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REVIEW ARTICLE Therapeutics targeting persistent inflammation in chronic kidney disease Q9
ANNA MACHOWSKA, JUAN JESUS CARRERO, BENGT LINDHOLM, and PETER STENVINKEL STOCKHOLM, SWEDEN
Systemic inflammation is a condition intrinsically linked to chronic kidney disease (CKD) and its other typical sequelae, such as acquired immune dysfunction, protein-energy wasting (PEW), and accelerated vascular aging that promote premature cardiovascular disease (CVD) and infections, the two leading causes of death in CKD patients. Inflammation is a major contributor to complications in CKD, and inflammatory markers, such as C-reactive protein and pro- and antiinflammatory cytokines, correlate with underlying causes and consequences of the inflamed uremic phenotype, such as oxidative stress, endothelial dysfunction, CVD, PEW, and infections, and are sensitive and independent predictors of outcome in CKD. Therefore, inflammation appears to be a logical target for potential preventive and therapeutic interventions in patients with CKD. Putative anti-inflammatory therapy strategies aiming at preventing complications and improving outcomes in CKD span over several areas: (1) dealing with the source of inflammation (such as cardiovascular, gastrointestinal or periodontal disease and depression); (2) providing nonspecific immune modulatory effects by promoting healthy dietary habits and other lifestyle changes; (3) promoting increased use of recognized pharmacologic interventions that have pleiotropic effects; and, (4) introducing novel targeted anticytokine interventions. This review provides a brief update on inflammatory biomarkers and possible therapeutic approaches targeting inflammation and the uremic inflammatory milieu in patients with CKD. (Translational Research 2015;-:1–10) Abbreviations: --- ¼ ---
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INTRODUCTION From the Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. Submitted for publication April 3, 2015; revision submitted June 16, 2015; accepted for publication June 18, 2015. Reprint requests: Peter Stenvinkel, Department of Renal Medicine, M99, Karolinska University Hospital at Huddinge, 141 86 Stockholm, Sweden; e-mail: [email protected]. 1931-5244/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2015.06.012
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he prevalence of chronic kidney disease (CKD) has reached epidemic proportions with 10%– 12% of the population and .50% of elderly showing signs of kidney dysfunction, a condition associated with high morbimortality.1 Among many complications linked to CKD that contribute to the high morbimortality, systemic low-grade inflammation has a prominent role as one of the most typical features and as major contributor to the uremic phenotype in advanced stages of CKD. End-stage renal disease (ESRD) is strongly associated with systemic inflammation, a condition intrinsically linked not only to renal 1
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dysfunction but also to its other sequela including among others a state of acquired immune dysfunction, metabolic and nutritional derangements, and proteinenergy wasting (PEW). Moreover, recent evidence suggests that persistent inflammation is also a major cause of premature general and vascular aging.2 It was hypothesized that allostatic overload may contribute to increased oxidative stress, activated innate immune system, and persistent low-grade inflammation and sympathetic–vagal imbalance. Therefore, as a response to this allostatic overload, activation of the ‘‘stress resistance response’’ pathways may occur that together with an impairment of antiaging pathways and increased age-promoting factors contribute to advanced biological ageing processes in CKD patients.3 These conditions interplay with inflammation in promoting and exacerbating processes that lead to the excessive high risk of cardiovascular disease (CVD) and infections, the two leading causes of death among these patients.4 In addition, inflammation is thought to play a major role also in the pathophysiology of CKD and progression of renal dysfunction5 and in the complex situation of acute kidney injury.6 Inflammatory markers such as C-reactive protein (CRP) and pro- and anti-inflammatory cytokines correlate with underlying causes and consequences of the inflamed uremic phenotype such as oxidative stress, endothelial dysfunction, CVD, PEW, and infections.7 As inflammatory biomarkers are sensitive predictors of the outcomes in patients with ESRD, inflammation appears to be a logical target for preventive and therapeutic interventions in patients with CKD.8,9 Many therapeutic strategies may intervene in inflammatory pathways on different levels by targeting the source of local and systemic inflammation, changing lifestyle and nutritional habits, implementing or enhancing commonly known therapeutic strategies inducing a multiple physiological effects, or by novel concepts requiring further investigation. In this review, we briefly describe sources and consequences of inflammation in CKD and the clinical evidence for effects of potential preventive and therapeutic antiinflammatory strategies in CKD patients. INFLAMMATION IS A COMMON FEATURE OF THE UREMIC PHENOTYPE
In CKD and especially in ESRD patients, systemic concentrations of both pro- and anti-inflammatory cytokines are often severalfold higher than in healthy individuals. As depicted in Fig 1, there are multiple causes of systemic inflammation in CKD and ESRD patients.10-13 One major underlying factor is that the uremic phenotype associates with a state of immune dysfunction affecting both the innate and adaptive
web 4C=FPO
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Fig 1. Causes and consequences of inflammation in chronic kidney disease patients. CKD, chronic kidney disease.
immune systems with immune activation resulting in inflammation, a key driver of CVD, and on the other hand, immune depression that increases the susceptibility to infections, a key driver of inflammation. These two major complications, CVD and infections, accounting for 50% and 20%, respectively, of total mortality in ESRD patients are thus closely linked to the altered immune state and presence of systemic inflammation.13 Another major underlying cause of systemic inflammation, conceivably linked to the uremic immune dysfunction, is renal dysfunction as such as it inevitably results in retention of fluid and small and large solutes many of which may act as proinflammatory uremic toxins, whereas others are in fact proinflammatory cytokines.14,15 Thus, in addition to inflammatory
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activation (due to a multitude of reasons, some of which are described below) resulting in increased production or release of cytokines, the observation that there is an inverse correlation between inflammatory biomarkers and markers of renal function indicates that decreased cytokine excretion or degradation in the kidney of inflammatory mediators may also play a role.16 The circulating levels of biomarkers of systemic inflammation, such CRP,17 pentraxin-3 (PTX3),18 interleukin-6 (IL-6), and also the anti-inflammatory IL-1015 increase progressively as renal function declines. IL-10 levels were shown to increase across worsening CKD stages and associate—together with IL-6 and PTX3—with the risk of CV events during follow-up.15 Moreover, the IL-6/IL-10 ratio was an independent predictor of composite end points suggesting a pivotal role of IL10 in a compensatory mechanism in response to the inflammatory status.15 Although CRP, the best studied of all acute-phase proteins, is the prototypical inflammatory marker, other specific inflammatory molecules, such as PTX3 and TWEAK, have gained increasing interest in the nephrology community. PTX3 because of its extrahepatic synthesis is—in contrast to CRP— believed to be a true independent indicator of disease activity produced at sites of inflammation and identified as a novel mortality risk factor in CKD stage 5, independent of traditional risk factors, but most importantly independent of CRP itself.19 PTX3 is elevated in hemodialysis (HD) patients as compared with healthy individuals.20 The retention of this and other circulating cytokines,21 advanced glycation end-products,22 and pro-oxidants23 contribute to a proinflammatory milieu when renal function declines. Systemic low-grade inflammation is also linked to and part of common complications among ESRD patients including malnutrition, inflammation, atherosclerosis (MIA syndrome).10,24 In addition to malnutrition (or PEW), CVD, infections, and retention of fluid and uremic toxins, other uremiarelated proinflammatory factors can also trigger an inflammatory response such as oxidative stress, endothelial dysfunction, bone-mineral disorders, vascular calcification, depression, altered metabolism of fat, carbohydrates and lipids, and intestinal dysbiosis.4,11 Although adequate dialysis treatment to some extent can ameliorate some uremia-related proinflammatory factors, there are many dialysis-related factors such as bio-incompatible dialysis membranes, central dialysis catheters, and unpure dialysis fluids, unpure water, and dialysis-related infections that may further aggravate chronic systemic inflammation in dialysis patients.4,8 A failed kidney transplant is another cause of persistent inflammation in dialysis patients that should be considered.25 Finally, as in the general population, there are several general proinflammatory conditions
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that should also be taken into account in CKD and ESRD patients, such unhealthy diets and lifestyle factors, obesity, and smoking.4 In addition to direct detrimental effects of inflammation, recent evidence suggests that persistent inflammation may act as a catalyst for other risk factors and enhance the development of complications, such as PEW and vascular calcification,26 which add further to the poor outcome among ESRD patients. Inflammation therefore appears to be a logical target for potential preventive and therapeutic interventions in CKD patients.12 GENERAL LIFESTYLE MODIFICATIONS THAT MAY HAVE ANTI-INFLAMMATORY EFFECTS
A healthy lifestyle has, apart from or perhaps as an integral part of its perceived value as a means to reduce sickness and prolong life, also anti-inflammatory effects that may contribute to improved physical, mental, and socioeconomic well-being. This could be of particular importance in patients with CKD. Yet, there is a scarcity of studies addressing the anti-inflammatory effects of general lifestyle modifications. Physical activity and lifestyle modifications. Physical activity and lifestyle modifications may positively influence the clinical outcomes of CKD patients. Exercise training in CKD patients showed favorable albeit inconsistent effect on the catabolic state in uremic muscles and on inflammatory markers.27,28 Dialysis patients with poor physical activity present with higher CRP levels,29 and in patients randomized to regular walking exercise (30 min/d, 5 times/wk), downregulated T-lymphocyte, monocyte activation, and reduction in the IL-6/IL-10 ratio was reported as compared to those with usual daily activities.30 As increased resistance exercise training may contribute to improvement in systemic inflammation, this opens interesting opportunities to reduce inflammation by physical training in sedentary dialysis patients. Depression. Depression is a common problem in ESRD patients31 and related to high mortality.32,33 In peritoneal dialysis (PD) patients, depression was strongly related to inflammation, malnutrition, and multiple cardiovascular risk factors, suggesting that depression is an integral part of the MIA syndrome.34 Indeed the state of depression associates with activation of proinflammatory cytokines, and patients on maintenance HD with symptoms of depression were more likely to have high levels of serum IL-6, higher prevalence of comorbidities, higher serum total cholesterol, and lower s-albumin levels.35 In depressed HD patients, sertraline, a selective serotonin reuptake inhibitor antidepressant, was found to have antiinflammatory effects in addition to improving
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depression symptoms in almost half of the HD patients. This suggests that selective serotonin reuptake inhibitors can be a promising therapeutic strategy to reduce systemic inflammation in depressed HD patients.36 Another RCT in HD patients showed that 4 months supplementation with omega-3 fatty acids not only decreased depressive symptoms but also reduced inflammatory status; however, results were considered as inconclusive.37 Finally, as cognitive behavioral therapy not only corrected disorganized sleep patterns but also reduced inflammation and oxidative stress in HD patients,38 this further support links between psychosocial health and inflammation. Periodontal disease. Since long, it is well known that oral health is a factor of major importance for many chronic diseases. Although periodontal disease is a well-described important contributor to local and chronic systemic inflammation in CKD, it is often overlooked.39,40 Periodontal disease may link also to problems in chewing/biting and may thereby affect appetite and food intake.41,42 One mechanism underlying the pathogenesis of periodontitis involves gram-negative bacteria that interact with toll-like receptors expressed on the surface of neutrophils and monocytes. Toll-like receptors–ligand complexes activate signal transduction pathways leading to the production of cytokines, which coordinate the local and proinflammatory cytokines and activate hepatocytes to produce acute-phase proteins including CRP.43 It is not known if anti-inflammatory–targeting strategies can be used to treat periodontal disease in CKD patients, but recent data from an uncontrolled study showed that treatment of periodontal disease may improve systemic inflammation, nutritional status, and erythropoietin responsiveness in dialysis patients.44,45 DIETARY FACTORS THAT MAY HAVE ANTIINFLAMMATORY EFFECTS
As the diet is a source of many both antiinflammatory and proinflammatory constituents, dietary habits and food patterns are probably of major relevance in modifying systemic inflammatory levels and perhaps affecting kidney function.46 Below are just a few examples of how dietary factors and interventions linked to these factors may have anti-inflammatory effects. Phosphate. Hyperphosphatemia, a typical feature of advanced CKD that plays a major role in the mineralbone disorders in CKD, seems to contribute to an inflammatory state. Phosphate binding therapies, such as sevelamer, may therefore have anti-inflammatory properties, and in addition, sevelamer in itself may reduce inflammation.47 In HD patients, 8 weeks of sevelamer treatment not only improved endothelial
function but also increased levels of the negative acute-phase protein fetuin-A (a major calcification inhibitor).48 Moreover, a study in HD patients treated with either sevelamer or calcium acetate showed that sevelamer was associated with a significant decrease in CRP, IL-6, serum endotoxin levels, and soluble CD14.49 Thus, the putative anti-inflammatory potential of sevelamer, a compound that possesses LPS binding properties, should be considered as a therapeutic strategy. Dietary fat intake. Considering that HD patients that are fish eaters have lower mortality50 and that in HD patients omega-3 fatty acids (fish oil) is reported to attenuate the inflammatory response to HD,51 it is not surprising that dietary fat modifications in the CKD population may have favorable effects. Both excess saturated fat intake52 and insufficient intake of polyunsaturated fat53 are strongly associated with systemic inflammatory biomarkers in dialysis patients. Long-chain n-3 polyunsaturated fatty acids (PUFAs) provided in fish oils may decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species and the expression of adhesion molecules.54 Several clinical studies showed that supplementation with n-3 PUFAs can have antiinflammatory beneficial effects and reduce inflammatory biomarkers. Recently, a dietary pattern with low linoleic and high saturated fat intake was associated with systemic inflammation, insulin resistance, and metabolic syndrome suggesting the potential beneficial effect of replacing SFA with PUFA, also from vegetable origins.55 However, little is known about the effect of n-6 PUFA apart from one study showing trend toward reduction of leukotriene B4 (proinflammatory eicosanoid) production.56 Intestinal microbiota. What we eat has a major impact on the status of the intestinal microbiota, and this may be of particular importance in patients with CKD. The progression of CKD is associated with metabolic alterations that change the balance of symbiotic and pathobiont bacteria in the lumen of the intestinal track leading to pathogen overgrowth (dysbiosis) in the gut, loss of barrier integrity, and an increased translocation of living bacteria and bacterial components.57 These processes may possibly contribute to CKD progression, accelerated atherogenesis, and PEW. Thus, therapeutic interventions to manipulate microbiota such as prebiotics or probiotics may have a potential in the stabilization of the immune state and prevention of ESRD complications.57 The bowel bacterial overgrowth syndrome is found frequently in dialysis patients and associates with gastrointestinal malabsorption and maldigestion, PEW, and systemic inflammation. This syndrome was found to be present
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in 25% of PD patients, who were in turn more often inflamed and had signs of PEW. It is of interest that antibiotic treatment improved appetite scores and led to increased s-albumin levels although it decreased the systemic inflammatory marker TNF.58 As higher dietary fiber intake associated with better kidney function and lower inflammation,59 adequate dietary intake of fiber may also benefit this pathway. Fructose. A high fructose intake is thought to contribute to obesity, hypertension, inflammation, elevated serum uric acid levels, and gout, and it may also be a factor that could promote CKD.60 According to a recent study in CKD stage 2–3 patients, a low fructose diet could decrease markers of inflammation61; thus, the vulnerable CKD patient population should be careful with high consumption of soft drinks (which also contain a lot of phosphate) and other food items that contain a high content of fructose. Oxidative stress. Because of close links between inflammation and oxidative stress, interventionstargeting oxidative stress could have a potential role in preventive and therapeutic anti-inflammatory strategies.62 The nuclear factor erythroid 2–related factor (Nrf2), a key transcription factor playing an important role in cytoprotection against inflammation, has gained increased attention because of its ability to antagonize the transcription factor nuclear factor-kB, a major trigger of the expression of inflammatory genes.63 In response to oxidative stress and inflammation with increased activity of nuclear factor-kB, activation of Nrf2 upregulates .250 cytoprotective and antioxidant genes that may limit processes leading to inflammation, endothelial dysfunction, and mesangial proliferation.64 Nutritional components modulating Nrf2 could potentially contribute to development of new therapies.65 Recently discussed pharmaceutical agents include among others bardoxolone methyl, a triterpenoid obtained from the fruit and leaves of the olive tree that activates Nrf2.65 Unfortunately, a recent randomized controlled trial (RCT) study had to be suspended because of increased mortality and higher risk of side effects due to volume retention in the bardoxolone intervention arm; however, further studies are warranted to reduce the risk of such complications and evaluate the real effect of this intervention.66 Decaffeinated green tea (catechin) was shown to decrease inflammatory biomarkers in HD patients.67 Thus, this may yet be considered another antiinflammatory dietary intervention to further investigation in CKD. In addition, an interesting RCT study in 101 HD patients showed that 12 months consumption of pomegranate juice reduced polymorphonuclear leukocyte priming and levels of inflammation
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biomarkers.68 Moreover, soy-derived isoflavones are thought to have anti-inflammatory effects and should be considered for nutritional antioxidative treatment strategies [44]. Q3 The influence of antioxidant therapy by supplementation with the vitamin E compounds, gamma-tocopherol (308 mg/d), and the omega-3 fatty acid, docosahexaenoic acid (800 mg/d) on oxidative stress and inflammation markers was evaluated in a RCT among 70 HD patients during 8 weeks. The results showed that administration of gamma-tocopherol and docosahexaenoic acid significantly decreases selected inflammatory biomarkers, such as IL-6, whereas no influence on CRP or F2-isoprostanes was observed. There were no adverse events attributed to either treatment or placebo group. These results suggest that the combination of antioxidant and fish oils could be a feasible treatment option for decreasing persistent inflammation in dialysis patients.69 On the other hand, another RCT, the provision of antioxidant therapy in hemodialysis conducted by the same group evaluated the impact on hsCRP, IL6, F2-isoprostanes, and isofurans of oral administration of tocopherols (666 IU/d) plus a-lipoic acid (600 mg/d), a thiol-containing antioxidant, or placebo among 238 HD patients who were followed up for 6 months; the effects on the level of inflammatory and oxidative stress biomarkers were not statistically significant, and also the intervention did not improve erythropoietin response.70 Regardless of the inconclusive results, the administration of other dosages or combinations should be evaluated, and the approach of targeting inflammation by antioxidants should not be discarded. N-acetylcysteine is a thiol-containing compound with antioxidant effects that can be attributed to its action as a free radical scavenger and as a reactive sulfhydryl compound that increases the reducing capacity of the cell. PD patients receiving N-acetylecysteine (2 3 600 mg/ daily) for 8 weeks had significantly lower serum level of IL-6 as compared with control groups.71 A RCT in 134 HD patients showed that patients randomized to N-acetylecysteine (600 mg BID) compared with placebo group showed reduced primary composite cardiovascular end points.72 COMMONLY USED DRUGS THAT MAY HAVE PLEIOTROPIC ANTI-INFLAMMATORY EFFECTS
Many commonly used drugs in CKD patients may have a positive impact on systemic inflammation. In some cases, the drug may have direct effects on inflammatory pathways over and above its main indication. In other cases (and this is more common), an impact on inflammation is likely explained by a beneficial effect on other pathways that also convey inflammation. Although some of these drugs are already commonly
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prescribed in CKD, yet, inflammation still exists among patients suggesting that these drugs—which seldom are prescribed with the sole intention of reducing inflammation—are not as effective as anti-inflammatory agents. Nevertheless, they are often considered as valuable adjuvants in strategies aiming at reducing systemic inflammation in CKD patients. Statins. A large number of randomized control trials have shown that statins help in the primary and secondary prevention of cardiovascular events, not only via their lipid-lowering effect, but also due to their antiinflammatory potential. According to a systematic review, statins may reduce CRP levels in dialysis patients, whereas there was no conclusive evidence that they may improve nutritional status.73 However, in a post hoc analysis of the 4D study found among 1255 HD patients with type 2 diabetes, there were no significant changes in CRP related to atorvastatin treatment.74 In a smaller RCT crossover study with 76 PD patients receiving either pravastatin or placebo for 2 months followed by a 1 month wash-out period and crossed over to another group for another 2 months period, pravastatin significantly reduced serum CRP and HDL-cholesterol levels compared with placebo.75 A secondary analysis from the JUPITER study showed that rosuvastatin reduced CRP levels by 37% and reduced cardiovascular events and all-cause mortality among patients with moderate CKD.76 These and other studies suggest that statins may be beneficial in suppressing the inflammatory status. Vitamin D. Vitamin D is a dietary constituent that is ingested in insufficient amounts in CKD patients, leading to deficiencies especially among patients deprived of exposure to the sun, and there is increased recognition that this prehormone has beneficial effects including anti-inflammatory actions that could motivate its prescription as a drug. Administration of cholecalciferol to ESRD patients was found to reduce circulating IL-8, IL-6, and TNF levels by approximately 55%, 30%, and 60%, respectively.77 It has also been demonstrated that high-dose cholecalciferol decreased serum monocyte chemotactic protein-1 concentrations by 12 weeks in patients with early CKD. In a prospective study of 158 HD patients, cholecalciferol supplementation resulted in decreased CRP and increased s-albumin levels.78 As one study showed that vitamin D deficiency in HD patients who had not taken vitamin D receptor agonists associated with an increased risk of all-cause mortality,79 the impact of vitamin D supplementation on long-term outcome needs to be evaluated. Targeting the renin–angiotensin system. Most patients with advanced CKD suffer from hypertension and CVD that should be treated by drugs; some of which
may have anti-inflammatory potentials. In HD patients, treatment by ramipril, an angiotensinconverting enzyme inhibitor and valsartan, an angiotensin receptor blockers, for 7 days in a crossover study, resulted in decreased IL-6 levels,80 and in another study, losartan lowered the percentage of monocytes expressing CD141CD161.81 In addition, in HD patients, 8-week administration with aliskiren, a direct renin inhibitor, was found to lower the CRP level.82 Ramipril treatment was presented as beneficial in reducing inflammation in diabetic CKD patients.83 Thus, the use of these common drugs that are indicated for treatment of hypertension and CVD come with the bonus of having also anti-inflammatory effects. This may be of particular value when trying to halt the progression of glomerular diseases and reducing albuminuria in these patients. TARGETED ANTICYTOKINE TREATMENT Interleukin receptor antagonists. Among a number of specifically targeted anticytokine treatment strategies, blockade of IL-1 and IL-6 may be the most interesting in the context of uremia. Indeed, on the basis of genetic evidence in human beings, IL-6R signaling seems to have a causal role in development of heart disease in nonrenal patients.84 A small pilot study in 22 HD patients showed that treatment with IL-1 receptor antagonist was associated with 40%–50% reduction in mean high sensitivity CRP and IL-6 levels and an increase in mean prealbumin level.85 This suggests that targeted anti-inflammatory interventions could be applicable in CKD patients. Such interventions could potentially include also humanized antibody (Toclizumab), which has a positive effect in inflammatory diseases such as rheumatoid arthritis.86 The Cardiovascular Inflammation Reduction Trial is an ongoing double-blind, placebo-controlled, multicenter study currently recruiting patients to investigate whether administration of low-dose methotrexate may reduce cardiovascular events by reducing inflammation.87 The Canakinumab Anti-inflammatory Thrombosis Outcomes Study conducted in .40 countries evaluates whether blocking IL-1b with canakinumab can reduce rates of cardiovascular events among patients who remain at high risk due to persistent elevation of CRP ($2 mg/L).88 However, given the risk for infectious complications in this immune-compromised patient, population selection of patients eligible for targeted anticytokine treatment should be very meticulous. Pentoxifylline. Pentoxifylline is a nonspecific phosphodiesterase inhibitor that inhibits the production of TNF, IL-6, and IL-10. In a RCT study in 36 HD
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patients, administration of pentoxifylline (400 mg/d) during 4 months significantly decreased serum concentrations of inflammatory biomarkers89 suggesting that this drug could be a promising therapeutic strategy to treat uremic inflammation. Strategies for specific anticytokine drug development may involve stimulation or repression of the synthesis of anti-inflammatory or proinflammatory cytokines and the enhancement or blockage of their receptors. However, blocking cellular or molecular functions that presumably have an important role in the host defense may increase the susceptibility to infections or the severity of infections. In addition, it should be considered that some of biological agents are chimeric or humanized antibodies, and further sensitization might occur, which can lead to both allergic reactions and reduction in efficacy. Although anticytokine therapies should be considered as promising putative strategies to treat inflamed CKD patients, there is a risk that blocking of pathways involved in host defense mechanism may lead to infections and other complications. Therefore, while identifying new therapeutics is essential, a more detailed understanding of how cytokine pathways and related mechanisms are affected by such interventions is needed.90
Statins ACE-inhibitors, angiotensin receptor blockers, and renin inhibitors Cholecalciferol and paricalcitrol Sevelamer Allopurinol Gamma-tocopherol Docosahexaenoic acid and eicosapentaenoic acid N-acetylcysteine Vitamin E–coated dialysis membranes Bardoxolone methyl (activation of Nrf2)
Blocking of TNF (such as etanercept, pentoxifylline and infliximab) Blocking of IL-1 (such as anakinra) Blocking of IL-6 (such as tocilizumab)
Drugs commonly used in nephrology Antioxidative treatment strategies
Targeted anticytokine treatment
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Abbreviations: IL, interleukin; Nrf2, nuclear factor erythroid 2.
Resistance training Appetite stimulants, such as ghrelin, megestrol acetate, cannabinoids Growth hormone Myostatin inhibition Increased fiber intake Fish intake and omega-3 fatty acids Soy (phytoestrogens) Pomegranate juice Decaffeinated green tea extracts (catechins) Decreased fructose intake Nuts and seeds (gamma-tocopherol) Probiotics (living microorganisms) Depression Physical inactivity Poor oral health Smoking
Dietary factors
Antiwasting treatment strategies
CONCLUSIONS
General lifestyle modifications
Table I. Potential anti-inflammatory treatment strategies that could be applicable in patients with chronic kidney disease
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Persistent low-grade inflammation is a common feature of CKD and an intrinsic part of the uremic phenotype. Inflammation is a consequence of many factors linked to renal dysfunction such as a state of immune dysfunction and acts as a catalyst of numerous other risk factors in CKD, promoting common complications such as PEW, CVD, bone-mineral disorders, depression, vascular calcification that contribute to the poor clinical outcomes in patients with advanced CKD. Because of its central role in the uremic phenotype, inflammation appears to be a logical target for preventive and therapeutic—general and specific antiinflammatory interventions in patients with CKD. There is no lack of measures that need to be taken to achieve control of the threats imposed by inflammation. First of all, it is important to identify and if possible treat, prevent, or eliminate as many as possible of the numerous potential sources of inflammation in CKD patients such as cardiovascular, gastrointestinal, or periodontal diseases; retention of fluid and solutes; and infections, to name a few. Second, promoting healthy dietary habits, increased physical activity, and other lifestyle changes including dealing with depression may have important nonspecific immune modulatory effects. Third, patients with CKD commonly receive drugs such as statins and angiotensin-converting enzyme inhibitors/angiotensin
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receptor blockers that apart from their specific indications also have pleiotropic effects that include antiinflammatory activity. This may speak in favor of prescribing such drugs although they cannot usually be prescribed with the sole intention of reducing inflammation. Finally, agents specifically targeting inflammation, such as anticytokine treatments, are likely to become more common interventions in the future, but because of their potent immune system modulating effects, they may have severe unwarranted effects such as infections. UNCITED TABLE
Table I. ACKNOWLEDGMENTS
Conflicts of Interest: J. J. Carrero and P. Stenvinkel do not declare any conflicts of interest. All authors have read the journal’s policy on disclosure of potential conflicts of interest. Swedish Medical Research Council supported P. Stenvinkel’s and J. J. Carrero’s research. A. Machowska is supported by EU Marie-Curie Initial Training Network, EuTRiPD, European Training and Research in Peritoneal Dialysis, Call: FP7-PEOPLEITN-2010, Proposal Number: 287813, and by additional funding provided by Baxter Healthcare Corporation. Baxter Novum is a result of a grant from Baxter Healthcare Corporation to Karolinska Institutet. A. Machowska and B. Lindholm are employed by Baxter Healthcare Corporation. Author contributions are as follows: The article has been reviewed by and approved by all named authors. REFERENCES
1. Stenvinkel P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 2010; 268:456–67. 2. Stenvinkel P, Larsson TE. Chronic kidney disease: a clinical model of premature aging. Am J Kidney Dis 2013;62:339–51. 3. Kooman JP, Kotanko P, Schols AM, Shiels PG, Stenvinkel P. Chronic kidney disease and premature ageing. Nat Rev Nephrol 2014;10:732–42. 4. Carrero JJ, Stenvinkel P. Inflammation in end-stage renal disease– what have we learned in 10 years? Semin Dial 2010;23:498–509. 5. Hiramoto JS, Katz R, Peralta CA, et al. Inflammation and coagulation markers and kidney function decline: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis 2012;60:225–32. 6. Pegues MA, McCrory MA, Zarjou A, Szalai AJ. C-reactive protein exacerbates renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2013;304:F1358–65. 7. Carrero JJ, Yilmaz MI, Lindholm B, Stenvinkel P. Cytokine dysregulation in chronic kidney disease: how can we treat it? Blood Purif 2008;26:291–9. 8. Meuwese CL, Stenvinkel P, Dekker FW, Carrero JJ. Monitoring of inflammation in patients on dialysis: forewarned is forearmed. Nat Rev Nephrol 2011;7:166–76.
9. Meuwese CL, Snaedal S, Halbesma N, et al. Trimestral variations of C-reactive protein, interleukin-6 and tumour necrosis factoralpha are similarly associated with survival in haemodialysis patients. Nephrol Dial Transplant 2011;26:1313–8. 10. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999;55:1899–911. Q4 11. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif 2015;39:84–92. 12. Miyamoto T, Carrero JJ, Stenvinkel P. Inflammation as a risk factor and target for therapy in chronic kidney disease. Curr Opin Nephrol Hypertens 2011;20:662–8. 13. Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008;3:1526–33. 14. Pecoits-Filho R, Heimburger O, Barany P, et al. Associations between circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis 2003;41:1212–8. 15. Yilmaz MI, Solak Y, Saglam M, et al. The relationship between IL-10 levels and cardiovascular events in patients with CKD. Clin J Am Soc Nephrol 2014;9:1207–16. 16. Gupta J, Mitra N, Kanetsky PA, et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin J Am Soc Nephrol 2012;7:1938–46. 17. Yilmaz MI, Stenvinkel P, Sonmez A, et al. Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes. Nephrol Dial Transplant 2011;26:3537–43. 18. Yilmaz MI, Sonmez A, Ortiz A, et al. Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes. Clin J Am Soc Nephrol 2011;6: 785–92. 19. Tong M, Carrero JJ, Qureshi AR, et al. Plasma pentraxin 3 in patients with chronic kidney disease: associations with renal function, protein-energy wasting, cardiovascular disease, and mortality. Clin J Am Soc Nephrol 2007;2:889–97. 20. Boehme M, Kaehne F, Kuehne A, et al. Pentraxin 3 is elevated in haemodialysis patients and is associated with cardiovascular disease. Nephrol Dial Transplant 2007;22:2224–9. 21. Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia–the good, the bad, and the ugly. Kidney Int 2005;67: 1216–33. 22. Suliman ME, Heimburger O, Barany P, et al. Plasma pentosidine is associated with inflammation and malnutrition in end-stage renal disease patients starting on dialysis therapy. J Am Soc Nephrol 2003;14:1614–22. 23. Dounousi E, Papavasiliou E, Makedou A, et al. Oxidative stress is progressively enhanced with advancing stages of CKD. Am J Kidney Dis 2006;48:752–60. 24. Avesani CM, Carrero JJ, Axelsson J, Qureshi AR, Lindholm B, Stenvinkel P. Inflammation and wasting in chronic kidney disease: partners in crime. Kidney Int 2006;70:S8–13. Q5 25. Lopez-Gomez JM, Perez-Flores I, Jofre R, et al. Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol 2004;15:2494–501. 26. Carrero JJ, Stenvinkel P. Persistent inflammation as a catalyst for other risk factors in chronic kidney disease: a hypothesis proposal. Clin J Am Soc Nephrol 2009;4(Suppl 1):S49–55. 27. Castaneda C, Gordon PL, Parker RC, Uhlin KL, Roubenoff R, Levey AS. Resistance training to reduce the malnutritioninflammation complex syndrome of chronic kidney disease. Am J Kidney Dis 2004;43:607–16.
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28. Cheema BS, Abas H, Smith BC, et al. Effect of resistance training during hemodialysis on circulating cytokines: a randomized controlled trial. Eur J Appl Physiol 2011;111:1437–45. 29. Cobo G, Gallar P, Gama-Axelsson T, et al. Clinical determinants of reduced physical activity in hemodialysis and peritoneal dialysis patients. J Nephrol 2014 Dec 12 [Epub ahead of print]. 30. Viana JL, Kosmadakis GC, Watson EL, et al. Evidence for antiinflammatory effects of exercise in CKD. J Am Soc Nephrol 2014;25:2121–30. 31. Wuerth D, Finkelstein SH, Finkelstein FO. The identification and treatment of depression in patients maintained on dialysis. Semin Dial 2005;18:142–6. 32. Kimmel PL, Peterson RA, Weihs KL, et al. Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis outpatients. Kidney Int 2000;57: 2093–8. 33. Riezebos RK, Nauta KJ, Honig A, Dekker FW, Siegert CE. The association of depressive symptoms with survival in a Dutch cohort of patients with end-stage renal disease. Nephrol Dial Transplant 2010;25:231–6. 34. Ko GJ, Kim MG, Yu YM, Jo SK, Cho WY, Kim HK. Association between depression symptoms with inflammation and cardiovascular risk factors in patients undergoing peritoneal dialysis. Nephron Clin Pract 2010;116:c29–35. 35. Hung KC, Wu CC, Chen HS, et al. Serum IL-6, albumin and comorbidities are closely correlated with symptoms of depression in patients on maintenance haemodialysis. Nephrol Dial Transplant 2011;26:658–64. 36. Taraz M, Khatami MR, Dashti-Khavidaki S, et al. Sertraline decreases serum level of interleukin-6 (IL-6) in hemodialysis patients with depression: results of a randomized double-blind, placebo-controlled clinical trial. Int Immunopharmacol 2013;17: 917–23. 37. Gharekhani A, Khatami MR, Dashti-Khavidaki S, et al. The effect of omega-3 fatty acids on depressive symptoms and inflammatory markers in maintenance hemodialysis patients: a randomized, placebo-controlled clinical trial. Eur J Clin Pharmacol 2014;70: 655–65. 38. Chen HY, Cheng IC, Pan YJ, et al. Cognitive-behavioral therapy for sleep disturbance decreases inflammatory cytokines and oxidative stress in hemodialysis patients. Kidney Int 2011;80: 415–22. 39. Ismail G, Dumitriu HT, Dumitriu AS, Ismail FB. Periodontal disease: a covert source of inflammation in chronic kidney disease patients. Int J Nephrol 2013;2013:515796. 40. Akar H, Akar GC, Carrero JJ, Stenvinkel P, Lindholm B. Systemic consequences of poor oral health in chronic kidney disease patients. Clin J Am Soc Nephrol 2011;6:218–26. 41. Carrero JJ, Stenvinkel P, Cuppari L, et al. Etiology of the proteinenergy wasting syndrome in chronic kidney disease: a consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM). J Ren Nutr 2013;23:77–90. 42. Carrero JJ, Qureshi AR, Axelsson J, et al. Comparison of nutritional and inflammatory markers in dialysis patients with reduced appetite. Am J Clin Nutr 2007;85:695–701. 43. Linden GJ, McClean K, Young I, Evans A, Kee F. Persistently raised C-reactive protein levels are associated with advanced periodontal disease. J Clin Periodontol 2008;35:741–7. 44. Siribamrungwong M, Yothasamutr K, Puangpanngam K. Periodontal treatment reduces chronic systemic inflammation in peritoneal dialysis patients. Ther Apher Dial 2014;18:305–8. 45. Yazdi FK, Karimi N, Rasouli M, Roozbeh J. Effect of nonsurgical periodontal treatment on C-reactive protein levels in maintenance hemodialysis patients. Ren Fail 2013;35:711–7.
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46. Xu H, Sjogren P, Arnlov J, et al. A proinflammatory diet is associated with systemic inflammation and reduced kidney function in elderly adults. J Nutr 2015;145:729–35. 47. Navarro-Gonzalez JF, Mora-Fernandez C, Muros M, Herrera H, Garcia J. Mineral metabolism and inflammation in chronic kidney disease patients: a cross-sectional study. Clin J Am Soc Nephrol 2009;4:1646–54. 48. Caglar K, Yilmaz MI, Saglam M, et al. Short-term treatment with sevelamer increases serum fetuin-a concentration and improves endothelial dysfunction in chronic kidney disease stage 4 patients. Clin J Am Soc Nephrol 2008;3:61–8. 49. Navarro-Gonzalez JF, Mora-Fernandez C, Muros de FM, DonateCorrea J, Cazana-Perez V, Garcia-Perez J. Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients. Clin J Am Soc Nephrol 2011;6:2272–9. 50. Friedman AN, Moe SM, Perkins SM, Li Y, Watkins BA. Fish consumption and omega-3 fatty acid status and determinants in longterm hemodialysis. Am J Kidney Dis 2006;47:1064–71. 51. Friedman A, Moe S. Review of the effects of omega-3 supplementation in dialysis patients. Clin J Am Soc Nephrol 2006;1: 182–92. 52. Huang X, Stenvinkel P, Qureshi AR, et al. Clinical determinants and mortality predictability of stearoyl-CoA desaturase1 activity indices in dialysis patients. J Intern Med 2013;273: 263–72. 53. Huang X, Stenvinkel P, Qureshi AR, et al. Essential polyunsaturated fatty acids, inflammation and mortality in dialysis patients. Nephrol Dial Transplant 2012;27:3615–20. 54. Calder PC. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 2006;83(6 Suppl): 1505S–19S. 55. Huang X, Sjogren P, Arnlov J, et al. Serum fatty acid patterns, insulin sensitivity and the metabolic syndrome in individuals with chronic kidney disease. J Intern Med 2014;275:71–83. 56. Huang X, Lindholm B, Stenvinkel P, Carrero JJ. Dietary fat modification in patients with chronic kidney disease: n-3 fatty acids and beyond. J Nephrol 2013;26:960–74. 57. Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int 2013;83:1010–6. 58. Aguilera A, Gonzalez-Espinoza L, Codoceo R, et al. Bowel bacterial overgrowth as another cause of malnutrition, inflammation, and atherosclerosis syndrome in peritoneal dialysis patients. Adv Perit Dial 2010;26:130–6. 59. Xu H, Huang X, Riserus U, et al. Dietary fiber, kidney function, inflammation, and mortality risk. Clin J Am Soc Nephrol 2014; 9:2104–10. 60. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 2013;62: 3307–15. 61. Brymora A, Flisinski M, Johnson RJ, Goszka G, Stefanska A, Manitius J. Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease. Nephrol Dial Transplant 2012;27:608–12. 62. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 2002;62:1524–38. 63. Kim J, Cha YN, Surh YJ. A protective role of nuclear factorerythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res 2010;690:12–23. 64. Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int 2013;83:1029–41.
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65. Cardozo LF, Pedruzzi LM, Stenvinkel P, et al. Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2. Biochimie 2013; 95:1525–33. 66. de ZD, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013; 369:2492–503. 67. Hsu SP, Wu MS, Yang CC, et al. Chronic green tea extract supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am J Clin Nutr 2007;86:1539–47. 68. Shema-Didi L, Sela S, Ore L, et al. One year of pomegranate juice intake decreases oxidative stress, inflammation, and incidence of infections in hemodialysis patients: a randomized placebocontrolled trial. Free Radic Biol Med 2012;53:297–304. 69. Himmelfarb J, Phinney S, Ikizler TA, Kane J, McMonagle E, Miller G. Gamma-tocopherol and docosahexaenoic acid decrease inflammation in dialysis patients. J Ren Nutr 2007;17:296–304. 70. Himmelfarb J, Ikizler TA, Ellis C, et al. Provision of antioxidant therapy in hemodialysis (PATH): a randomized clinical trial. J Am Soc Nephrol 2014;25:623–33. 71. Nascimento MM, Suliman ME, Silva M, et al. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Perit Dial Int 2010;30:336–42. 72. Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial. Circulation 2003;107:992–5. 73. Deng J, Wu Q, Liao Y, Huo D, Yang Z. Effect of statins on chronic inflammation and nutrition status in renal dialysis patients: a systematic review and meta-analysis. Nephrology (Carlton) 2012;17: 545–51. 74. Krane V, Winkler K, Drechsler C, Lilienthal J, Marz W, Wanner C. Effect of atorvastatin on inflammation and outcome in patients with type 2 diabetes mellitus on hemodialysis. Kidney Int 2008;74:1461–7. 75. Cueto-Manzano AM, Angel-Zuniga JR, Ornelas-Carrillo G, Rojas-Campos E, Martinez-Ramirez HR, Cortes-Sanabria L. Anti-inflammatory interventions in end-stage kidney disease: a randomized, double-blinded, controlled and crossover clinical trial on the use of pravastatin in continuous ambulatory peritoneal dialysis. Arch Med Res 2013;44:633–7. 76. Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the use of statins in prevention-an intervention trial evaluating rosuvastatin) trial. J Am Coll Cardiol 2010;55:1266–73. 77. Stubbs JR, Idiculla A, Slusser J, Menard R, Quarles LD. Cholecalciferol supplementation alters calcitriol-responsive monocyte
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proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol 2010;21:353–61. Matias PJ, Jorge C, Ferreira C, et al. Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters. Clin J Am Soc Nephrol 2010;5:905–11. Ogawa T, Kyono A, Sato M, Sugimoto H, Otsuka K, Nitta K. Vitamin D receptor agonist supplementation and suppression of inflammation may have advantage for all-cause mortality in hemodialysis patients. Clin Exp Nephrol 2012;16:779–85. Gamboa JL, Pretorius M, Todd-Tzanetos DR, et al. Comparative effects of angiotensin-converting enzyme inhibition and angiotensin-receptor blockade on inflammation during hemodialysis. J Am Soc Nephrol 2012;23:334–42. Merino A, Alvarez-Lara MA, Ramirez R, Carracedo J, MartinMalo A, Aljama P. Losartan prevents the development of the pro-inflammatory monocytes CD141CD161 in haemodialysis patients. Nephrol Dial Transplant 2012;27:2907–12. Morishita Y, Hanawa S, Chinda J, Iimura O, Tsunematsu S, Kusano E. Effects of aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysisdependent chronic kidney disease patients with hypertension. Hypertens Res 2011;34:308–13. Yilmaz MI, Axelsson J, Sonmez A, et al. Effect of renin angiotensin system blockade on pentraxin 3 levels in type-2 diabetic patients with proteinuria. Clin J Am Soc Nephrol 2009;4:535–41. Swerdlow DI, Holmes MV, Kuchenbaecker KB, et al. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379: 1214–24. Hung AM, Ellis CD, Shintani A, Booker C, Ikizler TA. IL-1beta receptor antagonist reduces inflammation in hemodialysis patients. J Am Soc Nephrol 2011;22:437–42. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371:987–97. Available at: https://clinicaltrials.gov/ct2/show/NCT01594333. 2015. Ref Type: Generic. Q7 Available at: http://www.thecantos.org/cantos-summary.html. 2015. Ref Type: Generic. Gonzalez-Espinoza L, Rojas-Campos E, Medina-Perez M, PenaQuintero P, Gomez-Navarro B, Cueto-Manzano AM. Pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial. Nephrol Dial Transplant 2012;27:2023–8. Carrero JJ, Park SH, Axelsson J, Lindholm B, Stenvinkel P. Cytokines, atherogenesis, and hypercatabolism in chronic kidney disease: a dreadful triad. Semin Dial 2009;22:381–6.
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REVIEW ARTICLE Therapeutics targeting persistent inflammation in chronic kidney disease Q9
ANNA MACHOWSKA, JUAN JESUS CARRERO, BENGT LINDHOLM, and PETER STENVINKEL STOCKHOLM, SWEDEN
Systemic inflammation is a condition intrinsically linked to chronic kidney disease (CKD) and its other typical sequelae, such as acquired immune dysfunction, protein-energy wasting (PEW), and accelerated vascular aging that promote premature cardiovascular disease (CVD) and infections, the two leading causes of death in CKD patients. Inflammation is a major contributor to complications in CKD, and inflammatory markers, such as C-reactive protein and pro- and antiinflammatory cytokines, correlate with underlying causes and consequences of the inflamed uremic phenotype, such as oxidative stress, endothelial dysfunction, CVD, PEW, and infections, and are sensitive and independent predictors of outcome in CKD. Therefore, inflammation appears to be a logical target for potential preventive and therapeutic interventions in patients with CKD. Putative anti-inflammatory therapy strategies aiming at preventing complications and improving outcomes in CKD span over several areas: (1) dealing with the source of inflammation (such as cardiovascular, gastrointestinal or periodontal disease and depression); (2) providing nonspecific immune modulatory effects by promoting healthy dietary habits and other lifestyle changes; (3) promoting increased use of recognized pharmacologic interventions that have pleiotropic effects; and, (4) introducing novel targeted anticytokine interventions. This review provides a brief update on inflammatory biomarkers and possible therapeutic approaches targeting inflammation and the uremic inflammatory milieu in patients with CKD. (Translational Research 2015;-:1–10) Abbreviations: --- ¼ ---
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INTRODUCTION From the Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. Submitted for publication April 3, 2015; revision submitted June 16, 2015; accepted for publication June 18, 2015. Reprint requests: Peter Stenvinkel, Department of Renal Medicine, M99, Karolinska University Hospital at Huddinge, 141 86 Stockholm, Sweden; e-mail: [email protected]. 1931-5244/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2015.06.012
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he prevalence of chronic kidney disease (CKD) has reached epidemic proportions with 10%– 12% of the population and .50% of elderly showing signs of kidney dysfunction, a condition associated with high morbimortality.1 Among many complications linked to CKD that contribute to the high morbimortality, systemic low-grade inflammation has a prominent role as one of the most typical features and as major contributor to the uremic phenotype in advanced stages of CKD. End-stage renal disease (ESRD) is strongly associated with systemic inflammation, a condition intrinsically linked not only to renal 1
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dysfunction but also to its other sequela including among others a state of acquired immune dysfunction, metabolic and nutritional derangements, and proteinenergy wasting (PEW). Moreover, recent evidence suggests that persistent inflammation is also a major cause of premature general and vascular aging.2 It was hypothesized that allostatic overload may contribute to increased oxidative stress, activated innate immune system, and persistent low-grade inflammation and sympathetic–vagal imbalance. Therefore, as a response to this allostatic overload, activation of the ‘‘stress resistance response’’ pathways may occur that together with an impairment of antiaging pathways and increased age-promoting factors contribute to advanced biological ageing processes in CKD patients.3 These conditions interplay with inflammation in promoting and exacerbating processes that lead to the excessive high risk of cardiovascular disease (CVD) and infections, the two leading causes of death among these patients.4 In addition, inflammation is thought to play a major role also in the pathophysiology of CKD and progression of renal dysfunction5 and in the complex situation of acute kidney injury.6 Inflammatory markers such as C-reactive protein (CRP) and pro- and anti-inflammatory cytokines correlate with underlying causes and consequences of the inflamed uremic phenotype such as oxidative stress, endothelial dysfunction, CVD, PEW, and infections.7 As inflammatory biomarkers are sensitive predictors of the outcomes in patients with ESRD, inflammation appears to be a logical target for preventive and therapeutic interventions in patients with CKD.8,9 Many therapeutic strategies may intervene in inflammatory pathways on different levels by targeting the source of local and systemic inflammation, changing lifestyle and nutritional habits, implementing or enhancing commonly known therapeutic strategies inducing a multiple physiological effects, or by novel concepts requiring further investigation. In this review, we briefly describe sources and consequences of inflammation in CKD and the clinical evidence for effects of potential preventive and therapeutic antiinflammatory strategies in CKD patients. INFLAMMATION IS A COMMON FEATURE OF THE UREMIC PHENOTYPE
In CKD and especially in ESRD patients, systemic concentrations of both pro- and anti-inflammatory cytokines are often severalfold higher than in healthy individuals. As depicted in Fig 1, there are multiple causes of systemic inflammation in CKD and ESRD patients.10-13 One major underlying factor is that the uremic phenotype associates with a state of immune dysfunction affecting both the innate and adaptive
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Fig 1. Causes and consequences of inflammation in chronic kidney disease patients. CKD, chronic kidney disease.
immune systems with immune activation resulting in inflammation, a key driver of CVD, and on the other hand, immune depression that increases the susceptibility to infections, a key driver of inflammation. These two major complications, CVD and infections, accounting for 50% and 20%, respectively, of total mortality in ESRD patients are thus closely linked to the altered immune state and presence of systemic inflammation.13 Another major underlying cause of systemic inflammation, conceivably linked to the uremic immune dysfunction, is renal dysfunction as such as it inevitably results in retention of fluid and small and large solutes many of which may act as proinflammatory uremic toxins, whereas others are in fact proinflammatory cytokines.14,15 Thus, in addition to inflammatory
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activation (due to a multitude of reasons, some of which are described below) resulting in increased production or release of cytokines, the observation that there is an inverse correlation between inflammatory biomarkers and markers of renal function indicates that decreased cytokine excretion or degradation in the kidney of inflammatory mediators may also play a role.16 The circulating levels of biomarkers of systemic inflammation, such CRP,17 pentraxin-3 (PTX3),18 interleukin-6 (IL-6), and also the anti-inflammatory IL-1015 increase progressively as renal function declines. IL-10 levels were shown to increase across worsening CKD stages and associate—together with IL-6 and PTX3—with the risk of CV events during follow-up.15 Moreover, the IL-6/IL-10 ratio was an independent predictor of composite end points suggesting a pivotal role of IL10 in a compensatory mechanism in response to the inflammatory status.15 Although CRP, the best studied of all acute-phase proteins, is the prototypical inflammatory marker, other specific inflammatory molecules, such as PTX3 and TWEAK, have gained increasing interest in the nephrology community. PTX3 because of its extrahepatic synthesis is—in contrast to CRP— believed to be a true independent indicator of disease activity produced at sites of inflammation and identified as a novel mortality risk factor in CKD stage 5, independent of traditional risk factors, but most importantly independent of CRP itself.19 PTX3 is elevated in hemodialysis (HD) patients as compared with healthy individuals.20 The retention of this and other circulating cytokines,21 advanced glycation end-products,22 and pro-oxidants23 contribute to a proinflammatory milieu when renal function declines. Systemic low-grade inflammation is also linked to and part of common complications among ESRD patients including malnutrition, inflammation, atherosclerosis (MIA syndrome).10,24 In addition to malnutrition (or PEW), CVD, infections, and retention of fluid and uremic toxins, other uremiarelated proinflammatory factors can also trigger an inflammatory response such as oxidative stress, endothelial dysfunction, bone-mineral disorders, vascular calcification, depression, altered metabolism of fat, carbohydrates and lipids, and intestinal dysbiosis.4,11 Although adequate dialysis treatment to some extent can ameliorate some uremia-related proinflammatory factors, there are many dialysis-related factors such as bio-incompatible dialysis membranes, central dialysis catheters, and unpure dialysis fluids, unpure water, and dialysis-related infections that may further aggravate chronic systemic inflammation in dialysis patients.4,8 A failed kidney transplant is another cause of persistent inflammation in dialysis patients that should be considered.25 Finally, as in the general population, there are several general proinflammatory conditions
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that should also be taken into account in CKD and ESRD patients, such unhealthy diets and lifestyle factors, obesity, and smoking.4 In addition to direct detrimental effects of inflammation, recent evidence suggests that persistent inflammation may act as a catalyst for other risk factors and enhance the development of complications, such as PEW and vascular calcification,26 which add further to the poor outcome among ESRD patients. Inflammation therefore appears to be a logical target for potential preventive and therapeutic interventions in CKD patients.12 GENERAL LIFESTYLE MODIFICATIONS THAT MAY HAVE ANTI-INFLAMMATORY EFFECTS
A healthy lifestyle has, apart from or perhaps as an integral part of its perceived value as a means to reduce sickness and prolong life, also anti-inflammatory effects that may contribute to improved physical, mental, and socioeconomic well-being. This could be of particular importance in patients with CKD. Yet, there is a scarcity of studies addressing the anti-inflammatory effects of general lifestyle modifications. Physical activity and lifestyle modifications. Physical activity and lifestyle modifications may positively influence the clinical outcomes of CKD patients. Exercise training in CKD patients showed favorable albeit inconsistent effect on the catabolic state in uremic muscles and on inflammatory markers.27,28 Dialysis patients with poor physical activity present with higher CRP levels,29 and in patients randomized to regular walking exercise (30 min/d, 5 times/wk), downregulated T-lymphocyte, monocyte activation, and reduction in the IL-6/IL-10 ratio was reported as compared to those with usual daily activities.30 As increased resistance exercise training may contribute to improvement in systemic inflammation, this opens interesting opportunities to reduce inflammation by physical training in sedentary dialysis patients. Depression. Depression is a common problem in ESRD patients31 and related to high mortality.32,33 In peritoneal dialysis (PD) patients, depression was strongly related to inflammation, malnutrition, and multiple cardiovascular risk factors, suggesting that depression is an integral part of the MIA syndrome.34 Indeed the state of depression associates with activation of proinflammatory cytokines, and patients on maintenance HD with symptoms of depression were more likely to have high levels of serum IL-6, higher prevalence of comorbidities, higher serum total cholesterol, and lower s-albumin levels.35 In depressed HD patients, sertraline, a selective serotonin reuptake inhibitor antidepressant, was found to have antiinflammatory effects in addition to improving
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depression symptoms in almost half of the HD patients. This suggests that selective serotonin reuptake inhibitors can be a promising therapeutic strategy to reduce systemic inflammation in depressed HD patients.36 Another RCT in HD patients showed that 4 months supplementation with omega-3 fatty acids not only decreased depressive symptoms but also reduced inflammatory status; however, results were considered as inconclusive.37 Finally, as cognitive behavioral therapy not only corrected disorganized sleep patterns but also reduced inflammation and oxidative stress in HD patients,38 this further support links between psychosocial health and inflammation. Periodontal disease. Since long, it is well known that oral health is a factor of major importance for many chronic diseases. Although periodontal disease is a well-described important contributor to local and chronic systemic inflammation in CKD, it is often overlooked.39,40 Periodontal disease may link also to problems in chewing/biting and may thereby affect appetite and food intake.41,42 One mechanism underlying the pathogenesis of periodontitis involves gram-negative bacteria that interact with toll-like receptors expressed on the surface of neutrophils and monocytes. Toll-like receptors–ligand complexes activate signal transduction pathways leading to the production of cytokines, which coordinate the local and proinflammatory cytokines and activate hepatocytes to produce acute-phase proteins including CRP.43 It is not known if anti-inflammatory–targeting strategies can be used to treat periodontal disease in CKD patients, but recent data from an uncontrolled study showed that treatment of periodontal disease may improve systemic inflammation, nutritional status, and erythropoietin responsiveness in dialysis patients.44,45 DIETARY FACTORS THAT MAY HAVE ANTIINFLAMMATORY EFFECTS
As the diet is a source of many both antiinflammatory and proinflammatory constituents, dietary habits and food patterns are probably of major relevance in modifying systemic inflammatory levels and perhaps affecting kidney function.46 Below are just a few examples of how dietary factors and interventions linked to these factors may have anti-inflammatory effects. Phosphate. Hyperphosphatemia, a typical feature of advanced CKD that plays a major role in the mineralbone disorders in CKD, seems to contribute to an inflammatory state. Phosphate binding therapies, such as sevelamer, may therefore have anti-inflammatory properties, and in addition, sevelamer in itself may reduce inflammation.47 In HD patients, 8 weeks of sevelamer treatment not only improved endothelial
function but also increased levels of the negative acute-phase protein fetuin-A (a major calcification inhibitor).48 Moreover, a study in HD patients treated with either sevelamer or calcium acetate showed that sevelamer was associated with a significant decrease in CRP, IL-6, serum endotoxin levels, and soluble CD14.49 Thus, the putative anti-inflammatory potential of sevelamer, a compound that possesses LPS binding properties, should be considered as a therapeutic strategy. Dietary fat intake. Considering that HD patients that are fish eaters have lower mortality50 and that in HD patients omega-3 fatty acids (fish oil) is reported to attenuate the inflammatory response to HD,51 it is not surprising that dietary fat modifications in the CKD population may have favorable effects. Both excess saturated fat intake52 and insufficient intake of polyunsaturated fat53 are strongly associated with systemic inflammatory biomarkers in dialysis patients. Long-chain n-3 polyunsaturated fatty acids (PUFAs) provided in fish oils may decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species and the expression of adhesion molecules.54 Several clinical studies showed that supplementation with n-3 PUFAs can have antiinflammatory beneficial effects and reduce inflammatory biomarkers. Recently, a dietary pattern with low linoleic and high saturated fat intake was associated with systemic inflammation, insulin resistance, and metabolic syndrome suggesting the potential beneficial effect of replacing SFA with PUFA, also from vegetable origins.55 However, little is known about the effect of n-6 PUFA apart from one study showing trend toward reduction of leukotriene B4 (proinflammatory eicosanoid) production.56 Intestinal microbiota. What we eat has a major impact on the status of the intestinal microbiota, and this may be of particular importance in patients with CKD. The progression of CKD is associated with metabolic alterations that change the balance of symbiotic and pathobiont bacteria in the lumen of the intestinal track leading to pathogen overgrowth (dysbiosis) in the gut, loss of barrier integrity, and an increased translocation of living bacteria and bacterial components.57 These processes may possibly contribute to CKD progression, accelerated atherogenesis, and PEW. Thus, therapeutic interventions to manipulate microbiota such as prebiotics or probiotics may have a potential in the stabilization of the immune state and prevention of ESRD complications.57 The bowel bacterial overgrowth syndrome is found frequently in dialysis patients and associates with gastrointestinal malabsorption and maldigestion, PEW, and systemic inflammation. This syndrome was found to be present
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in 25% of PD patients, who were in turn more often inflamed and had signs of PEW. It is of interest that antibiotic treatment improved appetite scores and led to increased s-albumin levels although it decreased the systemic inflammatory marker TNF.58 As higher dietary fiber intake associated with better kidney function and lower inflammation,59 adequate dietary intake of fiber may also benefit this pathway. Fructose. A high fructose intake is thought to contribute to obesity, hypertension, inflammation, elevated serum uric acid levels, and gout, and it may also be a factor that could promote CKD.60 According to a recent study in CKD stage 2–3 patients, a low fructose diet could decrease markers of inflammation61; thus, the vulnerable CKD patient population should be careful with high consumption of soft drinks (which also contain a lot of phosphate) and other food items that contain a high content of fructose. Oxidative stress. Because of close links between inflammation and oxidative stress, interventionstargeting oxidative stress could have a potential role in preventive and therapeutic anti-inflammatory strategies.62 The nuclear factor erythroid 2–related factor (Nrf2), a key transcription factor playing an important role in cytoprotection against inflammation, has gained increased attention because of its ability to antagonize the transcription factor nuclear factor-kB, a major trigger of the expression of inflammatory genes.63 In response to oxidative stress and inflammation with increased activity of nuclear factor-kB, activation of Nrf2 upregulates .250 cytoprotective and antioxidant genes that may limit processes leading to inflammation, endothelial dysfunction, and mesangial proliferation.64 Nutritional components modulating Nrf2 could potentially contribute to development of new therapies.65 Recently discussed pharmaceutical agents include among others bardoxolone methyl, a triterpenoid obtained from the fruit and leaves of the olive tree that activates Nrf2.65 Unfortunately, a recent randomized controlled trial (RCT) study had to be suspended because of increased mortality and higher risk of side effects due to volume retention in the bardoxolone intervention arm; however, further studies are warranted to reduce the risk of such complications and evaluate the real effect of this intervention.66 Decaffeinated green tea (catechin) was shown to decrease inflammatory biomarkers in HD patients.67 Thus, this may yet be considered another antiinflammatory dietary intervention to further investigation in CKD. In addition, an interesting RCT study in 101 HD patients showed that 12 months consumption of pomegranate juice reduced polymorphonuclear leukocyte priming and levels of inflammation
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biomarkers.68 Moreover, soy-derived isoflavones are thought to have anti-inflammatory effects and should be considered for nutritional antioxidative treatment strategies [44]. Q3 The influence of antioxidant therapy by supplementation with the vitamin E compounds, gamma-tocopherol (308 mg/d), and the omega-3 fatty acid, docosahexaenoic acid (800 mg/d) on oxidative stress and inflammation markers was evaluated in a RCT among 70 HD patients during 8 weeks. The results showed that administration of gamma-tocopherol and docosahexaenoic acid significantly decreases selected inflammatory biomarkers, such as IL-6, whereas no influence on CRP or F2-isoprostanes was observed. There were no adverse events attributed to either treatment or placebo group. These results suggest that the combination of antioxidant and fish oils could be a feasible treatment option for decreasing persistent inflammation in dialysis patients.69 On the other hand, another RCT, the provision of antioxidant therapy in hemodialysis conducted by the same group evaluated the impact on hsCRP, IL6, F2-isoprostanes, and isofurans of oral administration of tocopherols (666 IU/d) plus a-lipoic acid (600 mg/d), a thiol-containing antioxidant, or placebo among 238 HD patients who were followed up for 6 months; the effects on the level of inflammatory and oxidative stress biomarkers were not statistically significant, and also the intervention did not improve erythropoietin response.70 Regardless of the inconclusive results, the administration of other dosages or combinations should be evaluated, and the approach of targeting inflammation by antioxidants should not be discarded. N-acetylcysteine is a thiol-containing compound with antioxidant effects that can be attributed to its action as a free radical scavenger and as a reactive sulfhydryl compound that increases the reducing capacity of the cell. PD patients receiving N-acetylecysteine (2 3 600 mg/ daily) for 8 weeks had significantly lower serum level of IL-6 as compared with control groups.71 A RCT in 134 HD patients showed that patients randomized to N-acetylecysteine (600 mg BID) compared with placebo group showed reduced primary composite cardiovascular end points.72 COMMONLY USED DRUGS THAT MAY HAVE PLEIOTROPIC ANTI-INFLAMMATORY EFFECTS
Many commonly used drugs in CKD patients may have a positive impact on systemic inflammation. In some cases, the drug may have direct effects on inflammatory pathways over and above its main indication. In other cases (and this is more common), an impact on inflammation is likely explained by a beneficial effect on other pathways that also convey inflammation. Although some of these drugs are already commonly
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prescribed in CKD, yet, inflammation still exists among patients suggesting that these drugs—which seldom are prescribed with the sole intention of reducing inflammation—are not as effective as anti-inflammatory agents. Nevertheless, they are often considered as valuable adjuvants in strategies aiming at reducing systemic inflammation in CKD patients. Statins. A large number of randomized control trials have shown that statins help in the primary and secondary prevention of cardiovascular events, not only via their lipid-lowering effect, but also due to their antiinflammatory potential. According to a systematic review, statins may reduce CRP levels in dialysis patients, whereas there was no conclusive evidence that they may improve nutritional status.73 However, in a post hoc analysis of the 4D study found among 1255 HD patients with type 2 diabetes, there were no significant changes in CRP related to atorvastatin treatment.74 In a smaller RCT crossover study with 76 PD patients receiving either pravastatin or placebo for 2 months followed by a 1 month wash-out period and crossed over to another group for another 2 months period, pravastatin significantly reduced serum CRP and HDL-cholesterol levels compared with placebo.75 A secondary analysis from the JUPITER study showed that rosuvastatin reduced CRP levels by 37% and reduced cardiovascular events and all-cause mortality among patients with moderate CKD.76 These and other studies suggest that statins may be beneficial in suppressing the inflammatory status. Vitamin D. Vitamin D is a dietary constituent that is ingested in insufficient amounts in CKD patients, leading to deficiencies especially among patients deprived of exposure to the sun, and there is increased recognition that this prehormone has beneficial effects including anti-inflammatory actions that could motivate its prescription as a drug. Administration of cholecalciferol to ESRD patients was found to reduce circulating IL-8, IL-6, and TNF levels by approximately 55%, 30%, and 60%, respectively.77 It has also been demonstrated that high-dose cholecalciferol decreased serum monocyte chemotactic protein-1 concentrations by 12 weeks in patients with early CKD. In a prospective study of 158 HD patients, cholecalciferol supplementation resulted in decreased CRP and increased s-albumin levels.78 As one study showed that vitamin D deficiency in HD patients who had not taken vitamin D receptor agonists associated with an increased risk of all-cause mortality,79 the impact of vitamin D supplementation on long-term outcome needs to be evaluated. Targeting the renin–angiotensin system. Most patients with advanced CKD suffer from hypertension and CVD that should be treated by drugs; some of which
may have anti-inflammatory potentials. In HD patients, treatment by ramipril, an angiotensinconverting enzyme inhibitor and valsartan, an angiotensin receptor blockers, for 7 days in a crossover study, resulted in decreased IL-6 levels,80 and in another study, losartan lowered the percentage of monocytes expressing CD141CD161.81 In addition, in HD patients, 8-week administration with aliskiren, a direct renin inhibitor, was found to lower the CRP level.82 Ramipril treatment was presented as beneficial in reducing inflammation in diabetic CKD patients.83 Thus, the use of these common drugs that are indicated for treatment of hypertension and CVD come with the bonus of having also anti-inflammatory effects. This may be of particular value when trying to halt the progression of glomerular diseases and reducing albuminuria in these patients. TARGETED ANTICYTOKINE TREATMENT Interleukin receptor antagonists. Among a number of specifically targeted anticytokine treatment strategies, blockade of IL-1 and IL-6 may be the most interesting in the context of uremia. Indeed, on the basis of genetic evidence in human beings, IL-6R signaling seems to have a causal role in development of heart disease in nonrenal patients.84 A small pilot study in 22 HD patients showed that treatment with IL-1 receptor antagonist was associated with 40%–50% reduction in mean high sensitivity CRP and IL-6 levels and an increase in mean prealbumin level.85 This suggests that targeted anti-inflammatory interventions could be applicable in CKD patients. Such interventions could potentially include also humanized antibody (Toclizumab), which has a positive effect in inflammatory diseases such as rheumatoid arthritis.86 The Cardiovascular Inflammation Reduction Trial is an ongoing double-blind, placebo-controlled, multicenter study currently recruiting patients to investigate whether administration of low-dose methotrexate may reduce cardiovascular events by reducing inflammation.87 The Canakinumab Anti-inflammatory Thrombosis Outcomes Study conducted in .40 countries evaluates whether blocking IL-1b with canakinumab can reduce rates of cardiovascular events among patients who remain at high risk due to persistent elevation of CRP ($2 mg/L).88 However, given the risk for infectious complications in this immune-compromised patient, population selection of patients eligible for targeted anticytokine treatment should be very meticulous. Pentoxifylline. Pentoxifylline is a nonspecific phosphodiesterase inhibitor that inhibits the production of TNF, IL-6, and IL-10. In a RCT study in 36 HD
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patients, administration of pentoxifylline (400 mg/d) during 4 months significantly decreased serum concentrations of inflammatory biomarkers89 suggesting that this drug could be a promising therapeutic strategy to treat uremic inflammation. Strategies for specific anticytokine drug development may involve stimulation or repression of the synthesis of anti-inflammatory or proinflammatory cytokines and the enhancement or blockage of their receptors. However, blocking cellular or molecular functions that presumably have an important role in the host defense may increase the susceptibility to infections or the severity of infections. In addition, it should be considered that some of biological agents are chimeric or humanized antibodies, and further sensitization might occur, which can lead to both allergic reactions and reduction in efficacy. Although anticytokine therapies should be considered as promising putative strategies to treat inflamed CKD patients, there is a risk that blocking of pathways involved in host defense mechanism may lead to infections and other complications. Therefore, while identifying new therapeutics is essential, a more detailed understanding of how cytokine pathways and related mechanisms are affected by such interventions is needed.90
Statins ACE-inhibitors, angiotensin receptor blockers, and renin inhibitors Cholecalciferol and paricalcitrol Sevelamer Allopurinol Gamma-tocopherol Docosahexaenoic acid and eicosapentaenoic acid N-acetylcysteine Vitamin E–coated dialysis membranes Bardoxolone methyl (activation of Nrf2)
Blocking of TNF (such as etanercept, pentoxifylline and infliximab) Blocking of IL-1 (such as anakinra) Blocking of IL-6 (such as tocilizumab)
Drugs commonly used in nephrology Antioxidative treatment strategies
Targeted anticytokine treatment
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Abbreviations: IL, interleukin; Nrf2, nuclear factor erythroid 2.
Resistance training Appetite stimulants, such as ghrelin, megestrol acetate, cannabinoids Growth hormone Myostatin inhibition Increased fiber intake Fish intake and omega-3 fatty acids Soy (phytoestrogens) Pomegranate juice Decaffeinated green tea extracts (catechins) Decreased fructose intake Nuts and seeds (gamma-tocopherol) Probiotics (living microorganisms) Depression Physical inactivity Poor oral health Smoking
Dietary factors
Antiwasting treatment strategies
CONCLUSIONS
General lifestyle modifications
Table I. Potential anti-inflammatory treatment strategies that could be applicable in patients with chronic kidney disease
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Persistent low-grade inflammation is a common feature of CKD and an intrinsic part of the uremic phenotype. Inflammation is a consequence of many factors linked to renal dysfunction such as a state of immune dysfunction and acts as a catalyst of numerous other risk factors in CKD, promoting common complications such as PEW, CVD, bone-mineral disorders, depression, vascular calcification that contribute to the poor clinical outcomes in patients with advanced CKD. Because of its central role in the uremic phenotype, inflammation appears to be a logical target for preventive and therapeutic—general and specific antiinflammatory interventions in patients with CKD. There is no lack of measures that need to be taken to achieve control of the threats imposed by inflammation. First of all, it is important to identify and if possible treat, prevent, or eliminate as many as possible of the numerous potential sources of inflammation in CKD patients such as cardiovascular, gastrointestinal, or periodontal diseases; retention of fluid and solutes; and infections, to name a few. Second, promoting healthy dietary habits, increased physical activity, and other lifestyle changes including dealing with depression may have important nonspecific immune modulatory effects. Third, patients with CKD commonly receive drugs such as statins and angiotensin-converting enzyme inhibitors/angiotensin
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receptor blockers that apart from their specific indications also have pleiotropic effects that include antiinflammatory activity. This may speak in favor of prescribing such drugs although they cannot usually be prescribed with the sole intention of reducing inflammation. Finally, agents specifically targeting inflammation, such as anticytokine treatments, are likely to become more common interventions in the future, but because of their potent immune system modulating effects, they may have severe unwarranted effects such as infections. UNCITED TABLE
Table I. ACKNOWLEDGMENTS
Conflicts of Interest: J. J. Carrero and P. Stenvinkel do not declare any conflicts of interest. All authors have read the journal’s policy on disclosure of potential conflicts of interest. Swedish Medical Research Council supported P. Stenvinkel’s and J. J. Carrero’s research. A. Machowska is supported by EU Marie-Curie Initial Training Network, EuTRiPD, European Training and Research in Peritoneal Dialysis, Call: FP7-PEOPLEITN-2010, Proposal Number: 287813, and by additional funding provided by Baxter Healthcare Corporation. Baxter Novum is a result of a grant from Baxter Healthcare Corporation to Karolinska Institutet. A. Machowska and B. Lindholm are employed by Baxter Healthcare Corporation. Author contributions are as follows: The article has been reviewed by and approved by all named authors. REFERENCES
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9. Meuwese CL, Snaedal S, Halbesma N, et al. Trimestral variations of C-reactive protein, interleukin-6 and tumour necrosis factoralpha are similarly associated with survival in haemodialysis patients. Nephrol Dial Transplant 2011;26:1313–8. 10. Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999;55:1899–911. Q4 11. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif 2015;39:84–92. 12. Miyamoto T, Carrero JJ, Stenvinkel P. Inflammation as a risk factor and target for therapy in chronic kidney disease. Curr Opin Nephrol Hypertens 2011;20:662–8. 13. Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008;3:1526–33. 14. Pecoits-Filho R, Heimburger O, Barany P, et al. Associations between circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis 2003;41:1212–8. 15. Yilmaz MI, Solak Y, Saglam M, et al. The relationship between IL-10 levels and cardiovascular events in patients with CKD. Clin J Am Soc Nephrol 2014;9:1207–16. 16. Gupta J, Mitra N, Kanetsky PA, et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clin J Am Soc Nephrol 2012;7:1938–46. 17. Yilmaz MI, Stenvinkel P, Sonmez A, et al. Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes. Nephrol Dial Transplant 2011;26:3537–43. 18. Yilmaz MI, Sonmez A, Ortiz A, et al. Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes. Clin J Am Soc Nephrol 2011;6: 785–92. 19. Tong M, Carrero JJ, Qureshi AR, et al. Plasma pentraxin 3 in patients with chronic kidney disease: associations with renal function, protein-energy wasting, cardiovascular disease, and mortality. Clin J Am Soc Nephrol 2007;2:889–97. 20. Boehme M, Kaehne F, Kuehne A, et al. Pentraxin 3 is elevated in haemodialysis patients and is associated with cardiovascular disease. Nephrol Dial Transplant 2007;22:2224–9. 21. Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia–the good, the bad, and the ugly. Kidney Int 2005;67: 1216–33. 22. Suliman ME, Heimburger O, Barany P, et al. Plasma pentosidine is associated with inflammation and malnutrition in end-stage renal disease patients starting on dialysis therapy. J Am Soc Nephrol 2003;14:1614–22. 23. Dounousi E, Papavasiliou E, Makedou A, et al. Oxidative stress is progressively enhanced with advancing stages of CKD. Am J Kidney Dis 2006;48:752–60. 24. Avesani CM, Carrero JJ, Axelsson J, Qureshi AR, Lindholm B, Stenvinkel P. Inflammation and wasting in chronic kidney disease: partners in crime. Kidney Int 2006;70:S8–13. Q5 25. Lopez-Gomez JM, Perez-Flores I, Jofre R, et al. Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol 2004;15:2494–501. 26. Carrero JJ, Stenvinkel P. Persistent inflammation as a catalyst for other risk factors in chronic kidney disease: a hypothesis proposal. Clin J Am Soc Nephrol 2009;4(Suppl 1):S49–55. 27. Castaneda C, Gordon PL, Parker RC, Uhlin KL, Roubenoff R, Levey AS. Resistance training to reduce the malnutritioninflammation complex syndrome of chronic kidney disease. Am J Kidney Dis 2004;43:607–16.
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