as the majority of recent randomized controlled trials ( rcts ) have been unable to demonstrate a beneficial effect of various interventions aimed at improving outcome in end - stage renal disease ( esrd ) , novel treatment strategies need to be tested in this high - risk patient group . among several novel risk factors , inflammation has attracted considerable interest in the last 10 years .
although cytokine production is necessary to protect against pathogens and promote tissue repair , excessive release or decreased clearance ( or both ) can lead to organ failure and premature death .
detailed reviews on causes of inflammation in the context of impaired renal function have recently been published .
prospective studies in hemodialysis , peritoneal dialysis , and renal transplantation patients show that even a single measurement of inflammatory biomarkers independently predicts poor outcome .
furthermore , inflammation has been identified as a strong prognosticator of sudden death in esrd patients , which indirectly supports a link between persistent inflammation and an imbalance between the sympathetic and parasympathetic nervous system . in 2008 , a large genetic study of patients with ischemic heart disease ( and controls ) showed that c - reactive protein ( crp ) polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease , therefore , available evidence suggests that although crp is a strong risk marker , it is not a risk factor of cardiovascular disease .
in fact , among numerous studies that have shown that inflammatory biomarkers or cells involved in the inflammatory cascade predict outcome , interleukin ( il)-6 seems to be the strongest predictor of cardiovascular morbidity and outcome .
another study showed that by defining specific cytokine ratios related to the inflammatory and immunologic states , it seems possible to fine tune the prediction of death from cardiovascular and non - cardiovascular causes .
based on the observation that persistent inflammation may serve as a catalyst and magnify the risk of poor outcome via mechanisms related to self - enhancement of the inflammatory cascade and exacerbation of the wasting and calcification processes , it can be argued that the effects of different interventions should be analyzed separately in inflamed and non - inflamed dialysis patients .
although inflammatory markers persistently predict outcome in dialysis patients or following kidney transplantation , few studies have studied the effect of various anti - inflammatory interventions on outcome . however , as small studies have shown encouraging results after examining the levels of inflammatory biomarkers following intervention with gamma - tocopherol , soy , green tea , cholecalciferol   and sevelamer , the renal community should conduct sufficiently powered rcts to prove the concept that treatment of persistent inflammation may provide benefit in reducing uremic morbidity and mortality . in a recent rct involving 2776 hemodialysis patients , the effects of rosuvastatin versus placebo were compared .
no effect on mortality was observed despite a small reduction of crp following statin treatment .
however , as the interaction between crp and the effect of rosuvastatin was not checked , we do not know if the effects of statins on the outcome differ between inflamed and uninflamed dialysis patients .
no large study has yet tested if anti - cytokine therapy affects surrogate biomarkers of inflammation , morbidity , and mortality . however , as therapy targeting il-1-mediated inflammation not only reduces inflammation biomarkers but also holds promise for the treatment of glycemic control in type 2 diabetic patients , it can be speculated that targeted il-1 antagonism may also benefit uremic patients . in a recent pilot study of 10 dialysis patients that were randomly assigned to receive either the tumour necrosis factor - alpha ( tnf- ) antagonist etanercept or placebo twice weekly for 44 weeks , no significant effects on inflammatory biomarkers were observed .
however , as a significant difference in the time - dependent effects of etanercept on prealbumin was observed ( levels increased by 20% in the etanercept group and decreased in the placebo group ) , favorable effects on nutritional markers may be anticipated .
as no adverse side effects were observed , administration of tnf- receptor antagonism seems safe in selected dialysis patients despite their documented increased risk of infectious complications .
thus , larger studies are now needed to test the effects of selective anti - tnf , il-1 , and il-6 therapies , respectively , not only on inflammatory and nutritional surrogate markers but also on morbidity and outcome .
no doubt , the major problem in such a rct will be to select the patients with persistent non - infectious uremic inflammation .
until adequately powered rcts have been performed with anti - inflammatory treatment strategies , no specific pharmacological treatment recommendations for uremic inflammation can be advocated .
however , clinicians should be aware of the strong association between persistent inflammation and outcome before carefully evaluating ( and if possible treating ) the multiple putative causes of persistent inflammation in this patient group .
although the clinician may minimize some aggravating factors that promote inflammation in the context of renal disease , it may not be possible to get rid of inflammation in a clinical situation .
due to the fact that causes both unrelated to dialysis ( such as intercurrent infectious and inflammatory complications , peridontitis , and ischemic heart disease ) and related to dialysis ( such as bioincompatibility , residual renal function , infections of vascular access , dialysis hypotension , impure dialysate , and volume overload ) can contribute to uremic inflammation , the clinician needs to carefully evaluate all chronic kidney disease patients with signs of inflammation such as elevated crp levels .
indeed , a recent study demonstrated lower cardiovascular mortality in dialysis units in which crp was regularly monitored .
 since the first reports in the late 1990s connecting elevated circulating levels of c - reactive protein in patients with end - stage renal disease with an atherogenic , wasted phenotype and poor outcome , more than 3600 publications related to the subject have appeared on the medline bibliographic database . 
 this reflects the exponential interest that this topic has evoked in the field of nephrology , and the possibility of treating this common uremic complication has been much discussed . 
 several small studies have implied that various nutritional and pharmacological treatment strategies have beneficial effects on surrogate markers of inflammation . 
 however , no randomized controlled trials on anti - inflammatory treatment have yet been performed to test the hypothesis that persistent low - grade inflammation contributes to uremic morbidity and mortality . 
Introduction and context
Recent advances
Implications for clinical practice
Competing Interests