Short-Chain Fatty Acids in Chronic Kidney Disease: Focus on Inflammation and Oxidative Stress Regulation.

Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress.

Effect of cryopreservation on DNA damage and DNA repair activity in human blood samples in the comet assay.

The comet assay is a commonly used method to determine DNA damage and repair activity in many types of samples. In recent years, the use of the comet assay in human biomonitoring became highly attractive due to its various modified versions, which may be useful to determine individual susceptibility in blood samples. However, in human biomonitoring studies, working with large sample numbers that are acquired over an extended time period requires some additional considerations. One of the most important issues is the storage of samples and its effect on the outcome of the comet assay. Another important question is the suitability of different blood preparations. In this study, we analysed the effect of cryopreservation on DNA damage and repair activity in human blood samples. In addition, we investigated the suitability of different blood preparations. The alkaline and FPG as well as two different types of repair comet assay and an in vitro hydrogen peroxide challenge were applied. Our results confirmed that cryopreserved blood preparations are suitable for investigating DNA damage in the alkaline and FPG comet assay in whole blood, buffy coat and PBMCs. Ex vivo hydrogen peroxide challenge yielded its optimal effect in isolated PBMCs. The utilised repair comet assay with either UVC or hydrogen peroxide-induced lesions and an aphidicolin block worked well in fresh PBMCs. Cryopreserved PBMCs could not be used immediately after thawing. However, a 16-h recovery with or without mitotic stimulation enabled the application of the repair comet assay, albeit only in a surviving cell fraction.

Inflammation and Oxidative Stress in Chronic Kidney Disease-Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites.

Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.

Supplementation of Short-Chain Fatty Acid, Sodium Propionate, in Patients on Maintenance Hemodialysis: Beneficial Effects on Inflammatory Parameters and Gut-Derived Uremic Toxins, A Pilot Study (PLAN Study)

BACKGROUND: In end-stage renal disease (ESRD), gut-derived uremic toxins play a crucial role in the systemic inflammation and oxidative stress promoting the excess morbidity and mortality. The biochemical derangement is in part a consequence of an insufficient generation of short-chain fatty acids (SCFA) due to the dysbiosis of the gut and an insufficient consumption of the fermentable complex carbohydrates. AIM OF THE STUDY: The primary end-point was to evaluate the potential efficacy of SCFA (specifically, sodium propionate (SP)) for patients on maintenance hemodialysis (MHD) on systemic inflammation. Secondary end-points included potential attenuation of oxidative stress markers, insulin resistance and production of gut-derived uremic toxins indoxyl sulfate and p-cresol sulfate, as well as health status after SP supplementation. STUDY DESIGN: We performed a single-center non-randomized pilot study in 20 MHD patients. They received the food additive SP with a daily intake of 2 × 500 mg in the form of capsules for 12 weeks. Pre-dialysis blood samples were taken at the beginning, after six weeks and at the end of the administration period, as well as four weeks after withdrawal of the treatment. RESULTS: The subjects revealed a significant decline of inflammatory parameters C-reactive protein (-46%), interleukin IL-2 (-27%) and IL-17 (-15%). The inflammatory parameters IL-6 and IFN-gamma showed a mild non-significant reduction and the anti-inflammatory cytokine IL-10 increased significantly (+71%). While the concentration of bacterial endotoxins and TNF-α remained unchanged, the gut-derived uremic toxins, indoxyl sulfate (-30%) and p-cresyl sulfate (-50%), revealed a significant decline. The SP supplementation reduced the parameters of oxidative stress malondialdehyde (-32%) and glutathione peroxidase activity (-28%). The serum insulin levels dropped by 30% and the HOMA-index by 32%. The reduction of inflammatory parameters was associated with a lowering of ferritin and a significant increase in transferrin saturation (TSAT). Four weeks after the end of the treatment phase, all improved parameters deteriorated again. Evaluation of the psycho-physical performance with the short form 36 (SF-36) questionnaire showed an enhancement in the self-reported physical functioning, general health, vitality and mental health. The SP supplementation was well tolerated and without important side effects. No patient had left the study due to intolerance to the medication. The SP supplementation in MHD patients reduced pro-inflammatory parameters and oxidative stress and improved insulin resistance and iron metabolism. Furthermore, SP effectively lowered the important gut-derived uremic toxins indoxyl and p-cresol sulfate. These improvements were associated with a better quality of life. Further controlled studies are required in a larger cohort to evaluate the clinical outcome.

DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers.

Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients' burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2'-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker's potential to predict clinical outcomes.

The Joint Society of Nephrology in Germany, Switzerland and Austria - Five Decades of Successful Activities.

The joint Society of Nephrology in Germany, Switzerland and Austria was founded on April 10th, 1961 in Wiesbaden. Board members were Hans Sarre, Kurt Kramer, Klaus Rother, Francois Reubi, Bruno Watschinger, Wolfgang Dutz, Ernst Wollheim and Karl Ullrich. The mission of the society was an intensive interaction between basic science of the kidney (anatomy, physiology, pathophysiology, biochemistry and molecular biology) and clinical research in nephrology and hypertension. Every year scientific symposia took place in different venues in one of the three countries, except in the years between 1963-1987, when the congresses of the International Society of Nephrology took place. Practical issues of clinical nephrology, in particular renal replacement therapy (dialysis and transplantation), were covered since 1971 by a specific Working Group. In 1994 the Advisory Board (Kuratorium) of the Society of Nephrology was founded as a result of an initiative of Peter Weidmann (Bern). Its main goals were Update Seminars in Nephrology and Hypertensionin Eastern Europe, in part together with the Joint Action of Nephrology and an Eastern European ScholarshipProgram. Despite the prosperous work of this European society within nearly five decades in Germany a national society was founded as well, which combined all activities of nephrology in one organization. The German Society of Nephrology was founded in 2009.

25-hydroxyvitamin d and advanced glycation endproducts in healthy and hypertensive subjects: are there interactions?

Advanced glycation endproducts (AGEs) accumulate during aging. Skin is the single organ of vitamin D synthesis, induced by ultraviolet B light. Accumulation of AGEs in the skin could interfere with synthesis of the vitamin, whereas the microinflammation and oxidative stress (associated with hypovitaminosis D) could amplify both the toxic effects of AGEs and their production. Clinical data on potential interactions between vitamin D3 deficiency and AGE accumulation are sparse. Here we investigated potential associations between levels of circulating vitamin D3 and those of AGEs in blood and skin with regard to markers of inflammation and oxidative stress in nondiabetic subjects. In a cross-sectional study, 146 subjects (119 healthy persons and 27 hypertensive patients; 73 male and 73 female; mean age, 57.0 ± 15.5 years) were included. Skin autofluorescence (SAF) and plasma levels of vitamin D3, AGE-associated fluorescence, high-sensitivity C-reactive protein level, and advanced oxidation protein products as well as renal function (estimated glomerular filtration rate) were determined. In a subgroup of 61 patients, N(ε)-carboxymethyllysine, soluble receptor of AGEs, and soluble vascular adhesion protein-1 were additionally analyzed. Vitamin D3 level averaged 22.5 ± 8.9 ng/mL. Prevalence of vitamin D insufficiency (20-29 ng/mL) was 43%, and that of deficiency (<20 ng/mL) 37%. The age-dependent rise in SAF was steeper in smokers and in subjects presenting arterial hypertension. No association between SAF and hypovitaminosis D was revealed. Among smokers, an inverse relationship manifested between vitamin D3 and plasma AGE-associated fluorescence as well as soluble vascular adhesion protein-1. Our data suggest that in nondiabetic adults, hypovitaminosis D does not enhance toxicity and accumulation of AGEs. Only in smokers interactions are conceivable.

High-tone external muscle stimulation in patients with acute kidney injury (AKI): beneficial effects on NO metabolism, asymmetric dimethylarginine, and endothelin-1.

OBJECTIVES: The aim of this study was to assess potential effects of high-tone external muscle stimulation (HTEMS) on parameters of endothelial dysfunction (ED) in patients with acute kidney injury (AKI). BACKGROUND: The bad outcome of AKI patients is markedly influenced by ED, microinflammation, oxidative stress and protein hypercatabolism. Recently, we have shown that intradialytic application of HTMS was associated with a faster resolution of AKI. Here, we investigated in the same cohort of patients whether parameters of ED such as nitric oxide (NO), asymmetric-dimethylarginine (ADMA), and endothelin 1 (ET-1) are modulated by HTEMS as compared to non-HTEMS-treated AKI patients. METHODS: In a post-hoc study we analyzed plasma samples of the 34 AKI patients stage 5, of whom 17 underwent intradialytic HTEMS treatment while the other 17 served as AKI dialysis controls. Measurements included plasma nitrate and nitrite (NOx), ADMA, ET-1 and were performed before and on days 3, 7, 14, 21, and 28 after start of daily dialysis. Additional 16 healthy volunteers served as controls. RESULTS: Initially, in both AKI groups NOx levels were markedly lower and ADMA and ET-1 levels were higher compared to the healthy controls. After initiation of daily hemodialysis the HTEMS group showed a faster improvement of NOx and ET-1 (after 1 week) and ADMA levels (after 2 weeks) compared to the No- HTEMS group. After 2 weeks, all parameters of the HTEMS group were not different from healthy controls, while the No-HTEMSAKI group needed 3 - 4 weeks. CONCLUSION: Our findings suggest for the first time that in AKI patients, application of HTEMS is associated with a faster normalization of lowered NOx and elevated ADMA and ET-1 plasma levels. We hypothesize that the more rapid amelioration of these parameters in the HTEMS group contributed to the accelerated recovery of AKI. With regard to the small study groups with different causes of AKI, investigations in a greater number of AKI patients is required.

Neuronal activation in the central nervous system of rats in the initial stage of chronic kidney disease-modulatory effects of losartan and moxonidine.

The effect of mild chronic renal failure (CRF) induced by 4/6-nephrectomy (4/6NX) on central neuronal activations was investigated by c-Fos immunohistochemistry staining and compared to sham-operated rats. In the 4/6 NX rats also the effect of the angiotensin receptor blocker, losartan, and the central sympatholyticum moxonidine was studied for two months. In serial brain sections Fos-immunoreactive neurons were localized and classified semiquantitatively. In 37 brain areas/nuclei several neurons with different functional properties were strongly affected in 4/6NX. It elicited a moderate to high Fos-activity in areas responsible for the monoaminergic innervation of the cerebral cortex, the limbic system, the thalamus and hypothalamus (e.g. noradrenergic neurons of the locus coeruleus, serotonergic neurons in dorsal raphe, histaminergic neurons in the tuberomamillary nucleus). Other monoaminergic cell groups (A5 noradrenaline, C1 adrenaline, medullary raphe serotonin neurons) and neurons in the hypothalamic paraventricular nucleus (innervating the sympathetic preganglionic neurons and affecting the peripheral sympathetic outflow) did not show Fos-activity. Stress- and pain-sensitive cortical/subcortical areas, neurons in the limbic system, the hypothalamus and the circumventricular organs were also affected by 4/6NX. Administration of losartan and more strongly moxonidine modulated most effects and particularly inhibited Fos-activity in locus coeruleus neurons. In conclusion, 4/6NX elicits high activity in central sympathetic, stress- and pain-related brain areas as well as in the limbic system, which can be ameliorated by losartan and particularly by moxonidine. These changes indicate a high sensitivity of CNS in initial stages of CKD which could be causative in clinical disturbances.

Neuromuscular electrostimulation techniques: historical aspects and current possibilities in treatment of pain and muscle waisting.

Application of electricity for pain treatment dates back to thousands of years BC. The Ancient Egyptians and later the Greeks and Romans recognized that electrical fishes are capable of generating electric shocks for relief of pain. In the 18th and 19th centuries these natural producers of electricity were replaced by man-made electrical devices. This happened in following phases. The first was the application of static electrical currents (called Franklinism), which was produced by a friction generator. Christian Kratzenstein was the first to apply it medically, followed shortly by Benjamin Franklin. The second phase was Galvanism. This method applied a direct electrical current to the skin by chemical means, applied a direct and pulsed electrical current to the skin. In the third phase the electrical current was induced intermittently and in alternate directions (called Faradism). The fourth stage was the use of high frequency currents (called d'Arsonvalisation). The 19th century was the "golden age" of electrotherapy. It was used for countless dental, neurological, psychiatric and gynecological disturbances. However, at beginning of the 20th century electrotherapy fell from grace. It was dismissed as lacking a scientific basis and being used also by quacks and charlatans for unserious aims. Furthermore, the development of effective analgesic drugs decreased the interest in electricity. In the second half of the 20th century electrotherapy underwent a revival. Based on animal experiments and clinical investigations, its neurophysiological mechanisms were elucidated in more details. The pain relieving action of electricity was explained in particular by two main mechanisms: first, segmental inhibition of pain signals to the brain in the dorsal horn of the spinal cord and second, activation of the descending inhibitory pathway with enhanced release of endogenous opioids and other neurochemical compounds (serotonin, noradrenaline, gamma aminobutyric acid (GABA), acetylcholine and adenosine). The modern electrotherapy of neuromusculo- skeletal pain is based in particular on the following types: transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS or electro-acupuncture) and spinal cord stimulation (SCS). In mild to moderate pain, TENS and PENS are effective methods, whereas SCS is very useful for therapy of refractory neuropathic or ischemic pain. In 2005, high tone external muscle stimulation (HTEMS) was introduced. In diabetic peripheral neuropathy, its analgesic action was more pronounced than TENS application. HTEMS appeared also to have value in the therapy of symptomatic peripheral neuropathy in end-stage renal disease (ESRD). Besides its pain-relieving effect, electrical stimulation is of major importance for prevention or treatment of muscle dysfunction and sarcopenia. In controlled clinical studies electrical myostimulation (EMS) has been shown to be effective against the sarcopenia of patients with chronic congestive heart disease, diabetes, chronic obstructive pulmonary disease and ESRD.

High-tone external muscle stimulation in endstage renal disease: effects on quality of life in patients with peripheral neuropathy.

OBJECTIVE: High-tone external muscle stimulation (HTEMS) has been shown to ameliorate painful peripheral neuropathy of dialysis patients. We hypothesized that HTEMS could also lead to improved parameters of health-related quality of life (HRQOL). METHODS: 25 end-stage renal disease (ESRD) patients (17 men/8 women, mean age 62.2 ± 14.2 years) were enrolled for the study. For evaluation of HRQOL the short form SF-36 was used. In addition, the Hospital Anxiety and Depression Scale (HADS) and the pain severity score were investigated. HTEMS was applied intradialytically for 1 hour, 3 times a week. Its effect was evaluated just before the beginning and both 6 and 12 weeks after onset of this study. RESULTS: SF-36 showed a significant effect of time for the subscales of physical role functioning and social functioning. A marginal significant positive trend could be observed for physical functioning. The pain symptom questionnaire sum scores improved significantly after 12 weeks. The HADS did not change significantly. CONCLUSION: The data indicate that intradialytic HTEMS treatment of ESRD patients with peripheral neuropathy ameliorates various components of physical health.

High-frequency external muscle stimulation in acute kidney injury (AKI): potential shortening of its clinical course.

BACKGROUND: The prognosis of acute kidney injury (AKI) is markedly influenced by the degree of muscle protein catabolism. Since the current therapeutic strategies are rather limited, for the first time, we attempted to attenuate the hypercatabolism by high tone electrical muscle stimulation (HTEMS) in AKI patients. This kind of therapy may lower protein degradation via its effect on muscle activity as well as improving insulin resistance. Moreover, electrotherapy may improve renal function due to circulatory effects as well as lowering the sympathetic tone. METHODS: 34 patients with AKI Stage 3 were included; all required daily hemodialysis with a dose of Kt/V urea > 1. The patients were randomized into two groups of 17 patients each with and without HTEMS. The groups were comparable with regard to age, gender, underlying diseases, causes of AKI and the baseline biochemistry. HTEMS was performed intradialytically for 1 h. This new electromedical device is characterized by changes in the frequency between 4,100 and 33,000 Hz in short intervals (3 s) and also the amplitude and frequency are modulated simultaneously. RESULTS: The treatment was well tolerated and associated with an improved clinical outcome. As compared to the untreated patients the HTEMS group showed a significant shorter duration of oliguria, a faster decline of serum creatinine and urea levels, less need of dialysis treatment and a shorter period of hospitalization. The decline of urea was more marked than that of serum creatinine resulting in a significant lowering of the urea/creatinine ratio. This finding suggests a reduced catabolism of muscle proteins which - via a lower release of amino acids into the circulation - results in a decline of hepatic ureapoiesis. We hypothesize that in our AKI patients the improved protein catabolism contributed to the shortening of the clinical course of acute renal failure. CONCLUSION: This study suggests for the first time that HTEMS treatment of patients with AKI during hemodialysis is associated with an improved clinical outcome. To support this novel observation, a randomized controlled trial with a greater number of homogenous AKI patients should be performed.

Behaviour and hormonal status in healthy rats on a diet rich in Maillard reaction products with or without solvent extractable aroma compounds.

Maillard reaction products (MRPs) are generated upon thermal processing of foods, modifying their colour and flavour. We asked whether aroma compounds generated via Maillard-type reactions modulate the in vivo effects of MRP-rich diets (MRPD). Male Wistar rats were fed for 3weeks either with a standard rat chow, an aroma compounds containing MRPD comprising 25% bread crust, or an aroma-extracted MRPD. In contrast to standard rat chow, consumption of MRPDs affected glucose control, induced hyper-leptinemia and hyper-adiponectinemia. Plasma adipokines were significantly higher in rats on aroma containing MRPD in comparison with those consuming aroma-extracted MRPD. Consumption of both MRPDs significantly increased the expression of the insulin receptor in the olfactory bulb, and mildly in the hypothalamus. Administration of the aroma containing MRPD significantly increased the leptin receptor expression in the olfactory bulb, and in the hypothalamus. Under both MRPDs, strong expression of c-fos indicated an increased neuronal activity in the olfactory bulb. Neuronal activity in brain areas involved in the central regulation of food intake and energy homeostasis was more pronounced in rats fed by the aroma containing MRPD. In conclusion, short-term consumption of a MRPD fortified with bread crust, particularly if containing solvent extractable volatile aroma compounds, affected the leptin-induced central signalling of anorexigenic/orexigenic hormones, and the neuronal activity in the central nervous system. Behavioural changes and altered glucose control were more evident in rats on the aroma containing MRPD. Our data suggest that volatile aroma compounds in foods might affect endocrine signalling and neuronal regulation of metabolism.

Advanced oxidation protein products and advanced glycation end products in children and adolescents with chronic renal insufficiency.

OBJECTIVE: Advanced oxidation protein products (AOPPs) represent dityrosine-containing cross-linked protein modifications formed mainly via myeloperoxidase reaction, supposed to accelerate the uremia-associated atherogenesis and renal fibrosis. DESIGN, SUBJECTS, AND MAIN OUTCOME MEASURES: In a cross-sectional study, we investigated the accumulation of AOPPs and advanced glycation end product (AGE)-specific fluorescence corrected for albumin in children and adolescents with chronic renal failure (CRF, n = 42), end-stage renal disease (ESRD, n = 12), kidney transplanted patients (Tx, n = 16), and age-matched healthy controls (n = 38). RESULTS: AOPP levels were 2.4-fold higher in the CRF and ESRD patients, and 1.6-fold higher in the transplanted subjects when compared with the controls (P < .001). In comparison with healthy controls, AGE levels rose 2-fold in the CRF, 7-fold in the ESRD, and 5-fold in the kidney transplanted children and adolescents, (P < .001). Patients with cardiovascular affliction presented with higher AGE levels than those without diagnosed cardiovascular disease (P < .02). In patients with stabilized renal function, AOPP and AGE levels did not change significantly during 12 months. CONCLUSION: Pattern of accumulation of AOPP and AGE in children and adolescents with chronic renal disease differs. Accelerated rise in AOPP levels in some children and adolescents in predialysis stage of chronic renal insufficiency, inadequate to deterioration of renal function, might require further attention.

The peroxisome proliferator-activated receptor-α agonist, BAY PP1, attenuates renal fibrosis in rats.

Recent studies have shown renoprotective effects of the peroxisome proliferator-activated receptor-α (PPAR-α), but its role in kidney fibrosis is unknown. In order to gain insight into this, we examined the effect of a novel PPAR-α agonist, BAY PP1, in two rat models of renal fibrosis: unilateral ureteral obstruction and the 5/6 nephrectomy. In healthy animals, PPAR-α was expressed in tubular but not in interstitial cells. Upon induction of fibrosis, PPAR-α was significantly downregulated, and treatment with BAY PP1 significantly restored its expression. During ureteral obstruction, treatment with BAY PP1 significantly reduced tubulointerstitial fibrosis, proliferation of interstitial fibroblasts, and TGF-ß(1) expression. Treatment with a less potent PPAR-α agonist, fenofibrate, had no effects. Treatment with BAY PP1, initiated in established disease in the 5/6 nephrectomy, halted the decline of renal function and significantly ameliorated renal fibrosis. In vitro, BAY PP1 had no direct effect on renal fibroblasts but reduced collagen, fibronectin, and TGF-ß(1) expression in tubular cells. Conditioned media of BAY PP1-treated tubular cells reduced fibroblast proliferation. Thus, renal fibrosis is characterized by a reduction of PPAR-α expression, and treatment with BAY PP1 restores PPAR-α expression and ameliorates renal fibrosis by modulating the cross-talk between tubular cells and fibroblasts. Hence, potent PPAR-α agonists might be useful in the treatment of renal fibrosis.

Karl Peter's fundamental contribution to the structural organization of the kidney.

Karl Peter provided the first detailed description of the structure and morphology of the human kidney and defined at least 9 major segments of the tubules. He showed that the nephrons were heterogeneous in their structure and could be divided in 2 categories: the short-looped and the long-looped ones. Peter's scheme of the human nephrons was published in many journals and textbooks. Another contribution was the demonstration of a relationship between the relative occurrence of long thin loops (versus short loops) and the maximal urinary concentration capacity. Peter was also the first to describe the cells of the macula densa, which are of fundamental importance in the tubuloglomerular feedback mechanism. Furthermore, Peter gave a detailed description of the principal zones of the human kidney: the cortex, the outer medulla with outer and inner stripes, and the inner medulla.

AT1 receptor antagonist candesartan attenuates genomic damage in peripheral blood lymphocytes of patients on maintenance hemodialysis treatment.

BACKGROUND: Angiotensin II (ANG II) and advanced glycation end products (AGEs) exert genotoxic effects in vitro which were prevented by the ANG II type 1 (AT1) receptor blocker, candesartan. In end-stage renal disease (ESRD) the incidence of genomic damage is increased. A stimulation of the renin-angiotensin system and accumulation of AGEs could be involved. METHODS: We tested whether oral co-administration of candesartan modulates enhanced DNA damage in ESRD patients. Fifteen maintenance hemodialysis (MHD) patients with mild hypertension were treated with candesartan for 4.5 months. Fourteen MHD patients served as conventionally treated uremic controls. DNA damage was measured as micronucleus frequency (MNF) in peripheral blood lymphocytes and evaluated three times before candesartan therapy and afterwards every 6 weeks. RESULTS: Compared to 14 healthy controls, MNF at baseline was significantly elevated in MHD patients. While in the conventionally treated MHD patients the enhanced DNA damage persisted, the co-administration of candesartan ameliorated the genomic damage significantly and independently of blood pressure changes. CONCLUSION: Blockade of AT1 receptors with candesartan can reduce DNA damage in MHD patients. Long-term studies in larger patient groups are needed to investigate whether the improved genomic damage lowers atherosclerotic complications and cancer development.