Genetic damage in patients with chronic kidney disease, peritoneal dialysis and haemodialysis: a comparative study

Abstract

Patients with chronic kidney disease (CKD) have signs of genomic instability and, as a consequence, extensive genetic damage, possibly due to accumulation of uraemic toxins, oxidative stress mediators and other endogenous substances with genotoxic properties. We explored factors associated with the presence and background levels of genetic damage in CKD. A cross-sectional study was performed in 91 CKD patients including pre-dialysis (CKD patients; n = 23) and patients undergoing peritoneal dialysis (PD; n = 33) or haemodialysis (HD; n = 35) and with 61 healthy subjects, divided into two subgroups with the older group being in the age range of the patients, serving as controls. Alkaline comet assay and cytokinesis-block micronucleus assay in peripheral blood lymphocytes were used to determine DNA and chromosome damage, respectively, present in CKD. Markers of oxidative stress [malondialdehyde (MDA), advanced glycation end products (AGEs), thiols, advanced oxidation protein products and 8-hydroxy-2′-deoxyguanosine] and markers of inflammation (C-reactive protein, interleukin-6 and tumour necrosis factor alpha) were also measured. Micronucleus (MN) frequency was significantly higher (P < 0.05) in the CKD group (46±4‰) when compared with the older control (oC) group (27.7±14). A significant increase in MN frequency (P < 0.05) was also seen in PD patients (41.9±14‰) versus the oC group. There was no statistically significant difference for the HD group (29.7±15.6‰; P = NS) versus the oC group. Comet assay data showed a significant increase (P < 0.001) of tail DNA intensity in cells of patients with CKD (15.6±7%) with respect to the total control (TC) group (11±1%). PD patients (14.8±7%) also have a significant increase (P < 0.001) versus the TC group. Again, there was no statistically significant difference for the HD group (12.5±3%) compared with the TC group. Patients with MN values in the upper quartile had increased cholesterol, triglycerides, AGEs and MDA levels and lower albumin levels. Multiple logistic regression analysis showed that male gender, diabetes and treatment modality were independently associated with higher levels of DNA damage. Our results suggest that oxidative stress, diabetes, gender and dialysis modality in CKD patients increased DNA and chromosome damage. To confirm these data, prospective clinical trials need to be performed.

Genomic damage as a biomarker of chronic kidney disease status

“…This would explain the contradictory results observed in the literature when pre‐ and HD patients were compared. Thus, although higher values were reported in HD patients [Stopper et al, ; Stoyanova et al, ], the opposite has recently been observed [Rangel‐López et al, ] i.e. greater genomic damage was found in pre‐dialysis than in HD patients.…”

“…The second problem is the low number of patients included in these studies (ranging from 12 to 141). The largest study was performed by our group [Stoyanova et al, ], and the next largest study included only 91 patients [Rangel‐López et al, ]. A description of all 12 studies is provided in Table .…”

“…The second problem is the low number of patients included in these studies (ranging from 12 to 141). The largest study was performed by our group , and the next largest study included only 91 patients [Rangel-L opez et al, 2013]. A description of all 12 studies is provided in Table I. While there is a wide range of techniques for measuring DNA damage the comet assay has become an increasingly standard tool for assessing DNA damage in the last decade, with applications in genotoxicity testing, human biomonitoring and molecular epidemiology, as well as in fundamental research on DNA damage and repair.…”

DNA damage in kidney transplant patients. Role of organ origin

“…In addition, time in hemodialysis was the only factor associated with increased levels of micronuclei in buccal cells, although this effect was not observed in patients submitted to peritoneal dialysis (Roth et al, ). Surprisingly, the contrary effects have been recently reported when peripheral blood lymphocytes were used (Rangel‐López et al, ). Perhaps this discrepancy can be attributed to sampling size more than to the targeted cell.…”

Oxidative DNA Damage Is Elevated in Renal Patients Undergoing Haemodialysis

“…Although previous studies have on the one hand measured levels of genomic damage in both healthy volunteers and in HD patients [10] [21] [25] and, on the other, have determined levels of oxidative specific DNA disruption in patients with kidney disease [4], no previous work has used oxidative specific endonucleases (Endo III and FPG) to assess oxidative DNA damage simultaneously in HD patients and healthy controls. Even though the unmodified comet assay allows for the measure of overall alkaline DNA damage, the use of these two enzymes is most valuable as they recognise oxidative damage [18].…”