Davide Bolignano

Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Progression of Chronic Kidney Disease

BACKGROUND AND OBJECTIVESnChronic kidney disease (CKD) has recently assumed epidemic proportion, becoming a troubling emerging cause of morbidity, especially if it progresses to terminal stage (ESRD). The authors aimed to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL), a novel specific biomarker of acute kidney injury, could predict the progression of CKD.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnSerum and urinary NGAL levels, together with a series of putative progression factors, were evaluated in a cohort of 96 patients (mean age: 57 +/- 16 years) affected by nonterminal CKD (eGFR > or =15 ml/min/1.73 m(2)) of various etiology. Progression of CKD, assessed as doubling of baseline serum creatinine and/or onset of ESRD, was evaluated during follow-up.nnnRESULTSnAt baseline, both serum and urinary NGAL were inversely, independently, and closely related to eGFR. After a median follow-up of 18.5 mo (range 1.01 to 20), 31 patients (32%) reached the composite endpoint. At baseline, these patients were significantly older and showed increased serum creatinine, calcium-phosphate product, C-reactive protein, fibrinogen, daily proteinuria, and NGAL levels, whereas eGFR values were significantly lower. Univariate followed by multivariate Cox proportional hazard regression analysis showed that urinary NGAL and sNGAL predicted CKD progression independently of other potential confounders, including eGFR and age.nnnCONCLUSIONnIn patients with CKD, NGAL closely reflects the entity of renal impairment and represents a strong and independent risk marker for progression of CKD.

Neutrophil Gelatinase–Associated Lipocalin (NGAL) as a Marker of Kidney Damage

Neutrophil gelatinase-associated lipocalin (NGAL) is a protein belonging to the lipocalin superfamily initially found in activated neutrophils, in accordance with its role as an innate antibacterial factor. However, it subsequently was shown that many other types of cells, including in the kidney tubule, may produce NGAL in response to various injuries. The increase in NGAL production and release from tubular cells after harmful stimuli of various kinds may have self-defensive intent based on the activation of specific iron-dependent pathways, which in all probability also represent the mechanism through which NGAL promotes kidney growth and differentiation. NGAL levels predict the future appearance of acute kidney injury after treatments potentially detrimental to the kidney and even the acute worsening of unstable nephropathies. Furthermore, recent evidence also suggests that NGAL somehow may be involved in the pathophysiological process of chronic renal diseases, such as polycystic kidney disease and glomerulonephritis. NGAL levels clearly correlate with severity of renal impairment, probably expressing the degree of active damage underlying the chronic condition. For all these reasons, NGAL may become one of the most promising next-generation biomarkers in clinical nephrology and beyond.

Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: A new protein enters the scene

The small 25 kDa peptide, neutrophil gelatinase-associated lipocalin (NGAL), first known as an antibacterial factor of natural immunity, and an acute phase protein, is currently one of the most interesting and enigmatic proteins involved in the process of tumor development. The aim of the present review is to point out the main contradictory, sometimes even paradoxical, effects attributed to NGAL in human neoplasias. For instance, acting as an intracellular iron carrier and protecting MMP9 from proteolytic degradation, NGAL has a clear pro-tumoral effect, as has already been observed in different tumors (e.g. breast, stomach, oesophagus, brain) in humans. Moreover, in thyroid carcinomas, NGAL is strongly induced by NF-kB, an important factor involved both in tumor growth and in the link between chronic inflammation and neoplastic development. However, on the contrary, some studies have demonstrated that NGAL can inhibit the pro-neoplastic factor HIF-1alpha, FA-Kinase phosphorylation and also VEGF synthesis, thus suggesting that, in alternative conditions, NGAL also, paradoxically, has an anti-tumoral and anti-metastatic effect in neoplasias of, for example, the colon, ovary and pancreas. Finally, in the field of clinical oncology, attention is currently focused on the potential use of NGAL levels in making an early diagnosis, establishing a prognosis and predicting response to different treatments.

Neutrophil Gelatinase-Associated Lipocalin as an Early Biomarker of Nephropathy in Diabetic Patients

Background/Aims: Renal tubulointerstitium plays an important role in the development and progression of diabetic nephropathy. Methods: With the present study, we aimed at evaluating the levels of neutrophil gelatinase-associated lipocalin (NGAL), a tubular stress protein, in serum (sNGAL) and urine (uNGAL) from a cohort of 56 patients with type 2 diabetes mellitus categorized into three groups (normoalbuminuria, microalbuminuria and diabetic nephropathy). Results: All groups showed increased NGAL values with respect to controls; interestingly, increased NGAL levels were already found in diabetic patients without early signs of glomerular damage (normoalbuminuric). Both sNGAL and uNGAL increased in parallel with the severity of renal disease, reaching higher levels in patients with manifest diabetic nephropathy. The assessment of Pearson coefficient evidenced significant relationships between sNGAL and, respectively, uNGAL, serum creatinine and GFR (inversely) and between uNGAL and, respectively, serum creatinine, proteinuria, albuminuria, serum albumin and GFR (both inversely). Conclusions: NGAL might play an important role in the pathophysiology of renal adaptation to diabetes, probably as a defensive mechanism aiming to mitigate tubular suffering. Furthermore, NGAL measurement might become a useful and noninvasive tool for the evaluation of renal involvement in diabetic patients as well as for the early diagnosis of incipient nephropathy.

Neutrophil Gelatinase-Associated Lipocalin Reflects the Severity of Renal Impairment in Subjects Affected by Chronic Kidney Disease

Neutrophil gelatinase-associated lipocalin (NGAL) is a small 25-kDa protein released from kidney tubular cells after harmful stimuli. It represents one of the most promising future biomarkers in the diagnostic field of acute kidney injury (AKI), as the increase in NGAL levels is a good predictor of a brief-term onset of AKI, notably anticipating the resulting increase in serum creatinine. However, recent studies also suggest a possible role for NGAL in chronic kidney disease (CKD). For this reason we evaluated serum (sNGAL) and urinary NGAL (uNGAL) in a cohort of CKD patients in order to verify the relationship with the severity of renal impairment. In CKD patients sNGAL, uNGAL and the fractional excretion of this protein were notably increased as compared to controls. Furthermore both sNGAL and uNGAL were correlated with serum creatinine and, inversely, with residual glomerular filtration rate (GFR): this last relationship was found to be even closer than that found between GFR and serum creatinine. Multivariate models validate these correlations as independent, confirming that in these patients NGAL is a better predictor of GFR than serum creatinine. The results confirm NGAL as an important biomarker in clinical nephrology, extending to CKD the pathophysiological role of this protein in tubular adaptations to renal damage.

From kidney to cardiovascular diseases: NGAL as a biomarker beyond the confines of nephrology.

Eur J Clin Invest 2010; 40 (3): 273–276

Neutrophil gelatinase-associated lipocalin serum evaluation through normal pregnancy and in pregnancies complicated by preeclampsia

Neutrophil gelatinase‐associated lipocalin (NGAL) was evaluated prospectively through normal pregnancy and pregnancies complicated by preeclampsia syndrome. Sixty women enrolled in the study were evaluated for serum NGAL levels at 9–11 weeks gestation, at 24–26 weeks gestation and at delivery. Thirty women were affected by preeclampsia and 30 women with uncomplicated pregnancies formed the control group. NGAL serum concentrations in the preeclampsia group were higher compared to the control group, with significant differences in each trimester. In the first trimester, the median values were: 29.9 ng/mL [interquartile range (IQR) 24.1–50.1] versus 13.6 ng/mL (IQR 9.1–19.9; p < 0.001); in the second trimester: 59.6 ng/mL (IQR 25.3–82.6) versus 16.3 ng/mL (IQR 11.3–23.3; p < 0.001); and in the third trimester: 57.2 ng/mL (IQR 18.7–70.9) versus 15.8 ng/mL (IQR 9.1–22.5; p < 0.001). NGAL serum values were positively correlated with systolic and diastolic blood pressure and with proteinuria.

Neutrophil gelatinase-associated lipocalin (NGAL) reflects iron status in haemodialysis patients

BACKGROUNDnAn iron deficiency is often present in haemodialysis (HD) patients; however, although transferrin saturation (TSAT) of <20% and/or serum ferritin of <200 ng/mL should express iron scarcity, in HD patients high ferritin levels could be related to inflammation rather than reflecting optimal iron stores.nnnMETHODSnThe aim of the present study was to evaluate serum levels of neutrophil gelatinase-associated lipocalin (NGAL), a small siderophore-binding protein, in a cohort of 56 chronic HD patients in order to determine its possible relationships with iron status.nnnRESULTSnNGAL levels were markedly higher in HD patients than in healthy controls; furthermore, HD patients with TSAT <20% had lower NGAL values than healthy controls, whereas the correction of iron deficiency by means of chronic i.v. iron administration significantly increased NGAL values from baseline. Findings from univariate and multivariate analyses demonstrated that NGAL was a significant predictor of hsCRP, spKT/V and TSAT. In ROC analysis, a NGAL cut-off level of <or=473 ng/mL had a greater sensitivity and specificity than a ferritin level of <200 ng/mL in identifying iron deficiency among HD patients.nnnCONCLUSIONSnThe findings demonstrated that HD patients have altered NGAL values probably because this protein is involved in the maintenance of iron equilibrium. Finally, NGAL might be proposed as a new tool in the assessment of iron deficiency and in the management of iron therapy for HD patients.

Dialysis and the Elderly: An Underestimated Problem

In developed countries, the incidence of end-stage renal failure is constantly increasing, and uremia will soon be a disease typically found in mature and elderly adults. Almost invariably, the physical condition of the elderly patient with terminal uremia is extremely poor, and therapeutic approach complex. Frequent co-morbidity, treatment with many different drugs, the high risk of iatrogenic damage, advanced age and socio-environmental conditions further complicate the management of these patients. While replacement therapy may become necessary, peritoneal dialysis may have advantages over hemodialysis. Peritoneal dialysis causes less hemodynamic stress, does not necessitate vascular access and allows mobility, although it incurs a high incidence of peritonitis and vascular disease. Where hemodialysis is the only feasible treatment, procedures used for vascular access are frequently followed by several complications, representing an important cause of morbidity and hospitalization. In addition, even if it may improve the patient’s quality of life, vascular condition, intradialytic hypotension, heart disease, intestinal bleeding and amyloidotic arthropathy are critical aspects of dialysis in the elderly patient. Therefore, particular attention from clinicians and administrators is required and the best possible strategies must be identified in order to provide effective and appropriate services to address these special patients’ needs.

Malnutrition in the Elderly Patient on Dialysis

Approximately one-third of all dialysis patients have mild to moderate malnutrition, while 6–8% have severe malnutrition, which is associated with increased morbidity and mortality rates and numerous pre-existing factors directly correlated with, or existing prior to, replacement hemodialysis. However, moderate to severe malnutrition (present in 10–30% of dialysis patients) is a prevalent cause of death among the elderly. Many of these patients have a particularly unstable cardiovascular and metabolic status that, independent of any underlying uremia and/or dialysis, impacts negatively on both their quality of life and clinical status. Moreover, their condition is often further exacerbated by dialysis itself, with its acute (e.g., hypotension and sensorial alterations) and chronic complications, including an exacerbation of malnutrition and systemic vascular disease. Malnutrition can occur secondary not only to erroneous dietary choices or uremia, but it may also depend on the patients level of tolerance to dialysis and on the dialysis modality. Despite the improvements made to dialysis techniques, the nutritional condition of elderly patients on dialysis for chronic renal failure remains a cause for concern. In this patient category, it is therefore mandatory to ensure the daily supervision of nutritional status and early control when the first signs of malnutrition appear.