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.

[1]  E. Siew.  Blind men and elephants and the biological markers of AKI. , 2011, Journal of the American Society of Nephrology : JASN.

[2]  C. Krawczeski,et al.  Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass. , 2011, The Journal of pediatrics.

[3]  Ewout W Steyerberg,et al.  Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers , 2011, Statistics in medicine.

[4]  C. Krawczeski,et al.  Serum cystatin C is an early predictive biomarker of acute kidney injury after pediatric cardiopulmonary bypass. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[5]  C. Parikh,et al.  Tubular proteinuria in acute kidney injury: a critical evaluation of current status and future promise , 2010, Annals of clinical biochemistry.

[6]  P. Devarajan,et al.  Review: Neutrophil gelatinase‐associated lipocalin: A troponin‐like biomarker for human acute kidney injury , 2010, Nephrology.

[7]  Krishna Prasad,et al.  Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium , 2010, Nature Biotechnology.

[8]  Joseph V Bonventre,et al.  Next-generation biomarkers for detecting kidney toxicity , 2010, Nature Biotechnology.

[9]  A. Garg,et al.  Prevention and Treatment of Acute Kidney Injury in Patients Undergoing Cardiac Surgery: A Systematic Review , 2010, American Journal of Nephrology.

[10]  F. Grenier,et al.  Evaluation of the ARCHITECT urine NGAL assay: assay performance, specimen handling requirements and biological variability. , 2010, Clinical biochemistry.

[11]  Rinaldo Bellomo,et al.  Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. , 2009, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[12]  R. Bellomo,et al.  The predictive performance of plasma neutrophil gelatinase-associated lipocalin (NGAL) increases with grade of acute kidney injury. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[13]  A. Hyder,et al.  A small post-operative rise in serum creatinine predicts acute kidney injury in children undergoing cardiac surgery. , 2009, Kidney international.

[14]  J. Burnett,et al.  Natriuretic peptides in the diagnosis and management of chronic heart failure. , 2009, Heart failure clinics.

[15]  Amit X Garg,et al.  Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. , 2009, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[16]  J. Schold,et al.  Acute Kidney Injury Is Associated With Increased Long-Term Mortality After Cardiothoracic Surgery , 2009, Circulation.

[17]  C. Schmid,et al.  A new equation to estimate glomerular filtration rate. , 2009, Annals of internal medicine.

[18]  H. Lee,et al.  Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery. , 2009, Clinical journal of the American Society of Nephrology : CJASN.

[19]  Susan L Furth,et al.  New equations to estimate GFR in children with CKD. , 2009, Journal of the American Society of Nephrology : JASN.

[20]  Mihwa Kim,et al.  Urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery. , 2008, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[21]  M. Zappitelli.  Epidemiology and diagnosis of acute kidney injury. , 2008, Seminars in nephrology.

[22]  Holly Janes,et al.  Practice of Epidemiology Adjusting for Covariates in Studies of Diagnostic, Screening, or Prognostic Markers: an Old Concept in a New Setting , 2022 .

[23]  F. Grenier,et al.  Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[24]  V. Hjortdal,et al.  Clinical outcome in children with acute renal failure treated with peritoneal dialysis after surgery for congenital heart disease. , 2008, Kidney international. Supplement.

[25]  H. Wong,et al.  Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock , 2008, Critical care medicine.

[26]  L. Jianping,et al.  Urinary IL-18 and NGAL as Early Predictive Biomarkers in Contrast-Induced Nephropathy after Coronary Angiography , 2008, Nephron Clinical Practice.

[27]  M. Pencina,et al.  Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond , 2008, Statistics in medicine.

[28]  N. Cook.  Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. , 2008, Clinical chemistry.

[29]  M. Mitsnefes,et al.  Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study , 2007, Critical care.

[30]  John A Kellum,et al.  Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury , 2007, Critical care.

[31]  Sean M. O'Brien,et al.  Bedside Tool for Predicting the Risk of Postoperative Dialysis in Patients Undergoing Cardiac Surgery , 2006, Circulation.

[32]  Mihwa Kim,et al.  Association between Increases in Urinary Neutrophil Gelatinase–associated Lipocalin and Acute Renal Dysfunction after Adult Cardiac Surgery , 2006, Anesthesiology.

[33]  H. Ham,et al.  Revisiting normal 51Cr-ethylenediaminetetraacetic acid clearance values in children , 2006, European Journal of Nuclear Medicine and Molecular Imaging.

[34]  C. Edelstein,et al.  Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. , 2006, Kidney international.

[35]  B. H. Patterson,et al.  Evaluating markers for the early detection of cancer: overview of study designs and methods , 2006, Clinical trials.

[36]  M. Okusa,et al.  Acute kidney injury associated with cardiac surgery. , 2005, Clinical journal of the American Society of Nephrology : CJASN.

[37]  T. Berl.  American Society of Nephrology Renal Research Report. , 2005, Journal of the American Society of Nephrology : JASN.

[38]  Qing Ma,et al.  Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery , 2005, The Lancet.

[39]  M. Mitsnefes,et al.  J Am Soc Nephrol 15: 3073–3082, 2004 Amelioration of Ischemic Acute Renal Injury by Neutrophil , 2004 .

[40]  D. Morrow,et al.  Troponins in acute coronary syndromes. , 2004, Progress in cardiovascular diseases.

[41]  D. Ruppert.  The Elements of Statistical Learning: Data Mining, Inference, and Prediction , 2004 .

[42]  R. Bellomo,et al.  Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group , 2004, Critical care.

[43]  L. Moldawer,et al.  Therapeutic neutralization of interferon-gamma in primates prevents lethality in Gram-negative bacteremic shock , 2004 .

[44]  M. Mitsnefes,et al.  Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. , 2003, Journal of the American Society of Nephrology : JASN.

[45]  Sudhir V. Shah,et al.  Acute renal failure: directions for the next decade. , 2003, Journal of the American Society of Nephrology : JASN.

[46]  B. Molitoris.  Transitioning to therapy in ischemic acute renal failure. , 2003, Journal of the American Society of Nephrology : JASN.

[47]  C. Edelstein,et al.  Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice. , 2002, The Journal of clinical investigation.

[48]  Kimberlee Gauvreau,et al.  Consensus-based method for risk adjustment for surgery for congenital heart disease. , 2002, The Journal of thoracic and cardiovascular surgery.

[49]  M. Lucia,et al.  Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. , 2001, The Journal of clinical investigation.

[50]  P. Venge,et al.  Lipocalins as biochemical markers of disease. , 2000, Biochimica et biophysica acta.

[51]  Macdonald Js.  Carcinoembryonic antigen screening: pros and cons. , 1999 .

[52]  C. Fraser,et al.  Early initiation of peritoneal dialysis after surgical repair of congenital heart disease , 1999, Pediatric Nephrology.

[53]  R. Hotchkiss,et al.  Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. , 1999, Critical care medicine.

[54]  K E Hammermeister,et al.  Independent association between acute renal failure and mortality following cardiac surgery. , 1998, The American journal of medicine.

[55]  J. Cowland,et al.  Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. , 1997, Genomics.

[56]  D Wybenga,et al.  Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. , 1996, The New England journal of medicine.

[57]  V. Salandin,et al.  Acute renal failure in the patient undergoing cardiac operation. Prevalence, mortality rate, and main risk factors. , 1994, The Journal of thoracic and cardiovascular surgery.

[58]  E. DeLong,et al.  Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. , 1988, Biometrics.