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      Relation between Different Treatment Modalities and Genomic Damage of End-Stage Renal Failure Patients

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          Background: Patients with end-stage renal disease display enhanced genomic damage. We investigated the relation between genomic damage and different treatment modalities. Methods: In a longitudinal study two groups of patients were analyzed in monthly intervals. We assessed the initiation of hemodialysis in 5 conservatively treated patients, and a switch from hemodialysis to hemodiafiltration in 7 patients. DNA damage was investigated in peripheral blood lymphocytes by micronucleus frequency and by comet assay analysis. With regard to potential genotoxicity of advanced glycation end products (AGEs), levels of imidazolone A and AGE-associated fluorescence (AGE-FL) were determined. Results: The initiation of hemodialysis did not alter the genomic damage. In patients who switched from hemodialysis to hemodiafiltration, a small but significant reduction in the comet assay but not in the micronucleus frequency was observed. Elevated plasmalevels of imidazolone A and AGE-FL were not influenced by the treatment modalities. Conclusion: In our small patient group no major reduction of the elevated genomic damage could be reached. Disease factors not influenced by altered dialysis modalities may have contributed considerably in our patient group. The persisting high levels of DNA damage suggest a need for further improvement. Inhibiting AGE formation may be one promising way for the future.

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          Most cited references 11

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          Poor long-term survival after acute myocardial infarction among patients on long-term dialysis.

          Cardiovascular disease is common in patients on long-term dialysis, and it accounts for 44 percent of overall mortality in this group. We undertook a study to assess long-term survival after acute myocardial infarction among patients in the United States who were receiving long-term dialysis. Patients on dialysis who were hospitalized during the period from 1977 to 1995 for a first myocardial infarction after the initiation of renal-replacement therapy were retrospectively identified from the U.S. Renal Data System data base. Overall mortality and mortality from cardiac causes (including all in-hospital deaths) were estimated by the life-table method. The effect of independent predictors on survival was examined in a Cox regression model with adjustment for existing illnesses. The overall mortality (+/-SE) after acute myocardial infarction among 34,189 patients on long-term dialysis was 59.3+/-0.3 percent at one year, 73.0+/-0.3 percent at two years, and 89.9+/-0.2 percent at five years. The mortality from cardiac causes was 40.8+/-0.3 percent at one year, 51.8+/-0.3 percent at two years, and 70.2+/-0.4 percent at five years. Patients who were older or had diabetes had higher mortality than patients without these characteristics. Adverse outcomes occurred even in patients who had acute myocardial infarction in 1990 through 1995. Also, the mortality rate after myocardial infarction was considerably higher for patients on long-term dialysis than for renal-transplant recipients. Patients on dialysis who have acute myocardial infarction have high mortality from cardiac causes and poor long-term survival.
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            Genotoxicity of advanced glycation end products in mammalian cells.

            In patients with chronic renal failure, cancer incidence is enhanced. Since levels of advanced glycation end products (AGEs) are markedly elevated in renal insufficiency, we investigated potential effects of various AGEs on structural DNA integrity in tubule cells. The comet-assay was employed, a method based on the computer-aided microscopic analysis of single cells after electrophoretic separation of their nuclear DNA. Incubation of pig kidney LLC-PK1-cells for 24 h with AGE-BSA (AGE-bovine serum albumin), carboxymethyllysine-BSA as well as methylglyoxal-BSA resulted in a significant increase in DNA damage. Pretreatment of the cells with the proteases trypsin and bromelain abolished the AGE-induced comet-formation. This is in agreement with the idea that the observed genotoxicity of AGEs could be receptor-mediated and that proteases inactivate the extracellular domain of the receptor for AGEs. Binding of AGEs to the RAGE receptor leads to an increased intracellular formation of active oxygen species, which are known to induce DNA damage. It is concluded that AGEs induce genotoxicity in tubule cells, which may be involved in the enhanced cancer development in advanced kidney diseases.
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              Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts.

              Some mutations in mitochondrial DNA (mtDNA) causing a number of neuromuscular diseases are suggested to arise spontaneously during the life of an individual. To substantiate the extent and the rate of these somatic mutations, mtDNA specimens from post-mortem human heart muscles of subjects in differing age groups were hydrolyzed. 8-Hydroxy-deoxyguanosine (8-OH-dG), a hydroxyl-radical adduct of deoxyguanosine, in mtDNA, was quantitatively determined using a micro high-performance liquid chromatography/mass spectrometry system. In each specimen, the mtDNA with a 7.4 kilo base-pair deletion was quantified by the kinetic polymerase chain reaction method. In association with age, the 8-OH-dG content accumulated exponentially up to 1.5% with a correlative increase in the content of the deleted mtDNA up to 7%. Clear correlation between the 8-OH-dG content in mtDNA and the population of mtDNA with a deletion (r = 0.93, P < 0.01) gives insight into the mechanism for the generation of a large deletion. These results indicate that accumulation of somatically acquired oxygen damage together with age-associated mutations in mtDNA which lead to bioenergetic deficiency and the heart muscle weakness are inevitable in human life.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                June 2006
                06 June 2006
                : 29
                : 1
                : 10-17
                aInstitute of Pharmacology and Toxicology, and dDepartment of Internal Medicine, University of Würzburg, and bKuratorium for Dialysis and Kidney Transplantation, Würzburg, and cFresenius Medical Care, Bioscience Department, Bad Homburg, Germany; eSlovak Medical University, Institute of Preventive and Clinical Medicine, Bratislava, Slovakia
                92482 Kidney Blood Press Res 2006;29:10–17
                © 2006 S. Karger AG, Basel

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                Figures: 8, Tables: 4, References: 22, Pages: 8
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