138 inflammatory cytokines are the major determinants of catabolism, and we have previously shown that circulating tumour necrosis factor-alpha, originally called ‘cachectin’, is the strongest predictor of the degree of previous weight loss in cachectic patients [56] and correlates with a poor prognosis [57]. Immune activation in HF patients can cause worsening cardiac function [58] through the induction of apoptosis [59] and nitric oxide downregulation [60], impaired exercise capacity [61] and skeletal muscle abnormalities [61, 62]. Cytokines also reduce constitutive nitric oxide synthase mRNA in endothelial cells [63] and therefore impair endothelial function. In fact, an inverse relationship between peripheral blood flow and TNF levels has been reported in chronic HF patients [64]. The third key mechanism in the development of cardiac cachexia is neurohormonal activation. Increased tone of the adrenergic and renin–angiotensin–aldosterone systems aim to maintain cardiac output, but at the expense of increased vascular resistance and afterload, with further left ventric- ular remodelling and dysfunction. Interestingly, the same hormonal systems play an important role in peripheral tissue wasting: Angiotensin II and catecholamines have pro-apoptotic effects and increase resting metabolic rate [65, 66]. Similarly, abnormalities in the growth hormone axis and cortisol systems have been reported in chronic HF patients [67, 68]. Taken together, these abnormalities lead to an imbalance between the catabolic and anabolic states, confirmed by the observation of significantly higher levels of catabolic hormones in cachectic as compared with non- cachectic patients [53], with consequent muscle wasting, a dominant feature of cachectic patients [69]. In fact, muscle weakness and early fatigue are two of the main symptoms of HF patients [70, 71] and occur most commonly in patients with advanced HF or cachexia [72]. Finally, regulation of feeding and energy balance may be altered in chronic HF patients, in particular in patients with cardiac cachexia. Ghrelin, mainly produced by the stomach fundus, induces the release of growth hormone and regulates appetite [73, 74]. It has been reported to be increased in cachectic patients [75], and the increase in ghrelin was correlated with the increase in circulating growth hormone; it may therefore have a role in attenuating the catabolic–anabolic imbalance via growth hormone- releasing effects. Insulin and growth hormone resistance may occur secondary to HF [76, 77], with consequent loss of their anabolic effects. 4.2 Chronic kidney disease CKD and ESRD are frequently complicated by progressive deterioration of nutritional status [8], which significantly affects prognosis and quality of life. Cachexia in CKD, similarly to HF, is a complex syndrome which derives not J Cachexia Sarcopenia Muscle (2011) 2:135–142 only by a reduced energy intake but is also the consequence of multiple pathogenetic mechanisms, including increased protein catabolism, reduced anabolism, increased energy expenditure and loss of adipose tissue. A variety of terms have been used to define this syndrome in CKD, like protein-energy wasting [78], malnutrition–inflammation complex syndrome [79] and kidney disease wasting [80], underlying the role of different pathways. As mentioned above, the accelerated cardio-renal syndrome type 4 in malnourished patients has also been defined as MIA syndrome based on the relation among malnutrition, inflam- mation and accelerated atherosclerosis. A major determinant of the disease process in CKD is anorexia. Amongst patients on renal replacement therapy, impaired appetite is reported in 38% and is associated with worse morbidity and mortality [81, 82]. Interestingly, anorexia was asso- ciated with increased inflammatory markers, suggesting a possible role for immune activation in regulating the stimuli for food intake. Furthermore, similarly to HF, it has been repeatedly reported that inflammation is closely related to qualitative and quantitative changes in the skeletal muscles of patients with CKD [83, 84]. Activation of the protease caspase-3 is the initial step of muscle protein degradation, and this inflammation-mediated pro- teolytic pathway is not counterbalanced by increased anabolic pathways in CKD [83]. Growth hormone (GH) resistance, due to the reduced density of GH receptors and abnormal intracellular signalling, contributes to increased skeletal muscle protein catabolism [80] and failure of anabolism in patients with end-stage renal disease. Increased protein breakdown in CKD is also associated with insulin resistance [85], which frequently occurs in end- stage renal disease [86] and is triggered by inflammation through an increase in oxidative stress [87]. Therefore, inflammation can contribute to the disease process directly, activating proteolysis, and indirectly, through insulin resis- tance and oxidative stress. IN CKD, an increase in C- reactive protein is common as it is a decrease of acute phase proteins such as albumin. The mechanism that leads to inflammation in ESRD is complex and not fully understood yet, but recent studies paid attention on the gut as a possible source of cytokine stimulus [88]. In states of intestinal under perfusion, as during haemodialysis [89], the perme- ability of the intestinal wall is increased as a result of hypoxia and local production of lipopolysaccharide (LPS) [90], allowing LPS leakage into the bloodstream, with consequent immune activation [91]. These complex inter- actions between gut and kidney, for which the term ‘intestinal–renal syndrome’ has been proposed [91], could explain the occurrence of cardiovascular abnormalities during dialysis, like arrhythmias, silent ischaemia [92] and myocardial stunning [93], through the production of pro- inflammatory cytokines with consequent cardiac and