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ABSTRACT: The term cytokine clusters denotes a copious family of molecules and correspondent receptors implicated in numerous processes mediating health and disease. In the context of chronic kidney disease (CKD), generation and metabolism of most of these cytokines are disturbed. Available evidence suggests that cytokine imbalances contribute to the progression of common CKD complications, such as atherosclerosis, mineral-bone disease, and protein-energy wasting via pleiotropic effects. The belief that cytokine CKD research is solely represented by interleukins (IL) and tumor-necrosis factors (TNF) (mainly IL-6 and TNF-alpha) is a common misconception among nephrologists. We here explore recent findings concerning the pathophysiological role of various cytokines in uremic complications, and discuss how cytokines could be used as novel potential therapeutic targets in CKD. At the same time, we provide a brief overview of current discoveries in the main transforming growth factors and chemokines.
Seminars in Dialysis 22(4):381-6. · 2.27 Impact Factor
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ABSTRACT: New, reliable circulating oxidative stress markers have become available in chronic kidney disease (CKD) patients and have confirmed the long held belief that CKD is a pro-oxidant state. However, several questions related to this state of oxidative stress remain largely unresolved. First, the relative importance of each type of oxidant involved has been insufficiently evaluated. Only two recent studies have addressed this issue, and both suggested that chlorinated stress played a central role. Second, as only few population-based studies are available, the prevalence of oxidative stress among CKD patients remains undetermined. Third, although the link between oxidative stress and inflammation in CKD is emerging as a key process contributing to the genesis of oxidative stress in these patients, its pathogenesis remains poorly defined. Fourth, data favoring the involvement of oxidative stress in uremic toxicity are still limited. Finally, while two recent pilot studies have demonstrated that treatment of CKD patients with antioxidants is able to reduce cardiovascular events, information related to the pharmacokinetic characteristics of antioxidants, as well as their efficacy to prevent oxidative stress, is still limited in this patient group. Thus, although existing data suggest a prominent role of CKD-associated oxidative stress in uremic toxicity, further studies are required to definitively prove this concept.
Seminars in Dialysis 22(4):405-8. · 2.27 Impact Factor
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Raymond Vanholder,
Angel Argilés,
Joachim Beige,
Philippe Brunet,
Tilman B Drüeke,
Danilo Fliser,
Stefan Herget-Rosenthal,
Walter H Hörl,
Achim Jörres,
Alessandra Perna,
Mariano Rodriguez-Portillo,
Goce Spasovski,
Bernd Stegmayr, Peter Stenvinkel,
Christoph Wanner,
Andrzej Wiecek,
Ziad A Massy
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ABSTRACT: In addition to extracorporeal renal replacement strategies, which in chronic kidney disease (CKD) are largely reserved for the treatment of end-stage kidney failure, conservative measures can be taken to reduce concentration, effects, or both concentration and effects of uremic retention solutes. In this overview, we will focus on those therapies, which are aimed at preventing or delaying cardio-vascular disease, retarding or halting the progression of CKD, or both. We will discuss, consecutively, inhibitors of the renin-angiotensin-aldosterone axis, beta-blockers, calcium-channel antagonists, anti-inflammatory drugs, intestinal sorbents, calcimimetics, and glitazones. Some of these approaches could lead to a therapeutic breakthrough in the future. In addition, comprehensive tables will be provided for more traditional therapeutic approaches, such as lifestyle changes and other pharmaceutical treatments.
Seminars in Dialysis 22(4):449-53. · 2.27 Impact Factor
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Raymond Vanholder,
Omar Abou-Deif,
Angel Argiles,
Ulrich Baurmeister,
Joachim Beige,
Peter Brouckaert,
Philippe Brunet,
Gerald Cohen,
Peter Paul De Deyn,
Tilman B Drüeke, [......],
Ziad A Massy,
Harald Mischak,
Alessandra F Perna,
Juan Mariano Rodriguez-Portillo,
Goce Spasovski,
Bernd G Stegmayr, Peter Stenvinkel,
Paul J Thornalley,
Christoph Wanner,
Andrzej Wiecek
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ABSTRACT: In this publication, we review the activities of the European Uremic Toxin Work Group (EUTox) in the field of uremic toxin research. Founded in 1999 under the umbrella of the European Society of Artificial Organs (ESAO), and active since 2000, this group focuses essentially on questions related to solute retention and removal during chronic kidney disease, and on the deleterious impact of those solutes on biological/biochemical systems. As of January 1, 2009, the group had met 28 times; it organized the third meeting, "Uremic Toxins in Cardiovascular Disease," which took place in October 2008 in Amiens, France. The current group is composed of 25 members belonging to 23 European research institutions. As of November 1, 2008, in total 69 papers had been published to which at least two different research groups belonging to EUTox have contributed in a collaborative effort. Of these, 40 papers were on original research and eight were specific EUTox reviews or position statements. A website (http://www.eutox.info) summarizes all relevant information concerning the work group. EUTox also developed an interactive uremic toxin database, where concentrations of known toxins are displayed, to be used by researchers in the field. In the future, EUTox intends to continue its focus on bench to bedside research with specific consideration of proteomics, metabonomics, secretomics, and genomics.
Seminars in Dialysis 22(4):323-8. · 2.27 Impact Factor
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ABSTRACT: The progression rate of chronic kidney disease (CKD) to its terminal stage, end-stage renal disease (ESRD), and the development and severity of various complications, are at least indirectly influenced by genetic--and epigenetic--factors. For years, scientists have held out hope that the rapidly evolving field of genetics could transform medical diagnosis and treatment, moving beyond a trial-and-error approach towards "personalized medicine." Indeed, there are now signs that the role of genetics and the pursuit of "personalized medicine" in medical care will be a priority for governments during years to come. But the vision of individualized treatment based on a patient's genetic makeup and other biological markers has yet to materialize in the field of CKD and ESRD. As the toxic uremic environment may render CKD patients more sensitive to the effects of genetic variants, it is likely that genetic factors could be of special importance in this high-risk population. Therefore, outcome in the CKD population may be improved by establishing individual genetic/epigenetic profiles, thus enabling physicians to design an individualized therapeutic strategy. Personalized medicine based on a more individualized therapy could be applied in, for example, pharmacotherapy (CYP genes), dialysis therapy, and nutritional and lifestyle modifications.
Seminars in Dialysis 22(4):417-22. · 2.27 Impact Factor
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Alessandra F Perna,
Diego Ingrosso,
Eleonora Violetti,
Maria Grazia Luciano,
Immacolata Sepe,
Diana Lanza,
Rosanna Capasso,
Elisabetta Ascione,
Ilaria Raiola,
Cinzia Lombardi, Peter Stenvinkel,
Ziad Massy,
Natale G De Santo
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ABSTRACT: Hyperhomocysteinemia is an independent cardiovascular risk factor, according to most observational studies and to studies using the Mendelian randomization approach, utilizing the common polymorphism C677T of methylene tetrahydrofolate reductase. In contrast, the most recent secondary preventive intervention studies, in the general population and in chronic kidney disease (CKD) and uremia, which are all negative (with the possible notable exception of stroke), point to other directions. However, all trials use folic acid in various dosages as a means to reduce homocysteine levels, with the addition of vitamins B6 and B12. It is possible that folic acid has negative effects, which offset the benefits; alternatively, homocysteine could be an innocent by-stander, or a surrogate of the real culprit. The latter possibility leads us to the search for potential candidates. First, the accumulation of homocysteine in blood leads to an intracellular increase of S-adenosylhomocysteine (AdoHcy), a powerful competitive methyltransferase inhibitor, which by itself is considered a predictor of cardiovascular events. DNA methyltransferases are among the principal targets of hyperhomocysteinemia, as studies in several cell culture and animal models, as well as in humans, show. In CKD and in uremia, hyperhomocysteinemia and high intracellular AdoHcy are present and are associated with abnormal allelic expression of genes regulated through methylation, such as imprinted genes, and pseudoautosomal genes, thus pointing to epigenetic dysregulation. These alterations are susceptible to reversal upon homocysteine-lowering therapy obtained through folate administration. Second, it has to be kept in mind that homocysteine is mainly protein-bound, and its effects could be linked therefore to protein homocysteinylation. In this respect, increased protein homocysteinylation has been found in uremia, leading to alterations in protein function.
Seminars in Dialysis 22(4):351-6. · 2.27 Impact Factor
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ABSTRACT: Background. A single oral dose of cyclosporin‐A (CsA) transiently reduces renal plasma flow (RPF) and glomerular filtration rate (GFR) in transplant patients and, in some patients, chronic administration of CsA leads to renal impairment and fibrosis. Based on experimental studies, several mediators including free radicals have been proposed to account for CsA‐nephrotoxicity. We have previously reported that administration of the antioxidant vitamin E in a rat model of chronic CsA‐nephrotoxicity reduces renal fibrosis and maintains renal function. Methods. In the present study, the effect on renal haemodynamics of a single dose of the new oral formulation of CsA (neoral) was assessed before and after 6 weeks of vitamin E (800 IU/day, 2‐fold increase in serum vitamin E). GFR (inulin clearance) and RPF (para‐amino hippuric acid clearance) were measured before and after a single dose of 5 mg/kg of neoral in 12 healthy subjects under standardised conditions. Results. Although the mean area under the curve of the CsA levels was 21% lower after the vitamin E period, the peak CsA level at 120 min after neoral was similar both before and after vitamin E administration. At 120 min after neoral, a transient reduction in RPF and GFR was noted both before and after vitamin E administration. The nadir of the reductions in RPF (−81±27 ml/min) and GFR (−14±6 ml/min) at 120 min compared with baseline tended to be lower before than after the treatment with vitamin E (−51±33 ml/min of RPF and −12±8, ml/min of GFR, respectively). Plasma and urine levels of F2‐isoprostanes (free radical‐catalysed vasoconstrictive prostanoids (F2‐iso) at 120 min after the administration of neoral were not different from the pre‐neoral levels. Conclusion. The findings demonstrate that a single oral dose of neoral causes transient, yet significant, reductions in RPF and GFR, and suggest that F2‐iso might not be involved in the CsA‐induced acute renal vasoconstriction. The tendency for a lower reduction in RPF and GFR following CsA during the vitamin E period in healthy humans warrants additional studies in transplant patients.
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ABSTRACT: Background and aims: Recently we reported on a genetically predisposed protection from C-reactive protein (CRP) related mortality in dialysis patients carrying the functional CC-chemokine receptor 5 deletion 32 allele (CCR5Δ32) mutation. Since CCR5Δ32 is associated with a less pro-inflammatory immune response in mice, we hypothesized that the observed protection is (in part) due to a less pro-inflammatory cytokine profile. Methods: Cross-sectional observational study including 263 incident dialysis patients aged 18–70 years, without clinical signs of infection and/or acute vasculitis. TNF-α, IL-6, IL-10 and hsCRP levels were determined and studied in relation to the CCR5 genotype. Results: In the presence of elevated hsCRP, IL-6 concentration was higher irrespective of the CCR5 genotype. However, in patients with the CCR5 deletion, TNF-α did not differ in the presence/absence of elevated hsCRP and was not correlated with hsCRP levels in carriers of the CCR5Δ32 polymorphism. Conclusions: A possible underlying mechanism of the impact of CCR5Δ32 genotype on inflammation driven mortality in dialysis patients could be a reduced Th1 immune response as represented by decreased TNF-α levels.
Cytokine.
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Lakartidningen 102(5):281-2.
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ABSTRACT: It has been increasingly apparent that end-stage renal disease (ESRD) patients carry an inflammatory burden, which may play a pivotal role in the evolution of not only wasting but also of the massive increase in the relative risk of cardiovascular disease (CVD). Also increased oxidative stress (an impairment of the pro- and antioxidant redox balance) is a common feature of ESRD, and it has been speculated that it is interrelated to inflammation. Myeloperoxidase (MPO) is a hemoprotein secreted during activation of neutrophils, which plays an important role in the defense of the organism by catalyzing the production of hypochloric acid (HOCl). MPO has been speculated to be a major oxidative stress pathway in ESRD. Emerging evidence suggests that enhanced MPO-activity, via increased generation of diffusible oxidants and consumption of nitric oxide, may be an important risk factor for vascular disease. Indeed, MPO serum levels are a powerful predictor of cardiovascular events in non-renal patients. As a functional polymorphism (SNP) has been identified at position -463 (where the A allele is associated with lower MPO expression) this sequence of event may be affected by genetic factors. Nutritional and pharmacological antioxidant strategies that interfere with chlorinated MPO-associated oxidative stress pathways need to be investigated in the ESRD patient population.
Journal of nephrology 17 Suppl 8:S72-6. · 1.65 Impact Factor
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Peter Stenvinkel
Lakartidningen 104(36):2495.
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Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 27(3):254-7. · 2.10 Impact Factor
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ABSTRACT: The homocysteine (Hcy) theory states that total homocysteine (tHcy) is a risk factor for atherosclerosis. Chronic kidney disease (CKD) is one of the most frequent causes of hyperhomocysteinemia in the presence of high prevalence of cardiovascular disease (CVD). However, there is not yet any conclusive answer to the question whether Hcy may contribute to, or predict, cardiovascular events or mortality in CKD patients or whether it is just an innocent bystander biologically related to other potential risk factors for CVD. Moreover, tHcy levels in CKD are influenced by several commonly occurring confounding factors, such as inflammation and protein-energy wasting (PEW). These factors are also associated with morbidity and mortality and altogether this may explain why Hcy does not show up as a cardiovascular risk but in fact is reversely associated with clinical outcome. Thorough evaluation of such reverse association may not necessarily imply that the principles of Hcy being a contributor to vascular pathophysiology are different in CKD patients but rather indicate that other superimposed factors, such as PEW and inflammation, are more important. These confounders contribute significantly to the unacceptably high mortality rate in this patient population and may require nutritional and anti-inflammatory interventions to improve clinical outcome. So far, the results of recent folic acid intervention trials do not support the use of folic acid supplementation for lowering tHcy and improving survival in CKD patients. Although we are still waiting for the results from several ongoing controlled randomized trials in this area, future studies are needed to evaluate if thiol-exchange agents, besides folic acid, as part of a future multifactorial intervention regime targeting inflammation, PEW, oxidative stress as well as hyperhomocysteinemia may decrease CVD risk in this high-risk patient population.
Seminars in Dialysis 20(6):523-9. · 2.27 Impact Factor
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Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 25(4):340-2. · 2.10 Impact Factor
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ABSTRACT: Dyslipidemia is an established cardiovascular risk factor in the general population. However, in patients suffering from chronic kidney disease (CKD) this relationship is less clear, and many studies show that low, rather than high, cholesterol levels predict mortality in this patient population. This review presents an overview of the major disorders of lipid metabolism in the course of CKD and their clinical implications. We also discuss the role of genetic determinants predisposing to dyslipidemia, as well as current therapeutic approaches. Finally, the mendelian randomization approach as a novel tool to elucidate the seemingly paradoxical association between hypercholesterolemia and mortality in CKD will be discussed.
Journal of nephrology 21(5):635-44. · 1.65 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) is associated with inflammation and malnutrition and carries a markedly increased risk of cardiovascular disease (CVD). High Mobility Group Box Protein-1 (HMGB-1) is a 30-kDa nuclear and cytosolic protein known as a transcription and growth factor, recently identified as a proinflammatory mediator of tissue injury. Recent data implicates HMGB-1 in endotoxin lethality, rheumatoid arthritis, and atherosclerosis. The aim of this post-hoc, cross-sectional study was to determine whether HMGB-1 serum levels are elevated in CKD patients. The study groups were categorized as follows: 110 patients starting dialysis defined as CKD 5; 67 patients with moderately to severely reduced renal function or CKD 3-4; and 48 healthy controls. High-sensitivity C-reactive-protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF), serum-albumin (S-albumin), hemoglobin A(1c) (HbA(1c)), hemoglobin, subjective global nutritional assessment (SGA), and glomerular filtration rate (GFR) were analyzed. Kruskal-Wallis test was used to compare groups and Spearman's rank correlation test was used for continuous variables. HMGB-1, measured by Western blot, was significantly (P < 0.001) elevated in CKD 5 (146.7 +/- 58.6 ng/mL) and CKD 3-4 (85.6 +/- 31.8) compared with controls (10.9 +/- 10.5). HMGB-1 levels were correlated positively with TNF (Rho = 0.52; P < 0.001), hs-CRP (Rho = 0.38; P < 0.001), IL-6 (Rho = 0.30; P < 0.001), HbA(1c) (Rho = 0.14; P = 0.02) and SGA (Rho = 0.21; P = 0.002) and negatively correlated with GFR (Rho = -0.69; P = 0.0001), Hb (Rho = -0.60; P < 0.001), S-albumin (Rho = -0.31; P < 0.001). The current study has revealed that HMGB-1 is elevated significantly in CKD patients and correlates with GFR as well as markers of inflammation and malnutrition. Future studies may delineate whether HMGB-1 is also a marker of disease activity and severity as well as a predictor of outcome in CKD.
Molecular Medicine 14(3-4):109-15. · 3.76 Impact Factor
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Siamak Haghdoost,
Yukio Maruyama,
Roberto Pecoits-Filho,
Olof Heimburger,
Astrid Seeberger,
Björn Anderstam,
Mohamed E Suliman,
Stefan Czene,
Bengt Lindholm, Peter Stenvinkel,
Mats Harms-Ringdahl
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ABSTRACT: 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.
Antioxidants and Redox Signaling 8(11-12):2169-73. · 8.46 Impact Factor
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ABSTRACT: 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.
ASAIO Journal 50(6):lii-lvii. · 1.39 Impact Factor
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ABSTRACT: 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.
Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 24(4):327-39. · 2.10 Impact Factor
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ABSTRACT: Chronic kidney disease (CKD) is characterized by an exceptionally high mortality rate, much of which results from cardiovascular disease (CVD). Chronic low-grade inflammation, as evidenced by increased levels of pro-inflammatory cytokines and C-reactive protein (CRP), is a common feature of CKD and may cause atherosclerotic CVD through various pathogenetic mechanisms. Evidence suggests that persistent inflammation may also be a risk factor for progression of CKD, which may result in a vicious inflammation-driven circle. The causes of inflammation in CKD are multifactorial. The influence of various comorbidities may contribute to inflammation in the setting of progressive loss of renal function. Available data suggest that pro-inflammatory cytokines also play a central role in the genesis of the metabolic syndrome. There is a lack of epidemiological data on the prevalence and consequences of inflammation in relation to protein-energy wasting (PEW) and CVD in CKD patients from developing countries. The 'westernization' of nutritional intakes and changes of life style besides the high prevalence of chronic infections in developing countries are possible additive contributors to a high prevalence of inflammation, PEW and CVD among CKD patients. Also, genetic differences may affect inflammatory responses and nutritional status and, thus, the susceptibility to CVD in different regions.
Saudi journal of kidney diseases and transplantation: an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia 19(3):329-45.
