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Objective: Fiber intake influences disturbances in the gastrointestinal tract and is associated with systemic inflammation in the general population. Systemic and intraperitoneal inflammation play an important role in defining outcomes in peritoneal dialysis (PD), but the relationship between dietary fiber intake and inflammatory biomarkers has not yet been reported in the population on PD. The objective of the present study is to analyze whether or not fiber intake in patients on PD is associated with serum and intraperitoneal levels of inflammatory biomarkers., Design and Methods: Adult and clinically stable PD patients were included in this observational and cross-sectional study. Fiber intake was assessed by means of a dietary survey and calculated using the DietPro program 5.6i. The population was divided into two groups according to the median fiber intake. We investigated interleukin (IL)-1β, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1 (MCP-1), B-cell-activating factor, and plasminogen-activator inhibitor-1 in both serum and peritoneal fluid. The latter was determined after a dwell time of 4 hours., Results: Fifty-two patients (42% men; aged 53 ± 14 years, 36% diabetics) were evaluated. Low intake of dietary fiber was found in 90% of patients, with a median of 12.2 g per day (3.4-33.3). The group with the highest fiber intake presented lower intraperitoneal levels of IL-6, IL-8, and MCP-1. In contrast, only MCP-1 was lower in the serum of those who consumed more fiber. All the associations remained significant after adjustment for confounders with plasminogen-activator inhibitor-1 included., Conclusions: Patients on PD frequently present inadequate dietary fiber intake, which appears to have an association with the inflammatory response, particularly in the intraperitoneal component. Further prospective studies, evaluating whether or not a dietetic intervention with a focus on fiber intake affects these biomarkers and clinical outcomes, are essential to determine causality and clinical relevance., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

In a recent study, Lambie and colleagues suggest that systemic and local intraperitoneal inflammation, evidenced by elevated levels of interleukin-6, are independent processes and have different consequences for patients undergoing peritoneal dialysis. Prevention of inflammation in these patients will, therefore, require different therapeutic approaches.

Peritoneal dialysis therapy has increased in popularity since the end of the 1970s. This method provides a patient survival rate equivalent to hemodialysis and better preservation of residual renal function. However, technique failure by peritonitis, and ultrafiltration failure, which is a multifactorial complication that can affect up to 40% of patients after 3 years of therapy. Encapsulant peritoneal sclerosis is an extreme and potentially fatal manifestation. Causes of inflammation in peritoneal dialysis range from traditional factors to those related to chronic kidney disease per se, as well as from the peritoneal dialysis treatment, including the peritoneal dialysis catheter, dialysis solution, and infectious peritonitis. Peritoneal inflammation generated causes significant structural alterations including: thickening and cubic transformation of mesothelial cells, fibrin deposition, fibrous capsule formation, perivascular bleeding, and interstitial fibrosis. Structural alterations of the peritoneal membrane described above result in clinical and functional changes. One of these clinical manifestations is ultrafiltration failure and can occur in up to 30% of patients on PD after five years of treatment. An understanding of the mechanisms involved in peritoneal inflammation is fundamental to improve patient survival and provide a better quality of life.

Background: Renal failure is associated with activation of inflammatory response, but the mechanisms behind this observation and potential anti-inflammatory strategies are yet to be defined. Endotoxin (ET) translocation from the intestinal lumen can potentially trigger systemic inflammatory response, and ET binding represents a potential anti-inflammatory strategy in renal failure. The aim of this study was to evaluate the ET-binding capacity of sevelamer carbonate in an animal model of renal failure., Material and Methods: Rats were 5/6 nephrectomized to induce uremia (U) and sham-operated rats were allocated to receive normal chow (controls) or a diet with 3% sevelamer carbonate added (+SC) for 60 days. Tumor necrosis factor-α (TNF-α) and ET were measured in plasma on days 7, 30 and 60 in all animals., Results: Renal failure induced an inflammatory response, since TNF-α levels were undetectable in all control animals in contrast to the uremic group (3.18 ± 0.62, 2.58 ± 0.54 and 1.86 ± 0.47 pg/ml, respectively, on days 7, 30 and 60; p < 0.05 at all time points). Similarly, uremic rats presented an increase in ET levels (0.038 ± 0.007 EU/ml) when compared to sham-operated animals (0.008 ± 0.006 EU/ml; p < 0.05). During the study, TNF-α levels in U + SC rats were significantly lower compared with U-control animals (p < 0.05). Similarly, ET levels in U + SC rats were lower when compared with U-control rats (p < 0.005)., Conclusion: In conclusion, induction of renal failure triggered inflammation and induced endotoxemia in this experimental model of chronic kidney disease, which were reduced by sevelamer treatment. This data suggests that sevelamer carbonate induces an anti-inflammatory effect in parallel to a reduction in ET., (Copyright © 2010 S. Karger AG, Basel.)

From the immunologic viewpoint, chronic kidney disease (CKD) is characterized by disorders of both the innate and adaptive systems, generating a complex and still not fully understood immune dysfunction. Markers of a chronically activated immune system are closely linked to several complications of CKD and represent powerful predictors for mortality in the CKD population. On the other hand, CKD patients respond poorly to vaccination and to challenges such as bacterial infection. Interestingly, the main causes of death in patients with CKD are cardiovascular and infectious diseases, both being pathologic processes closely linked to immune function. Therefore, accelerated tissue degeneration (as a consequence of chronic inflammation) and increased rate of sepsis (because of a poorly orchestrated immune response) represent the most important targets for interventions aiming to reduce mortality in CKD patients. Understanding the mechanisms behind the immune dysfunction that is peculiar to CKD generates a perspective to improve outcomes in this group of patients.

Malnutrition and inflammation are closely linked in adult chronic kidney disease (CKD) patients and are both related to poor outcome, but data on pediatric patients are lacking. To describe the prevalence of inflammation, evaluate nutritional status, their correlation to each other, and their possible determinants in pediatric patients with CKD in predialysis, on hemodialysis (HD), and peritoneal dialysis (PD) who were submitted to demographic, nutritional, and inflammatory evaluations. Patients' nutritional status was evaluated according to anthropometric parameters and body composition assessed by measurements of skinfold thickness and bioelectrical impedance. Inflammation was assessed by measurement of highly sensitive C-reactive protein (CRP), ferritin, and albumin. Patients with CRP > 1 mg/l were considered inflamed. Sixty-four pediatric patients (mean age 9 +/- 4 years-, 40% on HD, 22% on PD, and 38% predialysis) were studied. Mean CRP concentration was 3.4 +/- 6.5 mg/l (median 0.78 mg/l, range 0.78-33.4 mg/l), and 41% presented CRP levels above 1 mg/l. Mean ferritin was 148 +/- 197 mg/dl and was above the normal reference values in 28% of patients. On the other hand, mean albumin was 3.9 +/- 0.5 mg/dl, below reference value in only 13% of patients. A larger proportion of HD patients (52%) were inflamed compared with those on PD (31%; p < 0.05). Malnutrition prevalence varied from 5% to 65% according to the method used. While inflamed patients presented lower serum bicarbonate and were on HD for a longer time, there were no consistent associations between malnutrition and inflammation. Inflammation is highly prevalent in the pediatric CKD population and was not consistently related to malnutrition. Other risk factors linked to high mortality and morbidity (acidosis and longer time on dialysis) were associated with inflammation. Prospective studies will need to analyze the predictive value of inflammation and malnutrition markers in the pediatric CKD population.

Cardiovascular (CV) disease is the main cause of death in peritoneal dialysis (PD) patients, but the mechanisms mediating the increased CV risk observed in this group of patients are still largely unknown, which limits the perspective on effective therapeutic strategies. Patients on PD are already exposed to a number of traditional risk factors from the start of their chronic kidney disease (CKD), because many of those risk factors are common to CV disease and CKD alike. As renal dysfunction progresses, CKD-related risk factors are introduced, changing the profile of both the CV disease and the markers of risk. In this phase, which usually starts when glomerular filtration rate falls below 60 mL/min, the list of risk factors is expanded to include disturbances of mineral metabolism, anemia, fluid overload, uremic toxicity, and increased signs of oxidative stress and inflammation. Although many of the risk factors linked to CV burden are not related to the dialytic procedure, additional harm is introduced after the initiation of PD--with, for example, the presence of chronic infections and factors related to PD fluids, particularly reabsorption of glucose. In the present article, we review the impact of the novel risk factors introduced with the initiation of PD therapy, and we propose potential therapeutic strategies (which remain to be tested) for reducing CV mortality in this group of patients.

Peritoneal dialysis (PD) patients present an extremely high mortality rate, but the mechanisms mediating the increased risk of mortality observed in this group of patients are still largely unknown, which limits the perspective of effective therapeutic strategies. The leading hypothesis that tries to explain this high mortality risk is that PD patients are exposed to a number of traditional risk factors for cardiovascular disease (CVD) already at the onset of their chronic kidney disease (CKD), since many of these risk factors are common to both CVD and CKD. Of particular importance, chronic inflammation recently emerged as an important novel risk factor related to multiple complications of CKD. There are many stimuli of the inflammatory response in CKD patients, such as fluid overload, decreased cytokine clearance, presence of uremia-modified proteins, presence of chronic infections, metabolic disturbances (including hyperglycemia), obesity. Many of these factors are related to PD. Latin America has made some progress in economic issues; however, a large portion of the population is still living in poverty, in poor sanitary conditions, and with many health-related issues, such as an increasing elderly population, low birth weights, and increasingly high energy intake in the adult population, which, in combination with changes in lifestyle, has provoked an increase in the prevalence of obesity, diabetes, and CVD. Therefore, in Latin America, there seems to be a peculiar situation combining high prevalence of low education level, poor sanitary conditions, and poverty with increases in obesity, diabetes, and sedentary lifestyle. Since inflammation and mortality risk are intimately related to both sides of those health issues, in this review we aim to analyze the peculiarities of inflammation and mortality risk in the Latin-American PD population.

Does inflammation, as assessed by high sensitivity C-reactive protein (hs-CRP), in patients with end-stage renal disease (ESRD) tightly associate with increased serum levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8- oxo-dG)? Increased oxidative stress and inflammation have both been highlighted among several nontraditional risk factors for cardiovascular disease, which is the main cause of mortality in ESRD patients. In contrast to oxidative stress effects on proteins and lipids, DNA base damage has not been well demonstrated in ESRD. Two groups of hemodialysis patients were studied, one group with persistent inflammation (n = 13, with constant elevation of CRP > 10 mg/L for 6 months) and one group of noninflamed patients (n = 19, with constant CRP < 10 mg/L for 6 months). Serum 8-oxo-dG was significantly elevated in persistent inflammation in comparison to noninflamed patients. At an individual level, a significant correlation was found between serum 8-oxo-dG and hsCRP. Extracellular 8-oxo-dG leads to intracellular oxidative damage on the nucleotide pool, thus providing a sensitive marker for inflammatory response. Serum levels of 8-oxo-dG, in combination with other inflammatory markers, serve as useful diagnostic tools for identification of patients in risk for inflammatory complications.

Background: Inflammation and malnutrition are common in chronic kidney disease (CKD) patients, and plasma concentrations of free amino acids (AAs) in these patients are often abnormal. Malnutrition contributes to alterations in AA concentrations., Objective: The objective was to study the effects of inflammation on plasma AA concentrations., Design: Concentrations of plasma AAs, serum albumin, and several inflammatory markers were analyzed in 200 fasting, nondiabetic CKD patients who were close to the start of renal replacement therapy. The nutritional status of these patients was assessed by a subjective global assessment., Results: The patients with inflammation [C-reactive protein (CRP) concentrations >10 mg/L] or malnutrition had lower AA concentrations than did the patients with no inflammation or malnutrition. The presence of both inflammation and malnutrition was associated with more marked reductions in AA concentrations than was malnutrition alone. Significant inverse correlations were observed between the plasma concentrations of most of the essential and nonessential AAs and inflammatory markers, whereas serum albumin concentrations were positively correlated with several AA concentrations. A stepwise multivariate regression analysis showed that serum CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs. An analysis of all-cause mortality with a Kaplan-Meier test showed that the patients with higher AA concentrations had significantly better survival than did the patients with lower AA concentrations., Conclusions: Plasma AA concentrations are low in CKD patients with inflammation and are inversely correlated with concentrations of inflammatory markers. Although inflammation and malnutrition are closely related, CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs, which suggests an independent role of inflammation as a cause of low plasma AA concentrations in CKD patients.

Although traditional risk factors for cardiovascular disease are common in dialysis patients, they alone cannot explain the unacceptably high prevalence of vascular disease in this patient group. Much recent interest has therefore focused on the role of various nontraditional cardiovascular risk factors, such as inflammation, wasting, obesity, vascular calcification, and oxidative stress. In addition, genetic factors such as single nucleotide polymorphisms (SNPs) may significantly influence the immune response, the levels of inflammatory markers and body composition, as well as the prevalence of vascular calcification in this patient group. While genetic variations in the tumor necrosis factor (TNF)-alpha-308 and interleukin (IL)-10 -1082 SNPs seem to be consistently associated with adverse clinical outcome in end-stage renal disease (ESRD) patients, the results regarding genetic variations in the IL-6 gene have been conflicting. To elucidate the respective role of DNA polymorphisms in the IL-6 and C-reactive protein (CRP) genes, as well as genes that encode vascular calcification inhibitors (such as fetuin-A, matrix Gla protein, and osteoprotegerin), sufficiently powered studies are needed in which both the protein product and the specific phenotype are determined. In addition, polymorphisms in genes related to body composition may be excellent candidates for analysis in the ESRD population, since nutritional parameters are strongly associated with adverse events in these patients. It seems conceivable that in the future, prognostic or predictive multigene DNA assays (which allow a simultaneous and rapid assessment of multiple genetic variants) will provide nephrologists with a more precise approach for the identification of "high-risk" ESRD patients and the development of accurate individualized treatment strategies.

Signs of an activated immune system can be observed already in the early stages of chronic kidney disease (CKD). Markers of a chronically activated immune system are closely linked to several complications of CKD, such as accelerated atherosclerosis, vascular calcification, insulin resistance, increased muscle catabolism, loss of appetite, bone remodeling, and increased peritoneal permeability. Interestingly, all the aforementioned pathological states resemble a state of accelerated ageing and are strongly associated with increased morbidity and mortality in CKD patients. In recent studies, signs of inflammation have been shown as predictors for mortality in dialysis patients, and the role of inflammation as a risk factor for complications of CKD in children has emerged. Although preliminary findings suggest that inflammation is highly prevalent in the pediatric population with CKD, information related pathogenic links and to clinical outcomes is lacking. For the future, it is crucial for investigations to address the mechanisms and complications of inflammation that are manifested in pediatric patients with CKD in all stages. Since early identification and intervention may generate the most efficient strategies for prevention and treatment of cardiovascular disease in CKD patients, the pediatric population deserves special attention in future studies. In this review, we discuss the mechanisms involved in the inflammatory activation and the main causes and consequences of the inflammatory state observed in the CKD patient, with special emphasis on the pediatric population.

Background: Wasting and inflammation are two common risk factors for death in patients with end-stage renal disease (ESRD). Interleukin-1beta (IL-1beta) 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., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: An activated inflammatory response is a common feature of end-stage renal disease (ESRD) and predicts outcome. Adipose tissue is an endocrine organ that may contribute to an inflammatory burden by secreting adipocytokines such as interleukin 6 (IL-6)., Objective: The objective was to relate plasma concentrations of IL-6 in ESRD patients to body composition, regional fat mass distribution, and blood lipid profiles., Design: One hundred ninety-seven ESRD patients (123 men; +/- SE age: 52 +/- 1 y) were evaluated shortly before dialysis started. Lean body mass and truncal and nontruncal fat mass were estimated by dual-energy X-ray absorptiometry. Nutritional status was evaluated on the basis of subjective global assessment and handgrip strength. Inflammatory biomarker and blood lipid concentrations were also evaluated., Results: Median IL-6 (8.5 compared with 4.5 pg/mL; P < 0.001) concentrations were significantly greater in malnourished than in well-nourished patients. Moreover, negative correlations were observed between IL-6 and serum creatinine (rho = -0.19, P < 0.01), handgrip strength (rho = -0.24, P < 0.001), and serum albumin (rho = -0.34, P < 0.001). A significantly higher truncal fat mass (12.8 +/- 0.7 compared with 10.5 +/- 0.4 kg; P < 0.005) was observed in ESRD patients with inflammation (C-reactive protein >/= 10 mg/L). Inverse correlations were observed between plasma IL-6 and HDL cholesterol (rho = -0.16, P < 0.05) and apolipoprotein A (rho = -0.23, P < 0.001)., Conclusions: Plausible relations exist between inflammatory biomarkers, such as IL-6 and high-sensitivity C-reactive protein, and regional fat distribution in ESRD patients. Moreover, the strong inverse relations between HDL cholesterol and apolipoprotein A and biomarkers of inflammation suggest that the chronic inflammatory response observed in ESRD patients is an important contributor to the atherogenic lipoprotein profile in uremia.

Mortality and morbidity in chronic kidney disease (CKD) patients are unacceptably high. The annual mortality rate due to cardiovascular disease (CVD) is approximately 9%, which, for the middle-aged person, is at least 10- to 20-fold higher than for the general population. Classic risk factors for CVD are highly prevalent in CKD patients, but they cannot fully account for the excessive rate of CVD in this population. Instead, it has become increasingly clear that nontraditional risk factors, such as systemic inflammation, may play a key role in the development of atherosclerosis. It is well established that inflammatory markers are very powerful predictors of high CVD morbidity and mortality not only in the general population, but particularly in CKD patients. Signs of a sustained low-grade inflammation, such as increased levels of C-reactive protein (CRP), are present in the majority of stage 5 CKD patients, even in patients in clinically stable condition, and they are also commonly observed after the initiation of dialysis therapy. Dialysis therapy--hemodialysis as well as peritoneal dialysis (PD)--may itself contribute to systemic inflammation. Local intraperitoneal inflammation can also occur in patients treated with PD. These local effects may result in a low-grade inflammation, caused by the bioincompatibility of conventional glucose-based dialysis fluids, to intense inflammation associated with peritonitis. Given these circumstances, it is reasonable to hypothesize that strategies aiming to reduce inflammation are potentially important and novel, and could serve to reduce CVD, thereby lowering morbidity and mortality in patients with CKD. In this review we provide information supporting the hypothesis that systemic inflammation is tightly linked to the most common complications of CKD patients, in particular those on PD, and that local inflammation in PD may contribute to various related complications. The aims of this review are to discuss the reasons that make inflammation an attractive target for intervention in CKD, the particular aspects of the inflammation-CVD axis during PD treatment that are likely involved, and possible means for the detection and management of chronic inflammation in PD patients.

Background: Inflammation and malnutrition are common findings in patients with chronic kidney disease (CKD). We hypothesized that in inflamed and malnourished patients, respiratory and peripheral muscle dysfunction may have significant consequences on pulmonary function. The aim of this study was to investigate possible associations between pulmonary function and inflammation and malnutrition in patients with CKD., Methods: We studied 109 patients (63% males; 53+/-12 years) at the initiation of dialysis treatment (GFR 7.5+/-2.5 ml/min). Pulmonary function tests [forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and peak expiratory flow (PEF)] were performed and the percentages of predicted values were calculated (%FEV(1), %FVC and %PEF). Systemic inflammation, assessed by high-sensitivity C-reactive protein (hsCRP) and nutritional status assessed by subjective global assessment (SGA), lean body mass (LBM) (estimated with dual energy X-ray absorptiometry) and hand-grip strength (HGS), were evaluated at the same time., Results: Significant negative correlations were found between hsCRP and the percent predicted values for all pulmonary function tests [%FEV(1) (Rho = -0.45), %FVC (Rho = -0.43) and %PEF (Rho = -0.38)], respectively. Malnourished patients defined as SGA >or=2 had lower %FEV(1) (64+/-19 vs 82+/-23%; P<0.001) and %FVC (67+/-18 vs 83+/-21%; P<0.001) than well nourished patients. Significant correlations were observed between HGS and %FVC (Rho = 0.38; P <0.001), %FEV(1) (Rho = 0.37; P<0.001) and %PEF (Rho = 0.22; P<0.05) and between LBM and %PEF (Rho = 0.20; P<0.05). Multivariate Cox analysis showed that cardiovascular disease and low %FVC were associated with poor survival., Conclusions: Impaired pulmonary function is associated with malnutrition and inflammation, and predicts mortality in CKD patients. This may reflect an impact of malnutrition and inflammation on respiratory muscle performance, leading to pulmonary dysfunction, which could influence the clinical outcome.

Pentosidine is an advanced glycation end-product (AGE), formed by glycosylation and oxidation, that accumulates markedly in end-stage renal disease (ESRD). It has been speculated that AGE and carbonyl stress contributes to long-term complications such as cardiovascular disease (CVD) in ESRD patients. This study determined plasma levels of pentosidine as well as the presence of inflammation (CRP > or = 10 mg/L), clinical CVD (CVD(clin)), and malnutrition (subjective global assessment [SGA] > 1) in a cohort of 191 ESRD patients, median age of 55 yr (range, 23 to 70 yr) and median GFR = 7 ml/min (range, 2 to 17 ml/min), close to start of renal replacement therapy. Fifty-one elderly subjects, median age of 82 yr (range, 71 to 110 yr), with mild renal impairment, median GFR = 67 ml/min (range, 38 to 113 ml/min), were also studied for comparative analysis of plasma pentosidine. The plasma pentosidine content was elevated in all patients compared with the levels in the elderly subjects and were negatively correlated with GFR both in the ESRD patients (Rho = -0.24; P < 0.01; n = 159) and in the elderly subjects (Rho = -0.31; P < 0.05). Moreover, the plasma pentosidine content was correlated with age in the ESRD patients (Rho = 0.26; P < 0.001) and in the elderly subjects (Rho = 0.44; P < 0.001). The 63 malnourished ESRD patients (35%) had a significantly higher (P < 0.05) median plasma pentosidine than the well-nourished patients (39 versus 27 pmol/mg albumin). Similarly, 73 inflamed patients (38%) had a significantly higher (P < 0.001) median pentosidine content compared with 118 non-inflamed patients (37 versus 24 pmol/mg albumin). Also, the plasma pentosidine content showed weak but significant positive correlations with CRP (Rho = 0.28; P < 0.0001), fibrinogen (Rho = 0.23; P < 0.01; n = 126), IL-6 (Rho = 0.22; P < 0.01; n = 169), and soluble vascular cellular adhesion molecule-1 (Rho = 0.38; P < 0.001; n = 74). On the other hand, no significant differences in plasma pentosidine content were noted between the patients with and those without CVD(clin) (32 versus 27 pmol/mg albumin, respectively). Analyses of all-cause mortality, by Kaplan-Meier, showed that mortality was not linked to the plasma pentosidine content. Moreover, survival analysis by the Cox regression model showed that age (P < 0.001), diabetes mellitus (P < 0.01), malnutrition (P < 0.01), and CVD(clin) (P < 0.01) independently predicted poor outcome, whereas an elevated plasma pentosidine content did not. The present study shows that an elevated plasma pentosidine content in ESRD patients is significantly associated with both inflammation and malnutrition and confirms that low residual renal function and high age further contribute to an increased plasma pentosidine content. However, in this small cohort, the plasma pentosidine content did not predict outcome. Thus, accumulation of plasma pentosidine is unlikely to be an appropriate clinically useful marker to predict mortality in ESRD patients.

Background: Circulating levels of cytokines and other inflammation markers are markedly elevated in patients with chronic renal failure. This could be caused by increased generation, decreased removal, or both. However, it is not well established to what extent renal function per se contributes to the uremic proinflammatory milieu. The aim of the present study is to analyze the relationship between inflammation and glomerular filtration rate (GFR) in 176 patients (age, 52 +/- 1 years; GFR, 6.5 +/- 0.1 mL/min) close to the initiation of renal replacement therapy., Methods: Circulating levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), hyaluronan, and neopterin were measured after an overnight fast. Patients subsequently were subdivided into two groups according to median GFR (6.5 mL/min)., Results: Despite the narrow range of GFR (1.8 to 16.5 mL/min), hsCRP, hyaluronan, and neopterin levels were significantly greater in the subgroup with lower GFRs, and significant negative correlations were noted between GFR and IL-6 (rho = -0.18; P < 0.05), hyaluronan (rho = -0.25; P < 0.001), and neopterin (rho = -0.32; P < 0.0005). In multivariate analysis, although age and GFR were associated with inflammation, cardiovascular disease and diabetes mellitus were not., Conclusion: These results show that a low GFR per se is associated with an inflammatory state, suggesting impaired renal elimination of proinflammatory cytokines, increased generation of cytokines in uremia, or an adverse effect of inflammation on renal function.

Despite major research efforts and improvements in dialysis technology, patients with end-stage renal disease (ESRD) experience an extremely high mortality, which seems to be increasingly related to cardiovascular disease. Cardiovascular disease has been linked to the presence of systemic inflammation and malnutrition (MIA syndrome), in addition to the high prevalence of traditional risk factors observed in ESRD patients. Since the mechanisms underlying the development of these complications of ESRD are largely unknown, new strategies for identification of risk factors, pathophysiologic pathways, and targets for intervention are warranted. Although the combined impact of MIA complications seems to determine the extremely poor clinical outcome in the ESRD patients, there are significant unexplained individual differences in the development of the MIA syndrome, implying that genetic differences might play a role. The vast information generated by the advances in molecular genetics offers a great opportunity to analyze the causes of differences not only in our susceptibility to (or protection from) various diseases, but also in the age of onset, severity of illness, and in the way our bodies respond to treatment. In this review, we summarize an integrated approach in the investigation of complex disorders, requiring the interactive collaboration between laboratory, clinical, and epidemiologic resources using the MIA syndrome as a prototype. We focus on the application of common genetic variations (single nucleotide polymorphisms [SNPs]) in association with studies to generate potential risk profiling using data from multiple vulnerability genes. The appropriate application of this approach may be essential in the early identification of high-risk individuals and groups of patients for whom specific therapeutic interventions are indicated, thus creating a tailor-made clinical management for the future.

The majority of patients starting dialysis already have signs of advanced atherosclerosis, and the risk factors for cardiovascular morbidity and mortality seen in patients with end-stage renal disease (ESRD) develop with the disease progression. Therefore, the predialysis period is the ideal time to start therapeutic interventions. Traditional risk factors alone may not adequately predict cardiovascular disease (CVD) outcome in patients with ESRD. Inflammation has been identified as playing a key role in atherosclerotic CVD. Pro-inflammatory cytokines are pivotal to the inflammation that is associated with malnutrition and atherosclerosis in ESRD. Malnutrition may worsen patient outcome by aggravating existing inflammation and heart failure, accelerating atherosclerosis and increasing susceptibility to infection. Atherosclerosis is itself a major risk factor for CVD mortality. Moreover, inflammation is associated with congestive heart failure. Strong associations between malnutrition, inflammation and atherosclerosis in this patient population suggest the presence of a syndrome we have called malnutrition, inflammation, and atherosclerosis (MIA), which is associated with an exceptionally high mortality rate.

Dialysis treatment has improved the survival of patients with kidney failure. However, the hospitalization and mortality rates remain alarmingly high, primarily due to incomplete uremic toxin elimination. High-volume hemodiafiltration (HDF) has emerged as a promising approach that significantly improves patient outcomes by effectively eliminating medium and large uremic toxins, which explains its increasing adoption, particularly in Europe and Japan. Interest in this therapy has grown following the findings of the recently published CONVINCE study, as well as the need to understand the mechanisms behind the benefits. This comprehensive review aims to enhance the scientific understanding by explaining the underlying physiological mechanisms that contribute to the positive effects of HDF in terms of short-term benefits, like hemodynamic tolerance and cardiovascular disease. Additionally, it explores the rationale behind the medium-term clinical benefits, including phosphorus removal, the modulation of inflammation and oxidative stress, anemia management, immune response modulation, nutritional effects, the mitigation of bone disorders, neuropathy relief, and amyloidosis reduction. This review also analyzes the impact of HDF on patient-reported outcomes and mortality. Considering the importance of applying personalized uremic toxin removal strategies tailored to the unique needs of each patient, high-volume HDF appears to be the most effective treatment to date for patients with renal failure. This justifies the need to prioritize its application in clinical practice, initially focusing on the groups with the greatest potential benefits and subsequently extending its use to a larger number of patients. [ABSTRACT FROM AUTHOR]

Background: Advanced glycation end products (AGEs) have been related to the pathogenesis of cardiovascular diseases (CVD), chronic kidney disease (CKD) and diabetesmellitus. We sought to investigate the binding capacity of sevelamer to both AGEs and uremic serumin vitro and then test this pharmaceutical effect as a potential vascular anti-inflammatory strategy. Methods: AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. Human endothelial cells were incubated in culturemedia containing AGEs and uremic serumwith or without sevelamer. Receptor for advanced glycation end product (RAGE) expression was evaluated through immunocytochemistry and western blot to explore the interactions between AGEs and the endothelium. Inflammatory and endothelial dysfunction biomarkers, such as interleukin 6 (IL- 6) and IL-8,monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and serumamyloid A (SAA) were alsomeasured in cell supernatant. The chemotactic property of the supernatant was evaluated. Results: AGEs significantly induced the expression of RAGE, inflammatory and endothelial activation biomarkers [IL-6, (P<0.005); IL-8, MCP-1, PAI-1 and SAA (P<0.001)] and monocyte chemotaxis as compared with controls. In addition, AGEs increased the levels of inflammatory biomarkers, which were observed after 6h of endothelial cell incubation with uremic serum [IL-6 (P<0.001) IL-8, MCP-1 and PAI-1 (P<0.05)]. On the other hand, after 6 h of endothelial cell treatment with sevelamer, RAGE expression (P<0.05) and levels of inflammatory biomarkers [IL-6 and IL-8 (P<0.001), MCP-1 (P<0.01), PAI-1 and SAA (P<0.005)] significantly decreased compared with the AGEs/uremic serum treatment alone. Conclusions: Sevelamer decreased both endothelial expression of RAGE and endothelial dysfunction biomarkers, induced by AGEs, and uremic serum. Further studies are necessary for a better understanding of the potential protective role of sevelamer on uremic serum and AGEs-mediated endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular calcification, accelerated atherosclerosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. As a consequence, inflammation is a predictor of mortality in this group of patients. Specific causes of the activation of the immune system in CKD are largely unknown. Endotoxin (ET) release to the circulation represents a potentially important target for interventions aiming to reduce mortality in CKD patients. In this minireview, we propose that there are several potential sources of endotoxemia in CKD and that gut translocation, leading to the generation of ligands of the innate immune response, represents a potentially reversible cause. Prevention of endotoxemia, through treating foci of ET (periodontal disease, catheters, vascular access) or reducing translocation from the gut, will potentially reduce the inflammatory response. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular calcification, accelerated atherosclerosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. As a consequence, inflammation is a predictor of mortality in this group of patients. Specific causes of the activation of the immune system in CKD are largely unknown. Endotoxin (ET) release to the circulation represents a potentially important target for interventions aiming to reduce mortality in CKD patients. In this minireview, we propose that there are several potential sources of endotoxemia in CKD and that gut translocation, leading to the generation of ligands of the innate immune response, represents a potentially reversible cause. Prevention of endotoxemia, through treating foci of ET (periodontal disease, catheters, vascular access) or reducing translocation from the gut, will potentially reduce the inflammatory response. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Although traditional risk factors, such as diabetes mellitus, hypertension, dyslipidemia and advanced age, are prevalent in ESRD patients they may not be sufficient by themselves to account for the high prevalence of CVD in patients with this condition. Thus, the search for other, non-traditional, risk factors that may be involved in the pathogenesis of uremic CVD has been an area of intense study. Data suggest that 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. The cause(s) 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 via several pathogenetic mechanisms. Available data suggest that pro-inflammatory 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 of these patients. [ABSTRACT FROM AUTHOR]

Background. It has been speculated that increased levels of circulating or intraperitoneal pro‐inflammatory cytokines such as interleukin 6, and pro‐angiogenic vascular endothelial growth factor (VEGF) may contribute to high peritoneal small‐solute transport rate (PSTR) in continuous ambulatory peritoneal dialysis (CAPD) patients. In this study we evaluated possible relationships between plasma and dialysate IL‐6 and VEGF levels and PSTR. [ABSTRACT FROM PUBLISHER]

Abstract: Aim: Since the impact of peritonitis on long‐term non‐infectious mortality has not been investigated until the present, the aim of this study was to analyze the impact of peritonitis on long‐term cardiovascular (CV) mortality in a large peritoneal dialysis (PD) cohort. Methods: The analysis was based on BRAZPD II, a national prospective cohort study that recruited patients in Brazilian centres from December 2004 to January 2011. Incident adult PD patients with at least 90 days on treatment were included in the analysis. Cardiovascular death occurring after a minimum of 30 days after a peritonitis episode was considered the primary endpoint. Cox regression analysis for time‐dependent variables was used for the adjustments. Results: There were 2405 episodes of peritonitis in 5707 patients (48% males, 44% diabetes, 73% hypertensive). Patients with one episode of peritonitis presented a 22% increase in the hazard ratio of late CV mortality compared to those who never experienced peritonitis (HR1.22; CI95%1.01–1.47). Adjusted hazard for CV mortality showed a stepwise negative effect on survival for each additional peritonitis episode of infection: two episodes (HR1.78; CI95%1.31–2.42), three episodes (HR2.81; CI95%1.83–4.32) and four episodes (HR3.84; CI95%2.01–7.32). Conclusion: Peritonitis was an independent predictor of CV mortality and the frequency of peritonitis was strongly associated with an increase in this risk. This is the first study to demonstrate the impact of peritonitis on late cardiovascular mortality of PD patients, suggesting a link between acute inflammation and cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Chronic kidney disease (CKD) and periodontitis (PD) are complex inflammatory disturbances, influenced by genetic factors. Interleukin (IL)-1 genes code for inflammatory mediators involved in the physiopathogenesis of both diseases. Functional polymorphisms in IL1 genes modulate cytokine levels and have been associated with susceptibility to immune-inflammatory conditions. Objectives: The aim of this study was investigate the association of functional IL1 gene polymorphisms and transcript levels with susceptibility to CKD and PD. Design: The sample consisted of 246 individuals, mean age 44.8years, divided into: group 1 (64 patients without CKD and without PD), group 2 (58 without CKD and with PD), group 3 (52 with CKD and without PD) and group 4 (72 with CKD and with PD). DNA was obtained from cells of oral mucosa and polymorphisms IL1AC−889T, IL1BC−511T, IL1BC+3954T and IL1RN (intron 2) were analyzed by PCR-RFLP. Transcript levels from gingival tissues were analyzed by real-time PCR. Results: IL1RN *1 allele was associated with almost 4-fold increased risk for CKD (OR 3.92 95% CI=1.6–9.4, p =0.002). IL1RN *2 allele was associated with 3-fold increased risk for PD in CKD patients (OR 3.08 95% CI=1.2–7.9, p =0.019). Allele T for polymorphism IL1B+3954 was associated with CKD in PD patients (OR 2.28 95% CI=1.1–4.7, p =0.019). Significantly increased levels of transcripts of IL1A, IL1B and IL1RN genes were found in PD patients. Conclusions: It was observed an evidence for association of IL1B and IL1RN alleles with susceptibility to CKD and PD. Higher levels of IL1 gene transcripts were found in PD patients. [Copyright &y& Elsevier]

Abstract: Chronic periodontitis (CP) and end-stage renal disease (ESRD) are complex inflammatory conditions. Higher levels of MMP-1 were found in fluids and gingival tissues from CP patients and in the blood and tissues from ESRD patients. MMP1-1607 (1G/2G) is a functional polymorphism, as it alters MMP-1 expression. Objective: The aim of this study was to investigate the association of the MMP1-1607 (1G/2G) polymorphism with CP and ESRD and evaluate differences in transcript levels between the groups. Design: A total of 254 individuals were divided into four groups: Group 1, without CP and without chronic kidney disease (CKD) (n =67); Group 2, with CP and without CKD (n =60); Group 3, without CP and with CKD stage 5 (ESRD) (n =52), and Group 4, with CP and with ESRD (n =75). The MMP1-1607 polymorphism was analysed by PCR-RFLP. MMP1 gene transcripts from gingival tissues were analysed by real-time PCR. Results: No association was found between the MMP1-1607 polymorphism and CP or ESRD. Increased levels of MMP1 transcripts were observed in CP patients with or without ESRD. No differences were observed in the transcript levels according to the genotypes. Conclusion: It was concluded that the MMP1-1607 polymorphism was not associated with either CP or ESRD. However, higher levels of MMP1 gene transcripts were found at gingival sites of CP in patients both with and without ESRD. [Copyright &y& Elsevier]

Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin.Background.Vascular calcification is common among end-stage renal disease (ESRD) patients and a central characteristic of the atherosclerotic cardiovascular disease observed in dialysis patients. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In the present study, we evaluated the association between fetuin-A, clinical phenotype, and outcome, as well as the impact of fetuin gene (AHSG) polymorphisms on the protein product and outcome.Methods. In a cohort of 258 (161 males) ESRD patients starting renal replacement therapy[glomerular filtration rate (GFR) 6.8± 0.2 mL/min] aged 52± 1 years the following parameters were studied: presence of malnutrition (subjective global assessment), comorbidity[diabetes mellitus and clinical manifest cardiovascular disease (CVD)], carotid plaques (N= 101), hs-CRP, fetuin-A, S-albumin, interleukin (IL)-6, and single nucleotide polymorphisms (SNPs) in the AHSG gene (N= 215) at amino acid positions Thr248Met (C→T), Thr256Ser (C→G), Asp276Asn (G→A), and Arg317Cys (C→T).Results.Both all-cause (P<0.001) and cardiovascular (P<0.001) mortality were associated with low fetuin-A levels independently of age, smokingdiabetes, S-albumin, CVD, and inflammation (CRP≥10 mg/L). Inflamed (0.199 vs. 0.247 g/L;P<0.01) and malnourished (0.207 vs. 0.262 g/L;P<0.05) patients had significantly lower median fetuin-A than noninflamed and well-nourished ESRD patients, respectively. In a logistic regression model (N= 101), fetuin-A was significantly (P<0.05) associated with the presence of carotid plaques independently of age, CVD, diabetes, S-albumin, gender, and inflammation. Significant correlations were observed between fetuin-A and both S-albumin (Rho= 0.30;P<0.0001) and IL-6 (Rho=−0.21;P<0.01). Patients with the AHSG 256Ser allele had lower serum fetuin-A levels, and higher all-cause and cardiovascular mortality rate if they were inflamed.Conclusion.The present study shows that a low fetuin-A level is associated with malnutrition, inflammation, and atherosclerosis (carotid plaques), as well as with increased cardiovascular and all-cause mortality. Because the present study demonstrates an effect of variations in the AHSG gene on both circulating fetuin-A levels and outcome, this indicates that ESRD patients with the AHSG 256Ser allele are at risk of accelerated vascular calcification. [ABSTRACT FROM AUTHOR]

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 nondialysis 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-α (TNF-α) 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. [ABSTRACT FROM AUTHOR]

Mortality, malnutrition, and atherosclerosis in ESRD: What is the role of interleukin-6? There is growing evidence that increased plasma concentrations of CRP strongly predict cardiovascular death in both non-renal and renal patient populations. The interleukin-6 (IL-6) system activity, which is the major mediator of the acute phase response, is often markedly up-regulated in uremic patients and has also been shown to predict outcome. This raises the issue of whether or not IL-6 per se may contribute to increased mortality from malnutrition and atherosclerotic cardiovascular disease in uremic patients. The causes of elevated IL-6 levels in the uremic circulation are not fully understood, although a number of factors prevalent in uremic patients, such as hypertension, adiposity, infections, and chronic heart failure may all contribute. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysate, may stimulate IL-6 production. Furthermore, available evidence suggests that genetic factors may also have an impact on circulating plasma IL-6 levels. We advance the hypothesis that IL-6 may play a central role in the genesis of inflammatory-driven malnutrition and that it may be regarded as a significant proatherogenic cytokine. This hypothesis may provide a rationale to test if targeted anti-cytokine therapy may be one way to combat the unacceptable high cardiovascular mortality rate among dialysis patients. [ABSTRACT FROM AUTHOR]