Eleonora Crascì

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.

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.

Arrhythmias and Hemodialysis: Role of Potassium and New Diagnostic Tools

Cardiovascular diseases represent the main causes of death in patients affected by renal failure, and arrhythmias are frequently observed in patients undergoing hemodialysis. Dialytic treatment per se can be considered as an arrhythmogenic stimulus; moreover, uraemic patients are characterized by a “pro-arrhythmic substrate” because of the high prevalence of ischaemic heart disease, left ventricular hypertrophy and autonomic neuropathy. One of the most important pathogenetic element involved in the onset of intra-dialytic arrhythmias is the alteration in electrolytes concentration, particularly calcium and potassium. It may be very useful to monitor the patients cardiac activity during the whole hemodilaytic session. Nevertheless, the application of an extended intradialytic electrocardiographic monitoring is not simple because of several technical and structural impairments. We tried to overcome these difficulties using Whealthy®, a wearable system consisting in a t-shirt composed of conductors and piezoresistive materials, integrated to form fibers and threads connected to tissutal sensors, electrodes, and connectors. ECG and pneumographic impedance signals are acquired by the electrodes in the tissue, and the data are registered by a small computer and transmitted via GPRS or Bluetooth.

Experimental Models of Acute Renal Failure and Erythropoietin: What Evidence of a Direct Effect?

The kidney can achieve a structural and functional recovery after the damage induced by ischemia and reperfusion. This is due to the regeneration of epithelial tubular cells, the intervention of immature cells mainly localized in the medulla, and a small number of bone marrow-derived stem cells. In many instances, however, recovery is delayed or does not occur at all. The mechanisms allowing the renal cells to de-differentiate still need to be clarified in order to find a therapeutic approach that can amplify this ability and then stop the fibroid involution and the progression toward renal failure. Several authors have hypothesized a protective effect of EPO against ischemic and cytotoxic renal damage and observed that patients precociously treated with EPO showed a slower progression of renal failure. EPO has been demonstrated to have proliferative and anti-apoptotic effects in ischemia-reperfusion models in the brain and cell cultures. Moreover, EPO can mobilize stem cells and increase the plasmatic levels and the renal expression of VEGF. These effects seem to be dose-dependent and could be due to the activation of signal transduction systems, like Jak and STAT. In the presence of high doses of exogenous EPO or during the treatment with long-acting EPO-like molecules, non-specific receptors may be activated through a low-affinity link. Further investigations are needed to determine new therapeutic applications for EPO and other analogous hormones. Very long-acting molecules or molecules with cyto-protective but no erythropoietic effect may represent useful tools in the study of the molecular mechanisms underlying EPOs action and may have a rapid and safe therapeutic application.

NGAL is a Precocious Marker of Therapeutic Response

NGAL (Neutrophil Gelatinase-Associated Lipocalin) is a small 25-kD peptide belonging to the lipocalin superfamily. Several studies highlight its role as an organ injury and disease activity biomarker. In the present review, instead, we wanted to study NGAL as a precocious marker of therapeutic response in renal and non-renal diseases (glomerulonephritis, vasculitis, LES, Crohns disease and other chronic inflammatory pathologies). The obtained outcomes support the hypothesis that NGAL could be employed as a biomarker of response to different therapeutic schemes, because its levels sensibly and precociously change compared to other haematologic and biochemical parameters.

Pregnancy in uremic patients: an eventful journey.

Renal damage, which can be caused by gestational anomalies such as pre‐eclampsia, carries a risk of gestational complications; the greatest risk being in women who become pregnant while on hemodialysis or peritoneal dialysis. If this rare event occurs, there is a marked increase in the risk of pre‐eclampsia, early uterine contractions and hydramnios, hypertensive crisis, preterm delivery and intrauterine growth retard. Furthermore, newborns are almost always of low birthweight. Patients who undergo renal transplantation are another high‐risk category. In such cases, the pregnancy itself can compromise the success of the transplant and the immunosuppressive therapy correlated to it can become a threat to the course of the pregnancy and normal fetal growth. Therefore, in view of the lack of appropriate guidelines for the best possible approach to the treatment of women on dialysis or of those with a renal transplantation, it is best to advise these patients against becoming pregnant and/or to provide a valid counselling service illustrating the extreme difficulties and dangers involved in becoming pregnant.

Circadian rhythm of hydration in healthy subjects and uremic patients studied by bioelectrical impedance analysis.

Background: Healthy subjects and patients after successful kidney transplantation show a circadian rhythm for glomerular filtration rate and for the glomerular transport of macromolecules. We aimed to evaluate by bioelectrical impedance analysis (BIA) whether body hydration status also follows a circadian rhythm in patients with impaired renal function. Methods: The study was conducted on 28 subjects divided into 3 groups: 8 healthy volunteers, 8 patients affected by chronic kidney disease and 12 end-stage renal disease (ESRD) patients on hemodialysis. During 24 h, 9 BIA measurements were taken in every subject every 180 min. Results: BIA findings demonstrate that normal subjects have a circadian rhythm in hydration status that reaches maximum body water content at night, between 21.00 and 23.00 h. In patients with chronic kidney disease, this rhythm, with maximum at night, is maintained. The rhythm is also present in ESRD patients, if the residual diuresis is at least 500 ml/day, while there is no rhythm when residual diuresis is <300 ml/day. Conclusions: In normal subjects, body hydration status shows a circadian rhythm, which is weakened or lost in oligoanuric patients on dialysis, but partially maintained in subjects with preterminal uremia and in hemodialyzed patients with residual diuresis >500 ml/day.

Cardiorenal Consequences of Atherosclerosis and Statins Therapy: From the Past to the Future

Complications from atherosclerosis cause most deaths in western countries, and their incidence appears to be markedly increasing in developing countries, thus suggesting a correlation that is directly proportional to social progress. In recent years, the different branches of medical research, from studies on vascular disease to those on lipid and glucose metabolism, and also clinical research on coronary, carotid and peripheral artery diseases, epidemiologic and pharmacologic research, have concentrated on these diseases with the common aim of reducing the incidence of cardiovascular diseases, and mortality. Scientific progress has greatly improved our understanding of the pathogenic mechanisms underlying the progression of cardiovascular disease, and efforts in this discipline now appear more necessary than ever.