Fibrosis, regeneration and cancer: what is the link?

Tubulo-interstitial fibrosis constitutes the final common pathway for all pathological conditions that evolve towards chronic kidney disease, and transforming growth factor-ß1 plays a key role in this process. Furthermore, neutrophil gelatinase-associated lipocalin appears not only to be a simple marker of renal injury but also an active player in disease progression. We are not yet able to control and modulate this phenomenon. Therefore, a better understanding of fibrogenic molecular mechanisms is necessary to detect possible therapeutic strategies that interfere with fibrosis and then stop the progression of renal disease. The line of research called 'regenerative medicine' works toward this. According to many authors, the formation of a fibrotic extracellular matrix disrupts the cells' polarity and stimulates their proliferation, creating conditions for cancer development. However, there is another plausible hypothesis: is it possible that fibrosis provides a sort of 'protection' from the development of a cancer as a consequence of the intense proliferation that characterizes any inflammatory process? In superior organisms, and also in humans, regeneration may have been selected negatively and replaced by fibrosis in the course of evolution, to warrant species survival: in fact, unchecked pluripotent cell production and proliferation can lead to tumour development and the potential death of a single individual. Hence, tumours might be the outcome of the failure of fibrotic processes, most likely due to some mediators predominating over others. So, valid experimental models are necessary to understand the interactions that exist between fibrosis and tumours and to evaluate the real advantage of therapies that aim to inhibit the fibrotic process at the renal level or that of other organs. The ideal approach would be to limit fibrosis and then organ function loss but without exposing the patient to risks of developing a tumour, starting from as early as the drugs prescribed.

Alterations of lipid metabolism in chronic nephropathies: mechanisms, diagnosis and treatment.

Nephropathic subjects show an increased tendency to develop cardiovascular diseases, mainly as the consequence of several risk factors including increased oxidative stress, inflammation, physical inactivity, anemia, vascular calcification, and endothelial dysfunction. The alterations in lipid metabolism represent a relatively lesser important cause of genesis and progression of atherosclerosis. Unfortunately, in these patients the atherogenic potential of dyslipidemia may depend more on apolipoproteins than on lipid abnormalities, and may not always be recognized by measurement of plasma lipids alone. The aim of this review was therefore to analyze the main lipid alterations that can occur in nephropathic patients, as well as their causes and their effects on the cardiovascular system. The clinical evidence and recommendations for the use of lipid-regulating drugs in patients with chronic kidney disease, nephrotic syndrome, in patients undergoing hemo- and peritoneal dialysis and in transplanted patients was also reviewed. Moreover, we analyzed the link between dyslipidemia and kidney disease onset and progression and the role of statins in preventing it.

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.

Renal complications in oncohematologic patients.

The aim of the present paper was to review recent developments in the management of patients with acute kidney injury or chronic kidney disease occurring secondary to either cancer itself or its therapy, with a focus on infiltration of the renal parenchyma, myeloma, tumor lysis syndrome, glomerular disease, thrombotic microangiopathy, chemotherapy-associated thrombotic microangiopathy, biphosphonate-induced renal diseases, acute kidney injury, and chronic kidney disease after hematopoietic cell transplantation. Further studies are awaited because a better knowledge of renal complications, which frequently occur in patients with oncohematologic diseases, would be conducive to making an early diagnosis and providing prompt therapy.

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.

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 patient's 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.

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.

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.