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Serum neutrophil gelatinase-associated lipocalin is associated with cardiovascular events in patients with chronic kidney disease

  • Nephrology - Original Paper
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Abstract

Background

Neutrophil gelatinase-associated lipocalin (NGAL) is a member of the lipocalin family best known as a novel and early marker of acute kidney injury (AKI). Recent data suggest that NGQueryAL is not only a marker of AKI, but also an important player in the vascular remodeling, atherosclerotic plaque stability and thrombus formation. We conducted this study to investigate the association of serum NGAL levels with fatal and composite (fatal and non-fatal) cardiovascular events (CVE) in a cohort of patients with stage 1–5 CKD.

Methods

This was an observational cohort study in which serum NGAL was obtained from 298 CKD (stages 1–5) patients. Fatal and composite CVE were recorded for a median 41 months. We examined alteration of serum NGAL through CKD groups as well as association with inflammatory markers. We also performed a Cox regression analysis to determine the association of NGAL with predefined clinical outcomes.

Results

The median value of NGAL was 50.5 ng/mL (IR 47.6–54.9 ng/mL), and higher NGAL values were recorded in diabetic patients. In a multiple linear regression model, including all univariate associates of NGAL, only log eGFR, log hs-CRP and log HDL cholesterol maintained an independent association with log NGAL. During the observational period, 30 patients died due to cardiovascular causes and 69 non-fatal CVE were registered. In the fully adjusted model, we observed a 2.08-fold increase in the risk of fatal CVE and a 1.50-fold increase in the risk of fatal and non-fatal CVE for each increment of 1 SD in log NGAL values.

Conclusions

This is the first study that shows that serum NGAL is associated with cardiovascular events (fatal and non-fatal) in patients with CKD, independently of traditional risk factors, renal function and inflammation.

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References

  1. Makris K, Rizos D, Kafkas N, Haliassos A (2012) Neutrophil gelatinase-associated lipocalin as a new biomarker in laboratory medicine. Clin Chem Lab Med 50(9):1519–1532

    Article  CAS  PubMed  Google Scholar 

  2. Hirsch R, Dent C, Pfriem H, Allen J, Beekman RH 3rd, Ma Q et al (2007) NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol 22(12):2089–2095

    Article  PubMed  Google Scholar 

  3. Schilcher G, Ribitsch W, Otto R, Portugaller RH, Quehenberger F, Truschnig-Wilders M et al (2011) Early detection and intervention using neutrophil gelatinase-associated lipocalin (NGAL) may improve renal outcome of acute contrast media induced nephropathy: a randomized controlled trial in patients undergoing intra-arterial angiography (ANTI-CIN Study). BMC Nephrol 12:39

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Valette X, Savary B, Nowoczyn M, Daubin C, Pottier V, Terzi N et al (2013) Accuracy of plasma neutrophil gelatinase-associated lipocalin in the early diagnosis of contrast-induced acute kidney injury in critical illness. Intensive Care Med 39(5):857–865

    Article  CAS  PubMed  Google Scholar 

  5. Alharazy SM, Kong N, Saidin R, Gafor AH, Maskon O, Mohd M et al (2014) Neutrophil gelatinase-associated lipocalin as an early marker of contrast-induced nephropathy after coronary angiography. Angiology 65(3):216–223

    Article  CAS  PubMed  Google Scholar 

  6. Filiopoulos V, Biblaki D, Vlassopoulos D (2014) Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker of contrast-induced nephropathy after computed tomography. Ren Fail 36(6):976–986

    Article  Google Scholar 

  7. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C et al (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365(9466):1231–1238

    Article  CAS  PubMed  Google Scholar 

  8. Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J et al (2007) Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 11(6):R127

    Article  PubMed Central  PubMed  Google Scholar 

  9. Prabhu A, Sujatha DI, Ninan B, Vijayalakshmi MA (2010) Neutrophil gelatinase associated lipocalin as a biomarker for acute kidney injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Ann Vasc Surg 24(4):525–531

    Article  CAS  PubMed  Google Scholar 

  10. Parikh CR, Coca SG, Thiessen-Philbrook H, Shlipak MG, Koyner JL, Wang Z et al (2011) Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery. J Am Soc Nephrol 22(9):1748–1757

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Bagshaw SM, Haase M, Haase-Fielitz A, Bennett M, Devarajan P, Bellomo R (2012) A prospective evaluation of urine microscopy in septic and non-septic acute kidney injury. Nephrol Dial Transplant 27(2):582–588

    Article  CAS  PubMed  Google Scholar 

  12. Lentini P, de Cal M, Clementi A, D’Angelo A, Ronco C (2012) Sepsis and AKI in ICU patients: the role of plasma biomarkers. Crit Care Res Pract 2012:856401

    PubMed Central  PubMed  Google Scholar 

  13. Camou F, Oger S, Paroissin C, Guilhon E, Guisset O, Mourissoux G et al (2013) Plasma neutrophil gelatinase-associated lipocalin (NGAL) predicts acute kidney injury in septic shock at ICU admission. Ann Fr Anesth Reanim 32(3):157–164

    Article  CAS  PubMed  Google Scholar 

  14. Xu S, Venge P (2000) Lipocalins as biochemical markers of disease. Biochim Biophys Acta 1482(1–2):298–307

    Article  CAS  PubMed  Google Scholar 

  15. van der Wal AC, Becker AE, van der Loos CM, Das PK (1994) Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89(1):36–44

    Article  PubMed  Google Scholar 

  16. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Unemori EN, Lark MW et al (1994) Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res 75(1):181–189

    Article  CAS  PubMed  Google Scholar 

  17. Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F et al (1998) Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol 32(2):368–372

    Article  CAS  PubMed  Google Scholar 

  18. Cruz DN, Gaiao S, Maisel A, Ronco C, Devarajan P (2012) Neutrophil gelatinase-associated lipocalin as a biomarker of cardiovascular disease: a systematic review. Clin Chem Lab Med 50(9):1533–1545

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Alvelos M, Lourenço P, Dias C, Amorim M, Rema J, Leite AB et al (2013) Prognostic value of neutrophil gelatinase-associated lipocalin in acute heart failure. Int J Cardiol 165(1):51–55

    Article  PubMed  Google Scholar 

  20. Yndestad A, Landrø L, Ueland T, Dahl CP, Flo TH, Vinge LE et al (2009) Increased systemic and myocardial expression of neutrophil gelatinase-associated lipocalin in clinical and experimental heart failure. Eur Heart J 30(10):1229–1236

    Article  CAS  PubMed  Google Scholar 

  21. Maisel AS, Mueller C, Fitzgerald R, Brikhan R, Hiestand BC, Iqbal N et al (2011) Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: the NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial. Eur J Heart Fail 13(8):846–851

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Falke P, Elneihoum AM, Ohlsson K (2000) Leukocyte activation: relation to cardiovascular mortality after cerebrovascular ischemia. Cerebrovasc Dis 10(2):97–101

    Article  CAS  PubMed  Google Scholar 

  23. Bolignano D, Basile G, Parisi P, Coppolino G, Nicocia G, Buemi M (2009) Increased plasma neutrophil gelatinase-associated lipocalin levels predict mortality in elderly patients with chronic heart failure. Rejuvenation Res 12(1):7–14

    Article  CAS  PubMed  Google Scholar 

  24. Shrestha K, Borowski AG, Troughton RW, Thomas JD, Klein AL, Tang WH (2011) Renal dysfunction is a stronger determinant of systemic neutrophil gelatinase-associated lipocalin levels than myocardial dysfunction in systolic heart failure. J Card Fail 17(6):472–478

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Whitman IR, Feldman HI, Deo R (2012) CKD and sudden cardiac death: epidemiology, mechanisms, and therapeutic approaches. J Am Soc Nephrol 23(12):1929–1939

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A et al (2008) Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis 52(3):595–605

    Article  CAS  PubMed  Google Scholar 

  27. Bolignano D, Coppolino G, Campo S, Aloisi C, Nicocia G, Frisina N et al (2008) Urinary neutrophil gelatinase-associated lipocalin (NGAL) is associated with severity of renal disease in proteinuric patients. Nephrol Dial Transplant 23(1):414–416

    Article  CAS  PubMed  Google Scholar 

  28. Bolignano D, Coppolino G, Lacquaniti A, Nicocia G, Buemi M (2008) Pathological and prognostic value of urinary neutrophil gelatinase-associated lipocalin in macroproteinuric patients with worsening renal function. Kidney Blood Press Res 31(4):274–279

    Article  CAS  PubMed  Google Scholar 

  29. Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR et al (2009) Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 4(2):337–344

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Smith ER, Lee D, Cai MM, Tomlinson LA, Ford ML, McMahon LP et al (2013) Urinary neutrophil gelatinase-associated lipocalin may aid prediction of renal decline in patients with non-proteinuric Stages 3 and 4 chronic kidney disease (CKD). Nephrol Dial Transplant 28(6):1569–1579

    Article  CAS  PubMed  Google Scholar 

  31. Furuya F, Shimura H, Yokomichi H, Takahashi K, Akiyama D, Asakawa C et al. (2013) Neutrophil gelatinase-associated lipocalin levels associated with cardiovascular disease in chronic kidney disease patients. Clin Exp Nephrol 18(5):778–783

    Article  PubMed  Google Scholar 

  32. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612

    Article  PubMed Central  PubMed  Google Scholar 

  33. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2013) KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 3:1–150

    Article  Google Scholar 

  34. Stejskal D, Karpísek M, Humenanska V, Hanulova Z, Stejskal P, Kusnierova P et al (2008) Lipocalin-2: development, analytical characterization, and clinical testing of a new ELISA. Horm Metab Res 40(6):381–385

    Article  CAS  PubMed  Google Scholar 

  35. Hanley JA, McNeil BJ (1983) A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 148(3):839–843

    Article  CAS  PubMed  Google Scholar 

  36. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27(2):157–172

    Article  PubMed  Google Scholar 

  37. Devarajan P (2008) NGAL in acute kidney injury: from serendipity to utility. Am J Kidney Dis 52:395–399

    Article  PubMed  Google Scholar 

  38. Devarajan P (2008) Neutrophil gelatinase-associated lipocalin—an emerging troponin for kidney injury. Nephrol Dial Transplant 23:3737–3743

    Article  PubMed Central  PubMed  Google Scholar 

  39. Daniels LB, Barrett-Connor E, Clopton P, Laughlin GA, Ix JH, Maisel AS (2012) Plasma neutrophil gelatinase-associated lipocalin is independently associated with cardiovascular disease and mortality in community-dwelling older adults: the Rancho Bernardo Study. J Am Coll Cardiol 59(12):1101–1109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Helmersson-Karlqvist J, Larsson A, Carlsson AC, Venge P, Sundström J, Ingelsson E et al (2013) Urinary neutrophil gelatinase-associated lipocalin (NGAL) is associated with mortality in a community-based cohort of older Swedish men. Atherosclerosis 227(2):408–413

    Article  CAS  PubMed  Google Scholar 

  41. Damman K, van Veldhuisen DJ, Navis G, Voors AA, Hillege HL (2008) Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure. Eur J Heart Fail 10:997–1000

    Article  CAS  PubMed  Google Scholar 

  42. Damman K, Masson S, Hillege HL, Maggioni AP, Voors AA, Opasich C et al (2011) Clinical outcome of renal tubular damage in chronic heart failure. Eur Heart J 32(21):2705–2712

    Article  CAS  PubMed  Google Scholar 

  43. van Deursen VM, Damman K, Voors AA, van der Wal MH, Jaarsma T, van Veldhuisen DJ et al (2014) Prognostic value of plasma neutrophil gelatinase-associated lipocalin for mortality in patients with heart failure. Circ Heart Fail 7(1):35–42

    Article  PubMed  Google Scholar 

  44. Nymo SH, Ueland T, Askevold ET, Flo TH, Kjekshus J, Hulthe J et al (2012) The association between neutrophil gelatinase-associated lipocalin and clinical outcome in chronic heart failure: results from CORONA*. J Intern Med 271(5):436–443

    Article  CAS  PubMed  Google Scholar 

  45. Hasegawa M, Ishii J, Kitagawa F, Takahashi K, Hayashi H, Koide S et al. (2013) Urinary neutrophil gelatinase-associated lipocalin as a predictor of cardiovascular events in patients with chronic kidney disease. Heart Vessels 30(1):81–88

    Article  PubMed  Google Scholar 

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Acknowledgement

Part of this study was performed by grants number 1640/01.02.2013 and IDEI—PCE 2011, PN-II-ID-PCE-2011-3-0637 from the University of Medicine and Pharmacy, Iasi.

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Sakarya University Medical School, Sakarya, Turkey

    Yalcin Solak

  2. Department of Nephrology, Gülhane School of Medicine, Ankara, Turkey

    Mahmut Ilker Yilmaz, Hilmi Umut Unal, Mahmut Gok, Hakki Cetinkaya & Tayfun Eyileten

  3. Nephrology Clinic, Dialysis and Renal Transplant Center, ‘C.I. PARHON’ University Hospital, and ‘Grigore T. Popa’ University of Medicine, Iasi, Romania

    Dimitrie Siriopol, Sebahattin Sari & Adrian Covic

  4. Department of Radiology, Gülhane School of Medicine, Ankara, Turkey

    Mutlu Saglam

  5. Department of Biochemistry, Gülhane School of Medicine, Ankara, Turkey

    Halil Yaman

  6. Department of Extracorporeal Hemocorrection, National Scientific Medical Research Center, Astana, Kazakhstan

    Abduzhappar Gaipov

  7. Department of Emergency, Gulhane School of Medicine, Ankara, Turkey

    Ali Osman Yildirim

  8. Department of Nephrology, Necmettin Erbakan University Meram School of Medicine, Konya, Turkey

    Halil Zeki Tonbul

  9. Division of Nephrology, Department of Internal Medicine, Selcuk University School of Medicine, Konya, Turkey

    Suleyman Turk

  10. Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey

    Mehmet Kanbay

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  1. Yalcin Solak
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  2. Mahmut Ilker Yilmaz
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Correspondence to Yalcin Solak.

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Solak, Y., Yilmaz, M.I., Siriopol, D. et al. Serum neutrophil gelatinase-associated lipocalin is associated with cardiovascular events in patients with chronic kidney disease. Int Urol Nephrol 47, 1993–2001 (2015). https://doi.org/10.1007/s11255-015-1136-4

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  • DOI: https://doi.org/10.1007/s11255-015-1136-4

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