Receiver operating characteristic (ROC) analysis of urinary ANGPTL-4 and KIM-1 in the combined form resulted in an area under curve (AUC) of 0.967  in the microalbuminuria group and 1  in the macroalbuminuria group. The association of urinary levels of ANGPTL-4 and KIM-1 with UACR and eGFR and significant prevalence in the diabetic kidney disease population illustrates the diagnostic potential of these biomarkers.The purpose of the study was to examine the urinary levels of kidney injury molecule-1 (KIM-1) and angiopoietin-like protein-4 (ANGPTL-4) in individuals with diabetic kidney disease (DKD) and their association with established DKD diagnostic markers such as albuminuria and estimated glomerular filtration rate (eGFR). Levels of ANGPTL-4 and KIM-1 were estimated in urine samples. A total of 135 participants were recruited into three groups: 45 diabetes type 2 patients in the control group and 90 DKD patients in two disease groups. Concentrations of ANGPTL-4 and KIM-1 were conclusively related to the urinary albumin–creatinine ratio (UACR). Also, the levels of both ANGPTL-4 and KIM-1 were negatively associated with the eGFR. Multivariable Poisson regression analysis showed that urinary ANGPTL-4 (PR: 3.40; 95% CI: 2.32 to 4.98;  One of the most significant microvascular consequences of diabetes is diabetic kidney disease (DKD) . About 2ANGPTL-4, a 50 kDa protein is secreted by a variety of cells and belongs to the family of angiopoietin-like proteins such as adipocytes, liver and endothelial cells, cardiomyocytes, and macrophages . RecentlKIM-1 is a glycoprotein, which is a type 1 cell membrane, manifesting on proximal tubule cells in the apical membrane, and being unstable, its ectodomain splits, sheds into the lumen of the tubule, and is excreted into the urine . The expThe purpose of the current study was to examine the implication of the combination of two distinct site markers, urinary ANGPTL-4 and urinary KIM-1, in the diagnosis of DKD. The existing evidence on ANGPTL-4 and KIM-1 as biomarkers of diabetes-related kidney damage among Indians is limited and consequently requires further investigation.n = 45, n = 45, n = 45, 2 for the micro- and microalbuminuria groups [At Jamia Hamdard’s Hakeem Abdul Hameed Centenary (HAHC) Hospital in New Delhi, this cross-sectional study was carried out from January 2018 to March 2020. Patients were enrolled in the study who met the inclusion and exclusion criteria and were categorized into three age-matched groups. The control group , education, employment, duration, and family history of T2DM were recorded in a validated and approved case recording form.Spot urine and blood samples were collected from the participants. Blood samples were centrifuged at 4500 rpm at 4.0 °C for 10 min, and separated plasma was stored at −80.0 °C until further analyses. Collected urine samples were centrifuged in a refrigerated centrifuge at 3500 rpm and aliquoted at −80.0 °C for further analyses. FPG was quantified with spectrophotometric  using the glucose oxidase and peroxidase  method. HbA1c was assessed using fully automated high-performance liquid chromatography , and values are reported in percentages as per the National Glycohemoglobin Standardization Programme  recommendations. Serum albumin was estimated with the bromocresol green method , and the albumin–globulin ratio was derived from albumin and globulin values. Protein total was determined with the biuret method, and serum creatinine and urine creatinine were analyzed with the Kinetic Jaffe method using an automatic analyzer (Beckman Coulter AU 480). The chronic renal disease epidemiology collaboration equation was used to determine eGFR (CKD-EPI Creatinine Equation), alkaline phosphatase was estimated with the modified International Federation of Clinical Chemistry (IFCC) method, and total cholesterol was determined by the enzymatic method using an automatic analyzer (Beckman Coulter AU 480) . Uric acThe mean and standard deviation (SD) are used in descriptive statistics to represent quantitative parameters, where as absolute numbers and corresponding percentages are used to represent categorical data. The Kolmogorov–Smirnov test was used to determine whether the data were normal. The Bonferroni correction (P ≤ α/n) after the one-way analysis of variance (one-way ANOVA) test in multiple comparisons was used for testing the statistical differences among the quantitative parameters between the groups. We performed the chi-square test to determine the correlation for categorical data. The correlations between urinary concentrations of ANGPTL-4 and KIM-1 with other metabolic parameters were examined using Spearman’s rank-order correlation.p < 0.1.The association of effect of urinary levels of ANGPTL-4 and KIM-1 and other potential risk factors , HbA1c, systolic blood pressure (SBP), diastolic blood pressure (DBP), urea, BUN, eGFR, and total cholesterol) of diabetic kidney disease were examined using multivariable regression analysis. The prevalence ratio rather than the odds ratio was estimated for diabetic kidney disease outcome since DKD was prevalent 67% in the study sample. This was done to avoid overestimating the strength of the link, as suggested by the literature . To invep-value < 0.05 was considered statistically significant except for Bonferroni corrected comparisons.The diagnostic value of ANGPTL-4 and KIM-1 urine levels was evaluated using ROC (receiver operating characteristic) curve analysis. Through the Youden index, the optimal cutoff values were determined and were derived with sensitivity (SN) and specificity (SP). The IBM SPSS 26.0 statistics program for Windows  and Stata software version 17.0  were used to conduct the statistical analysis. Two-sided The study enrolled 135 participants with a mean age of 60.1 ± 10.8 years. They were categorized into three groups, with 45 each in the normoalbuminuria, microalbuminuria, and macroalbuminuria groups. Age, SBP, DBP, total protein, total cholesterol, and electrolytes including Na, K, and Cl did not significantly differ between the three study groups. The patients with macroalbuminuria, as compared to those with normoalbuminuria and microalbuminuria, had a longer duration of T2DM and increased FPG, HbA1c, urea, uric acid, BUN, and serum creatinine. Demographic details and biochemical parameter comparisons are presented in p < 0.001). Further, urinary KIM-1 levels were also positively related to UACR and increased successively. Macroalbuminuria group patients had a significantly elevated value of KIM-1  in comparison to the other two groups  as compared to the patients in the normoalbuminuria and microalbuminuria groups   .p < 0.001) and ANGPTL-4  on the log scale.The urinary levels of ANGPTL-4 and KIM-1 were significantly associated with diabetic kidney disease even after adjustments were made for demographic, clinical, and laboratory parameters . Four rep < 0.0001) as compared to ANGPTL-4  whereas panel had a similar AUC  to that of KIM-1. Furthermore, in the macroalbuminuria group, urinary ANGPTL-4 had a slightly higher AUC as compared to that of urinary KIM-1; the AUC for ANGPTL-4 was 1.000 , and the AUC for KIM-1 was 0.998 , while the panel analysis of the biomarkers yielded a perfect AUC of 1 .To assess the diagnostic utility and accuracy of urinary ANGPTL-4 and KIM-1 as individual markers and in the combined form as a panel, ROC analysis was performed A,B. In mGlobally, DKD is the most common reason of end-stage renal disease and is classically presented by glomerular hyperfiltration and albuminuria. However, it is evident that microalbuminuria may not be considered a specific and sensitive predictor of DKD . The preIn the current investigation, we demonstrated that the urinary concentrations of both ANGPTL-4 and KIM-1 were elevated in macroalbuminuria patients as compared to the patients in the normoalbuminuria group. Moreover, ANGPTL-4 and KIM-1 levels increased with the deterioration of kidney function, as both the markers were negatively correlated with eGFR. DKD pathogenesis is most likely to occur as a result of the interplay between metabolic factors, such as the accumulation of glycated end products and hemodynamic processes including increased intraglomerular and systemic pressure and various hormone pathways, such as the renin–angiotensin–aldosterone system . These iAn ROC curve was plotted to assess the diagnostic performance of urinary ANGPTL-4 and urinary KIM-1, while the Youden index was used for the calculation of optimal cutoff value. Both the parameters were found to perform excellently individually as well as in a combined form. Following the study conducted by Vanarsa K et al.  that shoAll the renal compartments are subjected to various hemodynamic and metabolic variables associated with diabetes mellitus, especially hyperglycemia, and glomerular alterations and tubulointerstitial damage may already be initiated even before proteinuria . IdentifSome limitations to the work presented here should be considered. The study was single center and cross-sectional in design, with a limited patient pool. The comparatively small sample size of the study limited the precision and power to ascertain associations of moderate strength. However, to remove the biases, we analyzed the effect of the biomarkers in two subgroups . A longitudinal follow-up investigation of normoalbuminuria T2DM patients with an eGFR in the normal range would be informative. Furthermore, only T2DM control patients were enrolled, and the absence of healthy age-matched controls limited the ability to account for persons without hyperglycemia. Finally, the impact of pharmacological therapy on the candidate biomarkers was also not ruled out.This is the first study to examine the combined expression of urinary ANGPTL-4 and urinary Kim-1 together for the detection of DKD in the Asian population. Even after the established risk variables were controlled for, the ANGPTL-4 and KIM-1 concentrations were independently linked with DKD. Both the biomarkers showed good stage-specific sensitivity individually as well as in combination. The study findings suggest that a combination of ANGPTL-4 and KIM-1 may strengthen the diagnostic approach to diabetic kidney disease. However, further longitudinal studies in different large ethnic populations are required to validate the marker’s suitability.


This meta-analysis and meta-regression of randomized clinical trials evaluates the association of magnitude of differential blood pressure reduction and recurrent stroke in patients with stroke or transient ischemic attack. How much better is more blood pressure reduction vs less blood pressure reduction for secondary stroke prevention?In this meta-analysis and meta-regression that included 10 randomized clinical trials comprising 40 710 patients with stroke or transient ischemic attack, the risk of recurrent stroke was 8.4% with more intensive blood pressure lowering vs 10.1% with less intensive or no blood pressure lowering, a statistically significant difference. The greater the amount of differential blood pressure reduction, the greater the amount of reduction risk of recurrent stroke.This study suggests that more intensive differential blood pressure–lowering therapy may be beneficial for secondary stroke prevention. The degree to which more intensive blood pressure reduction is better than less intensive for secondary stroke prevention has not been delineated.To perform a standard meta-analysis and a meta-regression of randomized clinical trials to evaluate the association of magnitude of differential blood pressure reduction and recurrent stroke in patients with stroke or transient ischemic attack (TIA).PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1, 1980, to June 30, 2022.Randomized clinical trials that compared more intensive vs less intensive blood pressure lowering and recorded the outcome of recurrent stroke in patients with stroke or TIA.PRISMA) reporting guideline was used for abstracting data and assessing data quality and validity. Risk ratio (RR) with 95% CI was used as a measure of the association of more intensive vs less intensive blood pressure lowering with primary and secondary outcomes. The univariate meta-regression analyses were conducted to evaluate a possible moderating effect of magnitude of differential systolic blood pressure (SBP) and diastolic blood pressure (DBP) reduction on the recurrent stroke and major cardiovascular events.The Preferred Reporting Items for Systematic Reviews and Meta-analyses  with stroke or TIA were included for analysis. The mean duration of follow-up was 2.8 years . Pooled results showed that more intensive treatment compared with less intensive was associated with a reduced risk of recurrent stroke in patients with stroke or TIA . Meta-regression showed that the magnitude of differential SBP and DBP reduction was associated with a lower risk of recurrent stroke in patients with stroke or TIA in a log-linear fashion . Similar results were found in the association between differential blood pressure lowering and major cardiovascular events.More intensive blood pressure–lowering therapy might be associated with a reduced risk of recurrent stroke and major cardiovascular events. These results might support the use of more intensive blood pressure reduction for secondary prevention in patients with stroke or TIA. Indeed, recurrent stroke has declined substantially over decades, with improved blood pressure control as a leading cause.3 Furthermore, some trials4 compared antihypertensive therapy with placebo, while other trials5 compared a lower systolic blood pressure (SBP) target with a higher SBP-lowering target. Pooling of data from these 2 types of trials is needed to clarify the association between degree of increased blood pressure lowering attained with therapy and secondary stroke prevention.However, most individual randomized clinical trials have not significantly showed that blood pressure–lowering therapy reduces recurrent stroke in patients with stroke or TIA. Relatively small magnitude of blood pressure reduction and relatively few participants and inadequate statistical power in single randomized clinical trials may have attenuated signals of efficacy.Therefore, we performed a systematic review and meta-analysis of all relevant randomized clinical trials to evaluate the association between magnitude of differential blood pressure reduction and risk of recurrent stroke and performed a meta-regression to clarify whether larger differential blood pressure reduction magnitude was monotonically associated with a lower recurrent stroke risk in patients with stroke or TIA.PRISMA) reporting guideline was used for abstracting data and validity of this meta-analysis.6 The protocol was registered with PROSPERO (CRD42022309056).The Preferred Reporting Items for Systematic Reviews and Meta-analyses  independently screened and identified potential trials, and discrepancies were resolved by discussion with a third investigator (M.L.).We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the clinical trial registry maintained at ClinicalTrials.gov from January 1, 1980, to June 30, 2022, using the following terms: stroke or cerebrovascular accident or brain vascular accident or cerebral infarct or cerebrovascular disorder or intracranial vascular disease or cerebrovascular disease or cerebrovascular occlusion or transient ischemic attack AND antihypertensive or blood pressure lowering or blood pressure reduction AND recurrent or secondary prevention or previous or prior or history. We restricted the search to studies in humans and randomized clinical trials and did not apply language restrictions. We also reviewed prior meta-analysesCriteria for inclusion of a study were as follows: (1) the study design was a randomized clinical trial; (2) all or an identifiable subset of participants had a history of stroke or TIA; (3) the study evaluated more intensive vs less intensive blood pressure–lowering therapy, including the following possible comparisons: antihypertensive drug(s) vs placebo and a lower blood pressure target vs a higher blood pressure target; (4) recurrent stroke was reported as an end point; (5) the magnitude of SBP reduction between more intensive and less intensive blood pressure lowering was reported; and (6) treatment duration was of at least 1 year.1; (2) the study adopted only nonpharmaceutical approach, such as salt restriction or exercise, in the active treatment arm; (3) the study compared one antihypertensive drug vs another antihypertensive drug; (4) achieved SBP was higher in more intensive blood pressure–lowering group than less intensive blood pressure–lowering group after treatment; (5) more than 10% of patients were enrolled within 3 days after stroke; or (6) more than 10% of patients had end-stage kidney disease because of differential hemodynamic vulnerability of this disease. We extracted characteristics of each trial, which included patient age, sex, baseline blood pressure, number of patients in more intensive and less intensive blood pressure–lowering groups, duration of follow-up, magnitude of differential blood pressure reduction between more intensive and less intensive blood pressure–lowering groups, and number of recurrent stroke events and other outcomes in more intensive and less intensive blood pressure–lowering groups. Two investigators (C.-Y.H. and M.L.) independently abstracted the data and any discrepant judgments were resolved by joint discussion and by referencing the original report.Criteria for exclusion of a study were as follows: (1) the study was published before 1980 because strategies for secondary stroke prevention, including antihypertensive drug use, were substantially different then11Because all of the included studies were randomized clinical trials, the risk of bias  of the included trials was assessed by the Cochrane risk-of-bias algorithm.The primary outcome was recurrent stroke. The lead secondary outcome was major cardiovascular events. Major cardiovascular events were defined as the composition of nonfatal stroke, nonfatal myocardial infarction, and death from cardiovascular causes. Additional secondary outcomes were recurrent ischemic stroke, hemorrhagic stroke, fatal or disabling stroke, myocardial infarction, death from cardiovascular causes, death from any cause, and heart failure.P values were from 2-sided tests, and results were deemed statistically significant at P < .05. Heterogeneity was assessed by a P value determined by the use of χ2 statistics and I2 statistics, and I2 values of 0% to 29%, 30% to 49%, 50% to 74%, and 75% to 100% represent not important, moderate, substantial, and considerable inconsistency, respectively.12The analysis plan was performed on an intention-to-treat basis. We computed the fixed-effects estimate based on the Mantel-Haenszel method. Risk ratio (RR) with 95% CI was used as a measure of the association of more intensive vs less intensive blood pressure lowering with the primary and secondary outcomes. To explore the association between magnitude of differential blood pressure reduction and risk of recurrent stroke, analyses were performed for thresholds of SBP reduction of 4 mm Hg or lower, 5 mm Hg or lower, more than 5 mm Hg, more than 7 mm Hg, and more than 11 mm Hg, as well as magnitude of differential diastolic blood pressure (DBP) reduction of 2 mm Hg or lower, 3 mm Hg or lower, more than 3 mm Hg, and more than 4 mm Hg between more intensive vs less intensive blood pressure–lowering groups. The univariate meta-regression analyses were conducted with the fixed-effects model to evaluate a possible moderating effect of magnitude of differential SBP and DBP reduction on the recurrent stroke and major cardiovascular events. All 13 A sensitivity test was conducted to identify any trial that might have exerted a disproportionate influence on the summary treatment effect on the primary outcome by removing each individual trial from the meta-analysis one at a time. Another sensitivity test was conducted by restricting analysis within trials with recurrent stroke being the primary outcome in the original trial design. Grading of Recommendations, Assessment, Development and Evaluations was used to evaluate summaries of evidence for the primary and secondary outcomes.15The trim-and-fill method to identify and correct for funnel plot asymmetry arising from publication bias was used.16 we also conducted a subgroup analysis for Asians vs non-Asians. The Cochrane Collaboration’s Review Manager Software Package version 5.4 (RevMan) and Stata/SE version 15.1 (StataCorp LLC) were used for this meta-analysis and mete-regression.Subgroup analyses of included trials were conducted according to different study characteristics: mean baseline SBP levels (≥150 mm Hg vs 140-149 mm Hg), mean achieved SBP levels in the more intensive and less intensive blood pressure–lowering groups (≥140 mm Hg vs 130 to <140 mm Hg vs <130 mm Hg), study duration (<3 years vs ≥3 years), sample size (<3000 vs ≥3000 patients), time interval from index stroke to randomization (within 6 months from stroke vs within 3-5 years from stroke), entry event (ischemic stroke vs hemorrhagic stroke), study design (antihypertensive drugs vs placebo and a lower blood pressure target vs a higher blood pressure target), definition of differential blood pressure reduction (mean difference throughout the studies vs other definitions), and antihypertensive drugs used in the more intensive treated arm (angiotensin-converting enzyme [ACE] inhibitors vs angiotensin receptor blockers vs β-blockers vs diuretics vs ACE inhibitors plus diuretics). Since the risk of recurrent ischemic and hemorrhagic stroke is greater in Asian populations with high blood pressure compared with several other groups around the world,22 The characteristics of the included trials are shown in 23 Overall, 40 710 patients  with stroke or TIA were enrolled. The mean duration of follow-up was 2.8 years . Among the 10 included trials, 6 compared antihypertensive drug(s) vs placebo or no antihypertensive therapy,20 and 4 compared a lower blood pressure target vs a higher blood pressure target.22 In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), 2 different active groups  were compared with placebo, and we analyzed separately perindopril alone vs placebo and perindopril plus indapamide vs placebo.4 Across all trials, the mean baseline SBP was 146 mm Hg and DBP was 85 mm Hg.We identified 21 full articles for detailed assessment, of which 11 did not meet the inclusion criteria; therefore, the final analysis included 10 randomized clinical trials ,17 1 adopted mean difference after 2 years,20 1 adopted difference at first 6 months of treatment,22 and 1 adopted difference at the last study visit.5 The mean SBP reduction was 6.7 mm Hg and the mean DBP reduction was 2.8 mm Hg between active treatment and comparator groups. The Cochrane risk-of-bias assessment for the included trials is summarized in eFigure 2 in The definition of differential blood pressure reduction varied among included trials. Among included trials, 5 adopted mean blood pressure difference between the 2 groups throughout the studyP < .001; number needed to treat [NNT] in 3 years, 58). There was considerable inconsistency among included trials   .2,3,4,5,P = .001)   A.2,3,4,5 = .003) B.2,3,4,121 or 5 mm Hg or lower 21 and associated with a greater effect magnitude when the amount of differential SBP reduction was more than 5 mm Hg ,22 more than 7 mm Hg ,22 and more than 11 mm Hg  NT = 14) .4,1921 or 3 mm Hg or lower 21 and associated with a greater effect magnitude when the amount of differential DBP reduction was more than 3 mm Hg 22 and more than 4 mm Hg  NT = 14) .4,19,22P < .001; NNT in 3 years, 61). There was substantial heterogeneity among included trials     A.2,3,4,5 = .048) B.2,3,4,1P < .001; NNT = 88). There was considerable inconsistency among included trials  . There was substantial heterogeneity among included trials  . Heterogeneity was not important among included trials  . Heterogeneity was not important among included trials  . Heterogeneity was not important among included trials  . Heterogeneity was not important among included trials  . Heterogeneity was not important among included trials        trials with patients enrolled within 3 to 5 years from stroke  than patients enrolled within 6 months from stroke  and the lead secondary outcome . In the forest plot of the recurrent stroke, the larger of the differential SBP reduction, the larger of the reduction of recurrent stroke was found visually. In the meta-regression analyses, magnitude of differential SBP and DBP reduction were significantly associated with a lower risk of recurrent stroke in patients with stroke or TIA. Therefore, heterogeneity might be primarily driven by the various magnitude of differential blood pressure lowering among included trials. Similar findings were noted in the major cardiovascular events.8 in several aspects. First, we excluded trials comparing one antihypertensive drug vs another antihypertensive drug 24 or achieved SBP higher in more intensive blood pressure–lowering group than less intensive blood pressure–lowering group after treatment.25 This approach was taken to be in line with the objective of our study. Second, the study by Katsanos et al8 only pooled data from trials with antihypertensive therapy vs placebo, whereas we pooled data from trials with antihypertensive therapy vs placebo and a lower blood pressure target vs a higher blood pressure target. The latter approach includes all relevant trials of blood pressure–lowering therapy for secondary stroke prevention. Third, the study by Katsanos et al8 adopted achieved blood pressure levels for meta-regression analyses, whereas this study adopted magnitude of differential blood pressure reduction for meta-regression analyses and showed that the larger the magnitude of differential blood pressure reduction, the larger the reduction of recurrent stroke and major cardiovascular events.The current study was distinct from the study by Katsanos et al27 It accords as well with studies in broader cardiovascular event qualifying event trials, including the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) trial,28 the Systolic Blood Pressure Intervention Trial (SPRINT),30 and a trial of older Asian individuals with hypertension.31 Furthermore, physiologically, intensive (SBP target <120 mm Hg) compared with standard (SBP target <140 mm Hg) blood pressure–lowering therapy was associated with increased, not decreased, cerebral perfusion, in participants with a history of cardiovascular disease.32 Taken together, this study does not refute the current practice guidelines recommending blood pressure lowering to an SBP target of less than 130 mm Hg as a major target for patients with stroke or TIA.The current study is consonant with and extends prior investigations. In the current study, greater achieved differential blood pressure lowering was beneficial even among patients at the lower end of the blood pressure spectrum. The degree of separation between more intensive and less intensive SBP lowering was associated with a uniform relative risk reduction regardless of whether patients with less intensive treatment SBP levels of 140 mm Hg or higher, 130-139 mm Hg, or less than 130 mm Hg. This finding accords with analyses of intensive blood pressure lowering in stroke qualifying event trials, including PROGRESS and the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial.34 However, post hoc analyses of several trials showed that treating SBP to a target of less than 140 mm Hg in patients with severe intracranial stenosis might be beneficial.37 Since the risk-benefit profile of more aggressive blood pressure lowering is not consistent among studies, secondary prevention guidelines recommend a less aggressive SBP target (<140 mm Hg) in patients with 50% to 99% stenosis of a major intracranial artery.38Among patients with high-grade vertebrobasilar or other intracranial stenoses, an inverse association of SBP with recurrent stroke risk was found in some studies.40 These findings support a strategy of a moderate blood pressure–lowering target during the first 6 months following stroke or TIA followed by a more aggressive target chronically.Although this meta-analysis excluded trials with blood pressure–lowering therapy used in acute stage of stroke or TIA, the time interval from stroke to randomization still varied among included trials. A subgroup analysis suggested that more intensive compared with less intensive blood pressure–lowering therapy was associated with substantial risk reduction of recurrent stroke in trials with patients enrolled within 3 to 5 years from stroke or TIA but only associated with modest risk reduction of recurrent stroke in trials with patients enrolled within 6 months from stroke or TIA. This finding accords with observational studies that have suggested that aggressive blood pressure lowering might not be beneficial within the first 6 months following the index ischemic stroke event.41 and this meta-analysis showed that more intensive compared with less intensive blood pressure–lowering therapy was associated with a substantial relative risk reduction in hemorrhagic stroke . Also, the risk of recurrent ischemic and hemorrhagic stroke was greater in Asian population with high blood pressure compared with several other groups around the world.16 Therefore, it is conceivable that more intensive blood pressure–lowering treatment might be especially beneficial for Asian populations.A subgroup analysis also suggested that more intensive compared with less intensive blood pressure–lowering therapy was associated with a larger risk reduction of recurrent stroke in trials with study duration of 3 years or more vs less than 3 years. It is conceivable that a longer duration of high blood pressure levels may cause more profound damage of vessels thereby leading to a higher likelihood of recurrent stroke in patients with stroke or TIA. Also, we found that more intensive compared with less intensive blood pressure–lowering therapy was associated with a larger risk reduction of recurrent stroke in Asian populations than non-Asian populations. In general, the ratio of hemorrhagic stroke to ischemic stroke is higher in Asian than in non-Asian populations,22 and in such settings, there might be a higher chance that stroke events were not well recorded. Still, a sensitivity test restricting analysis within trials with recurrent stroke reported as the primary outcome obtained similar results. Third, although we excluded trials before 1980, the included trials reflect a long period of clinical practice during which concomitant treatments for stroke prevention further evolved.1 However, the consistency in benefit of blood pressure lowering suggests substantial benefit on top of a wide range of background therapies. Fourth, the individual studies mostly have wide CIs and many of the pooled results of secondary outcomes are driven by a single study with a large weight. Fifth, more than half of the participants are contributed by the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS)2 and PROGRESS4 trials. Still, sensitivity testing removing either trial yielded pooled results similar to the overall pooled estimates of the primary outcome.There are several limitations to this study. First, although it was conceivable that some patients in the included trials had baseline SBP less than 140 mm Hg, none of included trials had mean baseline SBP less than 140 mm Hg. Granular analysis related to baseline BP levels could not be conducted because this study was a trial-level meta-analysis, rather than an individual, patient-level pooled analysis. Second, the purpose of some included trials was not to evaluate association between blood pressure lowering and risk of recurrent stroke,This meta-analysis and meta-regression of randomized clinical trials for blood pressure–lowering therapy found that more intensive compared with less intensive blood pressure–lowering therapy may be associated with a reduction of recurrent stroke; further, the larger the magnitude of differential blood pressure reduction, the larger the reduction of cerebrovascular events. More intensive blood pressure–lowering therapy may be also associated with a risk reduction of major cardiovascular events, ischemic stroke, hemorrhagic stroke, fatal or disabling stroke, and death from cardiovascular causes in patients with stroke or TIA. These results might support the use of more intensive blood pressure reduction for secondary stroke prevention chronically.


Eosinophils play a key role in airway inflammation in many diseases, such as allergic and non-allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic obstructive pulmonary disease. In these chronic disabling conditions, eosinophils contribute to tissue damage, repair, remodeling, and disease persistence through the production a variety of mediators. With the introduction of biological drugs for the treatment of these respiratory diseases, the classification of patients based on clinical characteristics (phenotype) and pathobiological mechanisms (endotype) has become mandatory. This need is particularly evident in severe asthma, where, despite the great scientific efforts to understand the immunological pathways underlying clinical phenotypes, the identification of specific biomarkers defining endotypes or predicting pharmacological response remains unsatisfied. In addition, a significant heterogeneity also exists among patients with other airway diseases. In this review, we describe some of the immunological differences in eosinophilic airway inflammation associated with severe asthma and other airway diseases and how these factors might influence the clinical presentation, with the aim of clarifying when eosinophils play a key pathogenic role and, therefore, represent the preferred therapeutic target. Eosinophils are the key actor in airway inflammation in many conditions such as allergic and non-allergic asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and in chronic obstructive pulmonary disease (COPD). In these disorders, eosinophils contribute to tissue damage, repair, remodeling, and disease persistence through the production of a variety of mediators, including basic proteins , chemokines CCL5, CCL11, CCL13), cytokines (interleukin (IL)-2, IL-3, IL-4, IL-5, IL-10, IL-12, IL-13, IL-16, IL-25), and growth factors  1, CCL13,.T2-high asthma encompasses several asthma subtypes, such as early-onset allergic, late-onset eosinophilic asthma, and aspirin-exacerbated asthma . The secThe pathobiology of T2-low asthma is thought to be characterized by neutrophilic inflammation driven by Th1 and/or Th1/17 cell activation . Although T2-high asthma is typically associated with eosinophils, their presence does not automatically mean that they play the most relevant pathogenetic role and that their ablation will be accompanied by a clinical response. Similarly, in subjects with systemic eosinophilia the presence of the atopic state does not guarantee an effective response to mAbs designed for patients with atopic asthma . However, it is equally true that biological treatment can often lead to clinical remission of asthma , suggestIn this review, we describe some of the immunological differences in eosinophilic airway inflammation associated with SA and other airway diseases and how these factors might influence clinical presentation, with the aim of clarifying when eosinophils play a key pathogenic role and, therefore, represent the preferred therapeutic target. + hematopoietic precursors upon stimulation with IL-3, GM-CSF, and IL-5, which bind to receptors sharing a common beta chain. Eosinophil development and maturation largely occur in the bone marrow from CD34+ cells at an early stage in eosinophil-lineage-committed progenitor cells (EoP) [IL-5 receptor, formed by a unique binging α chain (IL-5Rα), is upregulated on CD34ls (EoP) . IL-5 plls (EoP) . The expls (EoP) .In addition to Th2 lymphocytes and ILC-2s, further sources of IL-5 are EoPs, invariant natural killer T cells, and mast cells . HoweverEosinophils recruitment from the blood into organs and tissues are favored by some chemokines, such as CCL5 (RANTES), CCL7 (MCP3), CCL11 (eotaxin 1), CCL13 (MCP-4), CCL15, CCL24, and CCL26. These chemokines act as eosinophil chemoattractant and bind to the CCR3 chemokine receptor, along with type 2 receptors (DP2 or CRTH2) and its ligand prostaglandin (PG) D2, orchestrating synergistically with IL-5 the migration of eosinophils from blood to the lungs ,17.There are data supporting the view that local maturational processes sustain the development of eosinophilia in the lung. Indeed, anti-CCR3 treatment has been reported to be insufficient to clear luminal airway eosinophils in moderately SA, likely because the treatment did not attenuate local eosinophil differentiation reflected in the lack of effect of the drug on sputum levels of either EoPs or mature eosinophils . Th2 cells favor eosinophil activation and survival by releasing primarily IL-5 . These dT2-high asthma phenotype as compared to T2-low phenotype is associated with higher blood eosinophil count, a greater expression of IL-5 in airway mucosa, more severe airway hyper-responsiveness, larger total serum IgE, and higher fractional exhaled nitric oxide (FeNO) . IL-5 and IL-4/IL-13 are considered the key drivers of type 2 pathways underlying eosinophilic airway inflammation in asthma. + T cells are activated via presentation of allergens by dendritic cells differentiating into Th2 cells. Th2 cells produce cytokines, such as IL-4, IL-5, and IL-13, and lead to IgE switching from B cells, airway eosinophilia, and mucous hypersecretion [In allergic asthma, in genetically predisposed individuals, naïve CD4ecretion . In eosiecretion . These eecretion . The keyecretion .FeNO and blood and sputum eosinophil count have been reported to predict T2-high phenotype in SA . Indeed,The ability to distinguish systemic eosinophilia with pathogenetic relevance in the airways from systemic non-inflammatory eosinophilia as an epiphenomenon linked to specific/non-specific stimuli promoting the production of Th2 cytokines helps to define whether eosinophils drive the disease.In type 2-low asthma, the upregulation of T2 immune pathways  and eosinophilic inflammation characteristic of type 2-high phenotype are classically absent, contributing to the poor response to corticosteroids . AlthougEosinophilic and neutrophilic asthma are not mutually exclusive subtypes. The concomitance of activation of type 2 immune pathways in these patients may sometimes occur, further worsening the clinical and functional outcome. Indeed, in the airway of patients with SA, eosinophils can accumulate together with neutrophilic count increase . In addiApproximately 40–50% of all patients with asthma develop the disease during childhood (early-onset asthma). Generally, these patients are atopic with multiple sensitizations to allergens . High toLate-onset eosinophilic asthma phenotype, often non-allergic, is present in about 25% of SA patients and present persistent airflow limitation, accelerated decline of lung function, often requiring high doses of inhaled corticosteroids (ICS) or being refractory to oral corticosteroids (OCS) treatment . AnotherIt has been widely demonstrated that in the late-onset eosinophilic phenotype, the presence of allergy does not represent a factor impacting the efficacy of the anti-eosinophilic therapeutic approach ,48, demoThe new therapeutic frontiers in SA reflect the need to identify reliable biomarkers capable of identifying different phenotypes and endotypes of asthmatics to guide the therapeutic choice. Blood eosinophil count is a commonly used indicator of T2 inflammation in routinary clinical practice. It is easily measured and reproducible. In addition, it has been shown to correlate with risk of exacerbations in patients with SA . MoreoveFeNO is an indirect biomarker of airway type 2 inflammation, and its production is enhanced by the IL-13 and IL-4 pathways that promote the activity of NO synthase ,83,84,85FeNO levels also correlate with the therapeutic response to dupilumab  since several studies showed that FeNO levels decreased during treatment with this drug ,88. Cont1) [Current and previous evidence have suggested FeNO as a surrogate marker for sputum eosinophilia . Contrar1) . In the 1) , a discrThe causes of these observations are not completely elucidated. A possible explanation may be found in the differences between molecular pathways leading to increase in FeNO and recruitment and activation of eosinophils. Overall, given the above conflicting evidence, further ad hoc studies are needed to clarify whether FeNO could be effectively considered in the near future for routine use as a biomarker of airway eosinophilia in different clinical and healthcare settings  ,96.Another molecule that has been proposed as surrogate marker of Th2 inflammation in SA is periostin, an extracellular matrix proteinase, produced by bronchial epithelial cells in response to IL-4 and IL-13. Periostin is also implied in asthma airway remodeling, as it promotes activation of fibroblasts and has autocrine effects on the epithelial cells . As a biHowever, periostin has low specificity, since its levels are influenced by age and other disease as atopic dermatitis, scleroderma, cancer, and diabetic nephropathy .T2-high asthma phenotype hosts up to 70% of SA patients and occurs in both allergic and non-allergic asthma. Owing to difference in blood eosinophil count , age at This observation suggests that the degree of activation of different T2 pathways varies among patients, underscoring the importance of multiple domains characterization of T2 pathways in order to achieve better patient stratification. Upper and lower airways are considered a unified morphological and functional unit, and the connection existing between them has been observed for many years . About 6Increased nasal polyposis and oral steroid courses for chronic rhinosinusitis (CRS) are reported in late-onset severe asthma as compared to early-onset asthma . In CRS,There is still no standardized process to establish the most appropriate therapy for asthmatic patients with nasal polyps. What is emerging quite clear from both randomized and real-world evidence studies is that, more than an asthma comorbidity, the presence of nasal polyposis is a hallmark of late-onset eosinophilic asthma identifying a phenotype particularly responsive to anti-eosinophilic therapy with improvement of quality of life, lung function, and reduction in asthma exacerbations . The preAnti-IL-5 and anti-IL-5Rα in real-life studies have shown to significantly reduce eosinophils number in nasal polyps, the latter with a complete reduction in eosinophils- and neutrophils-infiltrated cells, with a significant reduction in the nasal polyp score (NPS) after 6 months . HoweverAnother comorbidity which should be actively investigated and treated as a possible trigger factor of uncontrolled asthma is gastroesophageal reflux disease (GERD) ,120. ThiObesity has been associated to airway inflammation and is generally considered a feature of late-onset non-eosinophilic asthma . HoweverThe role of eosinophils is under investigation in several other chronic respiratory conditions including allergic fungal airway disease and chronic idiopathic eosinophilic pneumonia ,126,127.Systemic hypereosinophilic diseases including eosinophilic granulomatosis with polyangiitis (EGPA) can also be associated with airway inflammation and severe asthma ,128,129.In recent years, understanding of the pathogenetic mechanisms involved in COPD has greatly increased . Indeed,In fact, several studies have shown that eosinophils may be involved in the inflammatory response in COPD, as under certain circumstances, inflammatory cues promote eosinophil recruitment to the lungs, where secretion of a variety of chemokines and cytotoxic granular products contributes to inflammation . 1% predicted, higher fat-free mass index, fewer symptoms, and lower BODE  [1 values [Increased levels of eosinophils can be detected in the sputum of approximately one-third of COPD patients, overcoming the old-fashioned concept that eosinophilia is a feature that can be used for distinguishing COPD from asthmatic patients ,140. In y index) . Interesy index) ,143. In 1 values .The above reported findings about the persistence of eosinophilia in COPD patients are also in contrast with data from the Acute Exacerbation and Respiratory Infections in COPD (AERIS) study, which reported persistent blood eosinophilia ≥2% in most of their cohort (58%) over 1 year . A few studies have attempted to establish a relationship between eosinophils blood count and the development of pneumonia in COPD patients, considering also the antimicrobial defense role of these cells, with mixed results. Some authors report no difference in pneumonia incidence between COPD patients with low and high eosinophils levels , while oIn conclusion, further studies are needed to better elucidate the fluctuation of eosinophils levels in COPD patients and correlate them with lung function and clinical outcome in long-term follow-up.OCS dependence is reported in a subset of SA phenotype that, although representing only a small proportion of the asthmatic population, requires personalized treatment because of its increased morbidity, hospitalization, and mortality. These patients remain symptomatic and present persistent airway eosinophilia despite treatment with high-dose ICS and OCS. Several cellular and molecular mechanisms related to immunological dysregulation, genetic and environmental factors, or respiratory infections have been related to OCS insensitivity in asthma . Eosinophils, during their migration from the bone marrow to tissues and then to airway lumen, undergo phenotypic changes in response to tissue microenvironmental cues, including altered morphology, enhanced responsiveness to cytokines, different susceptibility to chemotactic mediators, and various degrees of cellular activation, likely acquiring a different susceptibility to pharmacological treatments ,150,151.Tissue eosinophils may be resilient to some extent against anti-IL-5 therapies because molecules other than IL-5, such as IL-3 and GM-CSF, can sustain them. The latter was also identified as a predictor of suboptimal response for anti-IL-5 mAbs treatment . These data are in contrast with what has been observed in 18 patients with SA and elevated blood eosinophils who relied on OCS therapy to control their disease. In this subset of patients, anti-IL-Rα  showed a significant reduction in both circulating and sputum numbers of mature eosinophils and EoP cells, suggesting that targeting IL-5Rα+ cells decreases EoP cell numbers both systemically and within the airways, thereby attenuating the potential IL-5–driven in situ eosinophilopoietic processes that may contribute to persistent airway eosinophilia in patients with severe, prednisone-dependent asthma . CollectIn recent years, a wide range of mAbs targeting IgE or type 2 cytokines have been proved to be highly effective and safe in reducing symptoms and exacerbation in patients with severe allergic and eosinophilic asthma . HoweverIn SA, the identification of specific biomarkers has become the basis for a personalized approach that has replaced the conventional treatment based on corticosteroids and bronchodilators drugs. However, the response to biologics targeting T2 pathways is variable and often unpredictable. Although the origin of this variability is multifactorial, the differences in baseline patient characteristics and the complexity and heterogeneity of biological pathways orchestrating T2 responses are the major determinants. The role played by individual cytokines in T2 inflammatory processes is variable as each of them may be involved to a greater or lesser extent in the initiation, maintenance, and amplification of the inflammatory process. A further complication derives from the fact that in the individual patient, the cytokines and the cells on which they act can vary during the course of the disease and in the different target organs. As a consequence, targeting a single cytokine generally does not result in complete abrogation of the inflammatory response in a large majority of patients. The selection of the most appropriate biologic for each patient should be made on the basis of the patient’s clinical characteristics  and taking into account the patient’s comorbidities  .Patients with asthma that is clearly driven by a clinical history of allergies (rather than just an elevated IgE level) are candidates for anti-IgE therapy.In subjects with severe T2 eosinophilic phenotype asthma, the presence of comorbidities affecting the upper airways increases as peripheral eosinophilia increases and, therefore, patients with these characteristics may benefit more from treatment with IL-5/Rα, even if the anti-IL-4/13 and anti-IgE treatment are recommended as first-line treatments in these patients. However, in asthmatic patients with overlapping phenotypes, the choice of the biological drug able to guarantee the best therapeutic response is still an unsolved problem.Several mAb targeting T2 inflammation  have been approved or are currently in phase 3 clinical trial as add-on therapy for CRSwNP. Dupilumab was the first Food and Drug Administration (FDA)-approved biologic agent in the United States and Europe for the treatment of CRSwNP. Two wide, double-blind, placebo-controlled, international phase 3 studies (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52) enrolling 724 patients with refractory CRSwNP, assessed the efficacy and safety of dupilumab (300 mg every 2 weeks or 4 weeks subcutaneously) in improving nasal symptoms, disease specific quality of life, use of systemic corticosteroids, and/or the need for nasal polyp surgery . Some of the strongest evidence regarding the effectiveness of mepolizumab in improving nasal polyp size and nasal obstruction in CRSwNP, which have led to the approval of the drug for this disabling condition, came from the SYNAPSE study .In this randomized, double-blind, placebo-controlled, parallel group study, the effect of subcutaneous mepolizumab was evaluated in 407 adult patients with highly symptomatic CRSwNP uncontrolled by previous surgery and treated with intranasal steroids. The treatment demonstrated significant improvement in terms of size of nasal polyps and nasal obstruction at week 52 compared with placebo.In a study conducted in 44 subjects with severe eosinophilic asthma and CRSwNP, mepolizumab administered for one year achieved clinical improvement in both asthma and rhinosinusitis. In addition, the mean percent of eosinophil count in nasal cytology, as compared to baseline, significantly decreased after 6 and 12 months of treatment, suggesting that clinical efficacy of mepolizumab is related to reduced inflammation at tissue level . Similarn = 138) and POLYP II (n = 127) phase 3 trials conducted over a treatment period of 24 weeks followed by a 4-week follow-up period [Omalizumab has also shown significant superiority to placebo in the POLYP I , demonstrating a reduction in nasal polyps score and improved nasal symptoms as nasal obstruction and difficulty with sense of smell . AnotherNo documented study in CRSwNP is presently available for mAb targeting IL-13, tralokinumab, and lebrikizumab.Although there is evidence supporting the existence of eosinophilic inflammation in a subgroup of COPD patients, findings from phase 2 and 3 trials evaluating the efficacy of T2-targeted therapies in COPD have been disappointing as compared to those in asthma patients .1, diffusing capacity of the lung for carbon monoxide values, radiological evidence of remodeling, COPD Assessment Test, Chronic Respiratory Disease Questionnaire, and exacerbation rate [A pilot randomized clinical trial (NCT01463644) evaluating 18 subjects treated with mepolizumab given once a month intravenously at the dose of 750 mg for 6 months versus placebo, demonstrated a reduction in blood and sputum eosinophils, without any significant change in FEVion rate . Other pion rate . The aution rate .3 gave disappointing results [A randomized, double-blind, placebo-controlled, phase 2a study investigated efficacy and safety of benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks in a cohort of 101 patients with moderate-to-severe COPD and a sputum eosinophil count of 3·0% or more within the previous year, reporting no significant reduction in the rate of acute exacerbations . Similar results .www.clincaltrials.gov. No documented study in COPD is currently available for reslizumab and tralokinumab.Other biological drugs investigated in moderate-severe COPD patients with T2 inflammation are dupilumab, for which two clinical trials are currently ongoing  and lebrikizumab , which have been completed, but the results are not yet available. The details of these studies are available at the website Collectively, this evidence demonstrates that the role of eosinophils in COPD is more complex than in asthma. Therefore, in order to obtain a substantial improvement in patients’ outcome and respiratory function tests, it would be necessary to act on multiple pathways or cells other than eosinophils, such as T and B cells, macrophages, basophils, and mast cells. In recent years, understanding the role of eosinophil as the driver of pathology in respiratory diseases has increased. The role of eosinophils as biomarkers of T2 inflammation is now established. Furthermore, new eosinophil-targeting therapies have been developed, allowing for better management and therapeutic care of patients. However, the full immunological differences across the spectrum of T2 eosinophilic inflammation and how these differences might influence the clinical presentation and evolution of the diseases are not completely known. Further studies should help understand the contribution of eosinophils in respiratory diseases.


The Bonferroni-corrected test reveals that only Class. Actinobacteria  have a significant causal relationship with IgAN. According to Cochrane’s Q test, there is no substantial heterogeneity across different single-nucleotide polymorphisms (p > 0.05). Furthermore, MR-Egger and MR-PRESSO-Global tests (p > 0.05) showed no evidence of pleiotropy. No reverse causal association was found between the risk of IgAN and microbiota or metabolites (p > 0.05). Clinical specimens demonstrated the effectiveness and accuracy of Actinobacteria in distinguishing IgAN patients from those with other glomerular diseases . Additionally, our correlation analysis revealed a potential association between Actinobacteria abundance and increased albuminuria (r = 0.85) and poorer prognosis in IgAN patients (p = 0.01). Conclusion: Through MR analysis, we established a causal link between Actinobacteria and the incidence of IgAN. Moreover, clinical validation using fecal samples indicated that Actinobacteria might be associated with the onset and poorer prognosis of IgAN. This finding could provide valuable biomarkers for early, noninvasive detection of the disease and potential therapeutic targets in IgAN.Background: Although recent research suggests that alterations in gut microbiota and metabolites play a critical role in the pathophysiology of immunoglobulin A nephropathy (IgAN), the causal relationship between specific intestinal flora and metabolites and the risk of IgAN remains unclear. Method: This study employed Mendelian randomization (MR) to investigate the causal association between gut microbiota and IgAN. To explore potential associations between gut microbiota and various outcomes, four MR methods were applied: inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. If the results of the four methods are inconclusive, we prefer the IVW as the primary outcome. Additionally, MR-Egger, MR-PRESSO-Global, and Cochrane’s Q tests were used to detect heterogeneity and pleiotropy. The stability of MR findings was assessed using the leave-one-out approach, and the strength of the causal relationship between exposure and outcome was tested using Bonferroni correction. Additional clinical samples were utilized to validate the results of Mendelian randomization, and the outcomes were visualized through an ROC curve, confusion matrix, and correlation analysis. Result: This study examined a total of 15 metabolites and 211 microorganisms. Among them, eight bacteria and one metabolite were found to be associated with the risk of IgAN ( Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerular disease worldwide , is alsop-cresyl sulfate, indole-3-acetic acid, trimethylamine N-oxide (TMAO), and phenylacetylglutamine, may compromise the integrity of the intestinal barrier [In recent years, modulating the crosstalk between the gut and kidney axis has emerged as a promising strategy for treating IgAN ,5,6. It  barrier ,14. This barrier ,16. TherWhile targeting bacteria and metabolites to treat IgAN may become an emerging therapeutic modality, identifying the specific gut microbiota and metabolites that have a causal relationship with IgAN remains challenging due to the complexity of the human gut microbiota. Previous studies primarily relied on animal models or observational cross-sectional data, and although some associations were suggested, none could elucidate the causal relationship. This makes it difficult to precisely target the flora for IgAN treatment. Notably, gene prediction based on GWAS data appears to hold potential in helping us solve this puzzle. Mendelian randomization (MR)  is basedhttps://www.ebi.ac.uk/gwas/studies/GCST90018866, accessed on 15 August 2022) came from a meta-analysis of 628,000 cross-population samples from the UK Biobank and FinnGen [We selected 211 intestinal microflora  and 12 metabolites  as exposure factors. The GWAS statistics data of microbiota primarily came from a large-scale multi-ethnic GWAS meta-analysis of 18,340 individuals from 24 cohorts, which recorded 211 gut microbiota and 122,110 related SNPs . IgAN wap-values below the locus-wide significance level (1 × 10−5) for analysis. To ensure the robust association between instrumental variables and exposure factors, we excluded instrumental variables with F values (formula: (R2/(R2 − 1))×((N − K − 1)/K)) < 10. Second, the chosen instrumental variables must meet an independence test. The SNP linkage disequilibrium value (r2) was set to 0.001 and the genetic distance to 10,000 kb to eliminate linkage disequilibrium impact and maintain the independence of selected instrumental variables. Those with an EAF value of less than 0.01 were also excluded. Third, instrumental variables should not be associated with outcomes. We excluded the instrumental variables associated with IgAN (p < 0.05). The Phenoscanner [Our study satisfied three assumptions of MR analysis. First, the single-nucleotide polymorphisms (SNPs) selected for MR analysis need to be strongly associated with the selected microbiota or metabolites. In our research, to ensure enough instrumental variables were included, we chose SNPs with oscanner  was alsoInverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode were used to examine the causal effects. IVW is a time-honored method for combining the Wald ratio estimates of all relevant instrumental variables. This strategy is analogous to using weighted linear regression to probe the relationships between the instrumental factors and the outcome. The intercept of the instrumental variables is constrained to zero. IVW can obtain unbiased estimates of the status without horizontal pleiotropy. Under the premise of InSIDE, the MR-Egger method primarily demonstrates the dosage relationship between instrumental variables and outcomes while accounting for some pleiotropy. The type I error rate can be lowered using the weighted median method, which also allows for the possibility of invalidity for some specific genetic variants. The weighted mode approach remains valid when the vast majority of instrumental variables with identical causal estimates are valid, even if certain instrumental variables do not satisfy the requirements of the MR technique for causal inference. If the results of these methods are inconsistent, we give priority to IVW as the main result.p-value was greater than 0.05, then it was deemed that horizontal pleiotropy was not present in a statistically significant way. When comparing MR-Egger to MR-PRESSO [−4), families: 0.05/35 (1.4 × 10−3), orders: 0.05/20 (2.5 × 10−3), classes: 0.05/16 (3.1 × 10−3) and phyla: 0.05/9 (5.5 × 10−3)), and metabolites (0.05/15 (3.3 × 10−3)). We performed additional reverse causal analysis to investigate whether IgAN would have an effect on the abundance of the identified microorganisms. It was determined that a causal effect was nominal when the p-value was between 0.05 and the corrected value. The statistical analyses were performed using R software version 4.1.2 (https://www.rproject.org/ accessed on 15 August 2022).The MR-Egger and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tests were employed to check for horizontal pleiotropy and outliers, respectively. Using MR-Egger , we may R-PRESSO , the latWe recruited a total of 10 patients with renal biopsy-confirmed IgAN, 5 patients with other types of glomerular disease, and 10 matched healthy controls who had not received corticosteroid, immunosuppressive, or antibiotic therapy prior to sampling. All participants were recruited from the Jiangsu Province Hospital of Chinese Medicine between May 2021 and August 2022. To ensure comparability between groups, we maintained consistency across all factors except kidney disease, including sex, age, medical history, medication use, lifestyle, and dietary habits. We excluded patients with intestinal disorders and autoimmune diseases from the study. Healthy controls were recruited from the Physical Examination Center of Jiangsu Hospital of Traditional Chinese Medicine. The study was reviewed and approved by the Ethics Committee of Jiangsu Provincial Hospital of Traditional Chinese Medicine and complied with the Declaration of Helsinki.The participants were provided with a special stool collection container and instructed to collect 5 g of feces immediately after defecation, which was then placed in a professional stool DNA preservation solution. The samples were stored at a temperature of −80 °C. Once a sufficient number of samples were collected, they were sent to a professional testing institution  for analysis.In this study, we employed the QIAamp DNA Stool Mini Kit method, utilizing silicone membrane technology to extract DNA from 25 frozen stool samples. Subsequently, all samples were assessed for quality and quantity via 3 µL test 1.2% agarose gel electrophoresis and qualitative evaluation of the extracted DNA. The target region and fusion primers were designed to meet the sequencing platform’s requirements, and PCR amplification was carried out using a two-step method. The PCR products were then recovered through 2% agarose gel and purified using the AxyPrep DNA Gel Extraction Kit. The resulting purified products were further eluted and analyzed using 2% agarose gel electrophoresis detection, and FTC-3000TM real-time PCR Quantification was employed for detection. All samples were high-throughput sequenced using the Illumina sequencing platform, followed by microbiome analysis.p-values less than 0.05 indicating statistical significance.Initially, we assessed whether the necessary variables adhered to a normal distribution and exhibited homogeneity of variance. If these criteria were met, we proceeded with a paired t-test to evaluate differences between groups. For comparisons involving multiple groups, we employed a one-way ANOVA test. In cases where these assumptions were not satisfied, we resorted to a Wilcoxon rank sum test for analysis or utilized the Kruskal-Wallis test to examine variables across various groups. This approach ensures a comprehensive, accurate, and elegant assessment of the data. For counting data, we used a chi-square test for comparison. The area under the receiver operating characteristic curve (AUC-ROC) was used to detect the distinguishing ability of biomarkers. The Pearson correlation coefficient was used to describe the correlation between measurement data. All statistical analyses were performed using R4.2.0, with p < 10−5). 3678 instrumental variables were excluded due to linkage disequilibrium. The final dataset included 3631 instrumental variables from 211 different microorganisms after removing variables with weak connections to the exposure factors and variables that might be associated with confounding factors of outcomes. Since there were not enough instrumental variables for screening metabolites that met the locus-wide significance level, we increased the p-value threshold to 5 × 10−5 , Family Erysipelotrichaceae , Genus Butyrivibrio , Genus Phascolarctobacterium , Genus Lachnospira , and Order Erysipelotrichales  were associated with a higher risk of IgAN, according to IVW analysis. In contrast, Genus Parabacteroides  and Genus Ruminococcus  were linked to a lower risk of IgAN. The weighted median method (p = 0.024) was associated with a higher risk of IgAN. The weight mode method produced a similar result . The MR-Egger, MR-PRESSO test (p > 0.05). Cochrane’s Q test (p > 0.05). Nonetheless, the leave-one-out method  was found to be associated with a lower risk of IgAN (p = 0.17), weight mode , and MR-Egger analysis  did not show a significant effect (p > 0.05). Cochrane’s Q test (p > 0.05). Nonetheless, the leave-one-out method  satisfied the Bonferroni-corrected test after analyzing the genetic association between 211 microbiota and IgAN (p > 3.3 × 10−3). p > 0.05).Only Class Actinobacteria . However, patients with IgAN and other glomerular diseases exhibited lower estimated glomerular filtration rate (eGFR), higher albuminuria levels, lower hemoglobin, and higher incidence of hypertension compared with healthy controls (p < 0.05). Based on these results, we conducted pairwise comparisons of Actinobacteria abundance between the three groups to investigate the potential association between Actinobacteria and IgAN.A total of 25 patients were included in the study , consistActinobacteria in the development and advancement of IgAN. Our first objective was to determine whether Actinobacteria could be utilized to differentiate between IgAN patients and healthy controls. To accomplish this, we utilized a paired sample t-test and observed that patients diagnosed with IgAN . The AUC was calculated to be 0.92 (95% CI: 0.80–1.00), indicating that this microflora possessed an exceptional ability to distinguish IgAN from healthy controls . The AUC value for distinguishing IgAN from other glomerular diseases was 0.90 (95% CI: 0.78–1.00). Notably, we compared the differential ability of 24-h urinary protein . Although we observed a trend of increased Actinobacteria richness and decreased eGFR (r = −0.53), the correlation coefficient (p = 0.108). Notably, in non-IgAN glomerular diseases, Actinobacteria showed no significant correlation (p > 0.05). This suggests that Actinobacteria may be a unique pathogenic factor specific to IgAN progression.To further explore the potential clinical relevance of Actinobacteria in IgAN patients, we investigated the correlation between Actinobacteria abundance and various indicators, including proteinuria, eGFR, and prognosis. Using the Pearson index to study the correlation among these indicators D, we foufficient E was notrelation  with prop = 0.01), suggesting that increased Actinobacteria abundance may be associated with a poorer prognosis in IgAN patients. In addition, we conducted a correlation analysis between the relative abundance of Actinobacteria and the pathological scores (MEST-C) of IgAN patients. Based on the median abundance (>20%), patients were divided into high-abundance and low-abundance groups. Although there were no significant differences (p > 0.05), a bar chart analysis  ,25. Targp = 0.0029). Furthermore, our research results show no significant heterogeneity or horizontal pleiotropy, suggesting stability. Notably, clinical sample validation also found that a high abundance of Actinobacteria can distinguish IgAN from other glomerular diseases (p < 0.05). As a gram-positive bacterium, Actinobacteria can produce numerous secondary metabolites and have been associated with various immune kidney diseases [In this study, we genetically predicted the causal relationship between 211 bacteria and IgAN. According to MR analysis, we identified a total of eight associations between gut microbiota and chronic kidney disease (CKD). Among them, Class Actinobacteria exhibited a strong causal relationship with a higher risk of IgAN . It has been reported that beta-hydroxybutyric acid plays a role in the immune modulation of kidney diseases. Beta-hydroxybutyric acid can act as an inhibitor of oxidative stress and the NLRP3 inflammasome, reducing inflammatory responses and apoptosis [p-cresyl sulfate) have been reported to be associated with the severity of immune kidney disease [Regarding gut metabolites, our study only found that beta-hydroxybutyric acid is associated with a reduced risk of IgAN  conditions compared to those with IgAN. Some baseline characteristics of IgAN patients also varied from other GN patients, which may result in some bias. Although we found consistent results, the level of evidence is insufficient. Further cohort studies are warranted in the future. Secondly, although we identified the specific microbiota and metabolites that may be causally associated with IgAN, the interactive dialogue between the intestine and kidney is a complex and diverse process. It is necessary to understand how these specific microbiota and metabolites are synergistically involved in the pathogenesis of IgAN. Thirdly, at present, the metagenomic sequencing of intestinal flora is still improving. The complexity of the gut microbiota extends far beyond the 211 bacteria mentioned in this study. Further gene association studies and clinical research verification are necessary as gut microbiota sequencing technology advances.In conclusion, our study provides valuable insights into the potential causal relationships between specific gut microbiota, metabolites, and IgAN. The identification of Actinobacteria as a strong causal factor, as well as the nominal causality of other microbiota, adds to our understanding of the intricate interplay between the gut and kidney in the development of IgAN. Moreover, the potential protective role of beta-hydroxybutyric acid offers an interesting avenue for future research and therapeutic intervention. While our findings contribute to the current knowledge base, further high-quality studies are necessary to validate these results and elucidate the underlying mechanisms. As precision medicine targeting the gut–kidney axis continues to evolve, a more comprehensive understanding of these complex relationships will pave the way for novel diagnostic and therapeutic strategies for IgAN and other immune kidney diseases.


There is a strong association between hypertension and cerebrovascular diseases, but most of the mechanistic bases to justify this correlation remains misunderstood.To evaluate intracranial pressure waveform in long-term essential hypertensive patients with a non-invasive device, brain4care (b4c).Cross-sectional study in patients with hypertension. Office blood pressure was measured with an automatic oscillometric device. Intracranial pressure evaluation was acquired through a strain sensor that could detect and monitor nanometric skull bone displacements for each cardiac cycle. Under normal physiological conditions, P1 is greater than P2, and the normal P2/P1 ratio is <1. Time to peak (TTP) is the measurement in seconds of the beginning of waveform inscription until P1 and normal values are <0.20 s. The cut-off points ≥1.2 and ≥0.25 s were used to define intracranial hypertension (ICHT).391 consecutive patients were evaluated . Mean value of P2/P1 ratio was 1.18 ± 0.25 and TTP 0.18 ± 0.63 s The obtained P2/P1 ratios were divided in three categories according to results of previous studies of normalcy (<1.0), intracranial compliance disturbance (1.0–1.19) and ICHT (≥1.2). Normal intracranial pressure was observed in 21.7% of patients, intracranial compliance disturbance in 32.7% and intracranial hypertension in 45.6%. Females showed a higher prevalence of ICHT (50.3%).The prevalence of 45.6% intra-cranial hypertension in patients with long-term hypertension, particularly in women, and in those over 65 years old, emphasizes the importance of evaluate intracranial pressure behaviour in these patients and raise a question concerning the real ability of cerebral autoregulation and vascular barriers to protect the brain.  According to World Health Organization (WHO), hypertension (HT) remains as the leading cause of death around the globe and the absolute number of hypertensive adults has doubled in the last three decades .There is a strong association between HT and cerebrovascular diseases, particularly with stroke and cognitive impairment. Despite of that, most of the mechanistic bases to justify this correlation remains to be established. Clearly there is a structural and functional damage in arterial bed concomitant with a pathological increase in blood pressure (BP) but, at least by the concept of cerebral autoregulation and vascular brain barrier, tissues and vessels inside the skull should be safe in early phases of HT –4.Using a minimally invasive system to monitor intracranial pressure (ICP), Mascarenhas et al.  showed iMore recently, in 2021, Fernandes et al.  reportedThere is a grey zone concerning ICP behaviour in chronic hypertensive patients, and very little is known on this subject. To our knowledge, this is the first report evaluating intracranial pressure behaviour in essential hypertensive patients, with the potential to bring some light to this dark side of human history concerning cerebrovascular and cognitive disorders.Since November 2022 to May 2023 all adult patients seen in the Research Center for Cardiometabolic Diseases of the Hypertension Unit, Federal University of Goias, Brazil, and scheduled to perform ambulatory (ABPM) or home blood pressure measurement (HBPM) were invited to participate in the study. The study was designed as part of a cross-sectional analysis approved by the Ethic Committee, Clinical Hospital—Federal University of Goias, number 70448823.1.0000.5078 with the main objective to evaluate the behaviour of non-invasive ICP waveform in patients with sustained hypertension.2, office systolic (SBP) and diastolic (DBP) blood pressure in mmHg, previous history of any cardiovascular (CV) clinical disease, myocardial infarction (MI), stroke, dyslipidemia, diabetes (DM), length of HT diagnosis in years and number and class of anti-hypertensive drugs.After a routine medical history and physical examination, the following parameters were obtained: age, sex, race, body mass index (BMI) in Kg/ mAll these variables were collected the same day when intracranial pressure waveform was measured and were managed by using the REDCap electronic data capture tool hosted in Federal University of Goias.Office blood pressure was measured according to the methodology recommended by the Brazilian Guidelines on Hypertension  with an Intracranial pressure evaluation was performed in a private and silent room with patients at lying position and monitoring waveforms for seven minutes. The first and last minutes were discarded. The non-invasive device brain4care sensor was positioned on the patient's scalp and the morphology of the ICP waves was acquired through a strain sensor that could detect and monitor nanometric skull bone displacements each cardiac cycle .The ICP waveform has two distinct amplitude peaks: P1 and P2. The first P1 amplitude results from transmission of systolic cerebral blood flow and P2 amplitude is associated with brain compliance to intracranial pressure .Under normal physiological conditions, P1 is greater than P2, and the normal P2/P1 ratio is <1. Time to peak (TTP) is the measurement in seconds of the beginning of waveform inscription until P1 and normal values are <0.20 s. The waveforms and data obtained during non-invasive ICP monitoring were automatically digitized, filtered and amplified by the device. Although intracranial hypertension (ICHT) is usually defined as a sustained (>5 min) intracranial pressure over 20 mmHg , using tData were first recorded on the REDCap platform and exported in an excel spreadsheet format. The database was organized and cleaned, removing duplicates, and then exported to SPSS IBM version 26.0 to proceed with statistical analysis. Categorical variables were presented with their frequencies and proportions. The analysis of categorical data associations was performed using the chi-square test. Quantitative variables with data of a continuous nature were firstly analysed in terms of distribution, applying the Kolmogorov-Smirnov test; the presentation of these data was done with mean values and standard deviation when normally distributed. For the analysis of these data, parametric tests were applied, when applicable, such as the T-student test or Analysis of Variance (ANOVA).2. The average of time since the hypertension diagnosis was 20.0 ± 12.8 years. Sociodemographic, anthropometric data and clinical variables are shown in Non-invasive b4c ICP waveform was performed in 401 patients with essential long-term hypertension evaluated during a period of seven months. Ten patients were excluded due to repeated exams or inadequate quality of the signal, thus the final sample included 391 patients. The mean age was 64.3 ± 12.0 years, 75% were female, and mean BMI was 29.8 ± 6.3 Kg/mMean value of P2/P1 ratio of all cohort was 1.18 ± 0.25 and TTP 0.18 ± 0.63 s. The evaluation of P2/P1 and TTP behaviours in the different clinical settings as well as in the sociodemographic and anthropometric situations, did not find differences concerning P2/P1 ratio; however, TTP showed significant increased values in patients over 65 years and in those with obesity .The obtained P2/P1 ratios were divided in three categories according to the results of previous studies of normalcy (<1.0), intracranial compliance disturbance (1.0–1.19) and ICHT (≥1.2). A normal intracranial pressure was observed in 21.7% of all patients, 32.7% exhibited intracranial compliance disturbance, and intracranial pressure was observed in 45.6%. Females showed a significant higher prevalence of ICHT (50.3%). When comparing the scenarios of P2/P1 ≥1.2 and P2/P1 <1.2 females also showed a significant higher prevalence of ICHT .The sample in our study was composed by adult patients with long-term essential hypertension with high prevalence of cardiovascular (CV) risk factors such as diabetes (41.2%) and dyslipidaemia (79.8%), and previous CV disease such as MI (11.0%) and stroke (7.4%). In addition, most of them were aged over 65 years and had overweight and obesity . DespiteDisturbances in blood flow delivery to the brain and blood-brain barrier (BBB) permeability seems to occur before neurodegeneration , 19. DisWe found an average value of P2/P1 ratio of 1.18 ± 0.25, and a TTP mean value of 0.18 ± 0.63 s in the whole sample of patients with hypertension, and the prevalence of P2/P1 >1.0 defining intracerebral hypertension was 78.3%. Even when using a stricter cut-off point P2/P1 ≥1.2 for ICHT the prevalence was 45.6%. The fact that at least half of the patients with long-term hypertension showed abnormal values of intracranial pressure deserves attention concerning the possibility of a lost in the capacity of cerebral autoregulation and BBB to protect brain tissue in hypertension. In opposition to what was believed, a previous publication in animal models revealed an increase in intracranial pressure just a few weeks after inducing renovascular hypertension, meaning that this injury begins in the early phases of BP elevation. The observed results in hypertensive rats and in patients with essential hypertension suggests that several concepts regarding cerebral autoregulation should be revisited , 21.When we look for differences in the mean values of P2/P1 ratio and TTP in the recorded sociodemographic, anthropometric, and clinical variables , the onlOur study has some limitations; It is important to note that it is a cross-sectional analysis of the cohort, and the data related to the behaviour of P2/P1 and TTP in different subsets of patients with hypertension regarding anthropometric, sociodemographic and comorbidities may express some differences in a larger sample of subjects and, of course, that longitudinal studies are needed to evaluate other features in a cause-and-effect relationship. The strengthen of this study is to show by the first time a huge prevalence of intracranial hypertension in patients with essential hypertension and long-term exposure to high blood pressure values.In conclusion, the observation of a prevalence of 45.6% of P2/P1 ratio over 1.2 equivalent to intracranial hypertension in patients with long-term hypertension, particularly in women, and in those over 65 years old emphasizes the importance of closely evaluate non-invasive intracranial pressure waveform in hypertensive patients. The strategy to maintaining optimal systolic blood pressure levels between 120 and 140 mmHg may help to reduce stress on blood vessels, minimizing the risk of BBB disruption. Our findings also raise a question about the accepted concept about the capacity and effectiveness of cerebral autoregulation and vascular barriers to protect the brain in the context of blood pressure elevations. This understanding can lead to a potential therapeutic avenue for hypertension-related brain complications.


The association between tissue oxygenation with postoperative acute kidney injury (AKI) in adult patients undergoing multiple valve surgery has not been specifically studied.In this prospective exploratory cohort study, 99 patients were enrolled. The left forehead, the left forearm, the left upper thigh, and the left renal region tissue oxygen saturation using near-infrared spectroscopy were monitored. The association between each threshold and AKI was assessed. The relative and absolute thresholds were < 70%, < 75%, < 80%, < 85%, < 90%, < 95%, and < 100% baseline, and baseline-standard deviation (SD), -1.5 SD, -2 SD, -2.5 SD, and -3 SD. Multivariate logistic regression analysis was adopted to explore the association.P = 0.023) and baseline-2.5 SD  after adjusting for the potential confounders, those are renal region tissue oxygen saturation of 55% and 60%, but not statistically significant after correcting for multiple testing .AKI occurred in 53 (54%) patients. The absolute value-based SrrO2 thresholds associated with AKI were baseline-3 SD (odds ratio [OR], 4.629; 95% confidence interval [CI], 1.238–17.314; The SrrO2 desaturation, defined as < baseline – 2.5 SD or < baseline – 3 SD, may be associated with AKI. The thresholds need to be verified in future large-scale studies.The study was registered at ClinicalTrials.gov, first trial registration: 26/10/2017, identifier: NCT03323203. Acute kidney injury (AKI) is a common and severe complication following cardiac surgery, especially in procedures involving prolonged cardiopulmonary bypass (CPB) . AKI is Cr) levels. Unfortunately, the delayed rise in SCr level after AKI develops, along with the complexity and intermittent nature in measuring renal injury biomarkers such as liver fatty acid binding protein (LFABP), cystatin C (CysC), neutrophil gelatinase-associated apolipoprotein (NGAL), etc. [The diagnostic criteria for AKI, Kidney Disease: Improving Global Outcomes (KDIGO) , rely onL), etc. , makes t2) in a non-invasive, continuous, and real-time manner [The etiology of cardiac surgery-associated AKI (CSA-AKI) is often linked to decreased oxygen delivery and hemodynamic changes during CPB , 8. Neare manner , 10. Cone manner –13, the e manner . During e manner . TherefoIn this prospective exploratory cohort study, the association of tissue oximetry in different tissue beds  with postoperative AKI was explored in patients undergoing multiple valve surgery (CPB ≥ 90 min). It was assumed that changes in oxygenation of cerebral, peripheral, or renal tissue bed might be associated with the incidence of CSA-AKI. If the association was confirmed, the tissue oximetry could be used as a point-of-care and continuous monitoring technique for perioperative AKI detection.The Institutional Review Board of Xijing Hospital  approved the study, and the study was registered at ClinicalTrials.gov . The research protocol was consistent with the principles outlined in the Declaration of Helsinki. The trial was conducted at Xijing Hospital . Both verbal and written informed consent were obtained from patients or their legal representatives before surgery.Between January 2018 and November 2019, patients aging above 18 years old who were scheduled for elective multiple valve surgery were screened for eligibility. None of patients needed oxygen supplementation before surgery. Patients with 1) trauma, deformity, or other abnormalities on the sensor placement site, which might affect the accuracy of monitoring; 2) preoperative renal failure requiring renal replacement therapy; 3) preoperative intubation requiring mechanical ventilation; 4) mental disorders and being unable to cooperate; 5) preoperative blood transfusion; and 6) patients scheduled for emergency or urgent surgery were excluded from this study.2) of 50%. After that, a central line was accessed via the right jugular vein. During the surgery, the bispectral index was maintained at 40 to 60. The anesthesia was maintained with continuous infusion of propofol or inhaled sevoflurane. After administration of heparin (400 IU/kg) for 5 min, CPB was started after waiting for the activated clotting time to 480 s. During CPB, the extracorporeal circulation speed was maintained at 2.0–2.8 L/kg/m2, so that the mean arterial pressure (MAP) was in the range of 50–80 mmHg. After CPB, heparin was antagonized with protamine sulfate. After the procedure, all patients were transferred to the cardiac intensive care unit (CICU) and care was provided by physicians and nurses in the CICU who were not involved in the present study.After entering the operating room, patients were first connected to standard monitoring, including electrocardiography (ECG), pulse oximetry, and left radical arterial blood pressure. Anesthesia was induced with a bolus injection of 0.02–0.04 mg/kg midazolam, 0.1–0.2 mg/kg etomidate, 0.5–1 µg/kg sufentanil, followed by 0.6–0.9 mg/kg rocuronium after the loss of consciousness. Then, intubation and mechanical ventilation were carried out. The mechanical ventilation mode was volume-controlled ventilation with a tidal volume of 6–8 ml/kg, a respiratory rate of 12–14 breaths/min, and a fraction of inspired oxygen , left upper thigh over the quadriceps (SlegO2), and the left renal region (SrrO2). NIRS probe was applied to the left side of the renal area to monitor SrrO2 under sonographic guidance  to identify the renal region closest to the skin. The depth of the kidney (distance from the skin surface to the kidney capsule) was measured on the long-axis image of the kidney. All four probes were placed before tracheal intubation when the patient was breathing at FiO2 of 0.21, and the acquired data were recorded as a baseline value. The monitoring and data recording were started and were stopped at the end of surgery. The tissue oximetry recorded the oximetry data every two seconds.Tissue oxygenation was monitored using a near-infrared spectroscopy-based tissue oximeter . In the present study, tissue oxygenation of four different tissue beds was monitored, including SctO2, SarmO2, SlegO2, and SrrO2) and the incidence of AKI. The degree of tissue desaturation may depend on magnitude and duration rather than changes in individual time points [The main objective of the present research was to explore the association between tissue desaturation measured at different tissue beds  within 48 h, or an increment in SCr to 1.5 times of baseline within 7 days, or urinary volume < 0.5 ml/kg/h for 6 h.The primary outcome measure was the incidence of AKI according to the KDIGO criteria , which dOther outcomes included the length of mechanical ventilation, the length of CCU stay, the length of hospital stay, and adverse events at the time of hospital discharge and at 30 days after surgery. The relationships between tissue oxygenation and non-renal outcomes in different tissue beds were also explored.Patients’ demographic data were collected, including age, gender, body mass index (BMI), and American Society of Anesthesiologists (ASA) physical status score. Medical history included stroke, hypertension, diabetes mellitus, dyslipidemia, peptic ulcer disease, gastrointestinal bleeding, peripheral vascular disease, coronary artery disease, coagulopathy, chronic obstructive pulmonary disease (COPD), and chronic kidney disease. Surgical data included operation time, CPB time, volume of crystalloid and colloid transfusion, intraoperative minimum hemoglobin level, urinary volume, blood loss, and blood transfusion. The intraoperative hemodynamics and arterial blood gas were also recorded.This study was conducted as an investigator-initiated pilot study to explore the.feasibility of the coherence effect. Due to its exploratory nature  and inestimable recruitment variables (patient flow and preoperative condition), no specific assumptions could be made regarding the effect size of the intervention. The analyses are, therefore, explorative; p values should be interpreted as such.Continuous variables were expressed as mean (SD) or median (interquartile range (IQR)). The difference between patients with AKI and those without AKI was tested using the parametric unpaired Student’s t-test or the non-parametric Mann–Whitney U test (as appropriate). Categorical variables were described as frequency (%).The associations between tissue desaturation and the incidence of AKI were analyzed using multivariate logistic regression analysis adjusted for confounders. For multivariate logistic regression analysis, variables were selected on the basis of previous findings and clinical constraints, i.e., Euroscore II, intraoperative inotropic score, length of CPB, the lowest MAP during CPB, and torsemide use during CPB , 19. TheOf the 5828 patients screened, 110 were enrolled. After excluding cases with missing tissue oximetry data, 99 cases were finally analyzed . Patients with AKI tended to receive more Torsemide 10  mg than those without AKI  mg) during CPB (P = 0.016), more inotropic drugs  vs. 5.0 , P = 0.002), and more crystalloid  vs. 700  ml, P = 0.009) during surgery. After surgery, patients who developed postoperative AKI needed longer mechanical ventilation  vs. 22.3  h, P = 0.0006), more packed red blood cell transfusion  vs. 0  ml, P = 0.002), and crystalloid infusion  vs. 2342.5  ml, P = 0.021), and they had a longer CICU stay  vs. 46.1  h, P = 0.006). Patients with AKI had a higher incidence of postoperative complications, including significantly higher incidence rates of acute hepatic injury , pulmonary infection , and atelectasis  , a receP = 0.023) and baseline -2.5 SD  after adjusting for the above-mentioned confounders  minus 3 and 2.5 standard deviations (SDs), respectively.The confounding factors included in the multivariate logistic regression analysis were Euroscore II, intraoperative inotropic score, length of CPB, the lowest MAP during CPB, and Torsemide during CPB, which were selected on the basis of previous findings and clinical constraints , 19. TheP = 0.045, corrected P = 0.179) and by AUT < baseline – 3 SD , was correlated with SrrO2 desaturation in patients with AKI, while this correlation was not statistically significant after correcting for multiple testing  in a non-invasive, continuous, and real-time manner [AKI is a frequent observed complication in patients with heart disease , 25. Clie manner , 10. In e manner . NowadayrtO2) to predict postoperative AKI and compare its predictive power with that of peripheral vascular and cerebral tissue oxygen saturation . In this small retrospective study, no association was identified between tissue oxygenation and cerebral oxygenation measured in the renal area and postoperative AKI, which was consistent with the findings of the present study. In contrast, a SptO2 decrease of > 10% from baseline was a reasonable predictor, and it was explained that SptO2 could be a better indicator of systemic tissue oxygenation, which was not shown in the present study. However, renal depth was not recorded in this study, which might explain the lack of predictive value in AKI. In contrast, the renal depth was recorded in the present study (3.3 ± 0.9 cm), which was theoretically reachable for oxygenation monitoring. In a prospective observational study, 95 adult patients undergoing elective valvular surgery had an absolute decrease of less than 55% in renal zone oxygenation SrtO2, which was significantly associated with the risk of postoperative kidney damage [Few studies have demonstrated that in infants who underwent cardiac surgery, prolonged low renal oxygen saturation values during surgery were associated with the development of postoperative AKI and might be superior to conventional biochemical markers , 13, 30.y damage . Of notey damage . They foy damage , 35, no 2 in the renal cortex in patients with renal depth < 30 mm. However, the measurement of renal depth > 30 mm rSO2 may be interfered by the perirenal adipose tissue surrounding the kidney. In addition, AKI may occur postoperatively due to several clinical factors, which were not assessed in the present study. This may partially explain deficiencies in the results of the present study.It is noteworthy that NIRS measures oxygen saturation levels in local tissues up to 3 to 4 cm below commercially available sensors . At presrrO2 during surgery and the degree of SrrO2 was associated with operation time. The present study and another study [In the present study, the oxygenation reference value was defined as the valve before tracheal intubation on the room air. Baseline values after induction of general anesthesia may be more representative of physiological conditions during surgery than awake baseline values and are therefore more likely to be the basis for determining the occurrence of associated adverse events . In the er study  used preThe present study has several limitations that should be acknowledged. Firstly, the small sample size may have limited the statistical power and precision of the estimated odds ratios, as evidenced by the wide range of confidence intervals. Moreover, due to the observational nature of the study and the small sample size, potential confounding factors may not have been adequately adjusted for. Secondly, the current study did not explore the dose-dependent association between tissue oximetry and the severity of AKI, primarily due to the limited sample size and limited number of events observed. Thirdly, the study was conducted in a single center and limited enrollment to valvular procedures, which enhanced internal validity but may compromise the external validity and generalizability of the findings. Fourthly, since there are various tissue oximeters approved by the Food and Drug Administration, it is uncertain whether the cutoff value determined in this study can be universally applied when using other products. In summary, the current study should be interpreted as a proof-of-concept and exploratory study. The findings warrant further validation in larger multi-center trials across various clinical scenarios before considering their application in clinical practice. Furthermore, future studies should prioritize determining the most sensitive sites for tissue oxygenation monitoring and identifying optimal cutoff values for early detection of AKI. It would be crucial to investigate whether early initiation of preventive and treatment strategies based on continuous point-of-care oximetry monitoring can provide clinical benefits for high-risk patients and improve their prognosis. Understanding the potential impact of early interventions on patient outcomes is essential for guiding clinical practice and optimizing AKI management in at-risk populations.In conclusion, AKI occurred in 54% of patients undergoing multiple valve surgery. The SrrO2 desaturation, defined as AUT either < baseline – 2.5 SD or < baseline – 3 SD, could increase the risk of AKI. Further research is required to clarify the generalizability of the findings for other populations and the use of SrrO2 desaturation as a potential indicator for AKI.