, which supply biologics for severe asthma.Data included in article/supp. material/referenced in article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.No additional information is available for this paper.


The aorta and its main branches are affected by the uncommon systemic vasculitis known as Takayasu's arteritis (TA). The gradual onset of the disease and early, very generalised symptoms may factor in the large delay in diagnosis and treatment. This is an interesting case report of a patient with the rare condition of TA, who was unaware of her disease. Her ailment was diagnosed during antenatal examination, and this report speaks of her further imminent management without any adverse effects on maternal or foetal outcomes. To enhance maternal and foetal prognosis, gynaecologists, cardiologists, radiologists, and neurologists must work together collaboratively. Here is a case study of a woman who had TA and bravely defied the condition's whims to give birth without issue. Pulseless disease/young female arteritis, often known as Takayasu's arteritis (TA), is an uncommon, chronic inflammatory large vessel vasculitis of unknown cause that affects women of childbearing age . The JapThe progression of the disease is unaffected by pregnancy per se; however, the second and third trimesters have the peak incidence of the condition. Due to the possibility of problems such as hypertension, multiple organ dysfunction, and stenosis obstructing regional blood flow, such patients require specific treatment throughout the peripartum period, which can result in intrauterine growth restriction and birth weight below 2500 grams (low birth weight) in newborns. Patients usually conceive without being aware they have TA or having started particular therapy for it because diagnosis delays are relatively typical . A diffiA 21-year-old pregnant woman with primigravida with 8.4 weeks gestational age came with complaints of cold and sneezing for 15 days. All basic investigations were sent and were within normal limits except, on clinical examination, it was found that the recordings of blood pressure in the two arms were different. The right upper arm had a blood pressure of 96/60 mmHg, whereas the left upper arm had 102/60 mmHg; the left upper arm had more blood pressure. The radial pulse of the patient was feeble (pulselessness); the patient had no history of hypertension in the past and no relevant family history for TA. Bruit was appreciated very well in the right and left carotid and left radial arteries. Since the patient was a young Asian female with clinical features pointing towards a systemic vasculitis pathology, the attending started thinking along the lines of TA. Chest X-ray showed widened mediastinum, as shown in Figure Two-dimensional (2D) echocardiogram and carotid Doppler were advised. Figure As term approached, after consultation with the treating cardiologists, aspirin and corticosteroids were discontinued, and induction of normal labour was initiated. Mechanical dilatation and prostaglandins were the methods of choice. Physician's opinion on intrapartum management of labour was also sought. After strict fetal heart sound monitoring and blood pressure, pulse, peripheral oxygen saturation (SpO2), and bleeding per vagina monitoring, the patient was managed. The risks versus benefits of epidural analgesia were also discussed with the patient. However, at 37.6 weeks of gestational age, owing to non-progress of labour, the patient was taken for emergency caesarean section and a 2.8-kilogram female baby was delivered. The intra and postoperative periods were uneventful with close surveillance [Women account for approximately 80% to 90% of TA cases, and the disease often manifests between the ages of 10 to 40 years . The aorPreconception treatment is essential for treating women of childbearing age having TA. However, such type of therapy will mainly concentrate on dosage adjustments, stopping cytotoxic medications, folic acid supplementation throughout the pre-conception phase, and the best time to become pregnant. Similarly, patients are recommended to plan an early visit for routine prenatal care because TA is possible throughout the remission phase; pregnancy should also be planned for better outcomes without much problem. In addition to standard antenatal checkups, serial monitoring of blood pressure, renal function, and cardiac status, and pre-eclamptic screening are critical in these patients. The daily count of foetal kicks, gravidogram, serial foetal biometry, biophysical profile, and foetal Doppler are also essential components of foetal surveillance. Pregnancy does not impact TA's progress. However, maintaining blood pressure control is crucial since any rise could cause an aneurysm to burst, causing hypotension or maternal cerebral ischemia. The ineffectiveness of peripheral blood pressure monitoring may also make it more challenging to treat hypertension in these people because upper extremity pulses may be absent. The monitoring of blood pressure several times in extremities or invasive blood pressure monitoring can benefit patients.However, managing blood pressure may be challenging because of the physiological changes that occur during pregnancy. Any patient with TA should make plans to get pregnant once their blood pressure and condition are stable. Antihypertensive medicine must be regulated, and angiotensin inhibitors and angiotensin-converting enzyme (ACE) inhibitors must be contraindicated. On the other hand, it has been demonstrated that hypertension which is out of control during pregnancy is associated with aortic dissection, cardiac and renal failure, stroke, and maternal death. Ultimately, for patients with TA, vaginal delivery has emerged as the optimal method of labour management. Epidural analgesia has also been promoted for use during childbirth.This is an exciting report of successful pregnancy and live birth after the diagnosis of TA in a pregnant female, who despite the cardiovascular risk was safely delivered with a healthy child. TA being a rare disease, not a lot has been studied about its correlation with pregnancy. Symptomatic treatment remains the mainstay of treatment for now. Obstetricians face a difficult problem while caring for pregnant women with TA. The ideal care for pregnant individuals with this condition remains elusive despite improvements in cardiovascular management and the introduction of cutting-edge medications. Further studies are required to further our understanding of disease progression.


Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly associated with asthma. Treatment of CRSwNP includes intranasal and systemic corticosteroids, with non‐responsive patients commonly considered for endoscopic sinus surgery (ESS). This nationwide register‐based study evaluated the incidence, prevalence, and treatment burden of CRSwNP in Finland, and their association with the presence and severity of comorbid asthma.Electronic health records of patients diagnosed with CRSwNP between 1.1.2012 and 31.12.2018 in Finnish specialty and primary care were included in the study. The patients were divided into subgroups based on presence, severity, and control of asthma: no asthma, mild to moderate asthma, severe controlled asthma, and severe uncontrolled asthma. A mean cumulative count of ESS was calculated over time per subgroup.p < 0.001). A total of 18,563 patients  had incident CRSwNP between 2012 and 2019, with 27% having asthma, 6% having severe asthma, and 1.5% having severe uncontrolled asthma. In the no asthma, severe controlled asthma, and severe uncontrolled asthma subgroups, systemic corticosteroids were used by 54.1%, 94.9% and 99.3% (p < 0.001), respectively, while the ESS count 3 years post diagnosis was 0.49, 0.68 and 0.80, respectively.The prevalence of CRSwNP increased from 602.2 to 856.7 patients per 100,000 population between years 2012 and 2019 (The prevalence of CRSwNP showed a significant increase in the recent decade in Finland. Comorbid asthma, and in particular severe asthma, increased the probability of receiving systemic corticosteroids and undergoing ESS. Thus, improved management of CRSwNP in patients with comorbid asthma is urgently needed. For patients with CRSwNP who do not respond to conservative therapy, endoscopic sinus surgery (ESS) is considered. CRS with nasal polyps patients have been demonstrated to benefit from ESS, although a part of the CRSwNP patients have polyp regrowth and a need for a revision ESS as signs of uncontrolled disease.A limited number of studies indicate that both medical interventions and FESS improve nasal outcomes in patients with CRS and asthma,2The study was conducted with permission from the Finnish Social and Health Data Permit Authority Findata (THL/4801/14.02.00/2020 [2020/576]) by the provision of the Act on the Secondary Use of Health and Social Data (finlex 552/2019), therefore no informed consent from the patients was required.2.1The data was available from 1 January 2000 to 31 December 2019. The study cohort included incident adult patients with a diagnosis of CRSwNP between 1 January 2012 and 31 December 2018. The patients were identified on their index date, the date of first CRSwNP diagnosis, by having any of the following ICD‐10 diagnosis codes: J32.4 or J33.0, J33.1, J33.8, J33.9, or a polypectomy of internal nose reported by the Nordic Classification of Surgical Procedures code DHB20. Furthermore, patients were considered to have severe uncontrolled CRSwNP if they had at least two purchases of systemic corticosteroid (SCS) (ATC‐code: H02*) in 1 year and at least one revision ESS during the follow‐up. Patients with cystic fibrosis (E84*) or ciliary dyskinesia  were excluded from the study. The patients were identified from the national Finnish Care Register for Health Care and Register of Primary Health Care (Avohilmo) visits, from where their diagnoses, procedures, visits, and resource utilization were extracted. The data from the Care Register for Health Care was complemented with data from the Social Insurance Institution for reimbursed medications and purchases, and with data from Statistics Finland for vitality status and causes of death.Data from 2000 to 2012 was used to assess comorbidities and clinical characteristics. The baseline period was set to 36 months prior to index, where baseline comorbidities and characteristics were described. Patients were followed up until the end of the study (31 January 2019) or death. Data for at least 1 year of follow‐up was available for all patients . Severe asthma was defined as asthma with a daily use of fluticasone propionate ≥800 μg or equivalent  complemented with at least one other controller . The daily average ICS use was calculated as fluticasone propionate equivalent based on a sliding window of three consecutive purchases . The patients with severe asthma were further divided into those with controlled and uncontrolled asthma. Asthma was considered uncontrolled in patients who had been hospitalized for asthma (ICD:10 J45‐J46), had a record of emergency room visit for asthma (ICD:10 J45‐J46), or had an outpatient visit for acute asthma (ICD‐10: J46).Further, to assess the proportion of CRSwNP and/or asthma patients with non‐steroidal anti‐inflammatory drug‐exacerbated respiratory disease (NERD), we analyzed the number of patients with ICD‐10 code J45.* (Asthma) and/or J33.*/J32.*  and Z88.6 .2.3The annual incidence and prevalence of CRSwNP were assessed during 1 January 2012–31 December 2019 by dividing the number of incident and prevalent cases by the total Finnish population. Patients who fulfilled the criteria for CRSwNP during 1 January 2000–31 December 2011 were included in the prevalence assessment. Incident patients were defined as patients with a first record fulfilling the criteria for CRSwNP during 1 January 2012–31 December 2019. The presence of a monotonic time trend in prevalence and incidence was assessed using the Mann‐Kendall test.Patient demographics, clinical characteristics and disease burden were tabulated at baseline, overall and by subgroups, and described using summary statistics . The Charlson comorbidity index was calculated using ICD‐10 codes as implemented in the comorbidity R package.Time to first and repeated ESS were assessed using Kaplan‐Meier fits, where time from index to surgery was defined as an event and the end of follow‐up or death as a censoring event. In the Kaplan‐Meier fit of repeated ESS, only patients with at least one ESS were included. The Kaplan‐Meier fits were visualized including the 95% Confidence Intervals (CIs), and median survival was reported, if reached. A mean cumulative count of ESS (with 95% CIs) was calculated over time overall and per subgroup using a Mean Cumulative Function.The impact of asthma  and other concomitant diseases on CRSwNP severity (non‐severe CRSwNP and severe uncontrolled CRSwNP) were assessed using a multivariable binary logistic regression model adjusted with age as a continuous covariate and sex and the following concomitant diseases as categorical covariable: chronic obstructive pulmonary disease (identified by ICD‐10 code J44.9), diabetes , gastroesophageal reflux disease (K21.9), hypertension (I10), obesity (E66), and thyroid dysfunction (E01‐E03).All statistical analyses were run using R version 4.0.3 on RStudio Server version 1.4.1103,33.1p < 0.001) .Altogether, 53,119 fulfilled the study diagnosis criteria for CRSwNP, and 18,563 (35%) were incident patients. The results show a continuous increase in lifetime prevalence of CRSwNP patients from 602.2 patients per 100,000 population in 2012 to 856.7 patients per 100,000 population in 2019 , 27.0% had been diagnosed with asthma, with 5.8% of the incident patients having severe asthma. The number of patients with severe uncontrolled asthma was 283 patients (1.5% of the incident patients). A total of 62.7% of the patients had used any systemic corticosteroids (SCS) during the study period (2012–2019). The use of SCS was more common in patients with comorbid asthma, especially in those with more severe asthma (p < 0.001). Similarly, the severe uncontrolled CRSwNP was more common in patients with comorbid asthma (p < 0.001) with the proportion ranging from 2.4% to 16.0% in patients with no asthma to severe uncontrolled asthma, respectively. At baseline, the most common comorbidities were upper airway diseases, dental problems, cardiovascular diseases, back pain, and obesity  are presented in Table During follow up, intranasal corticosteroids purchases (ATC subgroup R01*) were found for 90% of the patients. For the baseline and follow up combined, 94.7% of patients had purchases for R01 category medications.3.3The mean cumulative count with 95% CIs for ESS for all incident CRSwNP patients during an 8‐year follow‐up is presented in Figure Overall, during the follow‐up period, 8673 patients out of the total 18,563 incident CRSwNP patients (46.7%) had undergone an ESS to treat the polyps. The probability of having an ESS was 40.6% (95% CI 39.9%–41.3%) for the CRSwNP patients during the first year after the diagnosis of polyps Figure . The medOut of the 8673 CRSwNP patients who had an ESS, 7227 (83.3%) had only one ESS, whereas 1446 (16.6%) patients had two or more sinus surgeries. Overall, the probability for at least one revision ESS during follow‐up within 2 years after the first ESS was 10.6% (95% CI 10.0%–11.3%) Figure . Figure 3.4p < 0.001) with adjusted odds ratios of 4.04 (95% CI 3.44–4.75), 7.01 (95% CI 5.50–8.93), and 8.82 (95% CI 6.25–12.43) for non‐severe, severe, and severe uncontrolled asthma, respectively. Moreover, age was negatively associated with CRSwNP severity (p < 0.001) with an odds ratio of 0.98 (95% CI 0.98–0.98). Asthma was a more important variable than age in the model with corresponding mean Shapley values  of 0.61 and 0.40 . In general, the average age of onset of CRSwNP was 52 years, and the typical age at diagnosis ranged from 50 to 60 years, which is in line with previously reported findings.In Finland, CRSwNP management is initiated rapidly after the diagnosis. About two thirds (62.7%) of the patients with CRSwNP were treated with SCSs and about half of them had ESS. In our study, more than 40% of the CRSwNP patients had ESS within the first‐year post diagnosis, 38.9% had only one ESS, whereas 7.8% needed ESS at least twice. Apart from a small study reporting a 7% revision rate in CRSwNP patients,Comorbid asthma and especially severe asthma increase the probability of being treated both with SCSs and surgical treatment. In line with previous studies, our study showed that asthma status and especially the severity of asthma was associated with the likelihood of having an earlier ESS.With regards to the CRSwNP patients with or without asthma, very low numbers were found to have the ICD‐10 code for NERD. This is likely explained by the fact that Z88.6 also code for any other allergic reactions due to analgetic agent, moreover, it is unfortunately rarely systematically coded by physicians. Hence the proportion of subjects with Z88.6 diagnosis was low which does not reflect the true prevalence of NERD in Finland. In the study by Nuutinen et al.,The management of patients with CRSwNP and severe uncontrolled asthma remains a challenge.Our results suggest that type‐2 high conditions (comorbid CRSwNP and asthma) increase probability of revision ESS. Although these findings require validation in other populations, in terms of patient counseling use, our results emphasize the importance of diagnostics and management of both CRSwNP and asthma to prevent uncontrolled disease, suffering and costs. Further, depending on the national reimbursement policies of biological medications, some patients with comorbid asthma and CRSwNP may find it easier to access these new treatments based on the severity of asthma rather than CRSwNP.The major strength of this study is that it includes an unselected population‐based cohort of Finnish CRSwNP patients, which limit the risk of selection bias. Furthermore, it includes real‐world data from mandatory national health‐care registries with high quality and coverage from both primary and secondary care, providing a solid and unique set of data.There are also several limitations related to this kind of retrospective database analyses. These include the risk that some information may not have been consistently recorded for all patients, potentially impacting the population size and other outcomes. Further, the asthma severity and the level of control were based on dispensed medication and health care visits without knowledge of asthma symptoms. Also, we acknowledge that the ICD‐10 code (J33.) also include antrochoanal polyps, which are rare, often unilateral, neutrophil‐rich, and usually do not reoccur after primary operation, and which have not been shown to be associated with asthma.In conclusion, CRSwNP is a prevalent and increasing health problem with frequent need for treatments with potentially severe side effects. As concurrent asthma and especially severe asthma is associated with need for even more intense treatment, these subjects need special attention. New treatment modalities, such as monoclonal antibodies, are needed to tackle airway inflammation and decrease the need for systemic corticosteroids and surgical procedures to improve burden of disease in subjects with CRSwNP.Sanna Toppila‐Salmi, Kaisa Nieminen, Gunilla Telg, Lauri Lehtimäki contributed to study design. All authors Sanna Toppila‐Salmi, Juhani Aakko, Bettina Mannerström, Jenni Hällfors, Kaisa Nieminen, Gunilla Telg and Lauri Lehtimäki contributed to interpretation of data and were involved in manuscript writing and revision. Juhani Aakko and Jenni Hällfors contributed to data acquisition and analyses. All authors Sanna Toppila‐Salmi, Juhani Aakko, Bettina Mannerström, Jenni Hällfors, Kaisa Nieminen, Gunilla Telg and Lauri Lehtimäki gave final approval for manuscript publication and agreed to be accountable for all aspects of their work.Sanna Toppila‐Salmi reports a grant of GSK and consultancies for ALK Abello, AstraZeneca, ERT, Novartis, Sanofi Pharma, and Roche. All these are outside the submitted work. Lauri Lehtimäki has received fees for lectures or advisory board meetings from ALK, AstraZeneca, Boehringer‐Ingelheim, Chiesi, Circassia, GSK, Mundipharma, Novartis, Orion Pharma and Sanofi. Lauri Lehtimäki owns shares of Ausculthing Oy. Gunilla Telg and Kaisa Nieminen are employees of AstraZeneca. The remaining authors has no conflicts to declare.Table S1Click here for additional data file.Table S2Click here for additional data file.Table S3Click here for additional data file.


Background and Objectives: Sexual function and nutritional status assessment are relevant topics in chronic kidney disease patients. This study was designed to investigate whether bioelectrical impedance analysis-derived nutritional parameters, nutritional biomarkers, and handgrip strength influence sexual function and to analyze the changes in sexual function after kidney transplantation in men. Materials and Methods: Fifty-four men with kidney failure who had undergone replacement therapy entered the study. In addition, sexual function and nutritional status were evaluated before kidney transplantation and 12 months after. We used the International Index of Erectile Function, bioelectrical impedance analysis, three different malnutrition screening tools, handgrip strength, and anthropometric measurements. The demographic profiles and biochemical nutritional markers were collected. Results: Sexual inactivity was associated with a lower phase angle (6 (1) vs. 7 (1), p < 0.05) and a higher fat mass index (7 (5) vs. 3 (4), p < 0.05). Normal erectile function before kidney transplantation was significantly related to higher fat-free mass (67 (11) vs. 74 (7), p < 0.05) and lean mass (64 (10) vs. 70 (7), p < 0.05). The improvement in erectile function after kidney transplantation was nonsignificant . Only a weak association between muscle mass and sexual desire 12 months after kidney transplantation was found . Further, linear regression revealed that higher muscle mass could predict better sexual desire after kidney transplantation following adjustment for age, estimated glomerular filtration rate, and diabetes mellitus. Conclusions: Kidney transplantation did not significantly improve erectile dysfunction in our study population. Sexual desire and intercourse satisfaction are the most affected domains in patients with chronic kidney disease. Higher muscle mass predicts higher sexual desire after kidney transplantation. Higher levels of fat-free and lean mass are associated with normal erectile function before kidney transplantation. Chronic kidney disease (CKD) is a leading public health problem worldwide, with a continuously rising incidence during the past decades, affecting quality of life despite the increase in life expectancy in these patients . In addiPoor nutritional status due to protein-energy wasting (PEW), malnutrition, and sarcopenia are frequent complications associated with increased mortality in patients with CKD . HoweverCurrently, a limited number of studies have investigated the impact of nutritional status on sexual function in KT recipients. Therefore, the primary endpoint of the study was whether any nutritional parameters influence any aspect of sexual function  before and after KT. The secondary endpoint was the impact of KT on specific domains of sexual function.This prospective observational study was carried out between January 2018 and March 2020 in a tertiary referral university hospital. The aim of this study was to evaluate male sexual function and investigate its associations with anthropometric measurements, handgrip strength, biochemical markers, and bioelectrical impedance analysis (BIA)-derived nutritional parameters at baseline (before KT) and 12 months posttransplant.The inclusion criteria were as follows: (1) male sex; (2) age greater than or equal to 18 years; (3) KFRT  or peritoneal dialysis (PD)) for more than 3 months; (4) being a kidney transplant recipient; and (5) signing an informed consent form. The exclusion criteria were as follows: limbless patients, patients with pacemakers, and patients who refused to participate in the study. The flowchart of patient selection is shown in The study was approved by the regional research ethics committee and complies with the principles of the Helsinki Declaration. Written informed consent was obtained from all patients before enrolment in the study.The blood samples for the assessment of albumin and prealbumin were collected twice during the study: at baseline (before KT) and 12 months later, after a 12-h overnight fast. BD Vacutainer SST-II Advance Serum Separator Tubes  were used. Samples were centrifuged at the local clinical chemistry laboratory  and analyzed the same day using standard automated methods.The International Index of Erectile Function (IIEF) is an extensively used, self-report diagnostic tool for the evaluation of male sexual function and ED severity. The IIEF is a 15-item tool that examines five domains of male sexual function: erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), and overall satisfaction (OS) . Each qu2). The waist circumference (cm) was examined 2.5 cm above the umbilicus using a measuring tape.The anthropometric measurements for all participants were performed by one trained nephrologist. Height (cm) and weight (kg) were measured using an automatic scale with a sensitivity of 0.1 cm and a resolution of 0.1 kg . BMI was calculated as a ratio between weight and height in metres squared (kg/mHandgrip strength (HGS) is an important tool for representing overall muscle strength and diagnosing sarcopenia. HGS in our study was measured using a Saehan hydraulic hand dynamometer  with a scale of strength up to 100 kg. HGS was evaluated on the nonfistula dialysis arm or, if there was no fistula or PD patient, on the dominant arm. Three measurements were performed with an interval of 5 s between measurements, and the highest value was used for analysis.Bioelectrical impedance analysis is a technology that is widely used for the assessment of body composition. The purpose of BIA is to measure the electric impedance of an electric current passing through the body. We performed measurements by using an InBody S10 portable body bioimpedance spectroscopy device . The analysis was conducted with patients in a supine position 30 min after HD or when patients had an empty abdomen in PD patients, and all recommendations from the European Society for Clinical Nutrition and Metabolism (ESPEN) and the manufacturers were followed .2 (kg/m2).BIA-derived parameter indices (fat mass index (FMI), fat free mass index (FFMI), muscle mass index (MMI), lean mass index (LMI), and body cell mass index (BCMI)) were calculated by dividing each type of tissue weight in kilograms by heightNutritional risk screening tools are very helpful in daily clinical practice to detect potential or existing malnutrition. Currently, more than 33 different nutritional risk screening tools are available . We chosThe Subjective Global Assessment Scale (SGA) is a validated tool to assess nutritional status and is recommended by the American Society of Parenteral and Enteral Nutrition (ASPEN). The SGA focuses on features of the medical history and physical examination and scores patients on a scale ranging from A-well nourished, B-mild to moderately malnourished, to C-severely malnourished .For the MIS, the cut-off proposed by Yamada et al. was used to classify nutritional status: 0 to 5 well-nourished, 6 to 10 mild PEW, and ≥11 moderate to severe PEW .The results are expressed as the mean ± standard deviation (SD) or the median with interquartile range (IQR), and categorical variables are expressed as percentages. Data were tested for normal distribution by Shapiro–Wilk statistics. To check the equality of two groups, an F test and, if appropriate, a paired Student’s t test for normally distributed data or a paired Wilcoxon signed rank test for nonparametric variables were applied, and for categorical variables, a chi-square test was used. For correlations between nutritional parameters and sexual function , Spearman’s rank test was performed.Linear regression analysis was used to evaluate the association of muscle mass ) with sexual desire 12 months after KT.p lower than 0.05 was considered significant. All analyses were performed using R Commander (Rcmdr) version 3.3.2.A value of Fifty-two male kidney transplant recipients were enrolled. Baseline characteristics are presented in The underlying causes of kidney disease included glomerulonephritis (60%), polycystic kidney disease (12%), inherited kidney diseases (13%), diabetic nephropathy (8%), amyloidosis (2%), pyelonephritis (2%), and kidney stones (4%). A total of 50 out of 52 enrolled patients (96 %) had primary or secondary hypertension. A total of 46% of patients received four or more antihypertensive agents. Only 8% were taking monotherapy, 27% were taking dual therapy, and 19 % triple therapy. Among all antihypertensive classes, the most common were calcium channel blockers (67%) and beta blockers (65%). Other antihypertensive agents were used more rarely: centrally acting (48%), angiotensin receptor blockers (ARB) (44%), diuretics (33%), alpha blockers (29%), and angiotensin-converting enzyme (ACE) inhibitors (13%).Identical immunosuppressive treatment with a combination of a calcineurin inhibitor, methylprednisolone, and mofetil mycophenolate was prescribed to all participants. The mean cold ischaemia time was 14 h 48 min ± 7 h, and in 34 cases (65%), delayed graft function without acute transplant rejection was observed.n = 41) and inactive (n = 11) KT recipients before KT  and only one-third (36%) of sexually inactive men had a sexual partner. Obesity was prevalent in 46% of sexually inactive men and in 15% of sexually active men. In addition, sexually active men had significantly higher BIA-derived PhA but lower body fat percent and fat mass index.Those who reported no sexual activity before KT remained sexually inactive after KT. Therefore, further data analysis was performed only with sexually active men.n = 18), and that following KT dropped to 33% (n = 13) (p = 0.57). All patients (n = 3) with DM had ED before and after KT. The results of ED are summarized in The prevalence of ED before KT was 44% (p < 0.05). No significant differences were found among any of the five domains of the IIEF-15 before and 12 months after KT   .p < 0.05) and soft lean mass . However, no differences were identified 12 months posttransplant.The BIA-derived nutritional parameters in men with ED (score < 26) compared to those with normal erectile function (score > 26) are shown in We also analysed whether BIA-derived nutritional parameters could predict sexual function  before and after KT. A weak association between muscle mass and sexual desire 12 months after KT was identified . Linear Sexual dysfunction is a common feature that reduces CKD patients’ quality of life and is often underestimated by clinicians . SuccessIn this population, ED has a multifactorial etiology, including abnormalities in the hypothalamic-pituitary-gonadal axis, autonomic nervous system disturbances, endothelial dysfunction, anaemia, secondary hyperparathyroidism, medication effects, and neurological and psychological derangements ,21. DistFurthermore, ED and CKD are associated with diseases causing endothelial impairment, such as hypertension, diabetes, dyslipidemia, obesity, and metabolic syndrome . EndotheSexual inactivity or absence of sexual intercourse is usually considered an exclusion criterion . HoweverA higher phase angle indicates better nutritional status . In factSexual desire and intercourse satisfaction were the most affected domains in men after KT. Raggi et al. found that both the desire and the frequency of sexual activity decreased after transplantation . Al KhalIn addition, we found no significant difference when comparing the mean values of the total IIEF score, erectile function, orgasmic function, intercourse satisfaction, or overall satisfaction score before and 12 months following kidney transplantation. It is worth mentioning that all patients received transplants in which an end-to-side vascular anastomosis was created between the renal artery of the graft and the external or common iliac artery of the recipient. Therefore, vascular anastomosis did not affect erectile function in our cohort.Due to the small number of living donations in our transplantology center, we could not compare sexual function between living and deceased kidney donor recipients. Interestingly, Branco et al. could only observe a higher level of intercourse satisfaction among living donor recipients .Some limitations need to be considered. First, we did not measure testosterone levels, which are meaningful in sexual disorders. Furthermore, the study had a relatively small sample size, which may have reduced the statistical power. Another limitation is that the BIA measurement used in the present study has lower accuracy in monitoring body composition than dual-energy X-ray absorptiometry. However, BIA is an easily applicable bedside method that is widely used in daily practice. Finally, quality of life and physical activity were not evaluated, which could be useful in interpreting the results.Despite these limitations, the present study provides valuable information as the first exploratory study to identify how the specific changes in body composition are related to male sexual function after kidney transplantation.This study confirmed that ED may persist after successful kidney transplantation. Sexual desire is one of the most impaired domains in male KT recipients and is associated with lower muscle mass. In addition, the promotion of physical activity and a healthy diet together with the management of immunosuppressive therapy may have beneficial effects in terms of the improvement of sexual dysfunction in this population before and after KT. Further, sexual function assessment should be considered an essential part of the clinical assessment of kidney transplant recipients. Early diagnosis of sexual dysfunction and early referral to specialists leads to improvements in mental health and quality of life.Additionally, large-scale prospective studies examining the impact of nutritional parameters and their relationship with sexual function in KT patients are needed to substantiate the findings of the present study.


Diabetic nephropathy (DN) is one of the specific complications of diabetes mellitus and one of the leading kidney-related disorders, often requiring renal replacement therapy. Currently, the tests commonly used for the diagnosis of DN, albuminuria (AU) and glomerular filtration rate (GFR), have limited sensitivity and specificity and can usually be noted when typical morphological changes in the kidney have already been manifested. That is why the extreme urgency of the problem of early diagnosis of this disease exists. The untargeted metabolomics analysis of blood plasma samples from 80 patients with type 1 diabetes and early and late stages of DN according to GFR was performed using direct injection mass spectrometry and bioinformatics analysis for diagnosing signatures construction. Among the dysregulated metabolites, combinations of 15 compounds, including amino acids and derivatives, monosaccharides, organic acids, and uremic toxins were selected for signatures for DN diagnosis. The selected metabolite combinations have shown high performance for diagnosing of DN, especially for the late stage (up to 99%). Despite the metabolite signature determined for the early stage of DN being characterized by a diagnostic performance of 81%, these metabolites as potential biomarkers might be useful in the evaluation of treatment of the disease, especially at early stages that may reduce the risk of kidney failure development. Diabetic nephropathy (DN) as a specific complication of diabetes mellitus, associated with significant microvascular kidney damage, is one of the leading kidney-related disorders in patients requiring renal replacement therapy , which determines the extreme urgency of the problem of early diagnosis of this disease ,2. CurreMetabolomics as one of the last post-genomics disciplines is also one of the most high-promising technology for researching new potential biomarkers due to its ability to study the end products of all biochemical processes in the organism (endogenous metabolites) including the environmental effect (exogenous metabolites) ,13,14,152, group 2 –type 1 diabetes patients with DN and eGFR between 60 and 89, group 3 –type 1 diabetes patients with DN and eGFR lower 60. The routine biochemical and blood parameters , and total cholesterol) were measured using standard automatic analyzers. The difference in baseline characteristics between the groups, including socio-demographic and anthropometric measurements, was analyzed by performing one-way ANOVA test and p-value < 0.05 was considered significant.The study samples consisted of 80 patients with type 1 diabetes (T1D) who visited the Diabetes Institute of the National Medical Research Center for Endocrinology  in 2014–2016 years. A cross-sectional study design with phenotypically well-defined cases and controls was chosen. The patients were divided into three specific groups. Group 1 –type 1 diabetes patients without diabetic nephropathy (DN) and with an estimated glomerular filtration rate  > 90 mL/min/1.73 mThe study was approved by the relevant ethical review committee of the Diabetes Institute of the National Medical Research Center for Endocrinology (protocol №11-13 from 13 November 2013). Informed consent was obtained from all the participants at recruitment before sample collection.g  for 15 min and the supernatant was transferred to another Eppendorf™ tube. To obtain the analyzed solution each sample was diluted 50-fold by methanol with 0.1% formic acid  and the internal standard (IS) Losartan  was added to an end concentration of 10 ng/mL. All chemicals and solvents were of HPLC and UHPLC grade.Blood samples were collected in the morning after 12-h fasting. Venous blood was collected from the patients into EDTA Vacutainer plasma tubes  and processed in accordance with the manufacturer’s instructions. The resultant blood plasma was frozen immediately and stored at −80 °C until further processing. The analyzed samples were subjected to one freeze/thaw cycle. The sample preparation was performed as described previously . In totam/z) ranging from 50 to 1000 and a mass accuracy of 1–3 parts per million (ppm) in the positive ion charge detection mode. The samples were injected into the ESI source with a flow of 180 µL/h using a glass syringe  and a syringe injection pump . All samples were analyzed in random order. The internal standard Losartan  added to each sample before MS analysis was used for monitoring of matrix suppression, reproducibility, and stability of the method. Tandem mass spectrometry (MS/MS) analysis of selected precursor ions with an intensity ≥ 5000 was performed at collision energy from 10 to 40 eV.Samples were analyzed by a hybrid quadrupole time-of-flight mass spectrometer  equipped with an electrospray ionization (ESI) source. The mass spectrometer was set up and calibrated by using ES Tuning Mix  to detect ions with a mass-to-charge ratio . Mass spectra preprocessing including recalibration, peak detection, and peak intensity calculation were carried out by DataAnalysis software using the following parameters: peak width, 2; signal-to-noise ratio, 2; relative and absolute threshold intensity, 0.01% and 100, respectively. The resulting mass spectrometry peak masses were pooled and processed using Matlab version R2010a . The alignment of mass spectrometry data was performed as described previously . If massp-values. The Wilcoxon rank-sum test  was used to identify each variable’s contribution to the model. The results are expressed as mean ± standard deviation (SD). To identify top pathways that are being affected by the development of diabetic nephropathy based on the putative identification of metabolites and the global interpretation of biochemical changes by the information deposited in the Kyoto Encyclopedia of Genes and Genomes (KEGG) [Data in peak intensities format where samples were entered in columns, and each metabolite (variable) was added in the rows to form a matrix, which was uploaded on the MetaboAnalyst 5.0 website , were uss (KEGG)  the Metas (KEGG) . Initially, the putative identification of metabolites was performed through the Functional Analysis tool of the MetaboAnalyst 5.0 using the information deposited in the Kyoto Encyclopedia of Genes and Genomes (KEGG) with mass tolerance up to 0.005 Da and allowing possible adducts in the positive ionization mode. The dysregulated metabolites were tentatively annotated via careful manual curation of all peak assignments by two orthogonal characteristics as accurate mass and isotopic distribution using the Human Metabolome Database (HMDB)  and METLClinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [The studied groups were classified based on the estimated glomerular filtration rate (eGFR) into T1D (type 1 diabetes (T1D) subjects without diabetic nephropathy (DN)), T1D-DN1 (T1D subjects with early stage of DN), and T1D-DN2 (T1D subjects with late stage of DN) according to the KDIGO 2012  Disease ,5. Albump-value < 0.001. In most patients, T1D was diagnosed during childhood or adolescence. Serum creatinine and urea levels increased with the progression of the disease and were significantly higher in T1D-DN2 than in T1D-DN1. The average age in the T1D-DN group, was significantly higher than in others. Systolic blood pressure was slightly higher in the T1D-DN2 group with a significant value of p = 0.029. The ACR in the control group was in the normal range, while the T1D-DN1 and T1D-DN2 groups are characterized by higher mean values but with such a high deviation that the difference between the groups is not significant.Analysis showed that body mass index (BMI), glycated hemoglobin (HbA1c), fasting glucose, triglycerides, high- and low-density lipoproteins , and total cholesterol were not different between the studied groups. The groups with both early and late stages of DN  were characterized by more years since T1D was diagnosed and, as expected, had higher levels of serum creatinine and urea with a significant m/z features (peaks), which registered in almost all 80 samples. DIMS is a typical workflow designed for rapid untargeted analysis of the polar blood metabolome, which is able to detect amino acids, free carnitine, acylcarnitines, glycerophospholipids, lysophosphatidylcholines, phosphatidylcholines, and sphingolipids [A total untargeted metabolomics analysis of the blood plasma samples using DIMS method has detected 4376 metabolite golipids . m/z features significantly differed between T1D and T1D-DN1, between T1D-DN1 and T1D-DN2 as well as between T1D and T1D-DN2 by the pairwise Wilcoxon rank-sum test was performed , only 18 significantly differed between T1D and T1D-DN1, between T1D-DN1 and T1D-DN2, as well as between T1D and T1D-DN2. A total of 136 and 283 m/z features were significantly different between T1D and T1D-DN1 and T1D-DN2, respectively, whereas 181 m/z features were different between T1D-DN1 and T1D-DN2. For further analysis, only m/z features with a p-value < 0.05 were selected.In order to identify metabolites significantly increased or reduced in both early and late stages of DN compared to the T1D group the selection of metabolites erformed . Among 4m/z features with significantly altered abundance has been performed using the Functional Analysis tool in MetaboAnalyst [m/z values and p-value were used to identify the dysregulated metabolites and associated pathways in the KEGG and HMDB databases. For the metabolites for which mass spectrometry peak intensity was sufficient, validation by MS/MS fragmentation was utilized. The annotated metabolites are listed in To identify significantly differing metabolites and discover the nature of their dysregulations associated with DN in T1D patients, the mapping of the metabolites’ oAnalyst . The obtThe majority of the emerging pathways indicated the distinct dysregulation of amino acid metabolism in DN and included aspartate and asparagine metabolism, arginine and proline metabolism, methionine and cysteine metabolism, alanine and aspartate metabolism, urea cycle/amino group metabolism and glycine, serine, alanine, and threonine metabolism . The relTaking into account the various numbers of significant hits in There were 17 annotated metabolites  with sigSubsequently, 15 potential biomarkers were used for the best metabolite combinations for the diagnosing of DN cases in patients with T1D . For theAs can be seen in To check whether the identified dysregulations in metabolite levels are a result of the DN progression from T1D or reflect a decrease in kidney function only, we have calculated the correlation between the above-mentioned metabolites and creatinine level. In the control group (T1D patients) and in the early-stage DN patients (T1D-DN1), the correlation coefficients were quite similar , while in the late-stage DN patients—0.2. This indicates that dysregulation of the detected metabolites is not a direct relation to kidney function and may be a result of DN development. That is why we used the diagnostic models’ combinations with creatinine to take this indicator into account to the necessary extent. In addition, it should be noted that due to the design of the experiment, creatinine can differentiate the studied groups, but its individual diagnostic score  is lowerClinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease [We have analyzed the untargeted blood plasma metabolomics profiles associated with both early and late stages of diabetic nephropathy (DN) in patients with type 1 diabetes (T1D) using the DIMS method. DIMS is a widely used approach for fast and sensitive analysis of sample-specific metabolite ions distribution. This method and liquid chromatography-mass spectrometry (LC-MS) have their limitations, but in contrast to LC-MS-based standard practice, DIMS is not time-consuming and more suitable for high-throughput analysis ,23,24,32 Disease . AU was  Disease ,7. It wa Disease . That isThe important findings of the study are the metabolites and associated pathways that are dysregulated in both early and late stages of DN and the potential metabolite signatures for diagnosing DN in patients with T1D. Statistical analysis of the metabolomics data coupled with functional analysis based on system biology knowledge allowed us to identify the involvement of some amino acids metabolism and urea cycle in the pathogenesis and progression of DN. In an attempt to identify metabolite signatures for detection, both early and late stages of DN 15 metabolites were identified as potential biomarkers in this study. The fact that most of the revealed dysregulated metabolites are amino acids and derivatives, and that the top metabolic pathways are directly related to amino acid metabolism points to the importance of these biochemical processes in the pathogenesis and progression of DN ,33,34,35As expected, creatinine was found in the study with an up-regulated profile in the DN subjects and was much higher in T1D-DN2 than T1D-DN1. It is well known that serum creatinine is the most commonly used indicator of renal function . HoweverFive out of the revealed amino acids and derivatives  with an up-regulation profile in the DN subjects are involved in the urea cycle/amino group metabolism. In our study, serum urea levels as well as serum creatinine were higher in the DN subjects compared with the T1D patients without DN and were much higher in the patients with late-stage than with early. The kidneys eliminate up to 90% of nitrogen from the human body through urine and thus have an effect on the urea cycle and the conversion of ammonia into uric acid and urea . RecentlAmong the revealed metabolites with potential prediction significance, there were the following chemical classes of compounds involved in amino acid metabolism: 4-guanidinobutanamide with N2-succinyl-L-ornithine—in arginine and proline metabolism, monosaccharide N-acetyl-b-glucosaminylamine with N-formyl-L-aspartate—in aspartate and asparagine metabolism, and 1-methylhistidine—in histidine metabolism . These rIn addition, one of the metabolites characterized by a significant difference between the T1D patients with and without DN was 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF). This metabolite included in all the determined diagnostic signatures is well known as an uremic toxin, which significantly accumulated in the blood of patients with chronic kidney disease ,43,44,45We have not analyzed for gender differences in the dysregulated metabolites because of the small size of the studied groups, but the reviews including a large number of studies on gender-related differences in DN in T1D populations were published ,48. It sThus, all the metabolites revealed in our study have shown a distinct association with the biochemical processes related to the pathogenesis and progression of DN, and each of them can be separately considered as a potential biomarker for diagnosing DN. The fact that these metabolites were detected in a number of other metabolomics studies of DN ,18,38,40Some limitations of our study should be considered. First, the sample size was relatively small, especially for patients with late stages of DN; therefore, we could not sufficiently determine the dysregulated metabolites and associated pathways at different stages of DN in the patients with T1D and analyze gender differences in the dysregulated metabolites. Second, as in any cross-sectional study, the causal relationship between T1D, DN, and metabolite changes could not be determined and mechanisms of disease development could be suggested only. For the same reason, the obtained results cannot be applied to predict the DN stage-to-stage progression risk, although some revealed metabolites are characterized by different dysregulation patterns at the early and late stages of the disease. The detection of predictive biomarkers requires a longitudinal study. Therefore, further investigations with huge cohorts, including the prospective longitudinal study, are needed to validate the proposed diagnostic metabolite signatures and determine the relationship between DN progression and the metabolites.The untargeted metabolomics analysis coupled with functional analysis based on system biology knowledge allowed us to identify the best combinations of 15 dysregulated metabolites, including amino acids and derivatives, monosaccharides, organic acids, and uremic toxin for DN diagnosis. The selected metabolite combinations have shown high performance in diagnosing DN, especially in the late stage (up to 99%). Despite the metabolite signature determined for the early stage of DN being characterized by a diagnostic performance of 81%, these metabolites as potential biomarkers might be useful in the evaluation of treatment of the disease, especially at early stages that may reduce the risk of kidney failure development than existing creatinine/albumin-based tests.


Chronic kidney disease presents a health challenge that has a complex underlying pathophysiology, both acquired and inherited. The pharmacotherapeutic treatment options available today lower the progression of the disease and improve the quality of life but cannot completely cure it. This poses a challenge to the healthcare provider to choose, from the available options, the best way to manage the disease as per the presentation of the patient. As of now, the recommended first line of treatment to control the blood pressure in chronic kidney disease is the administration of renin–angiotensin–aldosterone system modulators. These are represented mainly by the direct renin inhibitor, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. These modulators are varied in their structure and mechanisms of action, hence showing varying treatment outcomes. The choice of administration of these modulators is determined by the presentation and the co-morbidities of the patient, the availability and affordability of the treatment option, and the expertise of the healthcare provider. A direct head-to-head comparison between these significant renin–angiotensin–aldosterone system modulators is lacking, which can benefit healthcare providers and researchers. In this review, a comparison has been drawn between the direct renin inhibitor , angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. This can be of significance for healthcare providers and researchers to find the particular loci of interest, either in structure or mechanism, and to intervene as per the case presentation to obtain the best possible treatment option. The classification of CKD is performed as per the underlying cause, glomerular filtration rate (GFR), and category of albuminuria (Chronic kidney disease (CKD) is a persistent health condition characterized by progressive renal dysfunction that leads to a permanent and irremediable loss of renal function . CKD affuminuria  (Cheung uminuria . The conuminuria . The conuminuria . The etiuminuria .Hypertension (HTN) is a critical contributor to the pathophysiology of CKD (27.2%), with HTN and CKD implicated in a cyclical manner . UnrestrAliskiren stands as the first direct renin inhibitor approved by FDA to date. It is a monomethoxy benzene and a monocarboxylic acid amide featuring a 3-methoxypropoxy group at the 2-position and a multi-substituted branched alkyl substituent at the 4-position . Aliskirvia the thiol moiety with the central Zn2+ ion of ACE -renin receptor can cause the membrane-accumulated aliskiren molecules to get expelled from the lipid bilayer, leading to the binding of the inhibitors to the active site from the extracellular fluid. This mechanism is particularly significant for the intracellular renin–angiotensin system .Captopril, which is studied as the prototype of ACE inhibitors, is generally present as an equilibrium mixture of cis and trans isomers, with respect to the proline amide bond at neutral pH in the solution, and the angiotensin I-converting enzyme takes only the trans-state of the inhibitor which bears reciprocity with its substrate binding groove both architecturally and stereoelectronically .1R. The drug moves from the aqueous environment to the lipid surface within the first few nanoseconds, expediating into the bilayer and percolating between the polar headgroups and the upper part of the alkyl chains of the lipids, and forming hydrogen bonds with the lipid glycerol backbone, phosphate groups, and isolated water molecules penetrating the lipid bilayer (Studies with losartan (the prototype for ARBs) report two main conformations in solution that position the tetrazole and imidazole moieties either in an anti or a syn orientation respective to the A phenyl ring plane. Losartan is observed to have a spontaneous insertion in the lipidic core in micellar and lipid bilayers, having embedded the AT bilayer .The recommendations are provided by the world bodies for the pharmacotherapy and management of hypertension in CKD. These recommendations aim to improve clinical practices and treatment outcomes, are drafted with inputs from field experts and other stakeholders, and are updated regularly to fill the gaps between targets and outcomes. The recommendations are not rigid, and the healthcare provider can consider resources and facilities available in addition to the nature and presentation of the patient for treatment; however, the recommendations aim to facilitate the management of hypertension in CKD. Numerous trials have inferred that RAAS inhibitors reduce the advancement of kidney disease in people presenting with BP and/or diabetes. RAAS inhibitors were observed to have considerably reduced kidney disease progression in comparison to placebo and other antihypertensive agents. There is no significant difference between ACEIs and ARBs when overall mortality, progression to ESRD, or their anti-proteinuric effects are concerned, and initially, the drug is selected based on patient preference, potential side effects, and cost. Various bodies provide guidelines for the management of CKD, and among them, the Kidney Disease Improving Global Outcomes (KDIGO) and the National Institute for Health and Care Excellence (NICE) are globally recognized bodies for the management of renal disorders, suggesting target BP in CKD (KDIGO 5). KDIGO guidelines suggest attaining a target of systolic blood pressure of <120 mm Hg, if tolerated, in adults with increased BP and CKD by using the standardized office BP measurement. This recommendation of a target BP of <120 mm Hg does not hold good when measured in a non-standardized manner. NICE recommends BP of below 140 mmHg for patients with CKD and an albumin creatinine ratio (ACR) under 70 mg/mmol and below 130 mmHg for patients with CKD and an ACR under 70 mg/mmol or above. RAAS inhibitors are recommended to obtain the target BP. When seen comparatively, clear and vivid recommendations are seen for ACEIs and ARBs but are lacking for DRI. Here, we provide the latest recommendations for the use of RAAS inhibitors for the management of BP in CKD as per KDIGO and NICE .It is mandatory, as per the current guidelines, to use RAAS inhibitors in patients with proteinuric CKD as first-line renoprotection since randomized trials have strongly demonstrated RAAS inhibitors to be superior in lowering the progression of nephropathy to end-stage renal disease when compared to other antihypertensive drug classes . They revia CYP3A4 and neither inhibits nor induces the cytochrome P450 system  and an extended bioavailability (13% for eprosartan to 60%–80% for irbesartan). Most of the ARBs show high plasma protein binding (95%–100%) and a variable plasma elimination half-life varying from short to intermediate to long . There is no significant accumulation of drugs and their active metabolites after repeated dosing, except for telmisartan (100%). Also, a major portion of the orally administered dose of ARBs undergoes biliary and fecal elimination; however, telmisartan (2%) and candesartan (33%) are excreted the dose . Losartathe dose . In hemothe dose . Telmisathe dose . Patientthe dose . The phaThere is no therapeutic agent specifically for CKD, but control of blood pressure is crucial in the treatment of CKD . The RAAAliskiren is a relatively new candidate for RAAS inhibition and was deemed to overcome the elevated plasma renin concentration and activity associated with ACEI and ARB therapy . The cliACEIs are regularly prescribed to patients with chronic kidney diseases. When introduced first in 1981, they were indicated only for the treatment of refractory hypertension but have since then been effective in improving the treatment outcome in various diseases, including chronic renal insufficiency . They arMost of the studies discuss ARBs along with ACEIs in CKD, indicating a similar outcome of therapy. ARBs have effects similar to ACEIs and are generally prescribed for patients unable to tolerate ACEIs . ARBs dePatients with mild or moderate chronic kidney disease have reliable improved outcomes with RAAS inhibitors, but less evidence supports their use in advanced CKD. The recently concluded STOP ACEI trial, which aimed to identify whether discontinuation of ACEIs/ARBs can improve or stabilize renal function in patients with advanced progressive CKD, reported that in such patients, the discontinuation of RAAS inhibitors was not observed to have a significant difference between the groups in the long-term rate of decrease in the eGFR. ESRD or the initiation of renal-replacement therapy was reported in 62% and 56% of the discontinuation group and the continuation group, respectively, and adverse events were similar in the discontinuation group and continuation group with respect to cardiovascular events .+ binders were contraindicated in CKD associated with hypercalcemia or vascular calcification, leading to poor adherence  and patiromer. SZC exchanges K+ for sodium and hydrogen ions in the gastrointestinal tract, while patiromer exchanges K+ for calcium ions in the gastrointestinal tract. These new potassium binders may present greater selectivity for potassium than other cations, hence resulting in a lower risk of clinical electrolyte abnormalities  occurring within a distal enhancer region. In vivo functional activity with aliskiren is reported for renin −5312C/T, with lesser reductions in BP observed in −5312T allele carriers than in CC homozygotes ; however, the generic availability of ARBs enables them to be included in insurance formularies. In autosomal dominant polycystic kidney disease, ARBs incurred an annual healthcare cost of $3,644,327.65, with an approximate 10-year survival of ARB at 34% compared to 47% for ACEIs . The valThe RAAS inhibitors are the preferred class of drugs recommended for the treatment of CKD; however, they slow down the progression of CKD by ∼20% compared with other therapies, instead of stopping its progression. The RAAS inhibitors have a wide array of structures, but their attribute to inhibit the RAAS places them on a comparable platform. Their mechanisms of action also vary with the DRI reckoned to overcome the side effects of ACEIs and ARBs. Amongst the RAAS inhibitors, ACEIs and ARBs seem to have a profound effect on treatment outcomes in CKD when compared to DRI. The ACEIs and ARBs are comparable in most of their attributes, but ARBs have an edge in the patients intolerant to ACEIs. The pricing favors the use of ACEIs to maintain sustained use. A direct comparison becomes difficult owing to differences in structure, mechanism of action, design model, region settings, etc., in the three groups of RAAS inhibitors, and this implies that drugs should be prescribed considering the balance of benefit and risk required by the individual. The drugs, however, face a challenge on account of new therapies targeting RAAS with higher renal protection conferred in comparison to DRI, ACEIs, and ARBs.