64. Novel Biomarkers Improve Estimation of Vancomycin Clearance in Critically Ill Children

Background There are a paucity of robust population PK (popPK) models to inform vancomycin (VAN) dosing in critically ill children. The majority of published models incorporate peak/trough data and rely on flawed estimates of renal function. We sought to develop a popPK model for IV VAN in critically ill children utilizing novel plasma and urinary biomarkers. Methods We conducted a prospective observational study of critically ill children prescribed VAN for a suspected infection in the CHOP pediatric ICU. Children < 1 year of age and those receiving ECMO or CRRT were excluded. Five VAN samples were collected from a single dosing interval for each subject. Plasma biomarkers (creatinine [Cr], cystatin C [CysC], NGAL) and urinary biomarkers (CysC, NGAL, KIM-1, osteopontin) were collected the morning of PK sampling; urinary biomarkers were corrected for urine creatinine. Nonparametric popPK modeling was performed using Pmetrics. The impact of renal function (GFR) on VAN clearance (CL) was estimated first, comparing model performance with each biomarker (Cr and plasma CysC). The influence of age, sex, additional biomarkers, PIM3 score, and receipt of vasopressors as covariates was then assessed for relevant PK parameters. Results 30 subjects completed the study. Median age was 10 years (range 1-17); 76% were male. The majority (90%) of children received VAN for suspected sepsis. PK sampling occurred at a median of 37.7 hours (range 24.6-94.8) into VAN treatment; 136 VAN samples were included. A 2-compartment model with fixed allometric scaling of 0.75 on clearances and 1 on volumes best described the data. CysC-based GFR as a covariate on VAN CL using the HOEK formula (GFR = -4.32 + (80.35/CysC)) resulted in the best model fit. Age and plasma NGAL were also informative on VAN CL in the final model (Figure 1). During model building, urinary NGAL was also associated with VAN CL (comparable to plasma NGAL) and outperformed Cr, although it was not retained in the final model. Figure 1. Final population PK model and parameter estimates. Conclusion Plasma CysC is a better renal function estimate than Cr to inform VAN clearance in critically ill children. Urinary and plasma NGAL also improved estimation of VAN CL during popPK modeling. Novel biomarkers can better describe VAN exposures in critically ill children than reliance on Cr alone. Disclosures Kevin J. Downes, MD, Merck (Individual(s) Involved: Self): Grant/Research Support Stuart L. Goldstein, MD, Bioporto (Consultant, Grant/Research Support)

FC 051PREDICTIVE VALUE OF PLASMA NGAL:HEPCIDIN-25 FOR MAJOR ADVERSE KIDNEY EVENTS AFTER CARDIAC SURGERY WITH CARDIOPULMONARY BYPASS: A PILOT STUDY

Background and Aims Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 appear to be involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We aimed to explore the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events after cardiac surgery. Method We compared the predictive value of plasma NGAL, hepcidin-25, and NGAL:hepcidin-25 with those of serum creatinine (Cr), and urinary output and urinary protein for primary endpoint major adverse kidney events (MAKE; acute kidney injury [AKI] stages 2 and 3, persistent AKI > 48 hrs, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses. Results At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77 [95% confidence interval (CI) 0.60–0.94], 0.79 [0.63–0.95], 0.74 [0.51–0.97]) and AKI (0.73 [0.53–0.93], 0.89 [0.81–0.98], 0.70 [0.48–0.93]). For AKI prediction, NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00–0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC < 0.70). Only plasma NGAL:hepcidin-25 correctly reclassified patients for MAKE or AKI (category-free net reclassification improvement: 0.82 [95% CI 0.12–1.52], 1.03 [0.29–1.77]). After adjustment to the Cleveland risk score, plasma NGAL:hepcidin-25 ≥ 0.9 independently predicted MAKE (adjusted odds ratio 16.34 [95% CI 1.77–150.49], P = 0.014), whereas Cr did not. Conclusion NGAL:hepcidin-25 is a promising plasma marker for predicting postoperative MAKE.

Neutrophil gelatinase–associated lipocalin as a biomarker of nephropathy in sickle cell disease

Sickle cell nephropathy (SCN) develops via altered hemodynamics and acute kidney injury, but conventional screening tests remain normal until advanced stages. Early diagnostic biomarkers are needed so that preventive measures can be taken. This study evaluates the role of neutrophil gelatinase–associated lipocalin (NGAL) as a biomarker of SCN in steady state and vaso-occlusive crisis (VOC). In this case-control study, 74 sickle cell disease (SCD) patients (37 in steady state and 37 in VOC) and 53 control subjects had hematological and biochemical measurements including plasma and urine NGAL. Univariate and logistic regression analyses were used to find the associations between variables. The receiver operating characteristic (ROC) curve was used to determine the diagnostic performance characteristics of plasma and urine NGAL for detection of VOC. Plasma and urine NGAL, urine microalbumin:creatinine ratio, and urine protein:creatinine ratio were significantly higher in VOC. Microalbuminuria was present in 17.1% steady state and 32.0% VOC patients. Microalbuminuria showed significant correlations with age, plasma NGAL, WBC, and hemolytic parameters. Area under the ROC curve for plasma NGAL was 0.69 (95%CI = 0.567–0.813; p = 0.006) and 0.86 (95%CI = 0.756–0.954; p < 0.001) for urine NGAL. Urine NGAL cut-off value of 12.0 ng/mL had 95% sensitivity and 65% specificity. These results confirm the presence of nephropathy during VOC and suggest that plasma and urine NGAL would be useful in the identification of SCN. Urine NGAL should be used as the screening biomarker, and patients with VOC and urine NGAL > 12.0 ng/mL should be selected for aggressive management to prevent progression of renal damage.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) measured at admission is associated with development of late cardiogenic shock and mortality in patients with STEMI

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Rigshospitalets Forskningsfond (Grant number: 07IO) Hjerteforeningen (Grant number A6024) Lundbeckfonden (Grant number R186-2015-2132) BACKGROUND In patients with ST-elevation myocardial infarction (STEMI) increased inflammatory response is associated with development of cardiogenic shock (CS). Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a glycoprotein released from mature neutrophils and the plasma concentration of NGAL likely increases immediately after STEMI. PURPOSE We aimed to assess whether admission NGAL plasma concentration in patients with STEMI was associated with CS development after leaving the catheterization laboratory (late CS) and 30-day all-cause mortality. MATERIALS AND METHODS From 1892 consecutive patients with STEMI 1626 (86%) had plasma NGAL concentration measured upon hospital admission before angiography throughout a 1-year period at two tertiary heart centers in Denmark. Patients were stratified according to NGAL quartiles (Q1-4). To assess late CS development, we adjusted for the Observatoire Régional Breton sur l’Infarctus (ORBI) risk score for late CS. For mortality assessment, we adjusted for gender, age, post-PCI culprit Thrombolysis in myocardial infarction (TIMI) flow, left ventricular ejection fraction (LVEF), kidney dysfunction, admission lactate concentration and being comatose after cardiac arrest. RESULTS Increasing NGAL concentration was associated with higher age, more comorbidities (hypertension, diabetes, heart failure, previous stroke, and kidney dysfunction) and more critical patient conditions at presentation including lower blood pressure and LVEF. Plasma NGAL concentration was associated with both late CS development and 30-day mortality (Figure). When adjusted for factors associated with poor outcome, NGAL remained independently associated with both late CS development (Q4 vs. Q1-3) (OR (95% CI) 2.64 (1.57-6.03)) and 30-day mortality (HR (95% CI) 3.18 (1.46-6.93)). CONCLUSION High admission plasma concentration of NGAL in patients with STEMI was independently associated late CS development and 30-day all-cause mortality. Abstract Figure. NGAL quartiles and late CS/mortality

Procalcitonin, C-reactive protein, neutrophil gelatinase-associated lipocalin, resistin and the APTT waveform for the early diagnosis of serious bacterial infection and prediction of outcome in critically ill children

Objective Bacterial Infections remains a leading cause of death in the Paediatric Intensive Care Unit (PICU). In this era of rising antimicrobial resistance, new tools are needed to guide antimicrobial use. The aim of this study was to investigate the accuracy of procalcitonin (PCT), neutrophil gelatinase-associated lipocalin (NGAL), resistin, activated partial thromboplastin time (aPTT) waveform and C-reactive protein (CRP) for the diagnosis of serious bacterial infection (SBI) in children on admission to PICU and their use as prognostic indicators. Setting A regional PICU in the United Kingdom. Patients Consecutive PICU admissions between October 2010 and June 2012. Measurements Blood samples were collected daily for biomarker measurement. The primary outcome measure was performance of study biomarkers for diagnosis of SBI on admission to PICU based on clinical, radiological and microbiological criteria. Secondary outcomes included durations of PICU stay and invasive ventilation and 28-day mortality. Patients were followed up to day 28 post-admission. Main results A total of 657 patients were included in the study. 92 patients (14%) fulfilled criteria for SBI. 28-day mortality was 2.6% (17/657), but 8.7% (8/92) for patients with SBI. The combination of PCT, resistin, plasma NGAL and CRP resulted in the greatest net reclassification improvement compared to CRP alone (0.69, p<0.005) with 10.5% reduction in correct classification of patients with SBI (p 0.52) but a 78% improvement in correct classification of patients without events (p <0.005). A statistical model of prolonged duration of PICU stay found log-transformed maximum values of biomarkers performed better than first recorded biomarkers. The final model included maximum values of CRP, plasma NGAL, lymphocyte and platelet count (AUC 79%, 95% CI 73.7% to 84.2%). Longitudinal profiles of biomarkers showed PCT levels to decrease most rapidly following admission SBI. Conclusion Combinations of biomarkers, including PCT, may improve accurate and timely identification of SBI on admission to PICU.

Neutrophil gelatinase-associated lipocalin as a biomarker for predicting acute kidney injury after coronary artery bypass grafting

Background Early and precocious determination of acute kidney injury (AKI) is essential to prevent morbidity and mortality following coronary artery bypass grafting (CABG). Evaluation of the perioperative renal function is substantial using novel biomarkers other than the late traditional method of using serum creatinine. Plasma neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker investigated for early detection of AKI in patients undergoing coronary artery bypass grafting, and its role has to be determined in this study. Results Twenty-five patients undergoing elective CABG were enrolled in this cohort study and were assigned into two groups: group I include the patients that did not develop AKI (no AKI group) and group II include the patients that developed AKI (AKI group). Acute kidney injury based on Kidney Disease: Improving Global Outcomes (KDIGO) classification had been developed in 7 patients (28%). Plasma NGAL levels at 6 h were higher in patients who developed AKI compared with those who did not (302 ± 88.02 vs. 116.50 ± 17.33 ng/m, p value < 0.001). The cut-off value of plasma NGAL levels measured 6 h postoperatively was 145 ng/ml and the area under the receiver-operating characteristic (ROC) curve was 0.965. Results of this study showed that plasma NGAL is a robust early biomarker of AKI, which preceded the rise in serum creatinine by many hours. Conclusion This study revealed that earlier diagnosis of acute kidney injury in patients undergoing CABG can be achieved by measuring postoperative plasma NGAL concentration at 6 h.

Plasma Neutrophil Gelatinase-Associated Lipocalin and Interleukin-9 as Acute Kidney Injury Predictors After Coronary Artery Bypass Graft Following Cardiopulmonary Bypass

Background: Acute Kidney Injury (AKI) incidence of postoperative Coronary Artery Bypass Graft (CABG) with Cardipulmonary Bypass (CPB) at Dr. Soetomo General Academic Hospital reached 69.8%, higher than the global average of 5-20%. Predictors of postoperative AKI are needed; potential biomarkers include plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Interleukin-9 (IL-9). This study aims to analyze the predictive ability of these two biomarkers. Methods: This is a prospective observational study in CABG patients with CPB without previous renal abnormalities at Dr. Soetomo in September-December 2020. Examination of plasma NGAL and IL-9 was carried out before, during, and after the CPB procedure. Results: 21 patients were included in the study, 17 people (81.0%) were male. AKI experienced 14 people (66.7%); 3 people (14.3%) died. Patients without AKI had higher plasma NGAL results at preinduction (17.9±10.3 vs 17.1±15.5), durante (20.5±8.2 vs 16.9±7.8), and early ICU (24.0±8.6 vs 22.9±10.4). Patients with AKI had higher plasma IL-9 results at preinduction (63.3±23.2 vs 55.7±15.8), durante (45.2±11.0 vs 44.2±9.2), and early ICU (49.6±11.3 vs 46.2±15.6). There was no statistically significant relationship between plasma NGAL and IL-9 results. Conclusion: Most CABG patients undergoing CPB have AKI. Patients without AKI had higher NGAL results and lower IL-9 in plasma. Statistically, neither of them can be used as predictive biomarkers of the incidence of AKI so far.

Diagnostic relevance of neutrophil gelatinase-associated lipocalin in early detection of acute kidney injury

Objective: To evaluate the predictive and diagnostic accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in acute kidney injury (AKI) and also to predict the renal replacement therapy (RRT) using NGAL as a marker. Methods: This prospective study was conducted among the patients admitted to intensive care units. Plasma samples were collected 24 hours after admission and NGAL was measured using Triage® NGAL test, a specific point of care test which is based on the mechanism of fluorescence immunoassay. The diagnostic accuracy of plasma NGAL (pNGAL) to predict AKI in critically ill patients of ICU was assessed by applying receiver operator curve (ROC) analysis and calculating the area under the curve (AUC). Results: In this study, 100 patients with the mean age of 49.56±19.2 years were included for the period of 18 months. The blood samples were withdrawn from the patients 24 and 44 hours after admission. Totally, 55% (n=55) of ICU patients were diagnosed with AKI. Plasma NGAL level was significantly increased in AKI patients as compared to non-AKI patients (742.65±734.72 vs. 255.62±440.09 μg/L; P<0.01). The sensitivity and specificity of NGAL for diagnosing AKI was 83.6% and 88.9%, respectively. The overall diagnostic accuracy was 86%. Diagnostic accuracy of NGAL for requirement of RRT was 51%. Conclusion: Plasma NGAL is a reliable marker for patients with AKI in ICU, in case the cause of kidney injury is not known. In addition, NGAL also predicts the RRT need based on AKI severity.

Abstract 13918: Prognostic Value of Plasma Ngal in the 12-month All-cause Mortality of Acute Heart Failure or Acute Decompensated Heart Failure

Introduction: The presence of acute kidney injury in the setting of acute heart failure (AHF) or acute decompensated heart failure (ADHF) is very common occurrence and was termed cardiorenal syndrome 1 (CRS1). Renal dysfunction is common in patients with AHF or ADHF and is associated with significant early and late morbidity and mortality. Neutrophil gelatinase-associated lipocalin (NGAL) is an early predictor of acute kidney injury and adverse events in various diseases; however, in AHF or ADHF patients, its significance remains poorly understood. This study was aimed to evaluate the 12 month prognostic value of plasma NGAL in AHF or ADHF patients Hypothesis: plasma NGAL has value in prognosis of 12-month all-cause mortality of Acute Heart Failure or Acute Decompensated Heart Failure Methods: This was a prospective cohort study Results: there were 46 all-cause mortality cases (rate 33.1%) 12 months follow up after discharge. There were 11 cases (rate 7.9%) lost to follow-up; mean age 66.12 ± 15.77, men accounted for 50.4%. The optimal cut-off of NGAL for 12-month all-cause mortality prognosis was > 383.74 ng/ml, AUC 0.632 (95% CI 0.53-0.74, p = 0.011), sensitivity 58.7 %, specificity 68.29 %, positive predictive value 50.9%, negative predictive value 74.7%. Kaplan-Meier analysis revealed that the high plasma NGAL (≥ 400 ng/ml) group exhibited a worse prognosis than the low plasma NGAL (< 400 ng/ml) group in 12-month all-cause death (Hazard Ratio 2.56; 95%CI 1.35-4.84, P=0.0039. Independent predictors of 12-month all-cause-mortality were identified using multivarable Cox proportional-hazards regression models with backward-stepwise selection method consisted of two variables: level of NGAL, mechanical ventialtion at admission. Conclusions: Plasma NGAL and mechanical ventilation at admission were independent predictors of 12-month all-cause mortality in patients with AHF or ADHF. The survival probability 12-month follow-up of high level NGAL (≥ 400 ng/ml) groups were lower than that of low level NGAL (<400 ng/ml,), difference was statistically significant χ2 = 8.31; p = 0.0047 by Kaplan-Meier curves.