| Acute kidney injury(AKI)is defined as a rapid increase in serum creatinine(SCr)levels and/or a decrease in urine output.The incidence of AKI is approximately 10%to 15%in hospitalized patients,and has been reported to be more than 50%in intensive care units(ICUs).AKI is a heterogeneous group of conditions and often arises as part of other syndromes,such as cardiac failure,liver failure and sepsis.AKI itself can cause electrolyte acid-base balance disorder,volume overload,metabolic dysfunction and impairing neutrophil function which reduces patient’s ability to fight infection,all of them lead to further increase of mortality.Therefore,early and rapid diagnosis and treatment of AKI is an important part of the integrated management of various syndromes causing or related to AKI.SCr and urine output are used as diagnostic and staging markers for AKI in current international guidelines.However,an increase in SCr or oliguria may not occur for several hours after an acute decrease in glomerular filtration rate(GFR).In addition,the heterogeneous nature of AKI is not reflected in current diagnostic methods.Thus,it is of great clinical significance to look for early indicators of renal parenchymal injury or renal function impairment for critically ill patients,especially those with specific etiology.Critical ultrasound is non-invasive,portable,repeatable and allows bedside examination.Several studies have demonstrated that Doppler-based renal resistive index(RRI)calculations,semi-quantitative renal perfusion(SQP)and semi-quantitative power Doppler ultrasound(PDU)scores can help to evaluate renal perfusion and renal function,and show a good application prospect with the increasing application of bedside ultrasound in critically ill patients.Based on this,we conducted a prospective observational study of 178 critical patients admitted to ICU and explored the diagnostic performances of RRI and semi-quantitative PDU scores on the assessment of AKI severity,and performed subgroup analysis according to cardiac index(CI)or etiology.In addition,we investigated time course of RRI and SQP scores and their temporal relationship with kidney injury and nitric oxide(NO)production in kidney tissue in a mouse model of sepsis associated AKI established by intraperitoneal injection of lipopolysaccharide(LPS).Part One The performances of RRI and semi-quantitative PDU scores on the assessment of AKI severity in critically ill patientsObjective:To investigate the performances of RRI and semi-quantitative PDU scores on the assessment of AKI severity in critically ill patients.Methods:A prospective observational study including 178 critically ill patients admitted to the emergency ICU of Cangzhou Central Hospital from January 2018 to August 2019 was conducted.The general information,including gender,age,body mass index,accompanying diseases,cause for admission and so on,was recorded on admission.RRI,semi-quantitative PDU scores and CI measurements by transthoracic cardiac ultrasonography were performed within 6 h after ICU admission.Acute Physiology and Chronic Health Evaluation(APACHE)II and Sequential Organ Failure Assessment(SOFA)scores were calculated 24 h after admission.Renal function assessment was performed within 5 days after admission according to the Kidney Disease Improving Global Outcomes(KDIGO)criteria.The differences in general data,renal function indicators and renal ultrasound indicators among non-AKI,AKI stage 1,AKI stage 2 and AKI stage 3 groups were compared by rank and column chi-square test,one-way ANOVA or non-parametric test.Ordinal Logistic regression was used to screen the independent risk factors of AKI stages.The diagnostic performance of RRI and PDU score in predicting AKI stage 3 was analyzed by receiver operator characteristic(ROC)curves.Results:Among the 178 critically ill patients enrolled,71 patients did not develop AKI(71/178,39.9%),31 patients developed AKI stage 1(31/178,17.4%),25 AKI stage 2(25/178,14.0%),and 51 AKI stage 3(51/178,28.7%).Of the general information and renal function indicators,the indicators with statistical differences among non-AKI,AKI stage 1,AKI stage 2 and AKI stage 3 groups included age,accompanying coronary heart disease[CHD],arterial lactate concentrations,use of vasoactive agent,use of mechanical ventilation,APACHE-Ⅱ score,SOFA score,28-day mortality,potassium,SCr,urine volume and use of continuous renal replacement therapy(CRRT)(P<0.05).RRI was statistically different among AKI stages(P<0.05).RRI was the lowest in patients without AKI and the highest in patients with AKI stage 3 with statistical difference between the two groups(P<0.05).RRI in patients with AKI stage 1 and stage 2 were higher than those in patients without AKI and lower than those in patients with AKI stage 3,and the difference between AKI stage 1 and AKI stage 2 was not statistically significant.PDU score was statistically different among AKI stages(P<0.05).With AKI aggravating,the semi-quantitative PDU score showed a gradually decreasing trend(P<0.05).Except for no statistical difference between AKI stage 1 and AKI stage 2,there were statistical differences between the two groups(P<0.05).Ordinal Logistic regression analysis showed that oxygenation index,SCr,urine volume and PDU score were independent risk factors for AKI severity.ROC curve analysis showed that RRI and semi-quantitative PDU score could predict AKI stage 3(RRI:area under the curve[AUC]=0.763,95%confidence interval 0.692-0.825,P<0.001;PDU score:AUC=0.777,95%confidence interval 0.709-0.836,P<0.001).Summary:RRI and PDU score were statistically different among AKI stages,and PDU score was one of independent risk factors for AKI severity.RRI and semi-quantitative PDU score could predict AKI stage 3.Part Two Determinants of RRI and semi-quantitative PDU scores in critically ill patientsObjective:In critically ill patients,RRI and PDU scores may be affected by a variety of intrarenal and extrarenal factors,thus limiting their value on AKI evaluation.This part of the study aimed to investigate the associated factors of RRI and semi-quantitative PDU scores in critically ill patients.Methods:A prospective observational study including 148 critically ill patients admitted to the emergency ICU of Cangzhou Central Hospital from January 2018 to August 2019(30 patients who did not obtain CI levels were excluded)was conducted.The general information was recorded on admission.RRI,semi-quantitative PDU scores and CI measurements by transthoracic cardiac ultrasonography were performed within 6 h after ICU admission.During the renal ultrasound examination,heart rate,mean arterial pressure(MAP),pulse pressure,use of vasoactive drugs,use of mechanical ventilation and oxygenation index were recorded.Renal function assessment was performed within 5 days after admission according to the KDIGO criteria.Correlation analysis was used to screen out the related factors of RRI or PDU score.Correlations between continuous variables with normal distribution were evaluated using Pearson correlation coefficients;correlations between categorical data or continuous variables without normal distribution were evaluated using Spearman correlation coefficients.Binary Logistic regression was used to screen the independent risk factors of RRI.Ordinal Logistic regression was used to screen the independent risk factors of PDU score.Results:The factors associated with RRI included age(r=0.394,P<0.001),body mass index(r=-0.215,P=0.011),accompanying CHD(r=0.186,P=0.027),heart rate(r=0.185,P=0.028),MAP(r=-0.182,P=0.031),pulse pressure(r=0.211,P=0.012),use of mechanical ventilation(r=0.237,P=0.005),use of vasoactive drugs(r=0.298,P<0.001),SCr(r=0.302,P<0.001),urea nitrogen(r=0.297,P<0.001),urine output(r=-0.291,P<0.001),PDU score(r=-0.517,P<0.001)and AKI stage(r=0.450,P<0.001).The above associated indicators were included in the binary Logistic regression analysis taking RRI as the dependent variable(defined as RRI<0.700 or>0.700),and it was found that only age and PDU score were independent related factors of RRI.The factors associated with PDU score included age(r=0.254,P=0.002),accompanying CHD(r=0.221,P=0.007),heart rate(r=0.184,P=0.025),CI(r=0.193,P=0.019),use of mechanical ventilation(r=0.221,P=0.007),use of vasoactive drugs(r=0.287,P<0.001),lactic acid(r=0.224,P=0.006),SCr(r=0.412,P<0.001),urea nitrogen(r=-0.334,P<0.001),urine output(r=0.449,P<0.001),RRI and AKI stage(r=-0.599,P<0.001).The above associated indicators were included in the ordinal Logistic regression analysis taking PDU score as the dependent variable(0,1,2,and 3,respectively),and it was found that only CI,lactic acid,RRI and AKI stage were independent related factors of PDU score.Summary:Age and PDU score were independent correlative factors of RRI.CI,lactic acid,RRI and AKI stage were independent correlative factors of PDU score.Part Three The predictive value of RRI and semi-quantitative PDU scores for severe AKI in critically ill patients with reduced or maintained CIObjective:Both RRI and PDU score are renal perfusion indicators,and CI is an independent correlation factor of PDU score.The evaluation value of RRI and PDU score on AKI may be affected by CI.This part of the study aimed to investigate the diagnostic performances of RRI and semi-quantitative PDU scores in predicting AKI stage 3 in critically ill patients with reduced or maintained CI.Methods:A prospective observational study including 148 critically ill patients admitted to the emergency ICU of Cangzhou Central Hospital from January 2018 to August 2019(30 patients who did not obtain CI levels were excluded)was conducted.The general information was recorded on admission.RRI,semi-quantitative PDU scores and CI measurements by transthoracic cardiac ultrasonography were performed within 6 h after ICU admission.Renal function assessment was performed within 5 days after admission according to the KDIGO criteria.According to CI levels,all patients were divided into patients with reduced CI(CI<3L·min-1·[m2]-1)and patients with maintained CI(CI>3 L·min-1·[m2]-1)for further analysis,respectively.The differences in general data,renal function indicators and renal ultrasound indicators were compared between AKI 0-2 group and AKI 3 group by chi-square test,t test or non-parametric test.The diagnostic performance of RRI and PDU score in predicting AKI stage 3 was analyzed by ROC curves.Results:Among the 148 critically ill patients enrolled,80 patients had reduced CI and 68 had maintained CI.APACHE-II score,SOFA score,arterial lactate concentration,use of mechanical ventilation,use of vasoactive drugs,and mortality on day 28 differed between the AKI 3 and AKI 0-2 groups in patients with reduced CI(P<0.05),but not in patients with maintained CI(P>0.05).Urine output,SCr,RRI,PDU score,and use of CRRT significantly differed between the AKI 3 and AKI 0-2 groups in patients with reduced CI(P<0.05)and in patients with maintained CI(P<0.05).Admission for sepsis and admission for acute heart failure significantly differed between CI-reduced and CI-maintained patients(P<0.05).ROC curves analysis revealed that the predictive value of RRI for AKI stage 3 was similar among all patients(AUC=0.753,95%confidence interval 0.674-0.822,P<0.001),CI-reduced patients(AUC=0.761,95%confidence interval 0.650-0.851,P<0.001),and CI-maintained patients(AUC=0.786,95%confidence interval 0.6650.878,P<0.001).PDU score could effectively predict AKI stage 3 in CI-reduced patients(AUC=0.872,95%confidence interval 0.778-0.936,P<0.001),and the optimal cut-off for PDU score was ≤1(sensitivity 69.6%,specificity 89.5%,Youden index 0.590,accuracy in our population 83.8%).However,PDU score could not predict AKI stage 3 in CI-maintained patients(AUC=0.669,95%confidence interval 0.544-0.778,P=0.071).Summary:The predictive value of RRI for AKI stage 3 was similar in CI-reduced patients and CI-maintained patients.PDU scores could effectively predict AKI stage 3 in CI-reduced patients but not in CI-maintained patients.Part Four The predictive value of RRI and semi-quantitative PDU scores for severe AKI in patients with sepsis or acute heart failureObjective:In Part Three of the study,there was a significant difference in the proportion of acute heart failure and sepsis between patients with reduced CI and patients with maintained CI.Do etiologies account for the differences in the evaluation value of RRI or PDU scores for AKI stage 3?This part of the study aimed to investigate the diagnostic performances of RRI and semi-quantitative PDU scores in predicting AKI stage 3 in patients with sepsis or acute heart failure.Methods:A prospective observational study including 70 patients with acute heart failure and 60 patients with sepsis admitted to the emergency ICU of Cangzhou Central Hospital from January 2018 to August 2019 was conducted.The general information was recorded on admission.RRI and semi-quantitative PDU scores were performed within 6 h after ICU admission.Renal function assessment was performed within 5 days after admission according to the KDIGO criteria.In patients with acute heart failure or sepsis,the differences in general data,renal function indicators and renal ultrasound indicators were compared between AKI 0-2 group and AKI 3 group by chi-square test,t test or non-parametric test.The diagnostic performance of RRI and PDU score in predicting AKI stage 3 was analyzed by ROC curves.Results:In patients with acute heart failure,APACHE-II score,SOFA score,arterial lactate concentration,use of mechanical ventilation,use of vasoactive drugs,mortality on day 28,urine output,SCr,and use of CRRT differed between the AKI 3 and AKI 0-2 groups(P<0.05).In patients with sepsis,only urine output,SCr,and use of CRRT differed between the AKI 3 and AKI 0-2 groups(P<0.05).In patients with acute heart failure,RRI and PDU score differed between the AKI 3 and AKI 0-2 groups(P<0.05).In patients with sepsis,RRI differed between the AKI 3 and AKI 0-2 groups(P<0.05),but PDU score did not(P>0.05).ROC curves analysis revealed that the predictive value of PDU score for AKI stage 3 was excellent in patients with acute heart failure(AUC=0.913,95%confidence interval 0.821-0.967,P<0.001),and the optimal cut-off for PDU score was ≤1(sensitivity 80.8%,specificity 93.2%,Youden index 0.740).However,PDU score could not predict AKI stage 3 in patients with sepsis(AUC=0.550,95%confidence interval 0.416-0.679,P=0.565).The predictive value of PDU score for AKI stage 3 was better in patients with acute heart failure than that in patients with sepsis(P<0.001).The predictive value of RRI for AKI stage 3 was better in patients with acute heart failure(AUC=0.845,95%confidence interval 0.731-0.924,P<0.001)than that in patients with sepsis(AUC=0.678,95%confidence interval 0.544-0.794,P=0.015),but the difference was not statistically significant(P=0.066).Summary:RRI was a poor predictor of AKI stage 3 in patients with sepsis and performed better in patients with acute heart failure.PDU scores could effectively predict AKI stage 3 in patients with acute heart failure but not in patients with sepsis.Part Five Time course of RRI and SQP scores and their temporal relationship with kidney injury and NO production in kidney tissue in a mouse model of sepsis associated AKI induced by LPSObjective:Clinical studies have shown that RRI and SQP scores have limited predictive value for sepsis associated AKI.In sepsis,a large amount release of NO leads to systemic vascular dilation and hemodynamic disorders.Does NO affect the evaluation value of RRI and SQP score for AKI?This study aimed to investigate the time course manifestation of RRI and SQP,as well as their temporal relationship with inflammatory markers,kidney injury indicators,nitric oxide synthase(NOS)expression and NO production in kidney tissue in a mouse model of sepsis associated AKI induced by LPS.Methods:Thirty-six healthy and clean C57BL/6JNIFDC male mice were randomly divided into 6 groups:control group and LPS 6 h,12 h,18 h,24 h and 48 h group,with 6 mice in each group.Mice in LPS groups were intraperitoneally injected with 10mg/kg body weight of LPS to establish sepsis associated AKI model.Mice in control group received an intraperitoneal injection of the same dose of normal saline.Mice in control group and LPS groups received renal ultrasound and echocardiography examination for RRI,SQP score and cardiac output measurements at corresponding time points after intraperitoneal injection.After ultrasound examination,plasma and renal tissue specimens were collected.Plasma creatinine,urea nitrogen,kidney injury molecule-1(Kim-1),tumor necrosis factor-α(TNF-α)and interleukins-1β(IL-1β)levels and the NO levels in the kidney tissues were detected.Hematoxylin-Eosin(HE)staining were done to observe renal tissue damage.The expression level and localization of inducible NOS(iNOS)and phosphor-endothelial NOS(p-eNOS)in kidney tissue were detected by western blotting and immunohistochemical examination.Results:1.RRI showed a significant decline in LPS 6 h group(P<0.05)and a minima in LPS 24 h group,and then an elevation in LPS 48 h group,which was statistically higher than that in the control group(P<0.05).There was no significant difference in peak systolic velocity,end diastolic velocity levels and SQP(P>0.05).Cardiac output showed a significant decline in LPS 6 h group(P<0.05)and a minima in LPS 24 h group,and an elevation in LPS 48 h group,which was statistically lower than that in the control group(P<0.05).2.Plasma creatinine,urea nitrogen,Kim-1,and renal tubular injury score showed a similar trend with a statistical increase in LPS 6 h group(P<0.05)and maximum in LPS 18h and 24 h groups,and then a decrease in LPS 48 h group,which was statistically higher than that in the control group(P<0.05).3.Plasma TNF-α and IL-1β showed a significant increase in LPS 6 h group(P<0.05),then a decrease in LPS 12h group,and the level in LPS 48h group was similar to that in the control group(P>0.05).4.NO and iNOS levels in renal tissue showed a significant increase in LPS 6 h group(P<0.05)and a maxima in LPS 18 group,and then a decrease in LPS 48h group which was still significantly higher than the level in control group(P<0.05).INOS was localized in renal interstitium and glomerulus.P-eNOS expression in renal tissues significantly decreased in LPS 6 h group(P<0.05),and showed sustained low level in LPS 12,18 and 24 h groups(P<0.05),and increased to the control level in LPS 48 h group(P>0.05).P-eNOS was localized in kidney tubules and peritubular capillaries.Summary:In sepsis associated AKI,RRI and SQP may be the combined effect of increased renal vascular resistance caused by renal injury and decreased renal vascular resistance resulted from NO.In addition,the differences in expression levels and locations of NOS subtypes in renal tissues may lead to uneven distribution of NO,which may be one of the reasons for microvascular dysfunction and impaired local perfusion in sepsis associated AKIConclusions:1.RRI and semi-quantitative PDU score could predict AKI stage 3 in critically ill patients,but the predictive values were poor.2.In critically ill patients,age and PDU score were independent correlative factors of RRI.CI,lactic acid,RRI and AKI stage were independent correlative factors of PDU score.3.In critically ill patients,the predictive value of RRI and PDU score for AKI stage 3 was affected by CI level.The predictive value of RRI for AKI stage 3 was similar in CI-reduced patients and CI-maintained patients.PDU scores could effectively predict AKI stage 3 in CI-reduced patients,but not in CI-maintained patients.4.In critically ill patients,the predictive value of RRI and PDU score for AKI stage 3 was affected by etiology.The predictive value of RRI for AKI stage 3 in patients with acute heart failure was slightly better than that in patients with sepsis,and the difference was nearly statistically significant.PDU scores could effectively predict AKI stage 3 in patients with acute heart failure,but not in patients with sepsis.5.In mouse model of sepsis associated AKI induced by LPS,renal SQP score did not change significantly,and RRI tended to decrease first and then increase,while NO and iNOS in renal tissues tended to increase first and then decrease,which was opposite to the change trend of RRI.Therefore,NO level may limit the application value of RRI and SQP scores in septic associated AKI. |
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