Inflammation In End-stage Renal Disease Patients Research Articles

Effect of Intradialytic Aerobic Exercise on C-Reactive Protein End Stage Renal Disease Patients

Background: Patients with end-stage renal disease (ESRD) have a high baseline level of systemic inflammation. Serum C-Reactive Protein is an inflammatory marker that is widely used because it is more affordable and available in most hospitals in developing countries. Patiens with ESRD tend to be less involved in physical activity when compared to sedentary patients in the same age group. The effect of intradialytic aerobic exercise on CRP levels has been widely studied, but the result studies about intradialytic aerobic exercise on CRP are still controversial. Objectives: To evaluate the effect of a 12-week intradialytic aerobic exercise program on serum CRP levels in ESRD at the Hemodialysis Installation of Dr. Soetomo Hospital, Surabaya Methods: The study was conducted from March to June 2021. Twenty-six ESRD patients divided into treatment and control groups were able to follow the study until the end. The treatment group did a low-intensity intradialytic exercise program for 12 weeks. Both groups were given education about inflammation in ESRD patients and continued drug therapy and diet as before. Serum CRP was checked before and after intervention. Results: There was a decrease in the mean CRP after the intervention, from 0.33 ± 0.33 to 0.27 ± 0.16 mg/dL but was no significant difference statistically (p=0.543) and the control group (p=0.08) and between the two groups (p=0.960). Conclusion: Intradialytic aerobic exercise has no effect on serum levels of C-reactive protein in end-stage renal disease patients

New Insights on End-Stage Renal Disease and Healthy Individual Gut Bacterial Translocation: Different Carbon Composition of Lipopolysaccharides and Different Impact on Monocyte Inflammatory Response.

Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.

Plasma oxalic acid as a trigger for oxidative processes in end-stage renal disease patients

The present study aimed to evaluate the changes in oxidative stress markers according to the concentration of plasma oxalic acid (POx) in end-stage renal disease (ESRD) patients.
 Methods. We conducted a cross-sectional observational study involving 72 ESRD patients and 30 relatively healthy individuals who served as a control reference group for evaluation of POx concentration. Among ESRD patients there were 32 hemodialysis (HD) patients and 40 peritoneal dialysis (PD). POx concentration was measured spectrophotometrically using a commercially available kit (MAK315, Sigma, Spain). Malonic dialdehyde (MDA), ceruloplasmin (CP), transferrin (TR), sulfhydryl groups (SH-groups), antioxidant blood capacity (AOC) and total peroxidase activity of erythrocytes (TPA) were measured and the oxidative stress index (OSI) was calculated in all examined patients.
 Results. A significant increase in POx concentration was observed in ESRD patients compared with healthy volunteers (p < 0.0001). The concentrations of MDA in serum, OSI in erythrocytes and serum of the examined patients were gradually increased, while serum levels of CP, AOC, SH-groups and TPA in erythrocytes, on the contrary, were decreased in accordance with the increasing trend of POx concentrations. Correlation analysis demonstrated a statistically significant direct relationship between POx concentration and MDA (r = 0.57; p <0.0001) and OSI (r = 0.64; p <0.0001). The inverse correlation was determined between POx and antioxidant markers: CP (r = -0.35; p = 0.007), SH-groups in serum (r = -0.3; p = 0.04) and erythrocytes (r = -0.53 ; p <0.0001).
 Conclusions. The intensity of oxidative-antioxidant balance disorders in the blood of ESRD patients has been associated with the POx concentration: the higher the concentration of POx was the more active oxidative processes and the more pronounced lack of antioxidant protective factors occurred. Further studies are needed to determine the role of POx in the initiation of oxidative stress and chronic inflammation in ESRD patients.

The effect of oral N-acetylcysteine on serum high sensitive CRP and plasma hemoglobin levels in end-stage renal disease patients under routine hemodialysis; a randomized placebocontrolled clinical trial

Background: Oxidative stress and systemic inflammation is increased in end-stage renal disease (ESRD) patients. Due to the various effects of oxidative stress in ESRD patients, different antioxidants have been evaluated. Objectives: In this study, we evaluated the effect of oral N-acetylcysteine (NAC) as an antioxidant on the serum high-sensitive C-reactive protein (hs-CRP) and plasma hemoglobin levels in the ESRD patients who were under routine hemodialysis. Patients and Methods: In this randomized placebo-controlled clinical trial, 51 ESRD patients under routine hemodialysis were randomly assigned to receive NAC 1200 mg daily for 1 month (n=26) or placebo (n=25). Laboratory findings including hemoglobin, ferritin, hsCRP were measured in patients before and after treatment. Results: NAC group compared to placebo group had significantly higher ferritin levels before treatment (p=0.02) and lower phosphorus levels after treatment (p=0.03). Comparing the results before and after treatment in each group, a significant reduction in hematocrit (p=0.002), ferritin (p=0.006), hs-CRP (p=0.02) and an increase in alkaline phosphatase levels (p=0.005) in NAC group and significant reduction in calcium levels (p<0.001) in placebo group was detected. No major side effects were seen. Conclusions: One month treatment with oral NAC resulted in reduced levels of hematocrit, ferritin and Hs-CRP, indicative of role of NAC in controlling inflammation in ESRD patients under hemodialysis. However, NAC was not effective in treatment of anemia, although the treatment duration was low.

End-Stage Renal Disease, Inflammation and Cardiovascular Outcomes.

Despite marked improvements in renal replacement therapy during the last 30 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients is still unacceptably high and comparable to that of many malignancies. Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in ESRD patients. However, traditional risk factors can only partially explain the high premature cardiovascular burden in this population. Nontraditional risk factors, including persistent low-grade inflammation, are critical in the pathogenesis of atherosclerosis, vascular calcification, and other causes of CVD and may also contribute to protein-energy wasting and other complications in chronic kidney disease (CKD) patients. Inflammatory biomarkers, such as high sensitivity C-reactive protein and interleukin-6, independently predict mortality in these patients. The causes of inflammation in CKD are multifactorial and include imbalance between increased production (due to multiple sources of inflammatory stimuli such as oxidative stress, acidosis, volume overload, co-morbidities, especially infections, genetic and epigenetic influences, and the dialysis procedure) and inadequate removal (due to decreased glomerular filtration rate or in ESRD patients, inadequate dialytic clearance) of pro-inflammatory cytokines. Though there are currently no established guidelines for the treatment of low-grade inflammation in ESRD patients, several strategies have been proposed, such as lifestyle modifications, pharmacological treatment, and optimization of dialysis. Further studies on pathways involved in pathogenic processes of inflammation in ESRD, and long-term effects of anti-inflammatory interventions targeting production or removal of cytokines or both on premature CVD and clinical outcomes in this patient group are warranted.

Neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio in evaluation of inflammation in end-stage renal disease

To evaluate the relationship between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and inflammation in end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). 100 ESRD patients on maintenance HD (mean ± SD age: 52.3 ± 1.7 years, 52% were males) were included in this cross-sectional study. Data on patient demographics, dry weight, body mass index, duration of HD (months), etiology of ESRD, delivered dose of dialysis (spKt/V), complete blood count, blood biochemistry and inflammatory markers including hs-CRP (mg/L), TNF-α (pg/mL), NLR, and PLR were recorded in all patients and compared in patients with hs-CRP levels of ≤ 3 mg/L vs. > 3 mg/L. other study parameters were also recorded. Compared to patients with lower hs-CRP levels, patients with hs-CRP levels of > 3 mg/L had significantly higher values for NLR (3.7 ± 0.2 vs. 2.7 ± 0.2, p < 0.01) and PLR (150.7 ± 6.9 vs. 111.8 ± 7.0, p < 0.001). Both NLR and PLR were positively correlated with hs-CRP (r = 0.333, p = 0.01 and r = 0.262, p = 0.001, respectively) and negatively correlated with transferrin saturation (%) (r = -0.418, p = 0.001 and r = -0.309, p = 0.002, respectively). Our findings in a cohort of ESRD patients on maintenance HD revealed higher values for NLR and PLR in patients with higher levels of inflammation along with a significant positive correlation of both NLR and PLR with hs-CRP levels. Being a simple, relatively inexpensive and universally available method, whether or not calculation of NLR and PLR offers a plausible strategy in the evaluation of inflammation in ESRD patients in the clinical practice should be addressed in larger scale randomized and controlled studies.

Association of E-selectin with hematological, hormonal levels and plasma proteins in children with end stage renal disease.

Background:Hypercoagulable state is a common serious problem in patients with end-stage renal disease (ESRD). ESRD patients are in a condition of chronic inflammation. An increased level of E-selectin, “a key adhesion molecule that regulates leukocyte bindings to endothelium at damaged sites,” accompanies the higher risk of inflammation in ESRD patients. We aimed to investigate the possible correlation among E-selectin as an adhesion molecule, coagulation factors, and inflammatory factors in children with ESRD.Materials and Methods:Thirty-five child patients with ESRD who had been on regular dialysis treatment were registered in our study. Nighteen sex- and age-matched healthy volunteers were used as the control group. Laboratory tests were requested for the evaluation of hematological and biochemical parameters, and parathyroid hormone (PTH), and for coagulation state; fibrinogen, protein C, and protein S were measured. The enzyme-linked immunosorbent assay (ELISA) (Biomerica, CA, and IDS, UK). for serum E-selectin assay was provided by R and D Systems (Abingdon, UK).Results:Hemoglubolin (Hb), blood urea nitrogen (BUN), creatinine, calcium, PTH, triglyceride (TG) concentrations in serum as well as E-selectin showed significant difference between the two study groups, as indeed was expected. Serum E-selectin was significantly higher (P value = 0.033) in dialysis patients than in healthy subjects. E-selectin was positively correlated only with phosphorus in ESRD children (r = 0.398, P = 0.018). No association was found for other parameters.Conclusion:Although in our study circulating E-selectin concentration “as an inflammatory maker” is independently positively associated with limited blood markers, for better evaluation, well-designed cohort studies should be examined in ESRD children.

Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients.

Approximately 5-10% of patients with end-stage renal disease (ESRD) exhibit hyporesponsiveness to erythropoiesis-stimulating agents (ESAs), defined as a continued need for higher than 300 IU/kg/week doses of epoetin or a 1.5 mg/kg/week dose of darbepoetin. ESA hyporesponsiveness contributes to the morbidity, mortality and health-care economic burden of ESRD patients. The most common causes of ESA resistance are absolute or functional iron deficiency and inflammation. Maintaining adequate iron stores is clearly accepted as the most important strategy for reducing the ESA requirement and for enhancing ESA efficacy. Recent clinical studies have shown that iron administration to ESRD patients is associated with an increased risk of infection and atherosclerosis. ESA hyporesponsiveness due to chronic inflammation in ESRD patients has been reported to be improved by a number of interventions, including the use of biocompatible hemodialysis membranes, ultrapure dialysate, ascorbic acid therapy, vitamin E supplementation, and statin therapy. Other causes of ESA hyporesponsiveness include inadequate dialysis, hyperparathyroidism, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, primary bone marrow disorders, myelosuppressive agents, hemoglobinopathies, hemolysis, and hypersplenism. This article summarizes the common causes of ESA hyporesponsiveness and the proposed therapeutic interventions.

Platelet‐to‐lymphocyte ratio better predicts inflammation than neutrophil‐to‐lymphocyte ratio in end‐stage renal disease patients

Neutrophil-to-lymphocyte ratio (NLR) was introduced as a potential marker to determine inflammation in end-stage renal disease (ESRD) patients. Recently, platelet-to-lymphocyte ratio (PLR) and NLR were found to positively correlated with inflammatory markers including tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in cardiac and noncardiac patients. Data regarding PLR and its association with inflammation are lacking in hemodialysis (HD) and peritoneal dialysis (PD) patients. Hence, we aimed to determine the relationship between PLR, NLR, and inflammation in ESRD patients. This was a cross-sectional study involving 62 ESRD patients (29 females, 33 males; mean age, 49.6 ± 14.6 years) receiving PD or HD for ≥6 months in the Dialysis Unit of Necmettin Erbakan University. PLR, NLR, C-reactive protein, TNF-α, IL-6 levels were measured. PLR, NLR, serum high sensitive C-reactive protein, IL-6, and TNF-α levels were significantly higher in PD patients when compared with HD patients. ESRD patients with PLR ≥ 140 had significantly higher NLR, IL-6, and TNF-α levels when compared to patients with PLR < 139. In the bivariate correlation analysis, PLR was positively correlated with NLR, IL-6, and TNF-α in this population. When we compared the association of PLR and NLR with IL-6 (r = 0.371, P = 0.003 vs. r = 0.263, P = 0.04, respectively) and TNF-α (r = 0.334, P = 0.008 vs. r = 0.273, P = 0.032, respectively), PLR was found to be superior to NLR in terms of inflammation in ESRD patients. Simple calculation of PLR can predict inflammation better than NLR in ESRD patients.

The Relationship Between Neutrophil-to-Lymphocyte Ratio and Inflammation in End-Stage Renal Disease Patients

Background: Patients with end-stage renal disease (ESRD) have elevated serum levels of inflammatory mediators including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6. Systemic inflammation was found to be correlated with coronary artery disease (CAD) in this population. Neutrophil-to-lymphocyte ratio (NLR) was introduced as a potential marker to determine inflammation in cardiac and non-cardiac disorders. Data regarding NLR and its association with inflammation are lacking. We aimed to determine the relationship between NLR and inflammation in ESRD patients. Material and methods: This was a cross-sectional study involving 61 ESRD patients (25 females and 36 males; mean age: 48.3 ± 14.5 years) receiving peritoneal dialysis (PD) or hemodialysis (HD) for ≥6 months in the Dialysis Unit of Selcuk University. NLR, CRP, TNF-α, and IL-6 levels were measured. Results: NLR, serum CRP, IL-6, and TNF-α levels were significantly higher in PD patients when compared with HD patients. ESRD patients with NLR ≥ 3.5 had significantly higher TNF-α levels when compared with patients with NLR < 3.5. In the bivariate correlation analysis, NLR was positively correlated with TNF-α in this population. Conclusions: Simple calculation of NLR can predict inflammation in ESRD patients.

Antioxidant Therapy Does Not Ameliorate Oxidative Stress and Inflammation in Patients With End-Stage Renal Disease

Oxidative stress and inflammation are common manifestations and major mediators of cardiovascular and many other complications of end-stage renal disease (ESRD). Oxidative stress and inflammation are intimately interrelated as each can cause the other. The present study tested the hypothesis that antioxidant therapy may alleviate oxidative stress and improve inflammation in ESRD patients. We studied 37 hemodialysis patients, of whom 20 were treated daily with a combination of vitamin E, 800 lU; vitamin C, 250 mg; vitamin B6, 100 mg; vitamin B12, 250 microg; and folic acid, 10 mg; whereas 17 patients were given placebo for 8 weeks. Predialysis levels of f-2 isoprostane and protein carbonyl (markers of oxidative stress), C-reactive protein (CRP) and IL6 (markers/ mediators of inflammation) were measured prior to and at 4 and 8 weeks after the onset of therapy. Kt/V, predialysis and postdialysis blood pressure, blood hemoglobin, erythropoietin requirement, plasma ferritin and transferrin saturation, and nutritional indexes were similar among the 2 groups at baseline and remained virtually unchanged throughout the study period. Likewise, plasma f-2 isoprostane, protein carbonyl, CRP, and IL-6 levels remained unchanged and were unaffected by antioxidant administration. In conclusion, the addition of a potent antioxidant cocktail to conventional vitamin supplements had no effect on severity of ESRD-induced oxidative stress, inflammation, hypertension, anemia, or nutritional disorders in hemodialysis patients. Thus, high doses of vitamins beyond the routinely prescribed vitamin supplements do not appear to be indicated in this population.

Tartrate-resistant acid phosphatase isoform 5a as an inflammation marker in end-stage renal disease

End-stage renal disease (ESRD) is often complicated by chronic inflammation and malnutrition. We tested whether serum tartrate-resistant acid phosphatase (TRACP) isoform 5a relates to other markers of inflammation in ESRD. Predialysis serum was collected from 99 ESRD patients (51 male, 48 female) aged 55 +/- 15 years and a control group of 36 healthy subjects (8 male, 28 female) aged 43.2 +/- 10.5 years. Serum TRACP 5a activity and protein, TRACP 5b activity and C-reactive protein (CRP) were estimated by in-house immunoassays. Commercial kits were used for serum bone-specific alkaline phosphatase, Ntelopeptides of Type I collagen, interleukin-6 (IL-6) and fetuin-A. Intact parathyroid hormone was determined by chemiluminescent assay. Albumin, cholesterol, triglycerides, ferritin and hemoglobin were compared to the hospital reference ranges. Bone mineral density (BMD) was measured at the heel in 69 patients and all control subjects and expressed as g/cm2 and age-corrected T-score. Mean (median) levels of all serum markers were significantly elevated in ESRD except fetuin-A, which was significantly reduced. Mean BMD (g/cm2) was not different than control, but mean T-score was significantly reduced. TRACP 5a protein correlated with CRP, triglycerides and ferritin, but not with IL-6 or any other nutritional or bone markers or BMD. TRACP 5b activity correlated with all bone markers and BMD, but not with inflammation or nutritional markers. Our findings suggest that TRACP 5a may be a useful marker to estimate the degree of inflammation in ESRD patients on chronic hemodialysis.

ANTIOXIDANT THERAPY DOES NOT AMELIORATE OXIDATIVE STRESS AND INFLAMMATION IN END-STAGE RENAL DISEASE PATIENTS.

Oxidative stress and inflammation are common manifestations of end-stage renal disease (ESRD) and major mediators of its cardiovascular and various other complications. Oxidative stress and inflammation are intimately interrelated as each can cause the other. The present study tested the hypothesis that antioxidant therapy may alleviate oxidative stress and thereby improve inflammation in ESRD patients. To test this hypothesis, we studied 37 hemodialysis patients of whom 20 (aged 53 ± 14 years) were treated with a combination of vitamin (V) E, 800 IU; VC, 250 mg; VB6, 100 mg; VB12, 250 μg; and folic acid, 10 mg daily for 8 weeks. The remaining 17 patients (aged 51 ± 15 years) received placebo. Predialysis levels of f-2 isoprostane (a marker of oxidative stress), C-reactive protein (CRP, a marker of inflammation), and interleukin (IL)-6 (a potent proinflammatory cytokine) were measured prior to and at 4 and 8 weeks after the onset of therapy. Diabetes was the cause of ESRD in 14 of the antioxidant-treated and 9 of the placebo-treated patients. Kt/V (1.56 ± 0.22 vs 1.61 ± 0.23), predialysis blood pressure (155 ± 79 vs 154 ± 8 mm Hg), hemoglobin (11.7 ± 1.3 vs 12.1 ± 1.2 g), and ferritin levels (217 ± 135 vs 301 ± 157 ng/mL) were similar among antioxidant- and placebo-treated groups at baseline and were virtually unchanged throughout the study period. Likewise, f-2 isoprostane, IL-6, and CRP concentrations remained unchanged and were unaffected by antioxidant or placebo administration. Moreover, no significant changes were observed in any clinical parameters. In conclusion, consumption of a high-dose antioxidant cocktail for 8 weeks failed to significantly change either the clinical or biochemical parameters or plasma markers of oxidative stress and inflammation in ESRD patients.

Interleukin-1 Gene Cluster Polymorphisms Are Associated with Nutritional Status and Inflammation in Patients with End-Stage Renal Disease

Background: Wasting and inflammation are two common risk factors for death in patients with end-stage renal disease (ESRD). Interleukin-1β (IL-1β) and its receptor antagonist (IL-1Ra) may play a pivotal role in the pathogenesis of wasting and inflammation. Methods: To investigate effects of the IL-1 gene cluster polymorphisms on wasting and inflammation, we studied 189 ESRD patients (52 ± 12 years, 62% males) close to the start of renal replacement therapy. 205 healthy volunteers served as controls. We analyzed the IL-1B –511C/T, –31C/T, and +3954C/T polymorphisms as well as a variable number of a tandem repeat (VNTR) in IL-1RN. Nutritional parameters included serum albumin level, subjective global nutritional assessment (SGA), and body composition evaluated by dual-energy X-ray absorptiometry (DXA). We used serum high-sensitivity C-reactive protein (hsCRP) as a marker of inflammation. Results: Wasting (SGA >1) was present in 31%, whereas inflammation (CRP ≧10 mg/l) was present in 36% of the patients. The male carriers of the –511T/T and –31C/C genotypes had a lower prevalence of wasting (p < 0.05), higher body mass index (BMI) (p < 0.05), and higher lean body mass (LBM) (p < 0.01). In a stepwise multiple regression model, age (p < 0.05), BMI (p < 0.01) and the IL-1B –511 genotype (p < 0.01) were independently associated with LBM. The carriers of the +3954T allele had a lower prevalence of inflammation (p < 0.05) and lower serum hsCRP (p < 0.05). The VNTR in IL-1RN was not associated with any markers. Conclusion: The investigated IL-1 gene cluster polymorphisms were associated with nutritional status and inflammation in ESRD patients, but marked differences were found between the genders. These polymorphisms could have prognostic utility for predicting wasting and inflammation in ESRD patients.

IL-10, IL-6, and TNF-α: 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.

Adipose tissue cytokines, insulin sensitivity, inflammation, and cardiovascular outcomes in end-stage renal disease patients

From an evolutionary perspective, Darwinian selection has favored insulin-resistant individuals, ie, those with a trait ensuring brain functioning in situations of extreme fuel deprivation. The ability to mount a powerful inflammatory response to infection was another survival advantage in our ancestors, and we now have solid evidence showing that these 2 traits, insulin resistance and inflammation (as measured by serum C-reactive protein [CRP]), are associated in modern human beings. In an analysis of 192 nondiabetic hemodialysis patients, leptin and adiponectin were related in an opposite fashion with insulin sensitivity in end-stage renal disease (ESRD) and interacted in determining insulin resistance in these patients. The risk of insulin resistance was about 6 times higher in ESRD patients with an unfavorable combination of the 2 adipokines (high leptin and low adiponectin) than in those with a favorable combination (low leptin and high adiponectin). Low adiponectin but not high leptin predicted incident cardiovascular events in this cohort. Neither leptin nor adiponectin were associated with CRP in a cross-sectional analysis, but they were linked in an opposite fashion to CRP in a longitudinal study in 21 patients with acute inflammation secondary to infection. High sympathetic activity predicts adverse cardiovascular outcomes in ESRD. Of note, we found that the risk for cardiovascular events is more than 3 times higher in patients with high sympathetic activity and low adiponectin than in those with high adiponectin and low sympathetic activity. The adipocyte hormones leptin and adiponectin are associated in an opposite fashion to insulin sensitivity and inflammation in ESRD patients. Relatively lower plasma adiponectin levels are associated with a higher rate of incident cardiovascular events. Finally, low adiponectin and high norepinephrine seem to be interacting factors in the dismal cardiovascular outcomes with ESRD.

Chronic Systemic Inflammation in Dialysis Patients: An Update on Causes and Consequences

Despite marked improvements in dialysis technology during the last 20 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients treated by dialysis is still unacceptably high and comparable to that of many cancer patients with metastases. The main cause of the increased mortality in ESRD patients is cardiovascular disease (CVD), which is twice as common and advances at twice the rate already in patients with early stages of chronic kidney disease as compared to the general population. Although traditional risk factors for CVD are common in dialysis patients, they can only in part explain the very high prevalence of CVD in this patient group. Recent evidence demonstrates that chronic inflammation, a non-traditional risk factor which is a commonly observed in dialysis patients, may cause progressive atherosclerotic CVD and malnutrition, itself an important risk factor for the development of CVD, by several pathogenetic mechanisms. The causes of inflammation in dialysis are multifactorial and include both dialysis-related and unrelated factors. While the long-term effects of chronic inflammation may be most important in the pathogenesis of CVD, the acute-phase reaction may also cause vascular damage by several pathogenic mechanisms. Indeed, it seems logical to speculate that suppression of the vicious cycle of malnutrition, inflammation, and atherosclerosis (MIA syndrome) in ESRD would improve survival and decrease co-morbidity in dialysis patients. As there are currently no established guidelines for the treatment of chronic inflammation in ESRD patients, more studies on the long-term effects of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status, as well as outcome in this patient group, are clearly warranted and will be helpful in identifying precisely which pathways are most involved in the pathogenic process.

Inflammation in ESRD: Causes and potential consequences

Malnutrition in end-stage renal disease (ESRD) is characterized by hypoalbuminemia, decreased serum creatinine and prealbumin, and decreased subjective global assessment (SGA) scores. Markers of malnutrition predict mortality and correlate closely with inflammatory markers, including serum cytokines and acute phase proteins. After multiple regression analysis, markers of inflammation become stronger predictors of mortality than nutritional markers, suggesting that malnutrition is a result of inflammation. The etiology of inflammation is variable and includes vascular access infection, bioincompatible dialyzers, back filtration of nonsterile dialysate, periodontal disease, urinary tract infections, and other pyogenic infections. Renal failure also may serve to promote inflammation through protein carbonylation. Differences in care patterns of ESRD patients and genetics may contribute to inflammation as evidenced by lower levels of C-reactive protein (CRP) in Asian populations. Inflammation results in loss of muscle mass and hypoalbuminemia as a consequence of its decreased synthesis and increased catabolism. Vascular disease occurs partly because of changes in lipoprotein structure and function, including oxidation of low-density lipoprotein (LDL) and modification of high-density lipoprotein (HDL) by serum amyloid A (SAA) and loss of apolipoprotein A-I. Leukocyte adhesion is promoted by changes in endothelial structure and function, whereas plasma proteins associated with cardiovascular disease (fibrinogen, lipoprotein[a]; SAA) are increased. Consequences of inflammation in ESRD patients include muscle wasting, erythropoetin resistance, and vascular disease. Whereas improvements in nutrition can increase serum albumin and creatinine levels, identification and removal of the underlying cause of inflammation should be one treatment goal. © 2003 by the National Kidney Foundation, Inc.

Importance of Periodontal Disease in the Kidney Patient

End-stage renal disease (ESRD) patients on hemodialysis experience a greatly increased rate of atherosclerotic complications. In both hemodialysis and general populations, it has become evident that inflammation plays a central role in the pathogenesis of atherosclerotic complications. C-reactive protein (CRP), the major acute phase protein in man, has been found to predict all-cause and cardiovascular mortality in ESRD patients on hemodialysis maintenance therapy. Hepatic CRP synthesis is upregulated by proinflammatory cytokines released locally at sites of infection or inflammation, although many patients experience elevated CRP values in the absence of overt infection or inflammation. Destructive periodontal diseases in the general population have been associated with both an increased prevalence of atherosclerotic complications and an elevation in serum CRP values. In view of the prevalence of destructive periodontal diseases in the general population, and since periodontal evaluations are normally not performed as part of a medical assessment, destructive periodontal diseases may be an over looked source of inflammation in ESRD patients on hemodialysis therapy. The intent of this report is to review the possible role destructive periodontal diseases and associated periodontal infections may play in the management of the ESRD patient on hemodialysis maintenance therapy.

Effects of dialyzer membrane on interleukin-1β (IL-1β) and IL-1β—converting enzyme in mononuclear cells

In vitro stimulation of mononuclear cells (peripheral blood mononuclear cells; PBMCs) with an endotoxin (lipopolysaccharide; LPS) revealed elevated cell-associated levels of interleukin-1beta (IL-1beta) in end-stage renal disease (ESRD) patients on Cuprophan hemodialysis (HD), suggesting a defect in the process of IL-1beta's release from activated cells. IL-1beta is initially synthesized as an inactive precursor called proIL-1beta. ProIL-1beta is processed into the biologically active mature form of IL-1beta (mIL-1beta) requiring the specific IL-1beta-converting enzyme (ICE). Using specific immunoassays (enzyme-linked immunosorbent assays), we measured cell-associated and extracellular proIL-1beta as well as mIL-1beta in LPS-stimulated PBMCs to test whether ICE-dependent processing of proIL-1beta and/or secretion of mIL-1beta was impaired in ESRD patients compared with healthy controls. PBMCs of healthy controls (N = 9), of ESRD patients on peritoneal dialysis (PD, N = 10), and of those patients on intermittent HD (N = 8) were studied. The same HD patients were studied three times with low-flux Cuprophan (GFS 12), low-flux polysulfon (F6 HPS), and high-flux polysulfon (F60S) in randomized order. PBMCs were separated from whole blood by Ficoll-Hypaque centrifugation and incubated in vitro for 18 hours in the presence LPS (10 ng/mL). Extracellular (PBMC culture supernatants) and cell-associated (cell lysates) levels of proIL-1beta and mIL-1beta were measured. The total production (cell-associated plus extracellular) of LPS-induced IL-1beta (proIL-1beta plus mIL-1beta) was similar in healthy controls (25.96 +/- 0.84 ng/2.5 x 10(6) PBMC), PD patients (29.53 +/- 1.31 ng/2.5 x 106 PBMC), and in Cuprophan-treated HD patients (23.28 +/- 1.24 ng/2.5 x 10(6) PBMC). In normal controls, 43.6% of the total IL-1beta was processed into mIL-1beta, which was significantly more than that in PD patients (27.3%, P < 0.02) but was similar to that in Cuprophan-treated HD patients (37.1%). Comparing cell-associated and extracellular concentrations of mIL-1beta, PBMCs of normal controls secreted 82.2% of mIL-1beta; this was significantly more than that in PD patients (59.4%, P < 0.01) and that in Cuprophan HD patients (54.2%, P < 0.01). When HD patients were switched from Cuprophan to F6 HPS or F60S, neither total IL-1beta production nor processing of IL-1beta changed. However, secretion of mIL-1beta increased significantly with F6 HPS (80.6%, P < 0.01) as well as with F60S (76.6%, P < 0.02) compared with Cuprophan. We conclude that the ability of PBMCs to produce IL-1beta in response to LPS is normal in PD patients as well as in HD patients. ICE-dependent processing of inactive proIL-1beta into biologically active mIL-1beta is reduced in PD patients, but not in HD patients. Secretion of mIL-1beta is impaired in PD and HD patients treated with Cuprophan. This impaired ability to secrete active mIL-1beta seems to be independent of ICE activity and is normalized when HD-patients are switched from Cuprophan to low- or high-flux polysulfon. Increased cell-associated levels of biologically active mIL-1beta in circulating PBMCs represent a state of inflammation that may contribute to chronic inflammatory diseases such as beta2-microglobulin amyloidosis. Replacement of Cuprophan by synthetic membranes normalizes PBMC function and reduces the state of inflammation in ESRD patients.