Inflammation and wasting in chronic kidney disease: Partners in crime

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1 & 2006 International Society of Nephrology Inflammation and wasting in chronic kidney disease: Partners in crime CM Avesani 1, JJ Carrero 1, J Axelsson 1, AR Qureshi 1, B Lindholm 1 and P Stenvinkel 1 1 Divisions of Baxter Novum and Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Protein energy malnutrition (PEM) is often present in patients with chronic kidney disease with or without ongoing renal replacement therapy. Muscle wasting (sarcopenia) is one of the hallmarks of PEM in these patients and recent studies have reported a link between sarcopenia and inflammation. The low-grade inflammation often observed in end-stage renal disease (ESRD) can lead to sarcopenia through an increase in protein catabolism, a decrease in protein syntheses or both. The activation of the ATP-ubiquitinproteasome pathway, insulin resistance, hypermetabolism, and decreased appetite are all plausible pathophysiological pathyways whereby inflammation can contribute to sarcopenia and PEM. In the present review we discuss these interactions between inflammation and wasting in ESRD patients and explore putative pathways involved in this condition.. doi: /sj.ki KEYWORDS: inflammation; cytokines; muscle wasting; sarcopenia; chronic kidney disease Correspondence: P Stenvinkel, K56, Karolinska University Hospital at Huddinge, Stockholm, Sweden. peter.stenvinkel@ki.se Protein energy malnutrition (PEM) is highly prevalent in patients with chronic kidney disease (CKD) and is a strong predictor of morbidity and mortality. 1 Indeed, PEM is reported to be present in as many as 37 48% of CKD patients, percentages that increase once renal replacement therapy starts. 1 Usually, this deterioration of the clinical nutritional status is characterized by a progressive weight loss, wasting of both fat tissue and skeletal muscle tissues, and a reduction of serum proteins, including albumin, prealbumin, and transferrin. Of these, muscle wasting (sarcopenia) is one of the strongest and most consistently associated with poor outcome. 1 Although the mechanisms leading to sarcopenia are not yet fully understood, both increased protein breakdown and decreased muscle protein synthesis are likely to contribute to this condition. In fact, muscle loss in dialysis is present in a variety of conditions associated with decreased muscle protein synthesis, including aging, a sedentary life style, and anorexia (pure malnutrition), as well as in conditions known to promote an increase in protein breakdown, including hormonal derangements, metabolic acidosis, diabetes mellitus, the dialysis treatment per se, and inflammation (Figure 1). Among the factors known to promote wasting, inflammation appears the one of the most important. Indeed, wasting and inflammation are often interrelated in the clinical setting and have additive effects on cardiovascular (CDV) outcome (Figure 2). 1 As inflammation plays a central role in the atherogenic process it is not surprising that chronic inflammation in CKD is also associated with increased CDV morbidity and mortality. 2 This review will focus on persistent low-grade inflammation as one of the key pathophysiological events behind the occurrence of muscle wasting in ESRD. ANOREXIA AND MUSCLE WASTING By definition, anorexia is defined as the spontaneous loss of appetite and poor food intake, whereas wasting is characterized by an inflammatory condition that leads to anorexia, progressive weight loss, and depletion of both adipose tissue and skeletal muscle. Although these conditions often coexist they have distinct physiological and adaptive responses. During periods of prolonged starvation or low food intake (anorexia), fat stores rather than skeletal protein S8

2 Renal disease per se Residual renal function Uremic toxins Endocrine abnormalities Amino-acid abnormalities Acidosis Dialysis procedure Dialysate endotoxins Graft and fistula infections Dialysis adequacy Membrane bioincompatibility Nutrient losses (dialysate) Malnutrition Reduced protein intake Reduced energy intake Reduced vitamin intake Wasted CKD patient Other factors Age Poor physical activity Social factors Drugs (corticosteroids) Genetic factors Comorbidity Congestive heart failure Vascular disease Diabetes mellitus Depression Other comorbidities Inflammation Infections Oxidative stress Accumulation of AGEs Genetic factors Comorbidity malnutrition, inflammation and atherosclerosis in ESRD. 5 We have speculated that the presence of inflammation and comorbidity determines two different types of malnutrition disorders in CKD. Patients with anorexia nervosa corroborate the first type (pure malnutrition), as they exhibit a markedly reduced food intake together with depleted muscle and fat stores, but normal levels of S-albumin. The other type of malnutrition in CKD resembles the inflammation-associated wasting process present in patients with cancer, acquired immune deficiency syndrome, sepsis, congestive heart failure (i.e. cardiac cachexia), and tuberculosis. 3,4 Figure 1 Factors contributing to the occurrence of wasting in CKD. Survival (%) SGA1+CRP <10 mg/l; n=160 SGA1+CRP 10 mg/l; n=45 SGA 2+CRP <10 mg/l; n=50 60 SGA 2+CRP 10 mg/l; n=55 n=310 Likelihood ratio=34.5 P < Observation time (months) Figure 2 Patients survival curve showing CDV mortality adjusted for age, gender, and diabetes in 310 CKD stage 5 patients divided according to the presence of wasting (subjective global assessment SGAX2) and inflammation (CRPX10 mg/l) at start of the dialysis treatment. are preferentially mobilized as body fuel, whereas there is a relative sparing of muscle mass until late starvation starts. 3 Meanwhile, a modulation of energy expenditure is observed. After a period of decreased food intake an important drop in the oxygen consumption and in the energy expenditure is observed as a way to preserve body energy stores. 3 However, in wasted patients energy expenditure will not drop even if energy intake decreases. 3 The ultimate result is that the development of PEM solely by anorexia is slow, whereas wasting-induced PEM is more rapid and pronounced. 3 In fact, patients with cancer cachexia develop severe states of muscle depletion in a relatively short period 3 and in other diseases associated with chronic inflammation, such as acquired immune deficiency syndrome, tuberculosis, chronic obstructive pulmonary disease, and congestive heart failure, wasting is a common finding. 4 Although anorexia is a common complication in advanced CKD, the malnutrition found on the majority of dialysis patients do not resemble a state of solely anorexia, but rather a state of wasting, as CKD is often accompanied by persistent low-grade inflammation. This is in agreement with the strong associations between CKD A CLINICAL STATE OF INFLAMMATION Increased circulating levels of inflammatory markers, such as C-reactive protein (CRP) and the proinflammatory cytokines interleukin (IL)-6, and tumor necrosis factor-alpha (TNF-a), have been described in CKD patients with or without ongoing dialysis treatment. 6 The prevalence of inflammation varies from 30 to 75% depending on multiple factors, such as residual renal function, geographic and genetic differences, dialysis therapy, comorbidities as well as the cutoff point used for diagnosing inflammation by CRP. 6 The reason(s) for the increased prevalence of persistent low-grade inflammation in ESRD patients are complex and include a variety of factors related to uremia (such as decreased clearance of cytokines, oxidative stress, accumulation of advanced glycation endproducts and infectious complications) and dialysis-related factors (such as membrane bioincompatibility, vascular access infections and endotoxin exposure) that stimulate the inflammatory response by activating the production of IL-1, IL-6, TNF-a, and interferon-gamma by the macrophages. 7 In addition, the impaired immune response characterized by hyporesponsive neutrophils and T-cells present in CKD patients also contributes to the low-grade inflammation seen in ESRD. The combination of an impaired immune response coupled with a persistent immune stimulation might have an important role in the low-grade inflammation and altered cytokine balance that is present in ESRD. 7 FAT TISSUE AS AN ENDOCRINE ORGAN LEADING TO INFLAMMATION The recent discoveries of leptin and adiponectin have revised the notion that adipocytes are simply a storage depot for body energy. Instead, hormones secreted by the adipocytes (adipokines) act as autogenic regulators of body fat depots modulating gastrointestinal activities, metabolic changes, and central nervous mechanisms. Thus, adipokines have been speculated to play a central role in the development of complications often observed in this patient group, such as insulin resistance, CVD, and sarcopenia. 8 Furthermore, there are intimate links among adipokines and proinflammatory cytokines as well as between fat and muscle tissue. 9 Considering the dramatic effect that loss of renal function has on the clearance of these substances, 10 the systemic effects of adipokines in CKD patients may be greater than in the S9

3 general population. It has been estimated that about 20% of the circulating IL-6 originates from fat tissue and a significant amount of the circulating TNF-a comes from macrophages present in the adipose tissue. 11 The cause of the increased circulating proinflammatory cytokines during obesity is not totally understood, but it seems to be related to a progressive infiltration of macrophages in the adipose tissue as obesity develops. 11,12 Several mechanisms have been claimed to cause this process, including secretion of low levels of TNF-a from adipocytes 13 and increased secretion of leptin (or decreased levels of adiponectin) by the adipocytes both of which may contribute to macrophage accumulation by stimulating transport of macrophages to the adipose tissue. 13 It should also be acknowledged that the physical damage to the endothelium, caused by the increasing lipolytic environment, can induce macrophage recruitment and a continuous production of inflammatory cytokines. 13 As visceral fat appears to produce adipokines more actively than subcutaneous adipose tissue, visceral abdominal fat may be the main producer of IL-6. In accordance, in ESRD patients evaluated shortly before the start of renal replacement therapy, we found a significant positive association between circulating IL-6 and truncal fat, but not between IL-6 and non-truncal fat. 14 Taken together, small adipocytes in lean individuals promote metabolic homeostasis, whereas the enlarged adipocytes of obese individuals recruit macrophages and promote inflammation and the release of a range of factors that predispose toward insulin resistance. As inflammation is linked to peripheral insulin resistance, resistance of the insulin like-growth factor 1, increased protein catabolism, hypermetabolism, and anorexia, it could be speculated that increased fat tissue-derived cytokine production may lead to muscle wasting and increased mortality. However, the effect of increased fat mass on morbidity and mortality in ESRD has been controversial. Whereas some studies demonstrated that elevated body mass index is associated with better survival in hemodialysis (HD) patients, others have shown that high-body mass index dialysis patients with inferred high body fat have increased prevalence of atherosclerosis and higher mortality. However, as Kalantar-Zadeh et al. 15,16 recently observed that gaining body fat was independently associated with better survival in HD patients, evidence suggest that accumulation of fat tissue constitutes a survival advantage in this patient group. Thus, further mechanistic studies are needed to ascertain if CKD patients, like many other patient groups, may indeed have adverse metabolic consequences of an increased fat mass, or if the pathophysiology of CKD makes increased adipokine levels more beneficial than the presumed detrimental effect of increased systemic inflammation associated with increased fat mass. It could also be hypothesized that fat tissue secretes to the uremic milieu one or more substances with beneficial CDV effects. Further research is also needed to study if a genetic predisposition to fat tissue accumulation is associated with other genetic traits constituting a survival advantage in the uremic milieu. MECHANISMS BY WHICH INFLAMMATION CAN LEAD TO MUSCLE WASTING Inflammation is a common feature in clinical conditions associated with loss of muscle mass, such as cancer, CKD, acquired immune deficiency syndrome, and aging. 3 In animal studies, infusion of TNF-a, IL-1, and IL-6 led to increased muscle protein breakdown and to muscle atrophy. 3 Also clinical studies in CKD patients have shown a link between inflammatory cytokines and muscle wasting. 7 In fact, Kaizu et al. 17 demonstrated that muscle mass was inversely correlated to circulating levels of both IL-6 and CRP in HD patients, even after adjustment for age and gender. In a longitudinal study, the reduction of a muscle mass marker during a HD period of 1 year was associated with a higher concentration of IL-1b. 18 Moreover, a study from our group showed that patients that lost lean body mass after 1 year in peritoneal dialysis had significant elevated initial CRP levels than patients who gained lean body mass. 19 Although the mechanisms by which inflammation can lead to muscle wasting are not fully understood, enhanced protein turnover seems to play a central role. However, it is still debated whether this negative protein balance results from reduced rates of synthesis, from increased rates of breakdown or from a combination of both. Whereas inflammation may affect the wasting process by multiple mechanisms, we focus in this review on the role of the ATP-ubiquitin-proteasome pathway, insulin resistance, resting energy expenditure, and anorexia in relation to inflammation (Figure 3). Ubiquitin proteasome pathway Metabolic acidosis is a common phenomenon in CKD that may lead to stimulation of protein breakdown and subsequent muscle wasting via stimulation of the ATPubiquitin-proteasome pathway. 20 As TNF-a modulates, at least in part, the ATP-ubiquitin-proteasome proteolytic pathway 20 inflammation may contribute to wasting by affecting this pathway. Indeed, it has been shown that TNF-a administration to rats resulted in increased skeletal muscle proteolysis, augmentation of ubiquitin, and increased gene expression of ubiquitin. 21 Also other cytokines, such as IL-1 Activity of the ATP ubiquitin proteasome pathway Chronic inflammation Cytokine imbalance Insulin resistance Wasting Resting energy expenditure Appetite Proteolysis Anabolic action Protein synthesis? Figure 3 Potential pathways linking chronic inflammation to the development of wasting in CKD. S10

4 and INF-g, upregulate ubiquitin gene expression. 21 However, while cytokines have the potential to enforce the acceleration of muscle protein breakdown, it is largely unknown how the proteolytic pathways involved are activated. Insulin resistance Recently, several studies in non-ckd patient groups have linked inflammation to insulin resistance and it has been speculated that inflammation is an integral part of the metabolic syndrome. 22 It was demonstrated that the administration of recombinant TNF-a to cultured cells or to animals impairs insulin action, and obese mice lacking functional TNF-a have improved insulin sensitivity compared with wild-type counterparts. 23 In addition, Bernstein et al. 24 recently demonstrated that administration of the TNF-a inhibitor Etanercept reduced CRP levels and tended to improve other inflammatory CDV risk indexes in patients with the metabolic syndrome. In this respect, it should also be noted that TNF-a increases lipolysis (which is highly correlated to insulin resistance) and that IL-6 inhibits insulin action both in vitro and in vivo muscle, liver, and adipocytes. 25 Although the exact pathophysiological mechanisms by which cytokines mediates insulin resistance are unknown, several mechanisms (such as a defect in insulin intracellular signaling pathways during inflammation, induction of lipolysis by TNF-a, and reduced production of adiponectin) are likely to contribute. Decreased insulin sensitivity caused by a persistent inflammatory condition can predispose to loss of muscle mass by decreasing the anabolic action of insulin on the skeletal muscle. In fact, in clinical conditions associated with insulin resistance, such as in advanced age and type-2 diabetes mellitus, muscle wasting is often observed. By using stable isotope tracer techniques, Pupim et al. 26 showed that HD patients with type-2 diabetes had significantly increased skeletal muscle protein breakdown as compared to nondiabetic HD patients. In a subsequent clinical study, 27 it was found that ESRD patients with diabetes mellitus had significantly accelerated loss of lean body mass as compared to non-diabetics during the first year of renal replacement therapy. Furthermore, increased energy expenditure (another factor contributing to sarcopenia) has been observed in CKD patients with diabetes mellitus in comparison to gender- and age-matched non-diabetic CKD patients. 28 Finally, as dialysis patients with hyperleptinemia, which may be related to inflammation, 10 have more severe degrees of insulin resistance, further studies are required to evaluate whether leptin plays a role in insulin resistance in CKD. Increased resting energy expenditure It should be emphasized that the inflammatory response is often associated with fever, elevated oxygen consumption, enhanced lipolysis and fat utilization, increased concentration of catabolic hormones, and extensive protein catabolism that consume high quantities of energy, accounting for as much as 15% of the daily energy expenditure. 29 The stimulatory effect of inflammation on energy expenditure has been demonstrated in several non-ckd inflamed patient groups, including rheumatoid arthritis, acquired immune deficiency syndrome, cancer, and sepsis. 30 In accordance, a recent study have shown that also inflamed CKD patients have higher resting energy expenditure. 31 Furthermore, both resting energy expenditure and inflammatory parameters decreased significantly after treatment of acute infection in CKD patients. 31 As increased resting energy expenditure has been associated with high mortality rates and worse nutritional status in dialysis patients, 32 the impact of increased energy expenditure on muscle mass and body fat stores needs further evaluation. Anorexia The cause(s) of anorexia among patients with ESRD are multifactorial, and include the release of neurotransmitters (e.g., serotonin), neuropeptides (e.g., neuropeptide Y, orexin), the concentrations of gut-to-brain signaling factors (e.g., cholecystokinin), uremic toxins, and cytokines (e.g., TNF-a, leptin, and IL1-b). 33 Inflammatory cytokines interact with several pathways in the central nervous system to affect specific brain areas related to the appetite regulation. In ESRD patients there are some studies showing associations between the loss of appetite and higher levels of inflammatory markers. Thus, peritoneal dialysis patients with anorexia and vomiting showed higher plasma levels of TNF-a than patients without these symptoms. 34 In accordance, levels of IL-6 and TNF-a progressively increased as appetite scores got worse in HD patients. 35 Moreover, HD patients with the worse appetite had the worst nutritional status and the worst clinical outcome, suggesting a link between inflammation, decreased appetite, nutritional status, and outcome. 35 There is also data linking adipokines to inflammation and anorexia. Thus, CKD patients have markedly elevated leptin levels owing to impaired renal clearance, and it is possible that this uremic hyperleptinemia contributes to anorexia. 10 Leptin is taken up into the central nervous system by a saturable transport system and binds to the long form of the leptin receptor in the arcuate nucleus of the hypothalamus. Recently, leptin signaling in the central nervous system has been shown to be an important cause of anorexia in uremic rats via signaling through the central melanocortin system. 36 In a clinical study, we found that increased serum leptin levels were inversely related to inflammation and predicted longitudinal changes in lean body mass in patients starting peritoneal dialysis. 19 However, as others found no correlation between hyperleptinemia and decreased appetite and wasting 10 it could be speculated that there is an impaired transport of leptin across the blood brain barrier indicating leptin resistance in the uremic milieu. As a recent study by Chen et al. 37 demonstrated that circulating CRP binds to leptin and attenuates its physiological function, further studies are needed to evaluate the impact of persistent inflammation on leptin transport across the blood brain barrier and subsequent action in CKD. S11

5 Several studies have found gender differences in the regulation of appetite. 38 These gender differences apparently include both hormonal effects, dependent on gonadal function and mediated mainly by estrogen levels, as well as lifelong effects, which arise directly from genetic differences or from the effects of gonadal hormones early in life. 38 In a recent study, inflammation-induced anorexia was more severe among male than female rats, whereas progesterone injections decreased the severity of anorexia among female rats. 39 Because gender differences involve not only metabolic and neural pathways responsible for controlling the systemic inflammatory response, 38 but also differences in the immune systemic response, the impact of gender on the development of the inflammation-induced anorexia associated with CKD should be further investigated. SUMMARY AND CONCLUSION Multiple factors link inflammation to malnutrition, anorexia and wasting, and poor outcome in uremia. Translational research focusing on the inflammation-wasting axis and how to improve metabolic abnormalities and reduce negative cytokine signaling could lead to new preventive and therapeutic strategies that may contribute to reduce the prevalence of muscle wasting and improve survival of ESRD patients. Such strategies may include multiple appetite stimulants (such as megestrol acetate and dronabinol), various anti-inflammatory nutritional supplements (such as soy, fish, and diets low in advanced glycation end-products), and new potentially useful anti-inflammatory pharmacologic agents (such as statins, angiotensin-converting enzyme inhibitors, D-vitamin, and peroxisome proliferator-activated receptor-g activators) that may be tested alone, or in combination with nutritional support programs. ACKNOWLEDGMENTS This work was supported by the Swedish Medical Research Foundation (PS), the Swedish Society of Nephrology (PS), Swedish Renal Foundation (PS, JA), Karolinska Institute Fund for Gender Research (PS), ESPEN European Society of Clinical Nutrition and Metabolism (JJC), and by CAPES Coordenac ão de Aperfeic oamento de Pessoal de Nível Superior Brazil (CMA). REFERENCES 1. Stenvinkel P, Lindholm B, Heimbürger O. Novel approaches in an integrated therapy of inflammatory-associated wasting in end-stage renal disease. Semin Dial 2004; 17: Stenvinkel P, Heimbürger O, Paultre F et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55: Delano MJ, Moldawer LL. The origins of cachexia in acute and chronic inflammatory diseases. Nutr Clin Pract 2006; 21: Morley JE, Thomas DR, Wilson MM. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 2006; 83: Stenvinkel P, Heimbürger O, Lindholm B et al. 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