Acute Kidney Injury
Neutrophil Gelatinase-associated Lipocalin in the Cardio–Renal Axis – Pathogenic Factor or Just a Risk Biomarker?
Davide Bolignano1 and Giuseppe Coppolino2
1. Medical Researcher, CNR-IBIM, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension; 2. Medical Researcher, Nephrology and Dialysis Unit, University ‘Magna Graecia’, Catanzaro
Abstract
The kidney and the heart are strictly and reciprocally connected in health as well as in disease. The discovery of new factors involved in the pathogenesis and complications of cardiovascular and renal disease is mandatory to improve our knowledge and clinical management of the so-called cardio–renal syndromes. Neutrophil gelatinase-associated lipocalin (NGAL), a small 25 kDa protein mainly produced by damaged tubular cells, is emerging as one of the most promising biomarkers for the early diagnosis of acute kidney injury and chronic kidney disease progression. Recent studies have underlined that NGAL also has a central role in the pathogenesis of atherosclerosis, myocardial infarction, heart failure and even anaemia. Future studies are thus eagerly awaited to ascertain whether NGAL can be considered a true pathogenic factor of both renal and cardiac disease, or whether it is just a useful risk marker.
Keywords
Neutrophil gelatinase-associated lipocalin (NGAL), acute kidney injury, chronic kidney disease, anaemia, cardiovascular disease, heart failure, atherosclerosis, risk factor, biomarker
Disclosure: The authors have no conflicts of interest to declare. Received: 13 April 2011 Accepted: 16 May 2011 Citation: European Nephrology, 2011;5(2):112–5 Correspondence: Davide Bolignano, CNR-IBIM, Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension, Via Vallone Petrara, 89100 Reggio Calabria, Italy. E:
netdavi@tiscali.it
The Cardio–Renal Connection in Physiology and Disease
Under physiological conditions, the kidney and the heart act in tandem, sharing the duty of supporting blood pressure, vascular tone, diuresis, intravascular homeostasis and peripheral tissue oxygenation and perfusion. Various neurohormonal systems are involved in maintaining the glomerular filtration rate (GFR) in conditions of decreased or increased perfusion pressure through myogenic control of arteriolar resistance.1 In Guyton’s model, the kidney is essential in regulating extracellular fluid volume, the renin–angiotensin–aldosterone system (RAAS), local vasodilators such as nitric oxide or prostaglandins and the sympathetic nervous system.2
However, this model was recently revised to explain systemic alteration under disease conditions, taking into account the extended effect of RAAS activation, inflammation and oxidative stress.3 The pathophysiological interaction between heart and kidney is strict as chronic or acute dysfunction of one organ induces chronic or acute impairment in the other. The different interactions in the cardio–renal axis led Ronco et al. to propose the classification of cardio–renal syndromes into five types, ranging from acute to chronic conditions:4
• •
•
• •
1: acute heart failure causes acute kidney injury;
2: chronic heart failure leads to progressive chronic kidney disease (CKD);
3: acute worsening of kidney function causes acute cardiac dysfunction;
4: chronic renal disease contributes to progressive cardiac disease;
5: acute or chronic systemic disorders such as sepsis or diabetes cause both renal and cardiac injury.
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Early identification of worsening kidney function is at the basis of the diagnosis of cardio–renal syndromes. In this perspective, the use of traditional tests for kidney function such as GFR or serum creatinine appears of modest importance. Many serum and urine biomarkers of renal injury have been explored, both alone and in combination with known cardiac parameters, to establish whether the construction of a hypothetical cardio–renal panel could help in prompt diagnosis and follow-up of cardio–renal disease. The cardiac biomarkers considered predictive of cardio–renal syndrome were troponins and natriuretic peptides – namely B-type natriuretic peptide and its precursor, N-terminal pro-brain natriuretic peptide (NT-proBNP)5
– while the most
important biomarkers of kidney injury were: •
•
cystatin C, a protease inhibitor freely filtered by glomerulus and completely reabsorbed by tubule which detects acute kidney injury (AKI) two days earlier than creatinine;6
interleukin-18 (IL-18), a proinflammatory cytokine;
• kidney injury molecule-1 (KIM-1), a tubular factor able to distinguish ischaemic AKI from pre-renal azotemia and CKD; and
• N-acetyl-β-glucosaminidase (NAG), a tubular enzyme that signals tubular injury after contrast and methotrexate toxicity.7
Neutrophil Gelatinase-associated Lipocalin and the Kidney – The Discovery of a New Key Factor in Renal Disease
Human neutrophil gelatinase-associated lipocalin (NGAL) was originally identified as a 25kDa protein associated with purified gelatinase obtained from the supernatant of activated neutrophils,8
© TOUCH BRIEFINGS 2011
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