Biomarkers for the diagnosis and risk stratification of acute kidney injury: A systematic review

The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, but such measurements are a poor marker of acute deterioration in kidney function. We performed a systematic review of publications that evaluated the accuracy and reliability of serum and urinary biomarkers in human subjects when used for the diagnosis of established AKI or early AKI, or to risk stratify patients with AKI. Two reviewers independently searched the MEDLINE and EMBASE databases (January 2000–March 2007) for studies pertaining to biomarkers for AKI. Studies were assessed for methodologic quality. In total, 31 studies evaluated 21 unique serum and urine biomarkers. Twenty-five of the 31 studies were scored as having 'good' quality. The results of the studies indicated that serum cystatin C, urine interleukin-18 (IL-18), and urine kidney injury molecule-1 (KIM-1) performed best for the differential diagnosis of established AKI. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin, IL-18, glutathione-S-transferase-π, and γ-glutathione-S-transferase performed best for early diagnosis of AKI. Urine N-acetyl-β-D-glucosaminidase, KIM-1, and IL-18 performed the best for mortality risk prediction after AKI. In conclusion, published data from studies of serum and urinary biomarkers suggest that biomarkers may have great potential to advance the fields of nephrology and critical care. These biomarkers need validation in larger studies, and the generalizability of biomarkers to different types of AKI as well as the incremental prognostic value over traditional clinical variables needs to be determined. The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, but such measurements are a poor marker of acute deterioration in kidney function. We performed a systematic review of publications that evaluated the accuracy and reliability of serum and urinary biomarkers in human subjects when used for the diagnosis of established AKI or early AKI, or to risk stratify patients with AKI. Two reviewers independently searched the MEDLINE and EMBASE databases (January 2000–March 2007) for studies pertaining to biomarkers for AKI. Studies were assessed for methodologic quality. In total, 31 studies evaluated 21 unique serum and urine biomarkers. Twenty-five of the 31 studies were scored as having 'good' quality. The results of the studies indicated that serum cystatin C, urine interleukin-18 (IL-18), and urine kidney injury molecule-1 (KIM-1) performed best for the differential diagnosis of established AKI. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin, IL-18, glutathione-S-transferase-π, and γ-glutathione-S-transferase performed best for early diagnosis of AKI. Urine N-acetyl-β-D-glucosaminidase, KIM-1, and IL-18 performed the best for mortality risk prediction after AKI. In conclusion, published data from studies of serum and urinary biomarkers suggest that biomarkers may have great potential to advance the fields of nephrology and critical care. These biomarkers need validation in larger studies, and the generalizability of biomarkers to different types of AKI as well as the incremental prognostic value over traditional clinical variables needs to be determined. The diagnosis of acute kidney injury (AKI—formally known as acute renal failure) is usually based on either an elevation of serum creatinine or the detection of oliguria.1.Mehta R.L. Chertow G.M. Acute renal failure definitions and classification: time for change?.J Am Soc Nephrol. 2003; 14: 2178-2187Crossref PubMed Scopus (251) Google Scholar Serum creatinine is a poor marker of early renal dysfunction, because serum concentration is greatly influenced by numerous non-renal factors (such as body weight, race, age, gender, total body volume, drugs, muscle metabolism, and protein intake).2.Bjornsson T.D. Use of serum creatinine concentrations to determine renal function.Clin Pharmacokinet. 1979; 4: 200-222Crossref PubMed Scopus (199) Google Scholar The utility of serum creatinine is worse in AKI, because the patients are not in steady state; hence, serum creatinine lags far behind renal injury. Thus, substantial rises in serum creatinine are often not witnessed until 48–72 h after the initial insult to the kidney.1.Mehta R.L. Chertow G.M. Acute renal failure definitions and classification: time for change?.J Am Soc Nephrol. 2003; 14: 2178-2187Crossref PubMed Scopus (251) Google Scholar,3.Star R.A. Treatment of acute renal failure.Kidney Int. 1998; 54: 1817-1831Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar In addition, significant renal disease can exist with minimal or no change in creatinine because of renal reserve, enhanced tubular secretion of creatinine, or other factors.4.Bosch J.P. Renal reserve: a functional view of glomerular filtration rate.Semin Nephrol. 1995; 15: 381-385PubMed Google Scholar,5.Herrera J. Rodriguez-Iturbe B. Stimulation of tubular secretion of creatinine in health and in conditions associated with reduced nephron mass. Evidence for a tubular functional reserve.Nephrol Dial Transplant. 1998; 13: 623-629Crossref PubMed Scopus (49) Google Scholar A 'troponin-like' biomarker of AKI that is easily measured, unaffected by other biological variables, and capable of both early detection and risk stratification would substantially assist the diagnosis of AKI. The American Society of Nephrology has designated the development of biomarkers for early detection of AKI as a top research priority.6.American society of nephrology American society of nephrology renal research report.J Am Soc Nephrol. 2005; 16: 1886-1903Crossref PubMed Scopus (161) Google Scholar Several biomarkers of AKI have been identified over the past few years that are elevated in ischemic renal injury in experimental animals, and also in humans with clinical AKI, in some cases prior to a 'gold standard' diagnostic threshold (for example, rise in serum creatinine by 50%).7.Mishra J. Ma Q. Prada A. et al.Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury.J Am Soc Nephrol. 2003; 14: 2534-2543Crossref PubMed Scopus (1329) Google Scholar,8.Mishra J. Mori K. Ma Q. et al.Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity.Am J Nephrol. 2004; 24: 307-315Crossref PubMed Scopus (418) Google Scholar These biomarkers include both serum tests such as cystatin C,9.Herget-Rosenthal S. Marggraf G. Husing J. et al.Early detection of acute renal failure by serum cystatin C.Kidney Int. 2004; 66: 1115-1122Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar and urinary tests such as interleukin-18 (IL-18)10.Parikh C.R. Abraham E. Ancukiewicz M. Edelstein C.L. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit.J Am Soc Nephrol. 2005; 16: 3046-3052Crossref PubMed Scopus (416) Google Scholar and neutrophil gelatinase-associated lipocalin (NGAL),11.Mishra J. Dent C. Tarabishi R. et al.Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.Lancet. 2005; 365: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (1812) Google Scholar along with several others. Uncertainty still exists, however, as to whether these biomarkers possess adequate prognostic accuracy for both established AKI and for early detection of AKI. Limited data are available that directly compare the performance of these biomarkers as tests for diagnosis of AKI, and their consistency across certain subgroups of patients (for example, post-cardiac surgery, sepsis, post-kidney transplant). Finally, the differences in the reporting criteria for 'positivity' have made it difficult to compare the performance of these various biomarkers directly. Our objectives were to evaluate, in human subjects, the accuracy and reliability of serum and/or urinary biomarkers for the diagnosis of established AKI, for the early diagnosis of AKI, and for risk stratification of AKI. The combined search identified a total of 830 citations, of which 715 were judged ineligible after title and abstract review (Figure 1). The major reasons for exclusion were study populations without AKI or acute renal failure, non-serum or non-urine biomarker of diagnosis of AKI, and duplicate publications. Full text analysis of the remaining 115 articles led to 31 studies9.Herget-Rosenthal S. Marggraf G. Husing J. et al.Early detection of acute renal failure by serum cystatin C.Kidney Int. 2004; 66: 1115-1122Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar, 10.Parikh C.R. Abraham E. Ancukiewicz M. Edelstein C.L. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit.J Am Soc Nephrol. 2005; 16: 3046-3052Crossref PubMed Scopus (416) Google Scholar, 11.Mishra J. Dent C. Tarabishi R. et al.Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.Lancet. 2005; 365: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (1812) Google Scholar, 12.Abu-Omar Y. Mussa S. Naik M.J. et al.Evaluation of Cystatin C as a marker of renal injury following on-pump and off-pump coronary surgery.Eur J Cardiothorac Surg. 2005; 27: 893-898Crossref PubMed Scopus (48) Google Scholar, 13.Biancofiore G. Pucci L. Cerutti E. et al.Cystatin C as a marker of renal function immediately after liver transplantation.Liver Transpl. 2006; 12: 285-291Crossref PubMed Scopus (48) Google Scholar, 14.Benohr P. Grenz A. Hartmann J.T. et al.Cystatin C—a marker for assessment of the glomerular filtration rate in patients with cisplatin chemotherapy.Kidney Blood Press Res. 2006; 29: 32-35Crossref PubMed Scopus (49) Google Scholar, 15.Stabuc B. Vrhovec L. Stabuc-Silih M. Cizej T.E. Improved prediction of decreased creatinine clearance by serum cystatin C: use in cancer patients before and during chemotherapy.Clin Chem. 2000; 46: 193-197PubMed Google Scholar, 16.Zhu J. Yin R. Wu H. et al.Cystatin C as a reliable marker of renal function following heart valve replacement surgery with cardiopulmonary bypass.Clin Chim Acta. 2006; 374: 116-121Crossref PubMed Scopus (42) Google Scholar, 17.Villa P. Jimenez M. Soriano M.-C. et al.Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients. [see comment].Crit Care (London, England). 2005; 9: R139-R143Crossref PubMed Google Scholar, 18.Wynckel A. Randoux C. Millart H. et al.Kinetics of carbamylated haemoglobin in acute renal failure.Nephrol Dial Transplant. 2000; 15: 1183-1188Crossref PubMed Scopus (44) Google Scholar, 19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google Scholar, 20.Parikh C.R. Jani A. Melnikov V.Y. et al.Urinary interleukin-18 is a marker of human acute tubular necrosis.Am J Kidney Dis. 2004; 43: 405-414Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 21.Boldt J. Brenner T. Lang J. et al.Kidney-specific proteins in elderly patients undergoing cardiac surgery with cardiopulmonary bypass.Anesth Analg. 2003; 97: 1582-1589Crossref PubMed Scopus (40) Google Scholar, 22.Han W.K. Bailly V. Abichandani R. et al.Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.Kidney Int. 2002; 62: 237-244Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar, 23.du Cheyron D. Daubin C. Poggioli J. et al.Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF.Am J Kidney Dis. 2003; 42: 497-506Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 24.Ahlstrom A. Tallgren M. Peltonen S. Pettila V. Evolution and predictive power of serum cystatin C in acute renal failure.Clin Nephrol. 2004; 62: 344-350Crossref PubMed Google Scholar, 25.Mazul-Sunko B. Zarkovic N. Vrkic N. et al.Proatrial natriuretic peptide (1–98), but not cystatin C, is predictive for occurrence of acute renal insufficiency in critically ill septic patients.Nephron Clin Pract. 2004; 97: c103-c107Crossref PubMed Scopus (31) Google Scholar, 26.Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (212) Google Scholar, 27.Rinder C.S. Fontes M. Mathew J.P. et al.Neutrophil CD11b upregulation during cardiopulmonary bypass is associated with postoperative renal injury.Ann Thorac Surg. 2003; 75: 899-905Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 28.Wagener G. Jan M. Kim M. et al.Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery.Anesthesiology. 2006; 105: 485-491Crossref PubMed Scopus (453) Google Scholar, 29.Parikh C.R. Jani A. Mishra J. et al.Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.Am J Transplant. 2006; 6: 1639-1645Crossref PubMed Scopus (413) Google Scholar, 30.Parikh C.R. Mishra J. Thiessen-Philbrook H. et al.Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.Kidney Int. 2006; 70: 199-203Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar, 31.Eijkenboom J.J. van Eijk L.T. Pickkers P. et al.Small increases in the urinary excretion of glutathione S-transferase A1 and P1 after cardiac surgery are not associated with clinically relevant renal injury.Intensive Care Med. 2005; 31: 664-667Crossref PubMed Scopus (29) Google Scholar, 32.Westhuyzen J. Endre Z.H. Reece G. et al.Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit.Nephrol Dial Transplant. 2003; 18: 543-551Crossref PubMed Scopus (263) Google Scholar, 33.Trachtman H. Christen E. Canaan A. et al.Urinary NGAL in D+HUS: a novel marker of renal injury.Pediatr Nephrol. 2006; 21: 989-994Crossref PubMed Scopus (164) Google Scholar, 34.Simmons E.M. Himmelfarb J. Sezer M.T. et al.Plasma cytokine levels predict mortality in patients with acute renal failure.Kidney Int. 2004; 65: 1357-1365Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 35.Herget-Rosenthal S. Poppen D. Husing J. et al.Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis.Clin Chem. 2004; 50: 552-558Crossref PubMed Scopus (236) Google Scholar, 36.Liangos O. Perianayagam M.C. Vaidya V.S. et al.Urinary N-Acetyl-beta-(D)-Glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure.J Am Soc Nephrol. 2007; 18: 904-912Crossref PubMed Scopus (406) Google Scholar meeting inclusion criteria (Tables 2, 3 and 4). The methodological quality based on scoring of the 10 validity criteria taken from the STARD (Standards for Reporting of Diagnostic Accuracy) recommendations is listed in Table 1. Only tests with results that were scored of good or fair quality are described in the text below.Table 1Scoring system for validity used in this systematic reviewValidity CriterionExplanationScoringCommentsParticipant recruitmentWas recruitment based on presenting symptoms, results from previous tests, or fact that participants received index tests?Presenting sx=1Previous tests or index tests=0Based on presenting symptoms in all 31 studies.Participant samplingWas it study population or a convenience sample or a consecutive series?Consecutive series=1Convenience sample=0Based on convenience sample in 510.Parikh C.R. Abraham E. Ancukiewicz M. Edelstein C.L. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit.J Am Soc Nephrol. 2005; 16: 3046-3052Crossref PubMed Scopus (416) Google Scholar, 19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google Scholar, 20.Parikh C.R. Jani A. Melnikov V.Y. et al.Urinary interleukin-18 is a marker of human acute tubular necrosis.Am J Kidney Dis. 2004; 43: 405-414Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 22.Han W.K. Bailly V. Abichandani R. et al.Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury.Kidney Int. 2002; 62: 237-244Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar, 25.Mazul-Sunko B. Zarkovic N. Vrkic N. et al.Proatrial natriuretic peptide (1–98), but not cystatin C, is predictive for occurrence of acute renal insufficiency in critically ill septic patients.Nephron Clin Pract. 2004; 97: c103-c107Crossref PubMed Scopus (31) Google Scholar, 37.Han W.K. Waikar S.S. Johnson A.M. et al.Urinary biomarkers for detection of acute kidney injury.Kidney Int. 2007Google Scholar studies.Data collectionWas data collection planned before the index test and reference standard were performed prospectively or retrospectively?Prospective=1Retrospective=0Planned and performed prospectively in all 31 studies.Reference standardWas the rationale for the reference standard stated?Stated=1Not stated=0Not stated for two12.Abu-Omar Y. Mussa S. Naik M.J. et al.Evaluation of Cystatin C as a marker of renal injury following on-pump and off-pump coronary surgery.Eur J Cardiothorac Surg. 2005; 27: 893-898Crossref PubMed Scopus (48) Google Scholar,18.Wynckel A. Randoux C. Millart H. et al.Kinetics of carbamylated haemoglobin in acute renal failure.Nephrol Dial Transplant. 2000; 15: 1183-1188Crossref PubMed Scopus (44) Google Scholar studies.Materials and methodsWere technical specifications of material and methods stated including how and when measurements were taken?Stated=1Not stated=0Stated in all but one19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google Scholar of the articles.Index testWere the definitions of and rationales for the units, cutoffs, and/or categories of the results of the index tests stated?Stated=1Not stated=0Not stated in two12.Abu-Omar Y. Mussa S. Naik M.J. et al.Evaluation of Cystatin C as a marker of renal injury following on-pump and off-pump coronary surgery.Eur J Cardiothorac Surg. 2005; 27: 893-898Crossref PubMed Scopus (48) Google Scholar,19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google Scholar of the 31 articles.BlindingWere readers of index test and reference standard blinded?Blinded=1Not blinded or not stated=0Stated that the readers of index test and reference standard were blinded in 1710.Parikh C.R. Abraham E. Ancukiewicz M. Edelstein C.L. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit.J Am Soc Nephrol. 2005; 16: 3046-3052Crossref PubMed Scopus (416) Google Scholar, 11.Mishra J. Dent C. Tarabishi R. et al.Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.Lancet. 2005; 365: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (1812) Google Scholar, 19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google Scholar, 29.Parikh C.R. Jani A. Mishra J. et al.Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.Am J Transplant. 2006; 6: 1639-1645Crossref PubMed Scopus (413) Google Scholar, 30.Parikh C.R. Mishra J. Thiessen-Philbrook H. et al.Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.Kidney Int. 2006; 70: 199-203Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar, 35.Herget-Rosenthal S. Poppen D. Husing J. et al.Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis.Clin Chem. 2004; 50: 552-558Crossref PubMed Scopus (236) Google Scholar, 36.Liangos O. Perianayagam M.C. Vaidya V.S. et al.Urinary N-Acetyl-beta-(D)-Glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure.J Am Soc Nephrol. 2007; 18: 904-912Crossref PubMed Scopus (406) Google Scholar, 37.Han W.K. Waikar S.S. Johnson A.M. et al.Urinary biomarkers for detection of acute kidney injury.Kidney Int. 2007Google Scholar, 38.Zappitelli M. Washburn K.K. Arikan A.A. et al.Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study.Crit Care. 2007; 11: R84Crossref PubMed Scopus (328) Google Scholar, 39.Washburn K.K. Zappitelli M. Arikan A.A. et al.Urinary interleukin-18 is an acute kidney injury biomarker in critically Ill children.Nephrol Dial Transplant. 2007Crossref Scopus (142) Google Scholar articles.CompletionWas the number of participants that did not undergo index tests (no. of tests vs sample size) stated?Stated=1Not stated=0Stated in all but one19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google Scholar of the studies.Time intervalWas the time interval from index test to reference standard stated?Stated=1Not stated=0The time interval between index test and reference standard (clinical diagnosis of AKI or severity end point such as dialysis or death) was not stated in five19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google Scholar, 20.Parikh C.R. Jani A. Melnikov V.Y. et al.Urinary interleukin-18 is a marker of human acute tubular necrosis.Am J Kidney Dis. 2004; 43: 405-414Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 25.Mazul-Sunko B. Zarkovic N. Vrkic N. et al.Proatrial natriuretic peptide (1–98), but not cystatin C, is predictive for occurrence of acute renal insufficiency in critically ill septic patients.Nephron Clin Pract. 2004; 97: c103-c107Crossref PubMed Scopus (31) Google Scholar, 34.Simmons E.M. Himmelfarb J. Sezer M.T. et al.Plasma cytokine levels predict mortality in patients with acute renal failure.Kidney Int. 2004; 65: 1357-1365Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar, 36.Liangos O. Perianayagam M.C. Vaidya V.S. et al.Urinary N-Acetyl-beta-(D)-Glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure.J Am Soc Nephrol. 2007; 18: 904-912Crossref PubMed Scopus (406) Google Scholar articles.Distribution of severity of diseaseWas there a representative distribution of severity of disease? (mild, moderate, severe AKI; non-oliguric vs oliguric)Yes=1No=0A broad distribution of disease severity was found in all but four 12.Abu-Omar Y. Mussa S. Naik M.J. et al.Evaluation of Cystatin C as a marker of renal injury following on-pump and off-pump coronary surgery.Eur J Cardiothorac Surg. 2005; 27: 893-898Crossref PubMed Scopus (48) Google Scholar, 25.Mazul-Sunko B. Zarkovic N. Vrkic N. et al.Proatrial natriuretic peptide (1–98), but not cystatin C, is predictive for occurrence of acute renal insufficiency in critically ill septic patients.Nephron Clin Pract. 2004; 97: c103-c107Crossref PubMed Scopus (31) Google Scholar, 27.Rinder C.S. Fontes M. Mathew J.P. et al.Neutrophil CD11b upregulation during cardiopulmonary bypass is associated with postoperative renal injury.Ann Thorac Surg. 2003; 75: 899-905Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 37.Han W.K. Waikar S.S. Johnson A.M. et al.Urinary biomarkers for detection of acute kidney injury.Kidney Int. 2007Google Scholar of the studies. Open table in a new tab Table 2Studies of biomarkers for diagnosis of established AKIReferencesBiomarkerClinical settingSubjectsSensitivity/specificityArea under ROCLRQuality scoreSerum Abu-Omar et al.12.Abu-Omar Y. Mussa S. Naik M.J. et al.Evaluation of Cystatin C as a marker of renal injury following on-pump and off-pump coronary surgery.Eur J Cardiothorac Surg. 2005; 27: 893-898Crossref PubMed Scopus (48) Google ScholarCystatin CCardiac surgery60NRNRN/A6 Biancofiore et al.13.Biancofiore G. Pucci L. Cerutti E. et al.Cystatin C as a marker of renal function immediately after liver transplantation.Liver Transpl. 2006; 12: 285-291Crossref PubMed Scopus (48) Google ScholarCystatin CPost-OLT680.967/0.85NR6.49 Benohr et al.14.Benohr P. Grenz A. Hartmann J.T. et al.Cystatin C—a marker for assessment of the glomerular filtration rate in patients with cisplatin chemotherapy.Kidney Blood Press Res. 2006; 29: 32-35Crossref PubMed Scopus (49) Google ScholarCystatin CCisplatin Rx41NRNRN/A9 Stabuc et al.15.Stabuc B. Vrhovec L. Stabuc-Silih M. Cizej T.E. Improved prediction of decreased creatinine clearance by serum cystatin C: use in cancer patients before and during chemotherapy.Clin Chem. 2000; 46: 193-197PubMed Google ScholarCystatin CCisplatin Rx720.87/1.00.967Infinity9 Zhu et al.16.Zhu J. Yin R. Wu H. et al.Cystatin C as a reliable marker of renal function following heart valve replacement surgery with cardiopulmonary bypass.Clin Chim Acta. 2006; 374: 116-121Crossref PubMed Scopus (42) Google ScholarCystatin CCardiac surgery60NR0.876N/A9 Villa et al.17.Villa P. Jimenez M. Soriano M.-C. et al.Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients. [see comment].Crit Care (London, England). 2005; 9: R139-R143Crossref PubMed Google ScholarCystatin CICU50NR0.927N/A9 Wynckel et al.18.Wynckel A. Randoux C. Millart H. et al.Kinetics of carbamylated haemoglobin in acute renal failure.Nephrol Dial Transplant. 2000; 15: 1183-1188Crossref PubMed Scopus (44) Google ScholarCarbamylated HbHospitalized410.94/0.92NR11.88 Mori et al.19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google ScholarNGALHospitalized37NRNRN/A5 Bachorzewska-Gajewska et al.26.Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (212) Google ScholarNGALPCI35NRNRNR9Urine Mori et al.19.Mori K. Lee H.T. Rapoport D. et al.Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia-reperfusion injury.J Clin Invest. 2005; 115: 610-621Crossref PubMed Scopus (751) Google ScholarNGALHospitalized46NRNRN/A5 Bachorzewska-Gajewska et al.26.Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (212) Google ScholarNGALPCI35NRNRN/A9 Parikh et al.20.Parikh C.R. Jani A. Melnikov V.Y. et al.Urinary interleukin-18 is a marker of human acute tubular necrosis.Am J Kidney Dis. 2004; 43: 405-414Abstract Full Text Full Text PDF PubMed Scopus (395) Google ScholarIL-18Hospitalized720.85/0.880.957.17 Boldt et al.21.Boldt J. Brenner T. 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