Anja Haase-Fielitz

Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis.

BACKGROUNDnNeutrophil gelatinase-associated lipocalin (NGAL) appears to be a promising biomarker for the early diagnosis of acute kidney injury (AKI); however, a wide range in its predictive value has been reported.nnnSTUDY DESIGNnMeta-analysis of diagnostic test studies using custom-made standardized data sheets sent to each author.nnnSETTING & POPULATIONnDifferent clinical settings of AKI.nnnSELECTION CRITERIA FOR STUDIESnMEDLINE, EMBASE, and CENTRAL databases and congress abstracts were searched for studies reporting the value of NGAL to predict AKI.nnnINDEX TESTSnPlasma/serum and urine NGAL within 6 hours from the time of insult (if known) or 24-48 hours before the diagnosis of AKI if the time of insult was not known.nnnREFERENCE TESTSnThe primary outcome was AKI, defined as an increase in serum creatinine level > 50% from baseline within 7 days or contrast-induced nephropathy (creatinine increase > 25% or concentration > 0.5 mg/dL in adults or > 50% increase in children within 48 hours). Other outcomes predicted using NGAL were renal replacement therapy initiation and in-hospital mortality.nnnRESULTSnUsing a hierarchical bivariate generalized linear model to calculate the diagnostic odds ratio (DOR) and sample size-weighted area under the curve for the receiver-operating characteristic (AUC-ROC), we analyzed data from 19 studies and 8 countries involving 2,538 patients, of whom 487 (19.2%) developed AKI. Overall, the DOR/AUC-ROC of NGAL to predict AKI was 18.6 (95% CI, 9.0-38.1)/0.815 (95% CI, 0.732-0.892). The DOR/AUC-ROC when standardized platforms were used was 25.5 (95% CI, 8.9-72.8)/0.830 (95% CI, 0.741-0.918) with a cutoff value > 150 ng/mL for AKI compared with 16.7 (95% CI, 7.1-39.7)/0.732 (95% CI, 0.656-0.830) for research-based NGAL assays. In cardiac surgery patients, the DOR/AUC-ROC of NGAL was 13.1 (95% CI, 5.7-34.8)/0.775 (95% CI, 0.669-0.867); in critically ill patients, 10.0 (95% CI, 3.0-33.1)/0.728 (95% CI, 0.615-0.834); and after contrast infusion, 92.0 (95% CI, 10.7-794.1)/0.894 (95% CI, 0.826-0.950). The diagnostic accuracy of plasma/serum NGAL (17.9 [95% CI, 6.0-53.7]/0.775 [95% CI, 0.679-0.869]) was similar to that of urine NGAL (18.6 [95% CI, 7.2-48.4]/0.837 [95% CI, 0.762-0.906]). We identified age to be an effective modifier of NGAL value with better predictive ability in children (25.4 [95% CI, 8.9-72.2]/0.930 [95% CI, 0.883-0.968]) compared with adults (10.6 [95% CI, 4.8-23.4]/0.782 [95% CI, 0.689-0.872]). NGAL level was a useful prognostic tool with regard to the prediction of renal replacement therapy initiation (12.9 [95% CI, 4.9-33.9]/0.782 [95% CI, 0.648-0.917]) and in-hospital mortality (8.8 [95% CI, 1.9-40.8]/0.706 [95% CI, 0.530-0.747]).nnnLIMITATIONSnSerum creatinine level was used for AKI definition.nnnCONCLUSIONSnNGAL level appears to be of diagnostic and prognostic value for AKI.

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

OBJECTIVESnThe 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.nnnBACKGROUNDnNeutrophil gelatinase-associated lipocalin detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function.nnnMETHODSnWe 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.nnnRESULTSnOf 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.nnnCONCLUSIONSnIn 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.

Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness

ObjectiveSepsis is the most common trigger for acute kidney injury (AKI) in critically ill patients. We sought to determine whether there are unique patterns to plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) in septic compared with non-septic AKI.DesignProspective observational study.SettingTwo adult ICUs in Melbourne, Australia.PatientsCritically ill patients with septic and non-septic AKI.InterventionsNone.Measurements and main resultsBlood and urine specimens collected at enrollment, 12, 24 and 48xa0h to measure plasma and urine NGAL. Eighty-three patients were enrolled (septic nxa0=xa043). Septic AKI patients had more co-morbid disease (pxa0=xa00.005), emergency surgical admissions (pxa0<xa00.001), higher illness severity (pxa0=xa00.008), more organ dysfunction (pxa0=xa00.008) and higher white blood cell counts (pxa0=xa00.01). There were no differences at enrollment between groups in AKI severity. Septic AKI was associated with significantly higher plasma (293 vs. 166xa0ng/ml) and urine (204 vs. 39xa0ng/mg creatinine) NGAL at enrollment compared with non-septic AKI (pxa0<xa00.001). Urine NGAL remained higher in septic compared with non-septic AKI at 12xa0h (pxa0<xa00.001) and 24xa0h (pxa0<xa00.001). Plasma NGAL showed fair discrimination for AKI progression (area under receiver-operator characteristic curve 0.71) and renal replacement therapy (AuROC 0.78). Although urine NGAL performed less well (AuROC 0.70, 0.70), peak urine NGAL predicted AKI progression better in non-septic AKI (AuROC 0.82).ConclusionSeptic AKI patients have higher detectable plasma and urine NGAL compared with non-septic AKI patients. These differences in NGAL values in septic AKI may have diagnostic and clinical relevance as well as pathogenetic implications.

Novel biomarkers early predict the severity of acute kidney injury after cardiac surgery in adults.

BACKGROUNDnThe purpose of this study was to investigate the ability of neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, and their combination in predicting the duration and severity of acute kidney injury (AKI) after cardiac surgery in adults.nnnMETHODSnUsing data from a prospective observational study of 100 adult cardiac surgical patients, we correlated early postoperative concentrations of plasma NGAL and serum cystatin C with the duration (time during which AKI persisted according to the Acute Kidney Injury Network criteria) and severity of AKI (change in serum creatinine) and with length of stay in intensive care.nnnRESULTSnWe found a mean AKI duration of 67.2 +/- 41.0 hours which was associated with prolonged hospitalization (p < 0.001). NGAL, cystatin C, and their combination on arrival in intensive care correlated with subsequent AKI duration (all p < 0.01) and severity (all p < 0.001). The area under the receiver operating characteristic curve for AKI prediction was 0.77 (95% confidence interval: 0.63 to 0.91) for NGAL and 0.76 (95% confidence interval: 0.61 to 0.91) for cystatin C on arrival in intensive care. Both markers also correlated with length of stay in intensive care (p = 0.037; p = 0.001). Neutrophil gelatinase-associated lipocalin and cystatin C were independent predictors of AKI duration and severity and of length of stay in intensive care (all p < 0.05). The value of cystatin C on arrival in intensive care appeared to be due to a carry-over effect from preoperative values.nnnCONCLUSIONSnImmediately postoperatively, NGAL and cystatin C correlated with and were independent predictors of duration and severity of AKI and duration of intensive care stay after adult cardiac surgery. The combination of both renal biomarkers did not add predictive value.

Oliguria as predictive biomarker of acute kidney injury in critically ill patients

IntroductionDuring critical illness, oliguria is often used as a biomarker of acute kidney injury (AKI). However, its relationship with the subsequent development of AKI has not been prospectively evaluated.MethodsWe documented urine output and daily serum creatinine concentration in patients admitted for more than 24 hours in seven intensive care units (ICUs) from six countries over a period of two to four weeks. Oliguria was defined by a urine output < 0.5 ml/kg/hr. Data were collected until the occurrence of creatinine-defined AKI (AKI-Cr), designated by RIFLE-Injury class or greater using creatinine criteria (RIFLE-I[Cr]), or until ICU discharge. Episodes of oliguria were classified by longest duration of consecutive oliguria during each day were correlated with new AKI-Cr the next day, examining cut-offs for oliguria of greater than 1,2,3,4,5,6, or 12 hr duration,ResultsWe studied 239 patients during 723 days. Overall, 32 patients had AKI on ICU admission, while in 23, AKI-Cr developed in ICU. Oliguria of greater than one hour was significantly associated with AKI-Cr the next day. On receiver-operator characteristic area under the curve (ROCAUC) analysis, oliguria showed fair predictive ability for AKI-Cr (ROCAUC = 0.75; CI:0.64-0.85). The presence of 4 hrs or more oliguria provided the best discrimination (sensitivity 52% (0.31-0.73%), specificity 86% (0.84-0.89%), positive likelihood ratio 3.8 (2.2-5.6), P < 0.0001) with negative predictive value of 98% (0.97-0.99). Oliguria preceding AKI-Cr was more likely to be associated with lower blood pressure, higher heart rate and use of vasopressors or inotropes and was more likely to prompt clinical intervention. However, only 30 of 487 individual episodes of oliguria preceded the new occurrence of AKI-Cr the next day.ConclusionsOliguria was significantly associated with the occurrence of new AKI-Cr, however oliguria occurred frequently compared to the small number of patients (~10%) developing AKI-Cr in the ICU, so that most episodes of oliguria were not followed by renal injury. Consequently, the occurrence of short periods (1-6 hr) of oliguria lacked utility in discriminating patients with incipient AKI-Cr (positive likelihood ratios of 2-4, with > 10 considered indicative of a useful screening test). However, oliguria accompanied by hemodynamic compromise or increasing vasopressor dose may represent a clinically useful trigger for other early biomarkers of renal injury.

A comparison of the RIFLE and Acute Kidney Injury Network classifications for cardiac surgery-associated acute kidney injury: a prospective cohort study.

OBJECTIVESnThere is an intense debate on whether the RIFLE (R-renal risk, I-injury, F-failure, L-loss of kidney function, E-end-stage renal disease) classification or its recent modification, the Acute Kidney Injury Network definition and classification system should be used to standardize research on acute kidney injury. In this study we compared these classifications with regard to (1) the detection of acute kidney injury, (2) their agreement according to the grading of acute kidney injury across classes, and (3) their prognostic value.nnnMETHODSnWe prospectively enrolled 282 cardiac surgery patients undergoing cardiopulmonary bypass and assigned a RIFLE and Acute Kidney Injury Network class to each patient. The incidence of acute kidney injury and in-hospital mortality across classes was compared by using the chi(2) test, and their prognostic value was compared by using the area under the curve receiver-operating characteristic for in-hospital mortality.nnnRESULTSnAccording to the RIFLE (45.8%) or Acute Kidney Injury Network (44.7%) classification, a similar proportion of patients had acute kidney injury. There was large agreement between classifications according to patients graded as having nonacute kidney injury; however, there was some disagreement across classes for staging the severity of acute kidney injury. The area under the curve for in-hospital mortality was similar for all classifications: 0.91 for the RIFLE classification (95% confidence interval, 0.82-0.99) and 0.94 for the Acute Kidney Injury Network classification (95% confidence interval, 0.81-0.97; P = .6 for area under the curve comparison).nnnCONCLUSIONSnIn patients undergoing cardiac surgery, modifications of the RIFLE classification for acute kidney injury do not materially improve the clinical usefulness of the definition. Other factors, such as the applicability of the acute kidney injury definition and classification system to be applied, need to be considered.

Novel Biomarkers, Oxidative Stress, and the Role of Labile Iron Toxicity in Cardiopulmonary Bypass-Associated Acute Kidney Injury

Cardiac surgery-associated acute kidney injury (AKI) is common and carries a poor prognosis. Hemodynamic and inflammatory factors and the release of labile iron, contributing to oxidation from reactive oxygen species are among the major determinants of cardiac surgery-associated AKI. The diagnosis of AKI is typically delayed because of the limitations of currently used clinical biomarkers indicating loss of renal function. However, several novel renal biomarkers, which predict AKI or protection from AKI after cardiopulmonary bypass (CPB), have been identified as early markers of kidney injury. In this state-of-the-art review, the authors analyze the pathophysiological implications of recent findings regarding novel renal biomarkers in relation to CPB-associated AKI. Neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and alpha-1 microglobulin predict the development of CPB-associated AKI, while hepcidin isoforms appear to predict protection from it, and these biomarkers are involved in iron metabolism. Neutrophil gelatinase-associated lipocalin participates in local iron transport. Liver-type fatty acid-binding protein and alpha-1 microglobulin function as high-affinity heme-binding proteins in different species, while hepcidin is central to iron sequestration and when increased in the urine appears to protect from CPB-associated AKI. Free iron-related, reactive oxygen species-mediated kidney injury appears to be the unifying pathophysiological connection for these biomarkers. Such novel findings on renal tubular biomarkers were further combined with other lines of evidence related to hemolysis during CPB, the associated excess of free heme and iron, knowledge of the effect of free iron on renal tubular cells, and recent trial evidence targeting free iron-mediated mechanisms of AKI. Novel biomarkers point toward free iron-mediated toxicity to be an important mechanism of AKI in patients receiving cardiac surgery with CPB.

Urinary interleukin-18 does not predict acute kidney injury after adult cardiac surgery: a prospective observational cohort study

IntroductionUrinary interleukin-18 (IL-18) measured during the immediate postoperative period could be a promising predictor of acute kidney injury following adult cardiac surgery.MethodsIn a single-centre prospective observational cohort study, we enrolled 100 adult cardiac surgical patients undergoing cardiopulmonary bypass at a tertiary hospital. We measured the urinary concentration of IL-18 and creatinine preoperatively, on arrival in the intensive care unit, and 24 hours postoperatively. We assessed urinary IL-18 concentration and urinary IL-18/urinary creatinine ratio in relation to the postoperative development of acute kidney injury defined as an increase in serum creatinine of greater than 50% from preoperative to postoperative peak value within 48 hours after surgery.ResultsTwenty patients developed acute kidney injury. On arrival in the intensive care unit and at 24 hours postoperatively, urinary IL-18 (median [interquartile range]) was not different in patients who subsequently developed acute kidney injury compared with those who did not: on arrival in the intensive care unit (168 [717] versus 104 [256] pg/mL; P = 0.70) and at 24 hours (195 [483] versus 165 [246] pg/mL; P = 0.47). On arrival in the intensive care unit (area under the curve for the receiver operating characteristic curve [AUC-ROCC] 0.53, 95% confidence interval [CI] 0.38 to 0.68; P = 0.70) and at 24 hours postoperatively (AUC-ROCC 0.55, 95% CI 0.40 to 0.71; P = 0.48), urinary IL-18 was not better than chance in predicting acute kidney injury. All findings were confirmed when urinary IL-18 was adjusted for urinary creatinine. Urinary IL-18 correlated with duration of cardiopulmonary bypass (P < 0.001).ConclusionIn adults, early postoperative measurement of urinary IL-18 appears not to be valuable in identifying patients who develop acute kidney injury after cardiac surgery, but rather represents a nonspecific marker of cardiopulmonary bypass-associated systemic inflammation.

The impact of Rapid Response System on delayed emergency team activation patient characteristics and outcomes—A follow-up study

OBJECTIVEnTo evaluate the impact of Rapid Response System (RRS) maturation on delayed Medical Emergency Team (MET) activation and patient characteristics and outcomes.nnnDESIGNnObservational study.nnnSETTINGnTertiary hospital.nnnPATIENTSnRecent cohort of 200 patients receiving a MET review and early control cohort of 400 patients receiving a MET review five years earlier at the start of RRS implementation.nnnMEASUREMENTS AND RESULTSnWe obtained information including demographics, clinical triggers for and timing of MET activation in relation to the first documented MET review criterion (activation delay) and patient outcomes. We found that patients in the recent cohort were older, more likely to be surgical and to have Not For Resuscitation (NFR) orders before MET review. Furthermore, fewer patients (22.0% vs. 40.3%, p<0.001) had delayed MET activation. When delayed activation occurred, there was a non-significant difference in its duration (early cohort: 12.0 [IQR 23.0]h vs. recent cohort: 9.0 [IQR 20.5]h, p=0.554). Similarly, unplanned ICU admissions decreased from 31.3% to 17.3% (p<0.001). Delayed MET activation was independently associated with greater risk of unplanned ICU admission and hospital mortality (O.R. 1.79, 95% C.I. 1.33.-2.93, p=0.003 and O.R. 2.18, 95% C.I. 1.42-3.33, p<0.001, respectively). Being part of the recent cohort was independently associated with a decreased risk of delayed activation (O.R. 0.45, 95% C.I. 0.30-0.67, p<0.001) and unplanned ICU admission (O.R. 0.5, 95% C.I. 0.32-0.78, p=0.003).nnnCONCLUSIONSnMaturation of a RRS is associated with a decrease in the incidence of unplanned ICU admissions and MET activation delay. Assessment of a RRS early in the course of its implementation may underestimate its efficacy.

Characteristics and outcomes of patients receiving a medical emergency team review for respiratory distress or hypotension

PURPOSEnTo describe the characteristics and outcomes of patients receiving a medical emergency team (MET) review for the MET syndromes of respiratory distress or hypotension and to assess the effect of delayed MET activation on their outcomes.nnnMATERIALS AND METHODSnWe retrospectively analyzed the medical records of 2 cohorts of 100 patients for each of the MET syndromes of respiratory distress and hypotension. We collected information on patient demographics, comorbidities, presence of sepsis, and patient outcome. We documented the presence and duration of delayed MET activation.nnnRESULTSnPatients with respiratory distress were more likely to be postoperative (40% vs 28%, P = .07), but less likely to have a history of congestive cardiac failure (12% vs 22%, P = .06). Sepsis was present in 58% of cases. The hospital mortality for MET calls due to respiratory distress and hypotension was 38% and 35%, respectively (P = .77). Delayed MET calls occurred in 50% of patients with the MET syndrome of respiratory distress and in 39% of those with hypotension (P = .11). The median duration of delay was 12 hours in patients with respiratory distress compared to 5 hours for patients with hypotension (P = .016). A delay in making a MET call was associated with an increase in mortality (odds ratio, 2.10; 95% confidence interval, 1.01-4.34; P = .045).nnnCONCLUSIONSnPatients receiving MET calls for respiratory distress or hypotension were elderly and had a mortality greater than 35%. In many cases, MET activation was delayed. This delay was associated with increased mortality.