Thromb Haemost 2014; 111(02): 365-372
DOI: 10.1160/TH13-05-0387
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Serum neutrophil gelatinase-associated lipocalin (NGAL) in patients with Shiga toxin mediated haemolytic uraemic syndrome (STEC-HUS)

Alexander Lukasz
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
2   Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Münster, Germany
,
Jan Beneke
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
,
Jan Menne
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
,
Frank Vetter
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
,
Bernhard M. W. Schmidt
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
,
Mario Schiffer
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
,
Hermann Haller
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
,
Philipp Kümpers*
2   Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Münster, Münster, Germany
,
Jan T. Kielstein*
1   Department of Nephrology & Hypertension, Hannover Medical School, Hannover, Germany
› Author Affiliations
Further Information

Publication History

Received: 13 May 2013

Accepted after major revision: 27 September 2013

Publication Date:
27 November 2017 (online)

Summary

Neutrophil gelatinase-associated lipocalin (NGAL) is an increasingly used biomarker for acute kidney injury (AKI). Its utility in adult patients with AKI caused by Shiga toxin producing Escherichia coli infection (STEC)-associated haemolytic-uraemic syndrome (HUS), remains unknown. We aimed to evaluate the prognostic value of serum NGAL admission levels for the need of renal replacement therapy (RRT) in STEC-HUS patients. Baseline serum NGAL was determined by ELISA in 39 patients with STEC O104:H4 infection cared for at Hannover Medical School during the outbreak in Germany through May-July 2011. Patients with HUS had significant higher NGAL levels than healthy controls (379 [248 – 540] vs 39.0 [37.5–45] ng/ml, p < 0.0001). During clinical course, 24 patients required RRT at a median of five days after admission. NGAL admission levels were higher in patients requiring RRT (476 (344–639) ng/ml) compared to patients not requiring RRT (257 (196–426) ng/ml; p < 0.001). Unadjusted and adjusted logistic regression analyses identified NGAL as an independent predictor for need of RRT. In a combined model, a joint NGAL/AKIN classification approach improved the predictive accuracy for need of RRT over either marker alone. The combined categorical cut-off point defined by NGAL ≥ 330 ng/ml and presence of AKI (AKIN ≥ I) on admission correctly identified 20 of 24 patients requiring RRT (odds ratio 20, sensitivity 83%, specificity 80%, negative predictive value 75%, positive predictive value 87%). NGAL may serve as an adjunctive tool to improve risk prediction in patients with STEC-HUS.

* JTK and PK contributed equally to the manuscript and are both considered senior authors.


 
  • References

  • 1 Buchholz U, Bernard H, Werber D. et al. German outbreak of Escherichia coli O104:H4 associated with sprouts.. N Engl J Med 2011; 365: 1763-1770.
  • 2 Frank C, Werber D, Cramer JP. et al. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany.. N Engl J Med 2011; 365: 1771-1780.
  • 3 Rasko DA, Webster DR, Sahl JW. et al. Origins of the E.. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. N Engl J Med 2011; 365: 709-717.
  • 4 Rohde H, Qin J, Cui Y. et al. Open-source genomic analysis of Shiga-toxin-producing E.. coli O104:H4. N Engl J Med 2011; 365: 718-724.
  • 5 Kielstein JT, Beutel G, Fleig S. et al. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E.. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry. Nephrol Dial Transplant 2012; 27: 3807-3815.
  • 6 Karpman D, Sartz L, Johnson S. Pathophysiology of typical hemolytic uremic syndrome.. Semin Thromb Hemost 2010; 36: 575-585.
  • 7 Bauwens A, Bielaszewska M, Kemper B. et al. Differential cytotoxic actions of Shiga toxin 1 and Shiga toxin 2 on microvascular and macrovascular endothelial cells.. Thromb Haemost 2011; 105: 515-528.
  • 8 Hughes AK, Stricklett PK, Kohan DE. Cytotoxic effect of Shiga toxin-1 on human proximal tubule cells.. Kidney Int 1998; 54: 426-437.
  • 9 Muthing J, Schweppe CH, Karch H. et al. Shiga toxins, glycosphingolipid diversity, and endothelial cell injury.. Thromb Haemost 2009; 101: 252-264.
  • 10 Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.. Lancet 2005; 365: 1073-1086.
  • 11 Nickolas TL, O’Rourke MJ, Yang J. et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury.. Ann Intern Med 2008; 148: 810-819.
  • 12 Bachorzewska-Gajewska H, Malyszko J, Sitniewska E. et al. Could neutrophilgelatinase-associated lipocalin and cystatin C predict the development of contrast-induced nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine values?. Kidney Blood Press Res 2007; 30: 408-415.
  • 13 Hirsch R, Dent C, Pfriem H. et al. NGAL is an early predictive biomarker of contrast-induced nephropathy in children.. Pediatr Nephrol 2007; 22: 2089-2095.
  • 14 Ling W, Zhaohui N, Ben H. et al. Urinary IL-18 and NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography.. Nephron Clin Pract 2008; 108: c176-181.
  • 15 Bennett M, Dent CL, Ma Q. et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study.. Clin J Am Soc Nephrol 2008; 3: 665-673.
  • 16 Haase M, Bellomo R, Devarajan P. et al. Novel biomarkers early predict the severity of acute kidney injury after cardiac surgery in adults.. Ann Thorac Surg 2009; 88: 124-130.
  • 17 Haase-Fielitz A, Bellomo R, Devarajan P. et al. The predictive performance of plasma neutrophil gelatinase-associated lipocalin (NGAL) increases with grade of acute kidney injury.. Nephrol Dial Transplant 2009; 24: 3349-3354.
  • 18 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: 1231-1238.
  • 19 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: 485-491.
  • 20 Wheeler DS, Devarajan P, Ma Q. et al. Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock.. Crit Care Med 2008; 36: 1297-1303.
  • 21 Mehta RL, Kellum JA, Shah SV. et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.. Crit Care 2007; 11: R31.
  • 22 Bellomo R, Ronco C, Kellum JA. 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.. Crit Care 2004; 8: R204-212.
  • 23 Levey AS, Stevens LA, Schmid CH. et al. A new equation to estimate glomerular filtration rate.. Ann Intern Med 2009; 150: 604-612.
  • 24 Bolignano D, Coppolino G, Romeo A. et al. Neutrophil gelatinase-associated lipocalin (NGAL) reflects iron status in haemodialysis patients.. Nephrol Dial Transplant 2009; 24: 3398-3403.
  • 25 StatPages website. Available at: http://www.statpages.org/ctab2x2.html Last accessed October 30, 2013.
  • 26 Haase M, Bellomo R, Devarajan P. et al. Accuracy of neutrophil gelatinase- associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis.. Am J Kidney Dis 2009; 54: 1012-1024.
  • 27 Vanmassenhove J, Vanholder R, Nagler E. et al. Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature.. Nephrology Dialysis Transplant 2013; 28: 254-273.
  • 28 Haase M, Devarajan P, Haase-Fielitz A. et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multi-center pooled analysis of prospective studies.. J Am Coll Cardiol 2011; 57: 1752-1761.
  • 29 Kumpers P, Hafer C, Lukasz A. et al. Serum neutrophil gelatinase-associated lipocalin at inception of renal replacement therapy predicts survival in critically ill patients with acute kidney injury.. Crit Care 2010; 14: R9.
  • 30 Srisawat N, Murugan R, Lee M. et al. Plasma neutrophil gelatinase-associated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia.. Kidney Int 2011; 80: 545-552.
  • 31 Trachtman H, Christen E, Cnaan A. et al. Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury.. Pediatr Nephrol 2006; 21: 989-994.
  • 32 Schmidt-Ott KM, Mori K, Li JY. et al. Dual action of neutrophil gelatinase-associated lipocalin.. J Am Soc Nephrol 2007; 18: 407-413.
  • 33 Mori K, Lee HT, Rapoport D. et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury.. J Clin Invest 2005; 115: 610-621.
  • 34 Cowland JB, Borregaard N. Molecular characterisation and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans.. Genomics 1997; 45: 17-23.
  • 35 Kjeldsen L, Cowland JB, Borregaard N. Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse.. Biochim Biophys Acta 2000; 1482: 272-283.
  • 36 Fjaertoft G, Foucard T, Xu S. et al. Human neutrophil lipocalin (HNL) as a diagnostic tool in children with acute infections: a study of the kinetics.. Acta Paediatr 2005; 94: 661-666.
  • 37 Klausen P, Niemann CU, Cowland JB. et al. On mouse and man: neutrophil gelatinase associated lipocalin is not involved in apoptosis or acute response.. Eur J Haematol 2005; 75: 332-340.
  • 38 Dent CL, Ma Q, Dastrala S. et al. Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study.. Crit Care 2007; 11: R127.
  • 39 Haase-Fielitz A, Bellomo R, Devarajan P. et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery--a prospective cohort study.. Crit Care Med 2009; 37: 553-560.