The importance of NGAL and cystatin C biomarkers in cardiovascular diseases

Authors: K. Helánová 1;  J. Pařenica 1;  V. Dlouhý 2;  M. Pávková Goldbergová 3;  Z. Čermákováihash2 4,5 4,5;  J. Špinar 1
Authors‘ workplace: Interní kardiologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jindřich Špinar, CSc., FESC 1;  Lékařská fakulta MU Brno, děkan prof. MUDr. Jiří Mayer, CSc. 2;  Ústav patologické fyziologie Lékařské fakulty MU Brno, přednostka prof. MUDr. Anna Vašků, CSc. 3;  Oddělení klinické biochemie FN Brno, pracoviště Bohunice, přednosta prim. doc. MUDr. Milan Dastych, CSc., MBA 4;  Katedra laboratorních metod Lékařské fakulty MU Brno, přednosta doc. MUDr. Milan Dastych, CSc., MBA 5
Published in: Vnitř Lék 2012; 58(4): 286-290
Category: Reviews


Cystatin C is an inhibitor of lysosomal proteases and extracellular cysteine protease, it participates in the regulation of metabolism of extracellular proteins. It is fully glomerular filterable, completely absorbed and catabolised in proximal tubule cells. NGAL (neutrophil gelatinase-associated lipocalin) is an acute phase protein, participating in antibacterial immunity and his important feature is the formation of complex with metalloproteinase 9 (MMP-9), thereby increasing its activity and prevents its degradation. NGAL is freely filtered across the glomerular membrane and is reabsorbed by endocytosis in the proximal tubule. NGAL detected in urine is produced mainly in the distal nephron. The serum cystatin C and NGAL can diagnose acute renal impairment one or two days earlier in the comparison with the monitoring of renal function by serum creatinine. Moreover, compared with the information provided by creatinine or by estimated GFR, the elevated cystatin C gives, in patients with cardiovascular disease, information about worse prognosis. Increased level of NGAL was detected in patients with acute myocardial infarction, heart failure or stroke. There is a lack of data about the prognostic significance of NGAL in patients after myocardial infarction or heart failure, no data about their comparison or interaction with natriuretic peptides exists up today.

Key words:
cystatin C – NGAL – biomarker


1. Grubb A, Löfberg H. Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis. Proc Natl Acad Sci U S A 1982; 79: 3024–3027.

2. Manetti L, Pardinin E, Genovesi M et al. Thyroid function differently affects serum cystatin C and creatinine concentrations. J Endocrinol Invest 2005; 28: 346–349.

3. Risch L, Herklotz R, Blumberg A et al. Effects of Glucocorticoid Immunosuppression on Serum Cystatin C Concentrations in Renal Transplant Patients. Clin Chem 2001; 47: 2055–2059.

4. Herget-Rosenthal S, Marggraf G, Hüsing J et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004, 66: 1115–1122.

5. Hertlová M, Šurel S, Šenkyřík M et al. Cystatin C in estimates of glomerular filtration in patients with renal dinase – initial experience. Vnitř Lék 2001; 47: 10–16.

6. Anavekar NS, McMurray JJV, Velazquez EJ et al. Relation between Renal Dysfunction and Cardiovascular Outcomes after Myocardial Infarction. N Engl J Med 2004; 351: 1285–1295.

7. Shlipak MG, Sarnak MJ, Katz R et al. Cystatin C and the Risk of Death and Cardiovascular Events among Elderly Persons. N Engl J Med 2005; 352: 2049–2060.

8. Shlipak MG, Katz R, Sarnak MJ et al. Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease. Ann Intern Med 2006; 145: 237–246.

9. Knight EL, Verhave JC, Spiegelman D et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004; 65: 1416–1421.

10. Luc G, Bard JM, Lesueur C et al. PRIME Study Group. Plasma cystatin-C and develop­ment of coronary heart disease: The PRIME Study. Atherosclerosis 2006; 185: 375–380.

11. Kilic T, Oner G, Ural E et al. Comparison of the long-term prognostic value of Cystatin C to other indicators of renal function, markers of inflammation and systolic dysfunction among patients with acute coronary syndrome. Atherosclerosis 2009; 207: 552–558.

12. Taglieri N, Fernandez-Berges DJ, Koenig W et al. SIESTA Investigators. Plasma cystatin C for prediction of 1-year cardiac events in Mediterranean patients with non-ST elevation acute coronary syndrome. Atherosclerosis 2010; 209: 300–305.

13. Koenig W, Twardella D, Brenner H et al. Plasma Concentrations of Cystatin C in Patients with Coronary Heart Disease and Risk for Secondary Cardiovascular Events: More than Simply a Marker of Glomerular Filtration Rate. Clin Chem 2005; 51: 321–327.

14. Xie L, Terrand J, Xu B et al. Cystatin C increases in cardiac injury: a role in extracellular matrix protein modulation. Cardiovasc Res 2010; 87: 628–635.

15. Xu SY, Carlson M, Engström A et al. Purification and characterization of a human neutrophil lipocalin (HNL) from the secondary granules of human neutrophils. Scand J Clin Lab Invest 1994; 54: 365–376.

16. Kjeldsen L, Johnsen AH, Sengeløv H et al. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 1993; 268: 10425–10432.

17. Flo TH, Smith KD, Sato S et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004; 432: 917–921.

18. Yan QW, Yang Q, Mody N et al. The Adipokine Lipocalin 2 Is Regulated by Obesity and Promotes Insulin Resistance. Diabetes 2007; 56: 2533–2540.

19. Yang J, Blum A, Novak T et al. An Epithelial Precursor Is Regulated by the Ureteric Bud and by the Renal Stroma. Dev Biol 2002; 246: 296–310.

20. Meldrum KK, Hile K, Meldrum DR et al. Simulated Ischemia Induces Renal Tubular Cell Apoptosis Through a Nuclear Factor-κB Dependent Mechanism. J Urol 2002; 168: 248–252.

21. Gupta K, Shukla M, Cowland JB et al. Neutro­phil gelatinase-associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9. Arthritis Rheum 2007; 56: 3326–3335.

22. Yan L, Borregaard N, Kjeldsen L et al. The High Molecular Weight Urinary Matrix Metalloproteinase (MMP) Activity Is a Complex of Gelatinase B/MMP-9 and Neutrophil Gelatinase-associated Lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 2001; 276: 37258–37265.

23. Devarajan P. The promise of biomarkers for personalized renal cancer care. Kidney Int 2010; 77: 755–757.

24. Schmidt-Ott KM, Mori K, Li JY et al. Dual Action of Neutrophil Gelatinase-associated Lipocalin. J Am Soc Nephrol 2007; 18: 407–413.

25. Grigoryev DN, Liu M, Hassoun HT et al. The Local and Systemic Inflammatory Transcriptome after Acute Kidney Injury. J Am Soc Nephrol 2008; 19: 547–558.

26. 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.

27. 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.

28. Bolignano D, Lacquaniti A, Coppolino G et al. Neutrophil Gelatinase-Associated Lipocalin Reflects the Severity of Renal Impairment in Subjects Affected by Chronic Kidney Disease. Kidney Blood Press Res 2008; 31: 255–258.

29. Malyszko J, Bachorzewska-Gajewska H, Malyszko JS et al. Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in hypertensive and normotensive patients with coronary artery disease. Nephrology 2008; 13: 153–156.

30. Elneihoum AM, Falke P, Hedblad B et al. Leukocyte activation in atherosclerosis: correlation with risk factors. Atherosclerosis 1997; 131: 79–84.

31. Hemdahl AL, Gabrielsen A, Zhu C et al. Expression of Neutrophil Gelatinase-Associated Lipocalin in Atherosclerosis and Myocardial Infarction. Arterioscler Thromb Vasc Biol 2006; 26: 136–142.

32. Leclercq A, Houard X, Philippe M et al. Involvement of intraplaque hemorrhage in atherothrombosis evolution via neutrophil protease enrichment. J Leukoc Biol 2007; 82: 1420–1429.

33. te Boekhorst BC, Bovens SM, Hellings WE et al. Molecular MRI of murine atherosclerotic plaque targeting NGAL: a protein associated with unstable human plaque characteristics. Cardiovasc Res 2011; 89: 680–688.

34. Kalousek I, Röselová P, Otevřelová P. NGAL – neutrophil gelatinase associated lipocalin in bio­chemistry, physiology and clinical praxis. Čas Lék Čes 2006; 145: 373–376.

35. Elneihoum AM, Falke P, Axelsson L et al. Leukocyte Activation Detected by Increased Plasma Levels of Inflammatory Mediators in Patients With Ischemic Cerebrovascular Diseases. Stroke 1996; 27: 1734–1738.

36. Yndestad A, Landrö L, Ueland T et al. Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure. Eur Heart J 2009; 30: 1229–1236.

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