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Acute Kidney Injury


ejection fraction and cholesterolaemia. Higher NGAL levels also predict cardiovascular mortality within two years of follow-up, thus confirming the potential utility of NGAL measurement in stratifying patients according to cardiovascular risk.


Although the damaged myocardium probably represents the main source of the increase in NGAL levels, other organs may also contribute to NGAL production as the expression of (ischaemic?) damage following the heart injury itself. For instance, high urinary NGAL excretion was reported in CHF patients with respect to control subjects and was correlated with levels of creatininaemia, GFR, albuminuria and NT-proBNP, an important biomarker of severity of cardiac impairment.39


Likewise, it was found that in patients with CHF


and normal renal function, serum NGAL levels were markedly higher than those in controls, the increase being independently correlated with NYHA class and estimated GFR values.40


It is therefore important


to establish whether the increase in systemic NGAL levels in patients with cardiovascular disease disease is, albeit partially, an expression of subclinical renal injury caused by CHF, thus representing a missing response in the pathological connections between kidney and heart.


Anaemia and Neutrophil Gelatinase-associated Lipocalin – Epiphenomenon or Protagonist? Anaemia is often associated with kidney and cardiovascular disease, representing a risk factor for the worsening of both conditions. Growing evidence suggests that NGAL is a key factor in the regulation of erythrocyte growth, as demonstrated by NGAL’s ability to inhibit the maturation and differentiation of erythroid cells and to induce their apoptosis in vitro and in animal models.41


The finding that also


in humans NGAL and its receptors are expressed by haematopoietic stem cells suggests that the protein may be involved in various diseases affecting red blood cells, such as anaemia. Accordingly, in patients with severe beta-thalassaemia, the expression of NGAL is systemically increased by the formation of reactive oxygen species (probably caused by the iron overload), with a consequent generalised oxidative state.42


This indicates that NGAL may be an important link between the systemic inflammation and anaemia found in these subjects and suggests the need to explore NGAL as a target in future therapeutic strategies designed to treat this condition.


Conclusions


NGAL levels in the blood, spleen and liver rise after experimental induction of different types of anaemia caused by phlebotomy (anaemia from bleeding), alimentary iron deprivation (sideropenic anaemia) and the administration of phenylhydrazine (haemolytic anaemia),43


implying that NGAL upregulation is probably


mediated by hypoxia rather than by iron demand. This would be confirmed by the finding that in mice, after exposure to low oxygen


1. Schrier RW, Abraham WT, Hormones and hemodynamics in heart failure, N Engl J Med, 1999;341:577–85.


2. Guyton AC, The surprising kidney-fluid mechanism for pressure control—its infinite gain!, Hypertension, 1990;16:725–30.


3. Bongartz LG, Cramer MJ, Doevendans PA, et al., The severe cardiorenal syndrome: ‘Guyton revisited’, Eur Heart J, 2005;26:11–7.


4. Ronco C, McCullough P, Anker SD, et al.; Acute Dialysis Quality Initiative (ADQI) consensus group, Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative, Eur Heart J, 2010;31:703–11.


5. McCullough PA, Sandberg KR, Sorting out the evidence on natriuretic peptides, Rev Cardiovasc Med, 2003;4(Suppl. 4):S13–9.


6. Bagshaw SM, Bellomo R, Cystatin C, in acute kidney injury, Curr Opin Crit Care, 2010; [Epub ahead of print].


7. Coca SG, Yalavarthy R, Concato J, Parikh CR, Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review, Kidney Int, 2008;73:1008–16.


8. Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N, Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase, J Biol Chem, 1993;268:10425–32.


9. Fjaertoft G, Foucard T, Xu S, Venge P, Human neutrophil lipocalin (HNL) as a diagnostic tool in children with acute infections: a study of the kinetics, Acta Paediatr, 2005;94:661–6. 10. Playford RJ, Belo A, Poulsom R, et al., Effects of mouse and


Nephrologists are discovering the central role played by NGAL in the pathophysiology of kidney disease and its diagnostic and predictive usefulness for the assessment of acute or chronic renal damage. However, many studies are now revealing that this factor is also involved in cardiovascular disease and some of its complications. It may therefore be intriguing to ask ourselves whether NGAL is more than just a biomarker, representing a heretofore missing connection between renal and cardiovascular homeostatis, in health as well as in disease. Likewise for other factors, such as BNP, NGAL may thus belong to the panel of biomarkers of the so-called cardio–renal axis. Future studies are thus awaited to clarify these issues and to confirm that the clinical value of NGAL measurement may be extended beyond the confines of nephrology. n


human lipocalin homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair, Gastroenterology, 2006;131:809–17.


11. Cowland JB, Sorensen OE, Sehested M, Borregaard N, Neutrophil gelatinase-associated lipocalin is up-regulated in human epithelial cells by IL-1 beta, but not by TNF-alpha, J Immunol, 2003;171:6630–9.


12. Mishra J, Mori K, Ma Q, et al., Neutrophil gelatinase- associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity, Am J Nephrol, 2004;24:307–15.


13. 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;14:2534–43


14. 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;115:610–21.


15. 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;365:1231–8.


16. 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;105:485–91.


17. Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, et al., Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions, Am J Nephrol,


2006;26:287–92.


18. Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, et al., Neutrophil gelatinase-associated lipocalin (NGAL) correlations with cystatin C, serum creatinine and eGFR in patients with normal serum creatinine undergoing coronary angiography, Nephrol Dial Transplant, 2007;22:295–6.


19. Shavit L, Dolgoker I, Ivgi H, et al., Neutrophil gelatinase- associated lipocalin as a predictor of complications and mortality in patients undergoing non-cardiac major surgery, Kidney Blood Press Res, 2011;34:116–24.


20. Wagener G, Minhaz M, Mattis FA, et al., Urinary neutrophil gelatinase-associated lipocalin as a marker of acute kidney injury after orthotopic liver transplantation, Nephrol Dial Transplant, 2011;26:1717–23.


21. Hollmen ME, Kyllönen LE, Inkinen KA, et al., Urine neutrophil gelatinase-associated lipocalin is a marker of graft recovery after kidney transplantation, Kidney Int, 2011;79:89–98.


22. Haase M, Bellomo R, Devarajan P, et al.; NGAL Meta-analysis Investigator Group, 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;54:1012–24.


23. Bolignano D, Donato V, Coppolino G, et al., Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage, Am J Kidney Dis, 2008;52:595–605.


24. Bolignano D, Lacquaniti A, Coppolino G, et al., Neutrophil gelatinase-associated lipocalin reflects the severity of renal


CKD is another important pathological condition associated with both anaemia and increased NGAL levels. In its end stage, CKD requires haemodialysis replacement therapy, and iron reserves become crucial to response to recombinant human erythropoietin treatment. Patients on chronic haemodialysis present an impressive increase in NGAL levels with respect to healthy subjects. Furthermore, these levels are closely related to the main indices of iron storage (ferritin, transferrin, transferrin saturation), inflammation indices such as high-sensitivity C-reactive protein and erythrocyte sedimentation rate and, inversely, to circulating levels of haematopoietic bone-marrow-derived stem cells.52,53


tension conditions (10 %) or the administration of CoCl2 (a powerful agent that induces hypoxia), increased synthesis of NGAL is observed


independently of the change in iron reserves.43


Various inflammatory and non-inflammatory diseases leading to secondary anaemia, such as osteoarthritis, chronic inflammatory bowel diseases, vasculitis, systemic lupus erythematosus and even cancer, are characterised by the presence of high tissue and circulating NGAL levels.44–49 erythropoiesis,50,51


Bearing in mind the capacity of NGAL to suppress


it is reasonable to hypothesise that NGAL may to some degree contribute to the onset and worsening of anemia itself rather than being a simple epiphenomenon.


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EUROPEAN NEPHROLOGY


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