Chronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.Chronic kidney disease (CKD) is becoming a major public health problem worldwide. CKD is defined as a progressive loss of renal function, measured by a decline in glomerular filtration rate (GFR < 60 mL/min/1.73 m 2 ) 1 , which is typically associated with irreversible pathological changes within the kidney. This pathology has a complicated interrelationship with other diseases 2,3 . Diabetes (DM) and hypertension (HT) are the primary risk factors for CKD 4 , and CKD is also associated with cardiovascular morbidity and mortality 5,6 , even in early stages and in young patients 7 .CKD patients are also characterized by a high genomic instability [8][9][10][11] . This instability could be translated to high levels of genetic damage measured by the incidence of chromosomal damage (micronuclei) when their cells are challenged with ionizing radiation 12 and could be either the cause or the consequence of renal pathologies. In addition, it has been observed that CKD patients repair less efficiently DNA damage 13 .CKD patients present increased levels of C-reactive protein (CRP), which is indicative of an inflammatory status 12,14,15 . Oxidative stress is also a characteristic usually shown by CKD patients [16][17][18][19] . Variants in genes reg...
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.
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.
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.
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.
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