Base excision repair capacity in chronic renal failure patients undergoing hemodialysis treatment.

The aim of this study was to determine if the differences observed in the levels of DNA damage in a group of patients suffering from chronic renal failure are due to differences in the repair capability. DNA damage was initially measured with the comet assay in 106 hemodialysis patients. A selected group of 21 patients representing high (ten patients) and low (11 patients) levels of DNA damage were obtained for determination of base excision repair capacity. This was measured in an in vitro assay where protein extracts from lymphocytes were incubated with a substrate of DNA containing 8-oxoguanine, and the rate of incision was measured with the comet assay. Patients with high levels of genomic damage showed, as an average, significantly lower repair capacity (12·73 ± 1·84) in comparison with patients with low levels of genomic damage (18·13 ± 1·13). Nevertheless, the correlation coefficient between repair ability and levels of genomic damage was found to be only close to the significance value (r:-0·423, p: 0·056). Although DNA damage was clearly related to time on hemodialysis, base excision repair capacity was not. This is one of the few studies providing information on the repair capacity of chronic renal failure patients undergoing hemodialysis. As a summary, our results would indicate that DNA damage levels are in part associated to the repair capacity of the patients, and this repair capacity is not associated with the duration of hemodialysis treatment.

Genomic damage as an independent predictor marker of mortality in hemodialysis patients.

AIM: Hemodialysis (HD) patients present an enhanced mortality. Since oxidative DNA damage can be considered a biomarker of genomic instability our aim was to evaluate the influence of this genetic biomarker in all-cause mortality in a group of HD patients followed for 4 years. MATERIAL AND METHODS: 123 chronic HD patients were included. Overall genomic damage was analyzed using the Comet assay. Oxidative DNA damage was measured using the Comet assay complemented with the use of Endo-III and FPG enzymes. Follow-up was carried out from January 2007 to July 2011. RESULTS: Selected HD patients had a mean age of 62 ± 15 years. During the follow-up 36% of patients died (48% due to cardiovascular disease) and 23% were transplanted. Older patients, with high CRP levels, low levels of cholesterol-HDL and albumin, and higher genetic damage at the beginning of the study showed an increased risk for mortality. Multivariate analysis showed that only genomic damage, age and CRP were independently associated with mortality. CONCLUSIONS: Our study shows for the first time that, in HD patients, the presence of high levels of genomic damage is a strong predictor of all-cause mortality. This association remains significant after adjustment for relevant covariates.

Expanded hemodialysis: what's up, Doc?

In recent years there has been an increasing interest in expanded hemodialysis (HDx), an emerging renal replacement therapy based on the use of medium cut-off membranes (MCO). Thanks to the internal architecture of these types of membranes, with a higher pore size and smaller fiber inner diameter to favor internal filtration rate, they can increase the removal of larger middle molecules in conventional hemodialysis. Secondarily, several reports suggest that this therapy potentially improve the outcomes for end-stage renal disease patients. However, HDx has not been defined yet and the characteristics of MCO membranes are not well stablished. The aim of this narrative review is to define HDx and summarize the dialyzers that have been used so far to perform this therapy, collect the evidence available on its efficacy and clinical outcomes compared with other hemodialysis techniques and settle the bases for its optimal prescription.

Genetic damage in chronic renal failure patients is associated with the glomerular filtration rate index.

Chronic renal failure (CRF) patients are considered to present genomic instability and, as a consequence, elevated levels of genetic damage. An open question is whether this damage is related to the stage of the pathology. To determine the background levels of genetic damage, a large population of 258 Caucasian adults (201 CRF patients and 57 controls) was analysed using the micronucleus (MN) assay. The frequency of MN in CRF patients was significantly higher than in controls and correlated with the progression of the disease, according to the glomerular filtration rate. In addition, a significant association was observed between genetic damage and serum creatinine levels. Genetic damage, measured as frequency of MN, increases when renal function decreases. The fact that an increased level of MN is already observed in patients' Stage 2 seems to indicate a genetic predisposition on these patients. Nevertheless, part of the observed damage can be attributed to the uraemic state itself.

Oxidative DNA damage in chronic renal failure patients.

BACKGROUND: Chronic renal failure (CRF) patients present a high incidence of cardiovascular pathologies and cancer. This has been attributed to the existence of genomic instability in these patients, and consequently they should present elevated levels of genetic damage. METHODS: To determine the background levels of genetic damage and its specific levels of oxidative damage, a large population of 253 CRF patients (77 in dialysis) was analysed using the comet assay. The percentage of DNA in the tail was used as a measure of basal genetic damage. In addition, the use of endo III and FPG enzymes allowed us to determine the levels of specific oxidative damage in DNA bases. RESULTS: This is the first study that uses endo III and FPG enzymes to measure oxidative damage in CRF patients. Overall genetic damage, as well as specific oxidative damage, was higher in dialysis patients than in the CRF patients with different stages of uraemic state; genetic damage increased when serum creatinine levels increased. Genomic damage in dialysis patients decreased in those patients submitted to dialysis for a long time. CONCLUSIONS: Genetic damage increases when renal function decreases, being maximum in haemodialysis patients. Although part of the observed damage can be attributed to the uraemic state itself, other individual genetic factors can influence a state of genomic instability responsible for the observed genomic damage.

Vitamin E-coated dialysis membranes reduce the levels of oxidative genetic damage in hemodialysis patients.

End-stage renal disease patients present oxidative stress status that increases when they are submitted to hemodialysis (HD). This increase in oxidative stress can affect their genetic material, among other targets. The objective of this study was to evaluate the effect of using polysulfone membranes coated with vitamin E, during the HD sessions, on the levels of genetic damage of HD patients. Forty-six patients were followed for 6 months, of whom 29 changed from conventional HD to the use of membranes coated with vitamin E. The level of genetic damage was measured using the micronucleus and the comet assays, both before and after the follow-up period. Serum vitamin E concentration was also checked. The obtained results showed that 24% of our patients presented vitamin E deficiency, and this was normalized in those patients treated with vitamin E-coated membranes. Patients with vitamin E deficiency showed higher levels of oxidative DNA damage. After the use of vitamin E-coated membranes we detected a significant decrease in the levels of oxidative damage. Additionally, hemoglobin values increased significantly with the use of vitamin E-coated membranes. In conclusion, the use of vitamin E-coated membranes supposes a decrease on the levels of oxidative DNA damage, and improves the uremic anemia status. Furthermore, the use of this type of membrane was also effective in correcting vitamin E deficiency.

DNA damage in kidney transplant patients. Role of organ origin.

Chronic kidney disease (CKD) patients are characterized by elevated levels of genomic damage. This damage increases when kidney function decreases being maximum in hemodialysis patients. As kidney transplantation improves renal function, and it is related with better survival, the aim of our study was to evaluate potential changes in DNA damage levels after kidney transplantation, and comparing living donor recipients with cadaveric donor recipients. The alkaline comet assay was used to determine DNA breaks and oxidative damaged DNA; and the micronucleus assay was used to determine chromosomal breakage and/or aneuploidy. Fifty CKD patients were followed up after 6 and 12 months of their kidney transplantation. All patients increased their genomic damage levels after 6 and 12 months of renal transplantation, compared with those observed before transplantation, despite of the improvement of their metabolic functions. Donor advanced age correlated positively with higher DNA damage. Genomic damage was lower in living donor transplants with respect to cadaveric donor transplants. Our conclusion is that DNA damage increased in kidney transplantation patients, whereas their renal function improved. Higher levels of DNA damage were found in cadaveric donor transplants when compared to living donor transplants. Environ. Mol. Mutagen. 58:712-718, 2017. © 2017 Wiley Periodicals, Inc.

Levels of DNA damage in peripheral blood lymphocytes of patients undergoing standard hemodialysis vs on-line hemodiafiltration: A comet assay investigation.

Chronic kidney disease (CKD) patients exhibit high levels of genetic damage. Part of this genetic damage is supposed to be caused by the hemodialysis (HD) therapy. Different and more efficient HD procedures could reduce the genetic damage and improve health status of CKD patients. In the present study, we analyzed if changing to online hemodiafiltration (OL-HDF) has a beneficial effect on the levels of genetic damage. The levels of genetic damage (DNA breaks and oxidatively damaged DNA) were analyzed in peripheral blood lymphocytes by using the comet assay. Forty-nine patients submitted to HD, 34 of them changing to OL-HDF and 15 patients continuing in low-flux HD, were included in the study. Plasma antioxidant capacity was also determined. Second sampling period was established after 6 months on the new or traditional HD protocol. A slight decrease in the levels of DNA damage was observed in patients who switched to OL-HDF (P=0.048) in relation to the reference group. This reduction is indicative that OL-HDF shows greater efficiency than low-flux HD in the reduction of basal levels of genetic damage.

Dyslipidemia and the progression of renal disease in chronic renal failure patients.

Dyslipidemia is a common complication of progressive kidney disease and contributes to the high cardiovascular morbidity and mortality of chronic kidney disease (CKD) patients. Recent evidence also suggests a role for dyslipidemia in the development and progression of renal disease. Experimental studies have demonstrated that lipids may induce glomerular and tubulointerstitial injury, and that lipid-lowering treatments ameliorate renal injury. Various lipid abnormalities have been associated with the development and progression of renal disease in diabetic and nondiabetic patients. Population-based studies and studies of diabetic patients have reported associations of various lipid abnormalities with the development of renal disease. In patients with CKD, lipid abnormalities have also been associated with renal disease progression. Post hoc analyses of some large clinical trials on patients with vascular disease, diabetes, or dyslipidemia, and a meta-analysis of small, prospective, controlled studies on patients with CKD (diabetics and nondiabetics) suggest that statins may slow the progression of kidney disease. It is unclear whether the beneficial renal effects of statins are due to the reduction of serum cholesterol levels and/or their pleiotropic effects. There is also evidence for synergistic renoprotective effects between statins and renin-angiotensin system inhibitors. According to the results of post hoc analysis of several studies, treatment with fibrates does not seem to confer renoprotection, but evidence is scarce. In summary, there is growing evidence that lipid abnormalities may be a risk factor for renal disease, and that statins appear to confer a renoprotective effect.

Genomic damage as a biomarker of chronic kidney disease status.

Patients suffering from chronic kidney disease (CKD) exhibit a high incidence of cancer and cardiovascular diseases, as well as high levels of genomic damage. To confirm the association of CKD with genomic damage we have carried out the largest study to date addressing this issue, using a total of 602 subjects (187 controls, 206 pre-dialysis CKD patients and 209 CKD patients in hemodialysis). DNA oxidative damage was measured in all individuals using the comet assay. Our results indicate that CKD patients have significantly higher levels of DNA damage than controls, but no significant differences were observed between pre-hemodialysis (pre-HD) and hemodialysis (HD) patients. When oxidative damage was measured, no differences were observed between patients and controls, although HD patients showed significantly higher levels of oxidative damage than pre-HD patients. In addition, a positive relationship was demonstrated between genomic damage and all-cause mortality. Our study confirms that genomic damage can be predictive of prognosis in CKD patients, with high levels of DNA damage indicating a poor prognosis in HD patients.

Radiosensitivity in patients suffering from chronic kidney disease.

PURPOSE: Patients suffering from chronic kidney disease (CKD) exhibit a high incidence of cancer, as well as high levels of genetic damage. We hypothesized that these patients show genomic instability detected as an increased chromosomal radiosensitivity in front of the genetic damage induced by ionizing radiation. MATERIAL AND METHODS: The background levels of genetic damage and the net genetic damage after in vitro irradiation with 0.5 Gy were analyzed using the micronucleus (MN) assay in peripheral blood lymphocytes. A total number of 552 individuals (179 controls and 373 CKD patients) were included in the study. RESULTS: The net radiation-induced genetic damage was significantly higher in CKD patients than in controls; but no differences between those patients submitted to hemodialysis and those in pre-dialytic stages were detected. A positive correlation was observed between basal and net micronucleus frequencies in CKD patients what would indicate an underlying genetic background modulating DNA damage levels. CONCLUSIONS: Our results indicate that CKD patients present genomic instability, measured as an increased chromosomal radiosensitivity in front of ionizing radiation.

Chronic hypotension in the dialysis patient.

Chronic hypotension, defined by a systolic blood pressure < 100 mmHg in the interdialytic period, affects 5-10% of hemodialysis patients, and is more prevalent among patients on long-term hemodialysis. This complication requires a substantial amount of medical and nursing care before and during dialysis to control its symptoms. Chronic hypotension is characterized hemodinamically by preserved cardiac index, heart rate or stroke volume, but reduced total peripheral vascular resistances. Although its pathophysiology is not well defined, a reduced cardiovascular response to vasopressor agents (such as norepinephrine and angiotensin II), associated with a down-regulation of their receptors, as well as an increased production of vasodilators (such as nitric oxide or adrenomedullin) are possibly involved. The treatment of this complication is not well defined and the measures recommended (contention in the lower limbs or the sympathomimetic agent midodrine) are of limited benefit.

Time in hemodialysis modulates the levels of genetic damage in hemodialysis patients.

It is assumed that hemodialysis treatment can diminish the levels of genetic damage in circulating lymphocytes by cleaning the blood of uremic toxins that cause oxidative stress. However, the hemodialysis process by itself may also induce genomic damage by producing reactive oxygen species (ROS). We conducted a follow-up study in a group of 70 hemodialysis patients followed for a mean time of 15 months. We investigated the effect of exposure time in hemodialysis on the levels of genetic damage in peripheral blood lymphocytes using the micronucleus assay. In addition, genetic damage after in vitro irradiation with 0.5 Gy was also analyzed to evaluate changes in radiosensitivity. Our results showed that, at the end of the study, there was a decrease in both the basal levels of genetic damage (9.9 ± 1.0 vs. 7.6 ± 0.7) and radiosensitivity values (38.5 ± 3.0 vs. 27.6 ± 2.4). We conclude that hemodialysis procedures may act as an ameliorating factor reducing the genetic damage present in chronic kidney disease patients.

Genomic instability in chronic renal failure patients.

Patients suffering chronic renal failure (CRF) exhibit a high incidence of cancer, as well as high levels of genetic damage. We hypothesized that these patients show genomic instability as measured by increased radiosensitivity to the induction of genetic damage. The background levels of genetic damage and the net genetic damage after in vitro irradiation with 0.5 Gy were analyzed using the micronucleus assay in peripheral blood lymphocytes of 174 CRF patients and 53 controls. The net radiation-induced genetic damage was significantly higher in CRF patients with respect to controls. Among CRF patients, the levels of genetic damage were higher in those with prior incidence of cancer than in those without cancer; in addition, those CRF patients undergoing hemodialysis presented with higher levels of genetic damage than those in the advanced Stages (4-5) of the pathology. A positive association was observed between basal and net micronucleus frequency among CFR patients. However, no association was found between net genetic damage and parameters linked to the different stages of the pathology, such as urine creatinine levels and glomerular filtration rate. Our results indicate that CRF patients show increased radiosensitivity and that the degree of radiosensitivity is associated with the progression of the pathological stage of the disease.