Susanna Campo

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 in Patients with Autosomal-Dominant Polycystic Kidney Disease

It is known that many tubular proteins are involved in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which causes 8–10% of the cases of end-stage renal disease (ESRD) worldwide. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein expressed on tubular cells of which the production is markedly increased in response to harmful stimuli such as ischemia or toxicity. In the present study, serum and urinary NGAL levels were evaluated in 26 ADPKD subjects. Both levels were significantly higher in patients than in controls (sNGAL 174 ± 52 vs. 50 ± 27 ng/ml, p < 0.05; uNGAL 119 ± 42 vs. 7 ± 6 ng/ml, p < 0.005) and a close correlation was also found between these parameters and the residual renal function (sNGAL/GFR: r = –0.8, p = 0.006; sNGAL/Creatinine: r = 0.9, p = 0.007; uNGAL/GFR: r = –0.49, p < 0.05; uNGAL/Creatinine: r = 0.84, p < 0.001). Patients were further divided into two groups according to the cystic development assessed with echotomography; subjects with higher cystic growth (HCG) presented higher sNGAL and uNGAL levels with respect to others (sNGAL: 242 ± 89 vs. 88 ± 34 ng/ml, p < 0.05; uNGAL: 158 ± 45 vs. 73 ± 27 ng/ml, p < 0.05). The strict correlation between NGAL levels and residual renal function is perfectly in accord with recent studies on patients with other ESRD-associated diseases. We can hypothesize that tubular cells produce big quantities of NGAL as a consequence of increased apoptosis following chronic damage or as a compensatory response, similar to that observed in acute stress conditions (ischemia, toxicity ...). Finally, our last finding that patients with HCG showed higher levels of NGAL suggests that this protein could be also involved in the cyst growth process, as previously reported about epithelial and tumoral expansion.

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.

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.

Dialysis-related genotoxicity: sister chromatid exchanges and DNA lesions in T and B lymphocytes of uremic patients. Genomic damage in patients on hemodiafiltration.

Background/Aims: Patients with chronic renal failure show the presence of massive oxidative genome damage but the role played by dialysis is still a controversial issue. The aim of our study was to verify the genomic damage in B- and T-lymphocyte subpopulations of uremic patients after a single hemodiafiltration session. Methods: We enrolled 30 patients on maintenance acetate-free biofiltration and 25 age-matched healthy volunteers and studied chromosomal alterations. Results: Our data show that the basal levels of DNA damage, the number of sister chromatid exchanges and basal high-frequency cells levels are significantly higher in patients on hemodiafiltration than in controls and in T lymphocytes than in B cells. Conclusions: These findings suggest that hemodialytic treatment could represent a potential source of damage, maybe through the oxidative action of the extracorporeal circuit components, which might explain the well-known T-specific immunodeficiency correlated with uremia.

Aquaretic Agents: Whats Beyond the Treatment of Hyponatremia?

Unlike the more commonly used diuretics, aquaretic agents can induce an increase in urinary volume without incurring a loss of electrolytes. These molecules belong to a family of vasopressin receptor antagonists, V2 in particular, that regulate optional renal water re-absorption via the synthesis and expression of aquaporin-2. In view of their properties, they have become the agent of choice in the treatment of hyponatremic states with water retention, and different studies have demonstrated that they are more effective and practical to use than other traditional approaches in the treatment of diseases such as cirrhosis-related ascites, SIADH and, above all, heart failure. However, the future probably holds the promise of new and unexpected applications for this type of drug in the treatment of several conditions, including polycystic kidney and glomerular disease, glaucoma and Menieres syndrome.

Effects of haemodialysis on circulating endothelial progenitor cell count

During haemodialysis (HD) the endothelium is the first organ to sense and to be impaired by mechanical and immunological stimuli. We hypothesized that a single HD session induces mobilization of endothelial progenitor cells (EPCs) and that cardiovascular risk factors may influence this process. We quantified EPCs at different maturational stages (CD34+, CD133+/VEGFR2+) in blood samples from 30 patients, during HD and on the interdialytic day, and in 10 healthy volunteers. Samples were drawn at the start of HD, 1, 2 and 3 h after, at the end of HD and at 24 h on the interdialytic day. Patients were divided into two groups based on a recent risk scoring system (SCORE project): low-risk (LR) and high-risk groups (HR). HD patients showed a significantly reduced basal number of EPCs with respect to healthy volunteers. In contrast, we observed increasing EPCs during HD whereas they diminished on the interdialytic day. The EPC number was directly correlated with HD time progression. The EPC number during HD was increased in the HR group with respect to the LR group. We had a direct correlation between risk score and number of EPCs. Cardiovascular risk factors influenced the mobilization of stem cells from the bone marrow. This feature could be the direct consequence of an augmented request of stem cells to respond to the most important endothelial impairment but could also show a defective capacity of EPCs to home in and repair the sites of vascular injury.

Pulmonary hypertension and erythropoietin.

Numerous uremic patients on hemodialysis have pulmonary hypertension attributable to the presence of arteriovenous fistulas, vascular calcification, and endothelial dysfunction due to alterations in the balance between vasoconstrictive and vasodilatory substances. For these reasons, the effects of recombinant human erythropoietin, a drug widely used in patients on dialysis, on the pulmonary circulation were studied. Some authors maintain that recombinant human erythropoietin has an antihypertensive effect, while others have observed that this hormone induces a reduction in pulmonary arterial pressure due to its vasoactive and stimulatory effects on endothelial and smooth muscle cell precursors.