| Background and ObjectiveAcute kidney injury (AKI) is one of the common clinical critical complications, which is associated with significantly increased mortality, hospital length of stay, medical costs, long-term loss of kidney function, and worsen existing disease or life threatening. In our country, the incidence of AKI is 5%-25% in hospitalized patients, and it reach up to 31.6% in critically ill patients. In specific illness cohort such as decompensated heart failure patients, the incidence of AKI can be as high as 45%. Hence early recognition and diagnosis of AKI, promptly carrying out effective intervention, is the key to reduce renal adverse events and mortality. However, the current clinical diagnostic criteria of AKI including AKIN, RIFLE and KDIGO criteria, all base on serum creatinine and urine output, which has obvious hysteresis and lead to clinical diagnosis and treatment of delayed. In recent years, most efforts have focused on the characterization of novel biomarkers such like troponin. Validating the forecasting ability new biomarkers or biomarker combination is becoming a hot spot of current research. Recently studies identified several biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase(NAG), interleukin-18(IL-18), cystatin C(CysC), which may detected renal injury more sensitively than serum creatinine will enable earlier identification of AKI and support a more rapid start of intervention. But it is still not clear what kind of marker or marker combination is the most ideal. In this prospective observational clinical study, we evaluated and validated the predictive abilities of combinations of urine N-acetyl-β-D-glucosaminidase(uNAG) and serum cystatin C (sCysC) for AKI diagnosis and prognosis in critically ill patients.Methods and materials1. Study design and patientsThis was a prospective, observational and clinical study, which was conducted in the adult mixed intensive care unit (ICU) of Guangdong Generel Hospital. The study protocol was approved by the Hospital Institutional Review Board. Informed consent was obtained from each participant or the participant’s family. All patients>18 yrs who had been admitted to the mixed ICU during during October 2014 to January 2015 were eligible for enrollment. Exclusion criteria included age under 18 years, pregnancy, refusal of consent, end-stage renal disease (ESRD), history of chronic dialysis, and organ transplantation nearly one year. Patients were excluded from the parent study if they died or were discharged within 24h of ICU admission. One patient who had insufficient data was also excluded from this cohort.Demographic and physiological data were obtained from medical records at the time of enrollment. The following clinical variables were evaluated:age and gender; admission type (medical or after surgery); complication of diabetes and hypertension; nephrotoxin exposure preceding 48 hrs of ICU admission; length of ICU stay; renal replacement therapy(RRT) and in-hospital mortality. The disease severity was assessed according to the Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ score within 24 hrs after admission to the ICU.2. Biomarker collection and measurementSpot urine and blood samples were collected at the time of ICU admission, which were shipped by commercial cold chain transportation. All of the biomarkers were measured in a central laboratory using a standard protocol, and all of the samples were labeled using study identification numbers without personal identifiers or clinical conditions. uNAG and sCysC were measured at Guangdong Generel Hospital Clinical Central Laboratory using the colorimetry method (Strong Biotechnologies, Beijing, China) and turbidimetric method (Dako Cytomotion, Denmark) respectively, both of which were commercially available assay kits. Serum creatinine was measured at admission and thereafter daily at 6:00 A.M. Creatinine levels were measured using an automatic biochemical analyzer.3. Outcome definitionsThe primary outcome was the development of AKI, which was defined as an increase in serum creatinine by 26.5 umol/L (0.3 mg/dl) within 48 hours of admission or a 50% increase in serum creatinine from the baseline level (mean of at least three measurements over a 6-month period before admission) within 7 days of admission according to the Kidney Disease Improving Global Outcomes Clinical Practice Guidelines for Acute Kidney Injury. We also use urine output criteria (0.5 ml/kg per hour for 6 hours) for AKI diagnosis because accurate calculation of urine volume is available and practical in ICU. Mild AKI was defined as KDIGO stages l,and severe AKI was defined as KDIGO stages 2 and 3.Baseline serum creatinine was defined as the minimum among the outpatient values measured within 6 months before hospital admission, the inpatient value before ICU admission and the last value before hospital discharge. For a patient with no creatinine measurement within 6 months before ICU admission, the baseline was defined as the minimum among the last value before hospital discharge and the estimated value using the Modification of Diet in Renal Disease equation as the KDIGO guidelines suggest.Secondary outcomes included the following:(1) severity of AKI; (2) ICU length of stay. (3) renal replacement therapy requirement; (4) in-hospital mortality.4. Statistical AnalysesIn this study, data were expressed as median(interquartile range),and continuous variables were compared using the two-sample t test or a Mann-Whitney rank sum test. Categorical variables were described as proportions and were compared using either the Pearson chi square test or Fisher’s exact test. The performance of biomarkers was determined using receiver operating characteristic (ROC) curve analysis. The differences in ROC curves were tested with a nonparametric method as described in the study by Delong et al. Statistical analysis was carried out using SPSS v17.0 for windows (SPSS Inc, Chicago, IL) and MedCalc v11.4.2.0 for windows. P values<0.05 were considered significant.Result1. Patient characteristics and outcomesBetween October 2014 and January 2015,198 patients were enrolled for this study. We found AKI in 51 patients (25.8%) within 1 week after ICU admission, of whom 32 developed mild AKI(16.2%) and 19 developed severe AKI(9.6%). The incidence of AKI in internal medicine cohort and emergency surgery patients was apparently higher than elective surgery patients (P<0.05). In-hospital mortality was 7.0% and require renal replacement treatment rate was 5.1% in this cohort. The AKI group showed significantly higher in-hospital mortality, higher RRT require rate and longer length of ICU stay than non AKI group (P< 0.05). But there were no obviously differences in gender, basis of chronic disease, APACHE Ⅱ score and serum creatinine baseline between the two groups(P>0.05).2. Biomarker levels between groups at ICU admissionThe levels of sCr, uNAG and sCysC were significantly higher in AKI than in non-AKI(P<0.05).The levels of uNAG and sCysC were obviously higher in mild AKI than in non-AKI (P<0.05),but the levels of sCr had no significant difference between the two groups(P>0.05).The levels of uNAG and sCysC were significantly higher in severe AKI than in non-AKI and mild AKI (P<0.05).3. Association between biomarkers and AKIUrine NAG and sCysC predicted AKI with AUC value of 0.743(95%CI: 0.660,0.825) and 0.716(95%CI:0.627,0.805) respectively, while the combination of uNAG and sCysC improved the AKI prediction with a higher AUC of 0.781 (95%CI: 0.700,0.862).4. Association between biomarkers and severe AKIUrine NAG and sCysC predicted severe AKI with AUC value of 0.893(95%CI: 0.831,0.955) and 0.891(95%CI:0.821,0.962) respectively, while the combination of uNAG and sCysC significantly improved the prediction with a higher AUC of 0.929(95%CI:0.829,0.99).5. Association between biomarkers and in-hospital mortalityUrine and sCysC predicted in-hospital mortality with AUC value of 0.905(95%CI:0.832,0.977) and 0.861(95%CI:0.757,0.964) respectively, while the combination of uNAG and sCysC significantly improved the in-hospital mortality prediction [AUC 0.947(95%CI:0.906,0.987)].6. Association between biomarkers and renal replacement therapyUrine NAG and sCysC predicted renal replacement therapy in the duration of hospital stay with AUC value of 0.909(95%CI:0.842,0.976) and 0.872(95%CI: 0.790,0.953) respectively, while the combination of uNAG and sCysC significantly improved the in-hospital mortality prediction [AUC 0.923(95%CI:0.860,0.986)].ConclusionsUrine NAG and sCysC are sensitive indexes for predicting diagnosis of AKI and its prognosis in adult critically ill patients. Combination of biomarkers improve the predictive performance of AKI detection and short-term prognosis such as in-hospital mortality and renal replacement therapy. |
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