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Uremic toxins contribute to clinical manifestations of kidney dysfunction. These toxins include organic and inorganic elements or compounds. While the kidney typically clears uremic toxins, gut dysbiosis, and tissue inflammation could lead to increased production of substances that can further the clinical manifestations of uremia. The uremic toxins are quantitatively measurable in biological fluids and have an established relationship with azotemia signs and symptoms. Their elimination is associated with mitigated uremic manifestations, while their administration to the uremic levels leads to uremic signs in animal or human models or in vitro studies. Besides, the uremic toxins have an established and plausible pathophysiologic relationship with uremic manifestations. The previous classification of uremic toxins was mainly focused on the physicochemical characteristics of these substances to divide them into three categories, (1) free water-soluble low-molecular-weight (500 Da and 12,000 Da). Unfortunately, the classification named above was not centered around patient outcomes and quality of life among those with severe kidney failure. Therefore, a panel of experts convened virtually to provide additional insights into the current state and propose a new uremic toxin classification. This article describes the group’s consensus recommendations regarding the new classification of uremic toxins into more clinically oriented categories.

Aims: To analyze changes in telomere length (TL) after dialysis initiation. Methods: In 59 Japanese incident dialysis patients, associations between TL in peripheral blood leukocytes, inflammatory biomarkers and nutritional status at baseline and changes in TL during 1 year of dialysis, were investigated. Results: Whereas relative TL decreased by 8.6% (median 14.4%), TL elongation occurred in 16 patients (27%). Change in TL (ΔTL), defined as TL at 1 year minus TL at baseline, was associated with baseline TL (ρ = -0.70, p < 0.0001) and leukocyte count (ρ = 0.26, p = 0.044). In a logistic regression model, baseline TL (p < 0.0001) and leukocyte count (p = 0.047) were associated with ΔTL. Conclusions: TL shortening was observed in most incident dialysis patients. In 16 of the 59 patients, TL elongation occurred, possibly reflecting a more robust biological aging in patients whose naïve leukocytes may have undergone less proliferation to replace lost leukocytes.

Chronic inflammation is highly prevalent among end-stage renal disease patients and is linked to, and thought to contribute to, the high morbidity and mortality in this patient population. Hemodiafiltration (HDF) may potentially reduce inflammatory stimuli induced by the bioincompatibility of conventional hemodialysis (HD) systems. In addition, HDF may more efficiently remove inflammatory mediators. This brief review shows that the circulating levels of various markers of systemic inflammation in general are somewhat reduced in patients treated by HDF as compared to HD. On the other hand, according to the current literature, this favorable small impact on inflammation biomarkers does not seem to translate into better clinical outcomes. It is possible that this is due to inadequate design, inadequate number of investigated patients and too short duration of previous studies. The results of larger, better-designed ongoing prospective studies may hopefully clarify this.

As the kidney is the major site for elimination of many cytokines, the delicate equilibrium of pro-inflammatory cytokines and their inhibitors is clearly dysregulated in chronic kidney disease (CKD) patients. The consequences of the altered immune response in uremia lead to a state of persistent inflammation which is highly prevalent among CKD patients and is linked to complications such as the development of protein-energy wasting and atherosclerotic vascular disease. The present review aims at reviewing this complex orchestration of uremic cytokines beyond the well-studied interleukin-6 and tumor necrosis factor-α. Finally, we update our current understanding on anti-inflammatory treatment strategies in CKD patients, including nutritional and lifestyle measurements, pharmacological intervention and specific anticytokine strategies targeting the dialytic procedure.

Inflammatory markers predict mortality in hemodialysis (HD) patients, whereas a possible association between oxidative stress (OS) markers and survival is less clear. We assessed the impact on all-cause mortality of baseline inflammatory [high-sensitivity C-reactive protein and interleukin-6 (IL-6)] and OS markers (advanced oxidation protein products, pentosidine, homocysteine) in 112 HD patients. We found no significant correlations between inflammatory and OS markers. During the 5.5 years of follow-up, 51 patients died. In a Kaplan-Meier analysis, the survival rate was reduced in patients with IL-6 higher than the median (IL-6 >4.2 pg/ml) (log- rank = 6.47; p = 0.01), in diabetics (log-rank = 12.26; p = 0.0005) and in older patients (log-rank = 11.22; p = 0.0008). Moreover, in Cox analysis only IL-6 and age were independently associated with mortality. We conclude that in this group of prevalent Brazilian HD patients, IL-6 was a better predictor of survival than other inflammatory and OS markers.

Background: Dyslipidemia is a common complication of chronic kidney disease. Lipoprotein lipase (LPL) 1595 C/G and hepatic lipase (HL) –480 C/T single nucleotide polymorphisms (SNPs) influence lipid profile and predisposition for cardiovascular disease in the general population. The present study was undertaken to clarify the impact of the two polymorphisms on lipid parameters and cardiovascular risk in incident dialysis patients. Methods: LPL 1595 C/G and HL –480 C/T SNPs were evaluated in 293 chronic kidney disease patients close to dialysis initiation. Associations with lipid parameters, presence of cardiovascular disease, and survival were assessed. Results: LPL 1595 C/G SNP was associated with significantly lower triglyceride levels [1.55 (1.00–2.20) vs. 1.90 (1.40–2.48) mM; p < 0.01], while HL –480 C/T polymorphism was associated with increased high density lipoprotein cholesterol concentration [1.30 (1.00–1.60) vs. 1.10 (0.90–1.40) mM; p < 0.05]. Neither of the polymorphisms showed any relationship with patient survival. Conclusions: LPL 1595 C/G and HL –480 C/T polymorphisms affect lipid profile in incident dialysis patients.

Background: To evaluate if peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have a potential protective effect on the peritoneum changes induced by bioincompatible peritoneal dialysis (PD) solution in vivo. Methods: Male Wistar rats were dialyzed three times daily for 28 days with 1.36% Dianeal® (two groups: with (D+R) or without (D) rosiglitazone) or 1.36% Physioneal® (two groups: with (P+R) or without (P) rosiglitazone). Peritoneal transport of fluid and small solutes was assessed. Nine rats that did not receive dialysis served as controls. Results: Significant morphological changes were found in the D group compared with controls. Additional use of rosiglitazone in the D+R group resulted in less morphological changes and expression of collagen I as well as an increased drainage volume. The expression of VEGF was inhibited by rosiglitazone while no apparent effect was found regarding TGF/Smad pathway. Conclusions: The addition of rosiglitazone to standard dialysis fluids can maintain the peritoneal morphology and increase ultrafiltration in a PD rat model.

Protein-energy malnutrition and wasting are common among patients with end-stage renal disease (ESRD) and these complications are strongly associated with poor survival in these patients. Whereas both under- and overweight predict in increased mortality risk in the general population, a high body mass index is associated with better outcome in ESRD patients. Circulating levels of pro-inflammatory cytokines are markedly elevated in uremia and also predictor of a poor clinical outcome in ESRD patients. Interleukin-1β (IL-1β), which is a major pro-inflammatory cytokine, may further amplify inflammation and lead to malnutrition, through inducing anorexia, and muscle wasting due to increased protein breakdown. Several clinical studies have shown that the circulating level of IL-1β may affect nutritional status, especially body composition. Several IL-1 gene cluster polymorphisms were reported, and they may affect the prevalence of cytokine-mediated diseases. Although a number of factors are related to malnutrition and wasting in ESRD, pro-inflammatory cytokines, such as IL-1β, may play an important role. This could in part be due to genetic factors. Further research, especially regarding the IL-1 gene cluster polymorphisms, is necessary to determine this hypothesis.

During the past few years, it has become increasingly evident that residual renal function (RRF) is an important and independent predictor of poor outcome in patients with chronic kidney disease (CKD). Although the causes of this observation are not fully understood, it appears that the loss of RRF impairs both fluid removal and clearance of solutes, which in turn leads to uremic toxicity and increased morbidity and mortality. There is increasing evidence that patients with CKD develop signs of fluid overload already in the early phases of the disease, and this may be a stimulus for inflammatory activation. Recently, an inflammatory component was identified in uremic atherosclerotic and non-atherosclerotic cardiovascular disease (CVD), which have been consistently associated with poor clinical outcome in patients with CKD. Signs of systemic inflammation occur in parallel to the impairment in renal function, and the pathophysiology is most likely multifactorial, including a decrease in cytokine clearance, advanced glycation end-product accumulation, oxidative stress, and principal fluid overload. Additionally, inflammation seems to be a predictor of accelerated loss of renal function. In this article, we discuss the evidence showing that patients with CKD generally have fluid overload, the mechanisms by which impaired renal function may lead to a chronic inflammatory state, and the available information linking fluid overload to accelerated loss of renal function and CVD through inflammation. Inflammation may lead to the development of complications of CKD, in particular CVD, but on the other hand may also lead to a faster progression of renal disease. Strategies aiming to reduce fluid overload may be useful to reduce cardiovascular morbidity and mortality, but also preserve RRF.

Background/Aims: N-Terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor of cardiac events and death in the general population and in chronic kidney disease. There is limited information on how natriuretic peptides vary in dialysis patients. The aim of this study was to analyze NT-proBNP variability, factors predicting its variability and survival related to NT-proBNP variability. Methods: A prospective 3-month observational study of prevalent hemodialysis patients with monthly measurements of NT-proBNP was carried out. A total of 211 hemodialysis patients were included, and mortality was recorded during 52 months of follow-up. Results: Inflammation was the strongest predictor of NT-proBNP variability. Patients with constantly high NT-proBNP had an increased risk of death adjusting for age, sex, dialysis vintage and comorbidity but not when also adjusting for nutritional status. Conclusions: Longitudinal changes in NT-proBNP are associated with changes in inflammation, nutritional status, age and comorbidity. Due to strong interactions with predictors of mortality such as nutritional status, we were unable to confirm NT-proBNP as an independent marker for mortality in dialysis patients.

Genetic variations in the NADPH/MPO system in chronic kidney disease (CKD) patients might lead to altered activity of these enzymes, and thus to altered risk for oxidative stress (OS) and cardiovascular disease (CVD). We evaluated the impact of 242C/T CYBA and –463G/A MPO polymorphisms on OS and CVD mortality in stage 5 CKD patients starting dialysis. Two hundred and fifty-seven patients were genotyped using Pyrosequencing. Plasmalogen [dimethylacetal (DMA) 16/C16:0] was used as OS marker. CVD was assessed from patient history and clinical symptoms. Prevalence of CVD was higher (35%) in GG patients (MPO) compared to AG (26%) and AA (0%) patients (p < 0.01). Patients with CC genotype (CYBA) had lower levels of DMA 16/C16:0 (ratio 0.071 ± 0.003) compared to TT patients (0.089 ± 0.006; p < 0.05). These patients also had increased CVD mortality compared to CT and TT patients (χ2 2.19; p < 0.05). We conclude that genetic variations in the NADPH/MPO system are associated with OS, presence of CVD and CVD-related mortality in CKD patients.

Background: Patients with chronic kidney disease (CKD) display endothelial dysfunction and are at a high risk for atherosclerotic cardiovascular disease (CVD). Recent studies suggest that circulating detached endothelial cells (CECs) and stimulated endothelial progenitor cells (EPCs) from the bone marrow may reflect endothelial damage. Methods: We correlated the levels of CECs expressing the endothelial cell inflammation marker (MICA+ cells) and EPCs (Tie-2+ or VEGFR-2+ cells) in a population of 19 (55 ± 3 years; 42% males) patients with advanced CKD (median glomerular filtration rate 8 ml/min). In addition, the levels of CD-31+ cells were investigated. Twenty healthy age- (49 ± 2 years) and gender- (50% men) matched subjects served as controls. Results: CECs expressing MICA were increased (7.6 ± 2.7 vs. 1.6 ± 0.3%; p < 0.05) in CKD patients, however EPCs expressing Tie-2 or VEGFR-2 were significantly decreased (0.16 ± 0.07 vs. 0.53 ± 0.15%; p < 0.05, and 0.42 ± 0.10 vs. 2.80 ± 0.72%; p < 0.01, respectively) as compared to controls. Furthermore, we also found that the levels of CD-31+ cells were significantly elevated (22.8 ± 4.2 vs. 9.4 ± 0.8%; p < 0.01) in CKD patients. Patients on angiotensin-converting enzyme (ACE) inhibitors tended (p = 0.06) to have higher levels of VEGFR-2+ cells (0.57 ± 0.14 vs. 0.16 ± 0.11%). Conclusion: Our results suggest that there is a marked imbalance between the CEC and EPC numbers in patients with CKD. Further research is needed to evaluate the independent role of inflammatory endothelial markers as well as the effects of ACE inhibitors on mobilization of EPCs in patients with advanced CKD.

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.

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 population, inflammation (a common phenomenon in ESRD), and other non-traditional risk factors are likely to contribute. Among several inflammatory biomarkers used to assess inflammation, high-sensitivity C-reactive protein (hs-CRP) has attracted the most interest. Indeed, in the general population the consistency of prognostic data for hs-CRP and the practicality of its use have led to suggestions that CRP should be used as a clinical criterion for global cardiovascular risk prediction. As CRP is so strongly associated with vascular disease, it has been suggested that this protein is not only a marker, but also a mediator, of atherogenesis. Indeed, recent in vitro data from studies on endothelial cells, monocytes-macrophages and smooth muscle cells support a direct role for CRP in atherogenesis. In ESRD, hs-CRP has been proven to be a strong predictor of both cardiovascular and all-cause mortality, and associated with oxidative stress, vascular calcification and endothelial dysfunction. As recent studies suggest that interleukin-6 may be a somewhat better outcome predictor than hs-CRP, comparative studies are needed to evaluate which inflammation biomarker is the most cost-effective predictor of outcome in the ESRD patient population.

Vascular calcification is a common complication of end-stage renal disease (ESRD). The mechanisms responsible are complex and have so far been considered to be mainly the result of a passive mechanism due to elevated PO4 levels and high Ca × PO4 ion product resulting in saturated plasma. However, recent results suggest that also other features, commonly observed in the uremic milieu, such as chronic inflammation, hyperleptinemia and a dysregulation of various mineral-regulating proteins might also contribute to an enhanced calcification process. Moreover, as an inverse relationship between vascular calcification and bone density has been documented in ESRD, it could be speculated that pathologically low bone remodelling (adynamic bone disease) associated with active vitamin D treatment and low parathyroid hormone (PTH) levels may predispose to ectopic calcification of vessels, valves and heart. As patients with vascular calcification have a higher intake of calcium-containing PO4 binders, novel, non-calcium containing PO4 binders may diminish the risk of progressive vascular calcification in this patient group. Further studies are needed to elucidate the respective role of chronic inflammation, hyperleptinemia and PTH-lowering therapies in this fatal complication of ESRD.

End-stage renal disease (ESRD) is characterized by an exceptional cardiovascular mortality rate. Although traditional risk factors are common in ESRD patients, they alone may not be sufficient to account for the high prevalence of cardiovascular disease (CVD). Recent evidence demonstrated that chronic inflammation, a non-traditional risk factor which is commonly observed in ESRD patients, may cause malnutrition and progressive atherosclerotic CVD by several pathogenetic mechanisms. Although both malnutrition and inflammation have been shown to be strong predictors of cardiovascular mortality in ESRD patients, it must be remembered that the majority of studies describing the presence of inflammation and malnutrition have been performed in Western and Asian industrialized countries. As it is evident that the prevalence of malnutrition and inflammation may differ markedly between different regions of the world and developing countries face a much higher prevalence of chronic infectious diseases, comparative inter-regional studies focusing on the etiology and prevalence of the malnutrition, inflammation and atherosclerosis syndrome are warranted.