Inflammation in end-stage renal disease: sources,consequences, and therapy

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Although traditional risk factors are common in ESRD patients, they alone may not be sufficient to account for the high prevalence of CVD in this condition. Recent evidence demonstrates that chronic inflammation, a nontraditional risk factor which is commonly observed in ESRD patients, may cause malnutrition and progressive atherosclerotic CVD by several pathogenetic mechanisms. The causes of inflammation in ESRD are multifactorial and, while it may reflect underlying CVD, an acute-phase reaction may also be a direct cause of vascular injury by several pathogenetic mechanisms. Available data suggest that proinflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. Thus it could be speculated that suppression of the vicious cycle of malnutrition, inflammation, and atherosclerosis (MIA syndrome) would improve survival in dialysis patients. Recent evidence has demonstrated strong associations between inflammation and both increased oxidative stress and endothelial dysfunction in ESRD patients. As there is not yet any recognized, or even proposed, treatment for ESRD patients with chronic inflammation, it would be of obvious interest to study the long-term effect of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status as well as outcome in these patients.     

Inflammation in end-stage renal disease: the hidden enemy

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in end-stage renal disease (ESRD) patients. As traditional risk factors cannot alone explain the unacceptable high prevalence and incidence of CVD in this high-risk population, inflammation (interrelated to insulin resistance, oxidative stress, wasting and endothelial dysfunction) has been suggested to be a significant contributor. Indeed, several different inflammatory biomarkers, such as high sensitivity C-reactive protein (hs-CRP), have been shown to independently predict mortality in ESRD patients. As CRP is so strongly associated with vascular disease it has been suggested that this hepatic-derived protein is not only a marker, but also a mediator, of vascular disease. Although in vitro data from studies on endothelial cells, monocytes-macrophages and smooth muscle cells support a direct role for CRP in atherogenesis, data from studies performed in vivo have been controversial. The causes of the highly prevalent state of inflammation in ESRD are multiple, including inflammatory signals associated with the dialysis procedure, decreased renal function, volume overload, comorbidity and intercurrent clinical events. As the prevalence of inflammation varies considerably between continents and races, dietary and/or genetic factors may have an impact on inflammation in ESRD. Elevated CRP in dialysis patients could be evaluated at three different levels: (i) national/regional level; (ii) dialysis unit level; and (iii) individual patient level.     

Role of nutrition for cardiovascular risk reduction in chronic kidney disease patients

Cardiovascular disease (CVD) is the major cause of death in end-stage renal disease (ESRD) patients. Uremic malnutrition and chronic inflammation are important comorbid conditions, closely associated with CVD risk in ESRD patients. A pathophysiologic link between uremic malnutrition, chronic inflammation, and atherosclerosis has been proposed in this patient population. Uremic malnutrition can result from chronic inflammation and can accelerate the progression of cardiovascular disease. Chronic inflammation can also directly predispose ESRD patients to a proatherogenic state. Both uremic malnutrition and chronic inflammation are also associated with increased oxidative stress, a condition proposed as a unifying concept of CVD in uremia. Although a single common etiology has not been identified in this complex process, nutritional, anti-inflammatory, and antioxidant interventions can provide potential treatment options to improve the high mortality and morbidity in ESRD patients.     

IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly

It has been increasingly apparent that wasting and cardiovascular disease (CVD) is associated with a persistent systemic inflammatory response in end-stage renal disease (ESRD) patients. The reasons for the increased risk of inflammation in ESRD patients appear to be complex, including non-dialysis as well as dialysis-related factors. The combination of an impaired immune response coupled with persistent immune stimulation may have a role in the low-grade systemic inflammation and altered cytokine balance that characterizes the uremic state and which may translate into increased risk for vascular disease. The accelerated atherosclerotic process of ESRD may involve several interrelated processes, such as oxidative stress, endothelial dysfunction, and vascular calcification, in a milieu of constant low-grade inflammation with impaired function of neutrophils and T cells, as well as a dysregulated cytokine network. Although a large number of pro- and anti-inflammatory cytokines are of importance, available data suggest that the anti-inflammatory cytokine interleukin (IL)-10 and the mainly proinflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNF-alpha) may play important roles in the development of Th imbalance, CVD and wasting in the uremic milieu. Given the strong association between proinflammatory cytokines and complications common in ESRD, such as vascular calcification and wasting, the potential role of both general and targeted anticytokine treatment strategies in ESRD patients needs further evaluation.     

Clinical assessment and management of dyslipidemia in patients with chronic kidney disease

Chronic kidney disease (CKD) is a common cause of cardiovascular disease (CVD). Several factors contribute to the onset and progression of atherosclerosis and CVD in CKD patients. Most of the cases of coronary heart disease in the general population can be explained by traditional risk factors, whereas non-traditional risk factors, including oxidative stress, anemia, inflammation, malnutrition, vascular calcification, and endothelial dysfunction, have been proposed to play a central role in the pathogenesis of CVD in CKD patients. However, the precise mechanism of CVD initiation in CKD patients remains unclear. Lipid-lowering therapies may decrease proteinuria, and increase or maintain renal function. Because the serum levels of triglyceride-rich lipoproteins are increased in CKD patients, particularly in advanced stages, the serum non-HDL cholesterol level may be a better biomarker of dyslipidemia than the serum LDL cholesterol level in this population. A meta-analysis showed that statin therapy was associated with decreased albuminuria in comparison with a placebo. Moreover, lipid-lowering therapy with statins is effective in reducing the risk of CVD in the early stages of CKD, whereas the benefit of statins in patients with end-stage renal disease may be limited.     

Oxidative stress in end-stage renal disease: an emerging threat to patient outcome.

INTRODUCTION: Patients affected by end-stage renal disease (ESRD) experience an excess of morbidity and mortality due to cardiovascular disease (CVD), which cannot be fully explained by the classical CVD risk factors. Among emerging CVD risk factors, oxidative stress is currently being given emphasis. METHODS: We achieved a consensus on key points relating to oxidative stress in ESRD patients. RESULTS: ESRD patients are subjected to enhanced oxidative stress, as a result of reduced anti-oxidant systems (vitamin C and selenium deficiency, reduced intracellular levels of vitamin E, reduced activity of the glutathione system) and increased pro-oxidant activity (advanced age, high frequency of diabetes, chronic inflammatory state, uraemic syndrome, bio-incompatibility of dialysis membranes and solutions). Oxidative stress and inflammation are deeply inter-related, as different oxidant free radicals are generated by phagocytic cells in response to inflammatory stimuli: both are related to endothelial dysfunction, as the endothelium is a source and a target of oxidants and participates in the inflammatory response. There is growing evidence, from experimental and clinical studies, that oxidative stress may be implicated in the pathogenesis of atherosclerosis and other complications of ESRD, namely dialysis-related amyloidosis, malnutrition and anaemia. Given that free radicals have very short half-lives (seconds), the clinical assessment of oxidative stress is based on the measurement of different stable oxidized compounds (such as lipid peroxidation products, advanced glycation and oxidation lipid and protein products, nucleic acid oxidation derivatives) or antibodies directed against oxidized epitopes (such as anti-oxidized low-density lipoprotein antibodies). At the same time, both enzymatic anti-oxidants (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic anti-oxidants (glutathione, vitamin C, vitamin E, negative inflammatory proteins) can be evaluated. However, many laboratory methods assessing various oxidative stress components still have to be standardized. Moreover, it is still uncertain whether it is better measuring plasma and/or intracellular concentrations or activities of these components. The possibility of improving patient outcome by therapeutic interventions aimed at reducing oxidative stress, e.g. by vitamin C or vitamin E supplementation, currently is to the fore, but results so far have remained inconclusive. CONCLUSIONS: It is important to consider oxidative stress as a potentially important source of patient morbidity and mortality, although this knowledge is not yet immediately applicable in the clinical arena. Further well-designed, randomized controlled clinical trials with anti-oxidants (e.g. vitamin E, vitamin C, N-acetyl cysteine, L-arginine) are required to establish evidence-based recommendations for clinical practice.     

Endothelial dysfunction and inflammation: what is the link?

Cardiovascular disease, resulting from arteriosclerotic remodeling of the vasculature, is the main cause of death in end-stage renal disease (ESRD) patients. Early during the course of arteriosclerosis, endothelial dysfunction can be detected in various vascular beds, including peripheral forearm arteries, as well as the coronary circulation. Furthermore, endothelial dysfunction seems to predict the prognosis of cardiovascular disease. Therefore, the question deserves attention whether endothelial dysfunction is simply a marker of cardiovascular disease, or an active player in the progress of the disease. A possible link between arteriosclerosis, endothelial dysfunction, and cardiovascular disease is increased oxidative stress. Inflammatory processes involved in the pathogenesis of arteriosclerosis enhance vascular O2- formation, leading to endothelial dysfunction. An activated renin angiotensin system, together with oxidized low-density lipoprotein, may play a prominent role for enhanced vascular oxidative stress. In this context, the endothelium is not only a target of oxygen radicals, but may also contribute to O2- formation. It is the aim of this article to highlight the interplay of inflammation, endothelial dysfunction, and oxidative stress.     

Different risk factors for vascular calcification in end-stage renal disease between diabetics and nondiabetics: the respective importance of glycemic and phosphate control

Vascular calcification is highly prevalent in dialysis patients, and significantly increases cardiovascular mortality. The presence and progression of vascular calcification is significantly associated with chronic inflammation and malnutrition. Disorders of mineral metabolism, particularly hyperphosphatemia, have been emphasized as risk factors for vascular calcification. Although vascular calcification has been reported to be highly prevalent in diabetic patients with end-stage renal disease (ESRD), the risk factors for vascular calcification in these patients have not been fully explored. Through a review of the literature and our recent studies examining vascular calcification in ESRD patients, hyperphosphatemia is significantly associated with vascular calcification in nondiabetic ESRD patients, while it may not be a significant risk factor for vascular calcification in diabetic ESRD patients. In diabetic patients, vascular calcification occurs long before the initiation of dialysis therapy, and the factors associated with vascular calcification in non-uremic diabetics appear to be hyperglycemia and related metabolic disorders, such as increased glycation and oxidative stress. In diabetic ESRD patients, hyperglycemia is also suggested to be a significant factor associated with the progression of vascular calcification. Thus, the importance of glycemic and phosphate control is suggested to be emphasized in diabetic and nondiabetic ESRD patients, respectively, for prevention of the progression of vascular calcification.     

POOR NUTRITIONAL STATUS AND INFLAMMATION: Linking Oxidative Stress and Inflammation in Kidney Disease: Which is the Chicken and Which is the Egg?

For end-stage renal disease (ESRD) patients, cardiovascular disease remains the single most common cause of excess morbidity and mortality. Furthermore, although the prevalence of traditional cardiovascular risk factors is high in the dialysis population, the extent and severity of associated cardiovascular morbidity and mortality remain disproportionate to traditional risk factor profiles. Consequently, considerable effort has been focused on "nontraditional" risk factors for cardiovascular events in this patient population. Among the examined nontraditional risk factors, increased oxidative stress as well as increased acute phase inflammation are postulated to be important contributors to uremic cardiovascular risk. Additional important uremic cardiovascular risk factors include malnutrition and endothelial dysfunction, both of which may be directly linked to the processes that cause increased oxidative stress and inflammation in uremia. In this context I review available data linking the pathogenesis of oxidative stress to acute phase inflammation and uremia. I also review data suggesting that oxidative stress in uremia directly contributes to the development of acute phase inflammation and that patients with higher levels of inflammation have higher levels of oxidative stress biomarkers. Similarly I review emerging data on the potential effects of antioxidant therapy on inflammatory biomarkers, as well as data suggesting that strategies to lower acute phase inflammation may also improve biomarkers of oxidative stress. Theoretical constructs evaluating the linkage of oxidative stress and inflammation in uremia and their contribution to the pathogenesis of atherosclerosis are suggested.     

Assessment of inflammation and nutrition in patients with end-stage renal disease

Malnutrition commonly occurs in patients with end-stage renal disease (ESRD), and hypoalbuminemia is considered the best clinical marker of malnutrition and mortality in this population. Recently, it has been recognized that a substantial number of patients with ESRD have serologic evidence of an augmented inflammatory response and moreover, inflammation may be as or more important than protein intake in causing hypoalbuminemia. In addition, the presence of inflammation may be a more powerful predictor of mortality than dietary protein intake. The presence of inflammation is often subtle and is detected by increased levels of the positive acute phase proteins, most notably C-reactive protein. The causes of the stimulation of the systemic inflammatory response may include reaction to dialyzer membranes, increased production of advanced glycosylated end-products, oxidative stress of uremia and overt and occult infections, especially unrecognized arteriovenous graft infections. There is a complex relationship between inflammation and nutritional status. Inflammation can cause both anorexia with protein-calorie malnutrition as well as wasting through mechanisms mediated by cytokines. Novel therapies will need to be developed to counter this systemic inflammation since it appears to be a major cause of mortality in patients with end-stage renal disease.     

A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients

Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD) patients and there is emerging evidence that genetic factors may contribute to the development of atherosclerosis. Myeloperoxidase (MPO) is an abundant enzyme involved in the production of free radicals. A functional G-->A single nucleotide polymorphism (SNP) has been identified at position -463, where the A allele is associated with lower MPO expression. To analyze the association between this SNP and inflammation, oxidative stress, and CVD, we studied a cohort of 155 ESRD patients (52 +/- 1 years, 62% males, 22% diabetics) shortly before the initiation of dialysis treatment. CVD was defined by medical history criteria; plasma interleukin-6 (IL-6) was used as a marker of inflammation, and plasma pentosidine as an estimation of oxidative protein damage. DNA from leukocytes was used for genotyping, performed by the pyrosequencing reaction. Only five patients (3%) had the genotype AA at the -463 position, whereas 38 (25%) had the GA and 112 (72%) had the GG genotype. No differences were noted in plasma IL-6 levels between the genotype groups, whereas the pentosidine levels were higher in the GG group (28.4 pmol/mg albumin [range, 8.5 to 123 pmol/mg albumin]) compared to the other two groups (21.4 pmol/mg albumin [range, 7.6 to 384 pmol/mg albumin; P < 0.05]). Patients with the GG genotype had a higher prevalence of positive serology for Chlamydia pneumoniae (51%) when compared to the carriers of the A allele (24%) (P < 0.05). The prevalence of CVD was lower in the AA (0%) and GA genotypes (18%), compared to the GG genotype (35%). The GG genotype was still associated with CVD after correction for age, diabetes, smoking, malnutrition, and inflammation. Our findings suggest that the -463 G-->A SNP, which supposedly results in lower MPO activity, is associated with a lower prevalence of CVD in ESRD patients. It could be speculated that this effect is mediated by a decreased oxidative stress due to lower production of free radicals.     

Thrombosis in end-stage renal disease

Although renal failure has classically been associated with a bleeding tendency, thrombotic events are common among patients with end-stage renal disease (ESRD). A variety of thrombosis-favoring hematologic alterations have been demonstrated in these patients. In addition, "nontraditional" risk factors for thrombosis, such as hyperhomocysteinemia, endothelial dysfunction, inflammation, and malnutrition, are present in a significant proportion of chronic dialysis patients. Hemodialysis (HD) vascular access thrombosis, ischemic heart disease, and renal allograft thrombosis are well-recognized complications in these patients. Deep venous thrombosis and pulmonary embolism are viewed as rare in chronic dialysis patients, but recent studies suggest that this perception should be reconsidered. Several ESRD treatment factors such as recombinant erythropoietin (EPO) administration, dialyzer bioincompatibility, and calcineurin inhibitor administration may have prothrombotic effects. In this article we review the pathogenesis and clinical manifestations of thrombosis in ESRD and evaluate the evidence that chronic renal failure or its management predisposes to thrombotic events.     

Diet, inflammation, and chronic kidney disease: getting to the heart of the matter

Cardiovascular disease (CVD) remains a leading cause of death in patients with chronic kidney disease (CKD). CVD is now thought to result from the interplay of several factors including inflammation, oxidative stress and endothelial dysfunction. Advanced glycation end products (AGE) are known to be elevated in patients with CKD and these compounds possess these pro-oxidant, pro-inflammatory and anti-endothelial properties. There has been a great deal of literature linking diet and inflammation, and recent work has shown the diet to be a significant contributor to the body's AGE pool. We herein hypothesize that a diet high in AGE plays an important role in the initiation of chronic subclinical inflammation that seems to underlie the high prevalence of CVD in CKD patients. Herein we will briefly examine the evidence linking different components of diet with inflammation in CKD patients. We will then focus on the role of dietary AGEs in inflammation and potentially CVD in CKD, and in conclusion, we will propose dietary modifications as part of a multifactorial approach to ameliorate unhealthy lifestyles among CKD patients. The most important message is that simple changes in culinary technique rather than in the food nutrient composition may be the most important part of preventing CVD in this population.     

Peritoneal dialysis and cardiovascular disease

Cardiovascular (CV) death is the most frequent cause of dying in peritoneal dialysis (PD) patients. Risk factors include not only those that can be present in the general population, but also those related to the presence of end-stage renal disease (ESRD) and factors that are specific for PD modality. Hypertension is the most important general risk factor in PD patients, while obesity remains controversial. Inflammation, malnutrition, calcifications and probably endothelial dysfunction and oxidative stress are all CV risk factors present in ESRD that contribute to mortality in PD patients. Additional CV risk factors in PD are related to the glucose load, leading to increasing insulin resistance and a more atherogenic lipid profile. The presence of glucose degradation products in conventional dialysis solutions is mainly related to the development of peritoneal abnormalities, but not directly to cardiovascular disease. Loss of residual renal function and ultrafiltration failure promote overhydration, which is the most important PD-related risk factor for CV disease.     

Characteristics and effects of inflammation in end-stage renal disease

Malnutrition and cardiovascular disease are associated with end-stage renal disease (ESRD) and both are closely associated with one another, both in cross-sectional analysis and when the courses of individual patients are followed over time. Inflammation, by suppressing synthesis of albumin, transferrin, and other negative acute-phase proteins and increasing their catabolic rates, either combines with modest malnutrition or mimics malnutrition, resulting in decreased levels of these proteins in dialysis patients. Inflammation also leads to reduced muscle mass by increasing muscle protein catabolism and blocking synthesis of muscle protein. More importantly, inflammation alters plasma protein composition and endothelial structure and function so as to promote vascular disease. Markers of inflammation, C-reactive protein (CRP), and interleukin (IL)-6 powerfully predict death from all causes and from cardiovascular disease in dialysis patients as well as progression of vascular injury. The causes of inflammation are likely multifactorial, including oxidative modification of plasma proteins, interaction of blood with nonbiocompatible membranes and lipopolysaccharides in dialysate, subclinical infection of vascular access materials, oxidative catabolism of endothelium-derived nitric oxide, and other infectious processes. Treatment should be focused on identifying potential causes of inflammation, if obvious, and reduction of other risk factor for cardiovascular disease.     

Pumping iron: revisiting risks, benefits and strategies in treatment of iron deficiency in end-stage renal disease

Iron deficiency is a common cause of anemia in patients with end stage renal disease (ESRD). Intravenous iron administration, especially in those requiring treatment with erythropoiesis stimulating agents (ESA) is an essential component of the management of anemia in ESRD patients. Iron improves hemoglobin, reduces ESA dose requirement and also has nonerythropoietic effects including improvement in physical performance, cognition and amelioration of restless leg syndrome. However, iron can promote oxidative stress, cause endothelial dysfunction, inflammation and tissue injury, and has a potential to cause progression of both CKD and cardiovascular disease. In this review, we discuss the benefits and risks associated with i.v. iron and the practical aspects of iron administration that can minimize the complications related to iron therapy in ESRD.     

Endothelial function, CRP and oxidative stress in chronic kidney disease

BACKGROUND: Chronic kidney disease (CKD) is associated with increased morbidity and mortality in cardiovascular disease (CVD). Apart from traditional risk factors, chronic inflammation, oxidative stress, malnutrition and endothelial dysfunction are important in CVD development in renal patients. Our aim was to investigate the relationship between high sensitivity C-reactive protein (CRP), endothelium dependent vasodilation (EDV) and oxidative stress markers in patients with CKD K/DOQI stage 3-5. METHODS: Measurements of CRP, conjugated dienes (CD), lipid hydroperoxide (LOOH), oxidized low density lipoprotein,glutathione and albumin were performed in 44 consecutive patients with CKD stage 3-5. EDV was measured by methacholine infusion in the brachial artery and venous occlusion plethysmography. RESULTS: Patients with high CRP had significantly lower glomerular filtration rates and albumin, but increased LOOH and CD. In multiple regression analysis, only LOOH and CD remained significant. Patients with poor EDV had increased urea and lower glutathione (GSH). In multiple regression analysis, GSH and urea were independently related to EDV. No correlation was found between CRP and endothelial function. CONCLUSION: CRP was related to lipid peroxidation, while endothelial function was related to intracellular oxidative stress in patients with CKD. CRP and EDV were unrelated to each other. Therefore, CRP and endothelial function could provide complementary prognostic information regarding future cardiovascular disorders in renal patients.     

Phospholipid plasmalogen, a surrogate marker of oxidative stress, is associated with increased cardiovascular mortality in patients on renal replacement therapy.

BACKGROUND: There is a high incidence of premature cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). Free radical-induced tissue damage is thought to play a major role in the pathogenesis of atherosclerosis, and there are several reports indicating an increased oxidative stress in ESRD. However, it is not well established that increased oxidative stress predicts cardiovascular mortality in ESRD. Plasmalogens, a group of phospholipids with a vinyl ether bond in the sn-1 position, are considered to be sensitive markers of oxidative stress. METHODS: Cardiovascular and non-cardiovascular mortality was recorded (follow-up time 1860+/-94 days) in 105 ESRD patients (mean age 51+/-2 years) in whom the fasting ratio of the erythrocyte levels of plasmalogens (DMA 16/C16:0 and DMA 18/C18:0) had been determined at the start of renal replacement therapy (RRT). The prevalence of malnutrition (subjective global assessment), diabetes mellitus (DM), smoking habits and CVD was also determined. RESULTS: Thirty-eight patients who died of CVD (0.066+/-0.003) had a significantly lower DMA 16/C16:0 ratio than 15 patients who died of non-cardiovascular causes (0.078+/-0.005; P<0.05) and 52 patients alive at follow-up (0.075+/-0.003; P<0.05). A Cox proportional hazard model analysis showed that a low (相似文献   

Use of single-nucleotide polymorphisms in the search for genetic modifiers of the uremic phenotype.

As the modern nephrology community continues to be burdened with growing numbers of patients with end-stage renal disease (ESRD) and exceptionally high mortality rates, it is obvious that progress in the development of preventive and therapeutic strategies has not been sufficient. This urges nephrologists to focus on the underlying mechanisms for ESRD morbidity and mortality, and in particular on cardiovascular disease (CVD), which is the major contributor to premature death in this patient group. The high prevalence of inflammation, vascular ossification, and oxidative stress in ESRD predisposes these patients to CVD. Because genetic risk factors may modulate the pathophysiologic response, genotype-phenotype association studies may provide ways of predicting individual disease progression and may shed some light on key regulatory pathways. Indeed, recent genetic association studies show that polymorphisms in candidate genes related to inflammatory signaling, vascular ossification, and oxidative stress response influence the uremic phenotype. DNA polymorphisms may also be used as nonconfounded tools in observational studies conducted to test causality, as stated by the mendelian randomization approach. To date, the collection of genetic data is no longer a limitation because genetic information is easily accessible in public databases and high-throughput genotyping technologies are available. Advanced bioinformatic tools are now warranted to facilitate the integration of accumulating genetic information with clinical and biochemical end points and, finally, to implement genotype-phenotype data in the care of patients with renal failure to better identify patients at high risk and to design novel personalized therapeutic and preventive strategies.     

Spontaneous leukocyte activation and oxygen-free radical generation in end-stage renal disease

Oxidative stress and inflammation are common features and major mediators of atherosclerosis in end-stage renal disease (ESRD). Available evidence for oxidative stress in ESRD is indirect and based on accumulation of byproducts of interactions of reactive oxygen species (ROS) with various molecules. Inflammation is a major cause of oxidative stress. To explore the direct link between oxidative stress and inflammation in ESRD, we studied leukocyte integrin expression and ROS production in 18 ESRD patients and 18 controls. ESRD patients showed elevated plasma malondialdehyde (MDA) and increased superoxide and hydrogen peroxide (H(2)O(2)) production by granulocytes and monocytes before dialysis. Hemodialysis resulted in a further rise in plasma MDA and H(2)O(2) production by granulocytes and monocytes. Surface expression of Mac-1 (CD11b and CD18) on granulocytes and monocytes was significantly increased (denoting cell activation) in ESRD patients. Granularity of granulocytes was significantly reduced before dialysis and declined further after dialysis. The magnitude of ROS production by granulocytes and monocytes was directly related with CD11b expression as well as plasma ferritin and parathyroid hormone levels and was inversely related to protein catabolic rate. Thus, this study provides direct evidence of spontaneous leukocyte activation and increased ROS generation (hence the link between oxidative stress and inflammation) in ESRD patients.