Valentina Donato

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

BACKGROUND AND OBJECTIVES Chronic 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Serum 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. RESULTS At 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. CONCLUSION In 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.

Obestatin: an interesting but controversial gut hormone.

Obestatin is a 23-amino acid peptide hormone released from the stomach and is present not only in the gastrointestinal tract, but also in the spleen, mammary gland, breast milk and plasma. Obestatin appears to function as part of a complex gut-brain network whereby hormones and substances from the stomach and intestines signal the brain about satiety or hunger. In contrast to ghrelin, which causes hyperphagia and obesity, obestatin appears to act as an anorectic hormone, decreasing food intake and reducing body weight gain. Further studies have shown that obestatin is also involved in improving memory, regulating sleep, affecting cell proliferation, increasing the secretion of pancreatic juice enzymes and inhibiting glucose-induced insulin secretion. This hormone has not only been studied in the field of physiology but also in the fields of obesity and diabetes mellitus, and in patients with psychogenic eating disorders. Obestatin has a role in regulating the cell cycle by exerting proliferative effects that may be seen in cell physiology and oncology. Given the current controversy regarding the effects of obestatin and its cognate ligand, this article provides the latest review of the physiological and pathological characteristics of this hormone.

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.

Obestatin: A New Element for Mineral Metabolism and Inflammation in Patients on Hemodialysis

Background: Obestatin plays a key role in the process of energy balance maintenance with an anorectic effect. The main aim of the study was to evaluate obestatin in uremic patients to determine whether it is correlated with nutritional and inflammatory status. Methods: We studied plasma obestatin in uremic patients (n = 50) undergoing hemodialysis therapy and in healthy subjects. Plasma obestatin was measured using an ELISA kit. Results: Obestatin levels in uremic patients were lower than in healthy subjects (p < 0.0001). Patients with a body mass index (BMI) >23 had lower obestatin levels than those with a BMI <23 (p = 0.001). After multivariate analysis, direct correlations were maintained between obestatin and high-sensitivity C-reactive protein (β = 0.68, p < 0.0001) and total alkaline phosphatases (β = 0.30, p = 0.03), while inverse correlations were found with iron (β = –0.32, p = 0.002) and calcium-phosphorous product (β = –0.40, p = 0.001). Conclusions: Based on the present observational data, obestatin might be implicated in the inflammatory state and the disturbances of calcium/phosphate metabolism of hemodialysis patients. However, further studies are warranted to determine whether this hormone plays a key role in contributing to malnutrition and to the chronic inflammatory process.

Apelin, Plasmatic Osmolality and Hypotension in Dialyzed Patients

Background/Aims: To evaluate the balance between arginine-vasopressin (AVP) and apelin during hemodialysis and its role in hypotension onset and in the inflammation status. Methods: We enrolled 50 patients chronically treated with hemodialysis. We assessed plasmatic osmolality, AVP, apelin, mean blood pressure (BP), high-sensitivity C-reactive protein (hsCRP) and β2-microglobulin. Results: Apelin rises during dialytic treatment (from 0.68 ± 0.34 to 1.89 ± 0.56 pg/ml, p < 0.0001), while plasmatic osmolality (from 325 ± 4.54 to 311 ± 1.20 mosm/kg H2O, p < 0.0001), AVP (from 4.28 ± 1.12 to 2.48 ± 0.50 pg/ml, p < 0.0001) and mean BP (from 124 ± 6 to 110 ± 7 mm Hg, p < 0.0001) decrease. At multivariate regression with respect to apelin, only mean BP remains (r = –0.95, p < 0.0001). We also correlated the AVP/apelin ratio with BP. Moreover, apelin is inversely related to hsCRP (r = –0.79, p < 0.0001). Conclusions: The AVP/apelin balance changes with plasmatic osmolality variations induced by hemodialytic sessions and could represent a physiopathological marker of arterial hypo- and hypertension. Finally, apelin appears inversely related to inflammation markers.

Down with the erythropoietin. Long live the erythropoietin

In recent years the use of erythropoietin has exploded, and the anaemia of patients with chronic renal failure has been practically resolved with the administration of rHuEpo (recombinant human, Erythropoietin). However, as a result of an intense commercial campaign, strong therapies with this growth hormone, prescribed to achieve surprising sporting performances, got athletes to run the risk of thrombosis and vascular accidents because of red blood cells increase. Erythropoietin represents a significant subject of research. In fact, besides the ability of stimulating erythrocyte production, it has many pleiotropic effects. Several studies allow the assertion that EPO, in different concentrations, has protective effects mainly on central nervous system and cardiovascular system through various mechanisms, among which a key role seems to be held by the ability to stimulate angiogenesis. The consequent problem is that anaemia therapy with rHuEpo in patients with cancer may accelerate the progression of neoplastic disease by promoting tumour angiogenesis and, thus, metastasization. The study of angiogenic process in tumours led to the synthesis of drugs that, blocking VEGF, exert an anti-angiogenic action, contrasting cancer spread. However, benefits are relatively modest. Is erythropoietin perhaps the further angiogenic hormone to block in tumour pathology? Therefore, Epo plays a role in Regenerative Medicine since it intervenes in a persistent natural regenerative activity of humans: angiogenesis. The understanding of the regeneration mechanisms of complex structures in the adult salamander has opened original lines of research. Regenerative Medicine tries to develop therapeutic pathways through the stimulation of natural regenerative processes in humans.