Gebhard Wagener

Association between Increases in Urinary Neutrophil Gelatinase–associated Lipocalin and Acute Renal Dysfunction after Adult Cardiac Surgery

Background:Acute renal dysfunction (ARD) and subsequent acute renal failure after cardiac surgery are associated with high mortality and morbidity. Early therapeutic or preventive intervention is hampered by the lack of an early biomarker for acute renal injury. Recent studies showed that urinary neutrophil gelatinase–associated lipocalin (NGAL or lipocalin 2) is up-regulated early (within 1–3 h) after murine renal injury and in pediatric ARD after cardiac surgery. The authors hypothesized that postoperative urinary NGAL concentrations are increased in adult patients developing ARD after cardiac surgery compared with patients without ARD. Methods:After institutional review board approval, 81 cardiac surgical patients were prospectively studied. Urine samples were collected immediately before incision and at various time intervals after surgery for NGAL analysis by quantitative immunoblotting. ARD was defined as peak postoperative serum creatinine increase by 50% or greater compared with preoperative serum creatinine. Results:Sixteen of 81 patients (20%) developed postoperative ARD, and the mean urinary NGAL concentrations in patients who developed ARD were significantly higher early after surgery (after 1 h: 4,195 ± 6,520 [mean ± SD] vs. 1,068 ± 2,129 ng/ml; P < 0.01) compared with patients who did not develop ARD. Mean urinary NGAL concentrations continued to increase and remained significantly higher at 3 and 18 h after cardiac surgery in patients with ARD. In contrast, urinary NGAL in patients without ARD decreased rapidly after cardiac surgery. Conclusions:Patients developing postoperative ARD had significantly higher urinary NGAL concentrations early after cardiac surgery. Urinary NGAL may therefore be a useful early biomarker of ARD after cardiac surgery. These findings may facilitate the early detection of acute renal injury and potentially prevent progression to acute renal failure.

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.

Urinary Biomarkers in the Early Detection of Acute Kidney Injury after Cardiac Surgery

BACKGROUND AND OBJECTIVES Serum creatinine (Scr) does not allow for early diagnosis of acute kidney injury (AKI). The diagnostic utility of urinary kidney injury molecule-1 (KIM-1), N-acetyl-beta-D-glucosaminidase (NAG), and neutrophil gelatinase associated lipocalin (NGAL) was evaluated for the early detection of postoperative AKI in a prospective study of 90 adults undergoing cardiac surgery. Designs, setting, participants, & measurements: Urinary KIM-1, NAG, and NGAL were measured at 5 time points for the first 24 h after operation and normalized to the urinary creatinine concentration after cardiac surgery. Receiver-operating characteristic curves were generated and the areas under the curve (AUCs) compared for performance of biomarkers in detection of postoperative AKI. RESULTS Thirty-six patients developed AKI, defined as an increase in Scr of > or =0.3 mg/dl within 72 h after surgery. The AUCs for KIM-1 to predict AKI immediately and 3 h after operation were 0.68 and 0.65; 0.61 and 0.63 for NAG; and 0.59 and 0.65 for NGAL, respectively. Combining the three biomarkers enhanced the sensitivity of early detection of postoperative AKI compared with individual biomarkers: the AUCs for the three biomarkers combined were 0.75 and 0.78. The performance of combining biomarkers was even better among 16 early postoperative AKI patients with AUCs of 0.80 and 0.84, respectively. CONCLUSIONS The results of this study support that a combination of urinary biomarkers may allow for early detection of postoperative AKI after cardiac surgery before a rise in Scr.

Urinary Neutrophil Gelatinase-Associated Lipocalin and Acute Kidney Injury After Cardiac Surgery

BACKGROUND Neutrophil gelatinase-associated lipocalin (NGAL) is proposed as an early marker of kidney injury. We report the association of urinary NGAL with indexes of intraoperative renal hypoperfusion (cardiopulmonary bypass time and aortic cross-clamp time) and acute kidney injury (AKI) after adult cardiac surgery. STUDY DESIGN Diagnostic test accuracy. SETTING & PARTICIPANTS Adult cardiac surgical patients (n = 426) in a single center from 2004 to 2006. INDEX TEST Urinary NGAL immediately and 3, 18, and 24 hours after cardiac surgery, using an enzyme-linked immunosorbent assay. REFERENCE TEST OR OUTCOME Serum creatinine-based definition for AKI (increase in serum creatinine from preoperative values by >50% or >0.3 mg/dL within 48 hours). RESULTS Mean urinary NGAL level was 165 +/- 663 (SD) ng/mL preoperatively, peaked immediately after cardiac surgery at 1,490 +/- 102 ng/mL, and remained significantly higher 3, 18, and 24 hours after surgery. 85 patients (20%) developed AKI. Areas under the receiver operating characteristic curve for urinary NGAL immediately after and 3, 18, and 24 hours later as a predictor for AKI were 0.573 (95% confidence interval [CI], 0.506 to 0.640), 0.603 (95% CI, 0.533 to 0.674), 0.611 (95% CI, 0.544 to 0.679), and 0.584 (95% CI, 0.510 to 0.657), respectively. Urinary NGAL, but not serum creatinine, level correlated significantly with cardiopulmonary bypass and aortic cross-clamp times. Areas under receiver operating characteristic curves for cardiopulmonary bypass time and aortic cross-clamp time to predict AKI were 0.592 (95% CI, 0.518 to 0.666) and 0.593 (95% CI, 0.523 to 0.665), respectively. LIMITATIONS Limited sensitivity of changes in serum creatinine levels for kidney injury. CONCLUSIONS Urinary NGAL has limited diagnostic accuracy to predict AKI defined by change in serum creatinine after cardiac surgery.

Neutrophil Gelatinase-Associated Lipocalin and Acute Kidney Injury after Cardiac Surgery: The Effect of Baseline Renal Function on Diagnostic Performance

BACKGROUND AND OBJECTIVES Neutrophil gelatinase-associated lipocalin (NGAL) is rapidly released by renal tubules after injury, potentially allowing early identification of acute kidney injury (AKI) after cardiac surgery. However, the diagnostic performance of NGAL has varied widely in clinical studies, and it remains unknown what factors modify the relationship between NGAL and AKI. We hypothesized the relationship between urinary NGAL and AKI would vary with baseline renal function, allowing a stratified analysis to improve diagnostic performance of this novel biomarker. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a prospective observational study in 426 adult cardiac surgical patients. Urinary NGAL was serially determined, commencing preoperatively and continuing 24 hours postoperatively. AKI was defined as increase in serum creatinine from baseline by either >50% or >0.3 mg/dl within 48 hours postoperatively. Patients were stratified by baseline estimated GFR (eGFR). NGAL levels were compared between patients with and without AKI and diagnostic characteristics determined according to baseline eGFR. RESULTS In patients with baseline eGFR >or=60 ml/min, urinary NGAL was higher at all postoperative time points in patients who developed AKI compared with those who did not. In patients with baseline eGFR <60 ml/min, urinary NGAL did not differ at any time between those who did and those who did not develop AKI. Postoperative NGAL best identified AKI in patients with baseline eGFR 90 to 120 ml/min. CONCLUSIONS The relationship between urinary NGAL and AKI after cardiac surgery varies with baseline renal function, with optimal discriminatory performance in patients with normal preoperative function.

Urinary neutrophil gelatinase-associated lipocalin as a marker of acute kidney injury after orthotopic liver transplantation

BACKGROUND Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a novel, sensitive and specific biomarker that is rapidly released after kidney injury. It predicts acute kidney injury (AKI) in multiple clinical scenarios. We hypothesized that urinary NGAL can predict AKI after liver transplantation. METHODS Urine was collected in 92 patients undergoing liver transplantation (18 living-related and 74 deceased) before surgery, after reperfusion of the liver graft and then 3, 18 and 24 h later. NGAL was analyzed with enzyme-linked immunosorbent assay and corrected for dilution/concentration by calculating urinary NGAL/urine creatinine ratios. AKI was defined by Risk-Injury-Failure-Loss-Endstage stage kidney disease (RIFLE)-risk criteria (increase of serum creatinine by >50%). RESULTS Urinary NGAL/urine creatinine ratio was low prior to surgery and increased immediately after reperfusion, peaked 3 h later and remained elevated at 18 and 24 h. Urinary NGAL/urine creatinine ratios were higher in patients with post-operative (post-OP) AKI defined by RIFLE--risk criteria 3 and 18 h after reperfusion. The area under the curve of the receiver operator characteristics curve of urinary NGAL/urine creatinine ratio to predict AKI was 0.800 (95% CI: 0.732-0.869, P < 0.0001) 3 h and 0.636 (95% CI: 0.551-0.720, P < 0.005) 18 h after reperfusion. CONCLUSIONS We conclude that urinary NGAL/urine creatinine ratio is able to predict post-OP AKI 3 and 18 h after transplantation with good discrimination.

Increased Incidence of Acute Kidney Injury with Aprotinin Use during Cardiac Surgery Detected with Urinary NGAL

Background: Use of aprotinin has been associated with acute kidney injury after cardiac surgery. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel, very sensitive marker for renal injury. Urinary NGAL may be able to detect renal injury caused by aprotinin. This study determined if the use of aprotinin is associated with an increased incidence of acute kidney injury and increased levels of urinary NGAL. Methods: In this prospective, observational study 369 patients undergoing cardiac surgery were enrolled. 205 patients received aprotinin and 164 received epsilon amino-caproic acid intraoperatively. Urinary NGAL was measured before and immediately after cardiac surgery and 3, 18 and 24 h later. The association of aprotinin use with the incidence of acute kidney injury (increase of serum creatinine >0.5 mg/dl) and NGAL levels was determined using logistic and linear regression models. Results: 51 of 205 patients (25%) who received aprotinin developed acute kidney injury compared to 19 of 164 patients (12%) who received epsilon amino-caproic acid (p = 0.0013). Aprotinin use was associated with a two-fold higher risk of acute kidney injury when adjusted for potential confounders (age, Parsonnet score, preoperative serum creatinine, cardiopulmonary bypass and cross-clamp times; multiple logistic regression: OR = 2.164; CI (95%) = 1.102 to 4.249; p = 0.0249. Urinary NGAL was 19 times higher immediately after cardiopulmonary bypass and 18 times higher 3 h later in patients who had received aprotinin (postoperative: 19.23; CI (95%) = 12.60 to 29.33; p < 0.0001; 3 h post-cardiopulmonary bypass 18.67; CI (95%) = 11.45 to 30.43; p < 0.0001). Conclusions: Postoperative urinary NGAL – a novel marker for renal injury – is increased in cardiac surgical patients receiving aprotinin compared to patients receiving epsilon amino-caproic acid. These results further support the hypothesis that aprotinin may cause renal injury. The substantial rise of urinary NGAL associated with aprotinin use may in part be due to aprotinin blocking the uptake of NGAL by megalin/gp330 receptors in the proximal tubules.

Biomarkers of acute kidney injury: an evolving domain.

DESPITE more than half a century of investigation, acute kidney injury (AKI) remains a major healthcare issue in medicine today. Reported to occur in 1–32% of all hospital admissions and 10–90% of intensive care unit admissions, the wide variation reflects different criteria used to define AKI. However, independent of definition, a diagnosis of AKI is consistently associated with an increase in both shortand long-term morbidity and mortality. Even the mildest forms of AKI are independently associated with increased early as well as long-term mortality, the risk increasing as severity of renal injury increases. Furthermore, the incidence of AKI is increasing. Based on a large administrative database study of hospital admissions from 1992 to 2001, Xue et al. estimated an 11% increase per year in the incidence of AKI. However, of even greater concern is the failure to develop effective interventions to prevent or treat AKI, meaning that the current management remains directed toward supportive therapy while awaiting recovery of renal function. A major impediment to developing effective therapeutic interventions to combat AKI has been the limited ability to accurately detect significant renal injury in a timely manner. Serum creatinine has been the predominant marker of renal function in clinical practice for more than half a century and its limitations are well documented. As a marker of renal function rather than injury, the nonlinear relationship between glomerular filtration rate and serum creatinine means glomerular filtration rate may decrease by more than 50% from normal before a significant rise in serum creatinine occurs, making creatinine insensitive to small but significant reductions in glomerular filtration rate. Furthermore, serum concentration is influenced by numerous nonrenal factors including age, race, gender, and muscle mass as well as factors such as drug metabolism, protein intake, perioperative fluid administration and hydration status. Consequently, it has proven difficult to define what change in creatinine constitutes significant AKI. The RIFLE criteria (an acronym of the sequentially graded Risk, Injury, Failure, Loss and End-stage classification system for AKI) and more recently the AKIN (Acute Kidney Injury Network classification of AKI) criteria represent attempts by international bodies of experts to standardize definitions and improve the understanding of the epidemiology of AKI. In validating these criteria, the significance of small changes in creatinine has been confirmed, emphasizing the enormous disease burden that AKI represents. However, a further limitation in the use of creatinine to diagnose AKI is the inevitable delay between injury and the subsequent rise in serum creatinine. Although serum creatinine may begin to increase on postoperative day 1 after cardiac surgery, the majority of patients who develop AKI do not meet diagnostic criteria until postoperative day 2 or beyond. Consequently, by the time serum creatinine can identify AKI, the inciting injury may be days old. Animal models of AKI consistently indicate that the window of opportunity for effective intervention to prevent or attenuate AKI is limited to within just a few hours of injury.

Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery

IntroductionThromboembolic complications contribute substantially to perioperative morbidity and mortality. Routine laboratory tests do not detect patients with acquired or congenital hypercoagulability who may be at increased risk of perioperative thromboembolism. Rotational thromboelastometry (ROTEM) is a digitized modification of conventional thromboelastography that is stable and technically easy to use. We designed a prospective observational study to evaluate whether preoperative ROTEM can identify patients at increased risk for postoperative thromboembolic complications after major non-cardiac surgery.MethodsPreoperative ROTEM analysis using extrinsic rotational thromboelastometry (EXTEM), intrinsic rotational thromboelastometry (INTEM), and fibrinogen rotational thromboelastometry (FIBTEM) activators was performed on 313 patients undergoing major non-cardiac surgery. Patients’ medical records were reviewed after discharge for results of standard coagulation studies - partial thromboplastin time (PTT), international normalized ratio (INR), platelet count - and evidence of thromboembolic complications during their hospital stay. A thromboembolic complication was defined as a new arterial or deep venous thrombosis, catheter thrombosis, or pulmonary embolism diagnosed by ultrasound or spiral chest computed tomography.ResultsTen patients developed postoperative thromboembolic complications, of whom 9 had received standard prophylaxis with subcutaneous enoxaparin or heparin. There was no indication of by PTT, INR, or platelet count. Preoperative EXTEM and INTEM activators that assess fibrin clot formation and platelet interaction indicated that these patients had significantly lower clot formation time (CFT) and significantly higher alpha angle (α) and maximum clot firmness (MCF), compared to patients without thromboembolic complications. There was no significant difference for any parameter using FIBTEM activator, which excludes platelet interaction. Receiver operating characteristic (ROC) curves were constructed for these variables. INTEM clot firmness at 10 min (A10) was the best predictor of thromboembolic complications, with an ROC area under the curve of 0.751.ConclusionsOur results indicate that preoperative ROTEM assays that include fibrin clot and platelet interaction may detect patients at increased risk for postoperative thromboembolic complications after major non-cardiac surgery. Future studies need to evaluate the clinical utility and cost effectiveness of preoperative ROTEM and better define the association between ROTEM values and specific hypercoagulable conditions.

Predicting early allograft failure and mortality after liver transplantation: The role of the postoperative model for end-stage liver disease score

Early allograft dysfunction (EAD) is a serious complication after liver transplantation (LT). There is no uniform definition of EAD, and most definitions are based on arbitrary laboratory values. The aim of this study was to devise a definition of EAD that maximizes the predictive power for early death and graft failure. In this single‐center, retrospective study, the ability of the international normalized ratio (INR), total bilirubin, aspartate aminotransferase (AST), physiological Model for End‐Stage Liver Disease (MELD) score, and serum albumin levels within 7 days after LT to predict 90‐day mortality or graft loss was compared with 2 previously used definitions of EAD: (1) peak total bilirubin level >10 mg/dL on days 2 to 7 and (2) either a total bilirubin level >10 mg/dL or an INR >1.6 on day 7 or an AST or alanine aminotransferase level >2000 IU/L within the first 7 days. Of 572 enrolled LT patients 38 died or required retransplantation within 90 days. Peak INR, total bilirubin level, AST levels, and MELD scores were predictors of 90‐day graft failure. MELD score on postoperative day 5 was the best predictor with an area under the curve of the receiver operating characteristic curve of 0.812 (95% CI: 0.739‐0.886, P < 0.001). The best cutoff of MELD score on day 5 for predicting 90‐day mortality or graft loss was 18.9. A MELD score >18.9 on postoperative day 5 was a better predictor than any other laboratory value or definition of EAD. This study has demonstrated that the MELD score can be a useful tool not only for pretransplant graft allocation but also for postoperative risk stratification. Liver Transpl 19:534–542, 2013.