Michael Zappitelli

The Outcome of Neutrophil Gelatinase-Associated Lipocalin-Positive Subclinical Acute Kidney Injury: A Multicenter Pooled Analysis of Prospective Studies

OBJECTIVES The aim of this study was to test the hypothesis that, without diagnostic changes in serum creatinine, increased neutrophil gelatinase-associated lipocalin (NGAL) levels identify patients with subclinical acute kidney injury (AKI) and therefore worse prognosis. BACKGROUND Neutrophil gelatinase-associated lipocalin detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function. METHODS We analyzed pooled data from 2,322 critically ill patients with predominantly cardiorenal syndrome from 10 prospective observational studies of NGAL. We used the terms NGAL(-) or NGAL(+) according to study-specific NGAL cutoff for optimal AKI prediction and the terms sCREA(-) or sCREA(+) according to consensus diagnostic increases in serum creatinine defining AKI. A priori-defined outcomes included need for renal replacement therapy (primary endpoint), hospital mortality, their combination, and duration of stay in intensive care and in-hospital. RESULTS Of study patients, 1,296 (55.8%) were NGAL(-)/sCREA(-), 445 (19.2%) were NGAL(+)/sCREA(-), 107 (4.6%) were NGAL(-)/sCREA(+), and 474 (20.4%) were NGAL(+)/sCREA(+). According to the 4 study groups, there was a stepwise increase in subsequent renal replacement therapy initiation-NGAL(-)/sCREA(-): 0.0015% versus NGAL(+)/sCREA(-): 2.5% (odds ratio: 16.4, 95% confidence interval: 3.6 to 76.9, p < 0.001), NGAL(-)/sCREA(+): 7.5%, and NGAL(+)/sCREA(+): 8.0%, respectively, hospital mortality (4.8%, 12.4%, 8.4%, 14.7%, respectively) and their combination (4-group comparisons: all p < 0.001). There was a similar and consistent progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(-)/sCREA(-): 4.2 and 8.8 days; NGAL(+)/sCREA(-): 7.1 and 17.0 days; NGAL(-)/sCREA(+): 6.5 and 17.8 days; NGAL(+)/sCREA(+): 9.0 and 21.9 days; 4-group comparisons: p = 0.003 and p = 0.040, respectively. Urine and plasma NGAL indicated a similar outcome pattern. CONCLUSIONS In the absence of diagnostic increases in serum creatinine, NGAL detects patients with likely subclinical AKI who have an increased risk of adverse outcomes. The concept and definition of AKI might need re-assessment.

Postoperative Biomarkers Predict Acute Kidney Injury and Poor Outcomes after Pediatric Cardiac Surgery

Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.

Fluid Overload and Mortality in Children Receiving Continuous Renal Replacement Therapy: The Prospective Pediatric Continuous Renal Replacement Therapy Registry

BACKGROUND Critically ill children with hemodynamic instability and acute kidney injury often develop fluid overload. Continuous renal replacement therapy (CRRT) has emerged as a favored modality in the management of such children. This study investigated the association between fluid overload and mortality in children receiving CRRT. STUDY DESIGN Prospective observational study. SETTING & PARTICIPANTS 297 children from 13 centers across the United States participating in the Prospective Pediatric CRRT Registry. PREDICTOR Fluid overload from intensive care unit (ICU) admission to CRRT initiation, defined as a percentage equal to (fluid in [L] - fluid out [L])/(ICU admit weight [kg]) x 100%. OUTCOME & MEASUREMENTS The primary outcome was survival to pediatric ICU discharge. Data were collected regarding demographics, CRRT parameters, underlying disease process, and severity of illness. RESULTS 153 patients (51.5%) developed < 10% fluid overload, 51 patients (17.2%) developed 10%-20% fluid overload, and 93 patients (31.3%) developed > or = 20% fluid overload. Patients who developed > or = 20% fluid overload at CRRT initiation had significantly higher mortality (61/93; 65.6%) than those who had 10%-20% fluid overload (22/51; 43.1%) and those with < 10% fluid overload (45/153; 29.4%). The association between degree of fluid overload and mortality remained after adjusting for intergroup differences and severity of illness. The adjusted mortality OR was 1.03 (95% CI, 1.01-1.05), suggesting a 3% increase in mortality for each 1% increase in severity of fluid overload. When fluid overload was dichotomized to > or = 20% and < 20%, patients with > or = 20% fluid overload had an adjusted mortality OR of 8.5 (95% CI, 2.8-25.7). LIMITATIONS This was an observational study; interventions were not standardized. The relationship between fluid overload and mortality remains an association without definitive evidence of causality. CONCLUSIONS Critically ill children who develop greater fluid overload before initiation of CRRT experience higher mortality than those with less fluid overload. Further goal-directed research is required to accurately define optimal fluid overload thresholds for initiation of CRRT.

Fluid overload is associated with impaired oxygenation and morbidity in critically ill children

Rationale: Fluid overload is common in the critically ill and is thought to contribute to oxygenation failure and mortality. Since increasing disease severity often requires more fluid for resuscitation, it is unclear whether fluid overload is a causative factor in morbidity or is simply an indicator of disease severity. Objective: Investigate the association between fluid overload and oxygenation while controlling for severity of illness by daily Pediatric Logistic Organ Dysfunction scores. Design and Setting: Retrospective chart review, tertiary children’s hospital. Patients and Methods: The oxygenation index, fluid overload percent, and daily Pediatric Logistic Organ Dysfunction scores were obtained in a retrospective chart review of 80 patients (mean age 58.7 ± 73.0 months) with respiratory failure. Univariate and multivariate approaches were used to assess the independent relation between fluid overload percent and duration of stay and ventilation. Interventions: None. Main Results: Higher peak fluid overload percent predicted higher peak oxygenation index, independent of age, gender, and Pediatric Logistic Organ Dysfunction (p = .009). Fluid overload percent ≥15% on any given day was also independently associated with that day’s oxygenation index, controlled for age, gender, and Pediatric Logistic Organ Dysfunction (p < .05). Peak fluid overload percent and severe fluid overload percent (≥15%) were both independently associated with longer duration of ventilation (p = .004, p = .01), and pediatric intensive care unit (p = .008, p = .01) and hospital length of stay (p = .02, p = .04), controlled for age, gender, Pediatric Logistic Organ Dysfunction, and in the case of ventilation, respiratory admission. Conclusion: This is the first study to report that positive fluid balance adversely affected the pediatric intensive care unit course in children who did not receive renal replacement therapy. While timely administration of fluids is lifesaving, positive fluid balance after hemodynamic stabilization may impact organ function and negatively influence important outcomes in critically ill patients.

A small post-operative rise in serum creatinine predicts acute kidney injury in children undergoing cardiac surgery

To predict development of acute kidney injury and its outcome we retrospectively studied children having cardiac surgery. Acute kidney injury (AKI) was defined using the serum creatinine criteria of the pediatric Risk Injury Failure Loss End-Stage (pRIFLE) kidney disease definition. We tested whether a small rise (less than 50%) in creatinine on post-operative days 1 or 2 could predict a greater than 50% increase in serum creatinine within 48 h in 390 children. AKI occurred in 36% of patients, mostly in the first 4 post-operative days. Using logistic regression, significant independent risk factors for AKI were bypass time, longer vasopressor use, and a tendency for younger age. Using Cox regression, AKI was independently associated with longer intensive care unit stay and duration of ventilation. Patients whose serum creatinine did not increase on post-operative days 1 or 2 were unlikely to develop AKI (negative predictive values of 87 and 98%, respectively). Percentage serum creatinine rise on post-operative day 1 predicted AKI within 48 h (area under the curve=0.65). Our study shows that AKI after pediatric heart surgery is common and is a risk factor for poorer outcome. Small post-operative increases in serum creatinine may assist in the early prediction of AKI.

Incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery – a prospective multicenter study

Objective: To determine the incidence, severity, and risk factors of acute kidney injury in children undergoing cardiac surgery for congenital heart defects. Design: Prospective observational multicenter cohort study. Setting: Three pediatric intensive care units at academic centers. Patients: Three hundred eleven children between the ages of 1 month and 18 yrs undergoing pediatric cardiac surgery. Interventions: None. Measurements and Main Results: Acute kidney injury was defined as a ≥50% increase in serum creatinine from the preoperative value. Secondary outcomes were length of mechanical ventilation, length of intensive care unit and hospital stays, acute dialysis, and in-hospital mortality. The cohort had an average age of 3.8 yrs and was 45% women and mostly white (82%). One-third had prior cardiothoracic surgery, 91% of the surgeries were elective, and almost all patients required cardiopulmonary bypass. Acute kidney injury occurred in 42% (130 patients) within 3 days after surgery. Children ≥2 yrs old and <13 yrs old had a 72% lower likelihood of acute kidney injury (adjusted odds ratio: 0.28, 95% confidence interval: 0.16, 0.48), and patients 13 yrs and older had 70% lower likelihood of acute kidney injury (adjusted odds ratio: 0.30, 95% confidence interval: 0.10, 0.88) compared to patients <2 yrs old. Longer cardiopulmonary bypass time was linearly and independently associated with acute kidney injury. The development of acute kidney injury was independently associated with prolonged ventilation and with increased length of hospital stay. Conclusions: Acute kidney injury is common after pediatric cardiac surgery and is associated with prolonged mechanical ventilation and increased hospital stay. Cardiopulmonary bypass time and age were independently associated with acute kidney injury risk. Cardiopulmonary bypass time may be a marker for case complexity.

Ascertainment and Epidemiology of Acute Kidney Injury Varies with Definition Interpretation

BACKGROUND AND OBJECTIVES Differences in defining acute kidney injury (AKI) may impact incidence ascertainment. We assessed the effects of different AKI definition interpretation methods on epidemiology ascertainment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Two groups were studied at Texas Childrens Hospital, Houston, Texas: 150 critically ill children (prospective) and 254 noncritically ill, hospitalized children receiving aminoglycosides (retrospective). SCr was collected for 14 d in the prospective study and 21 d in the retrospective study. Children with known baseline serum creatinine (bSCr) were classified by the pediatric Risk, Injury, Failure, Loss, End-Stage Kidney Disease (pRIFLE) AKI definition using SCr change (pRIFLE(DeltaSCr)), estimated creatinine clearance (eCCl) change (pRIFLE(DeltaCCl)), and the Acute Kidney Injury Network (AKIN) definition. In subjects without known bSCr, bSCR was estimated as eCCl = 100 (eCCl(100)) and 120 ml/min per 1.73 m(2) (eCCl(120)), admission SCr (AdmSCr) and lower/upper normative values (NormsMin, NormsMax). The differential impact of each AKI definition interpretation on incidence estimation and severity distribution was evaluated. RESULTS pRIFLE(DeltaSCr) and AKIN led to identical AKI distributions. pRIFLE(DeltaCCl) resulted in 14.5% (critically ill) and 11% (noncritical) more patients diagnosed with AKI compared to other methods (P 0.05). Different bSCr estimates led to differences in AKI incidence, from 12% (AdmSCr) to 87.8% (NormsMin) (P 0.05) in the critically ill group and from 4.6% (eCCl(100)) to 43.1% (NormsMin) (P 0.05) in the noncritical group. CONCLUSIONS AKI definition variation causes interstudy heterogeneity. AKI definition should be standardized so that results can be compared across studies.

Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study

IntroductionIn adults, small (< 50%) serum creatinine (SCr) increases predict mortality. It is unclear whether different baseline serum creatinine (bSCr) estimation methods affect findings of acute kidney injury (AKI)-outcome associations. We characterized pediatric AKI, evaluated the effect of bSCr estimation approaches on AKI-outcome associations and evaluated the use of small SCr increases to predict AKI development.MethodsWe conducted a retrospective cohort database study of children (excluding postoperative cardiac or renal transplant patients) admitted to two pediatric intensive care units (PICUs) for at least one night in Montreal, QC, Canada. The AKI definition was based on the Acute Kidney Injury Network staging system, excluding the requirement of SCr increase within 48 hours, which was impossible to evaluate on the basis of our data set. We estimated bSCr two ways: (1) the lowest SCr level in the three months before admission or the average age- and gender-based norms (the standard method) or (2) by using average norms in all patients. Outcomes were PICU mortality and length of stay as well as required mechanical ventilation. We used multiple logistic regression analysis to evaluate AKI risk factors and the association between AKI and mortality. We used multiple linear regression analysis to evaluate the effect of AKI on other outcomes. We calculated diagnostic characteristics for early SCr increase (< 50%) to predict AKI development.ResultsOf 2,106 admissions (mean age ± SD = 5.0 ± 5.5 years; 47% female), 377 patients (17.9%) developed AKI (using the standard bSCr method) during PICU admission. Higher Pediatric Risk of Mortality score, required mechanical ventilation, documented infection and having a bSCr measurement were independent predictors of AKI development. AKI was associated with increased mortality (adjusted odds ratio (OR) = 3.7, 95% confidence interval (95% CI) = 2.1 to 6.4, using the standard bSCr method; OR = 4.5, 95% CI = 2.6 to 7.9, using normative bSCr values in all patients). AKI was independently associated with longer PICU stay and required mechanical ventilation. In children with no admission AKI, the initial percentage SCr increase predicted AKI development (area under the curve = 0.67, 95% CI = 0.60 to 0.74).ConclusionsAKI is associated with increased mortality and morbidity in critically ill children, regardless of the bSCr used. Paying attention to small early SCr increases may contribute to early AKI diagnosis in conjunction with other new AKI biomarkers.

Performance of kidney injury molecule-1 and liver fatty acid-binding protein and combined biomarkers of AKI after cardiac surgery.

BACKGROUND AND OBJECTIVES AKI is common and novel biomarkers may help provide earlier diagnosis and prognosis of AKI in the postoperative period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a prospective, multicenter cohort study involving 1219 adults and 311 children consecutively enrolled at eight academic medical centers. Performance of two urine biomarkers, kidney injury molecule-1 (KIM-1) and liver fatty acid-binding protein (L-FABP), alone or in combination with other injury biomarkers during the perioperative period was evaluated. AKI was defined as doubling of serum creatinine or need for acute dialysis. RESULTS KIM-1 peaked 2 days after surgery in adults and 1 day after surgery in children, whereas L-FABP peaked within 6 hours after surgery in both age groups. In multivariable analyses, the highest quintile of the first postoperative KIM-1 level was associated with AKI compared with the lowest quintile in adults, whereas the first postoperative L-FABP was not associated with AKI. Both KIM-1 and L-FABP were not significantly associated with AKI in adults or children after adjusting for other kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and IL-18). The highest area under the curves achievable for discrimination for AKI were 0.78 in adults using urine KIM-1 from 6 to 12 hours, urine IL-18 from day 2, and plasma neutrophil gelatinase-associated lipocalin from day 2 and 0.78 in children using urine IL-18 from 0 to 6 hours and urine L-FABP from day 2. CONCLUSIONS Postoperative elevations of KIM-1 associate with AKI and adverse outcmes in adults but were not independent of other AKI biomarkers. A panel of multiple biomarkers provided moderate discrimination for AKI.

Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery

In this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 and 17.2, respectively). The highest tertile of percent change in CysC independently predicted AKI, whereas the highest tertile of SCr predicted stage 1 but not stage 2 AKI. Postoperative CysC levels independently predicted longer duration of ventilation and intensive care unit length of stay, whereas the postoperative SCr change only predicted longer intensive care unit stay. Thus, postoperative serum CysC is useful to risk-stratify patients for AKI treatment trials. More research, however, is needed to understand the relation between preoperative renal function and the risk of AKI.