J Cachexia Sarcopenia Muscle (2011) 2:135–142 vascular dysfunction [60, 94]. Further mechanisms have been indicated as potential causes of accelerated muscle wasting and intestinal abnormalities such as the lack of vitamin D receptor activation [95] and the lack of the anti- apoptotic effect at tissue levels of erythropoietin [96]; both conditions are typical of CKD and tend to worsen with progression of renal dysfunction. Finally, abnormalities in ghrelin system have been reported in patients with CKD. Plasma ghrelin levels increase in dialysis patients [97] because of reduced ghrelin degradation—which occurs mainly in the kidney [98]. Two major forms of circulating ghrelin are acylated and des-acyl ghrelin. Acylated ghrelin stimulates food intake [99], downregulates pro-inflammatory cytokines [100] and improves lean body mass [101], whilst the des-acyl form induces a negative energy balance and could be involved in anorexia in CKD patients [98]. The different effects of the two forms can explain the conflicting results of previous studies on the exact role of this peptide on energy metabolism and regulation of food intake. 5 The cardio-renal cachexia syndrome: a cachexia-mediated negative heart–kidney cross talk Chronic HF and CKD can be both complicated by the occurrence of cachexia, and interestingly, the underlying pathophysiological mechanisms are similar in the two 139 conditions, as reviewed in the present article. Thus, since chronic heart and kidney interactions are at the base of CRS types 2 and 4, we could propose a new entity called cardio- renal cachexia syndrome (CRCS). It had been previously suggested that common pathogenetic mechanisms underlie body wasting in cachectic states of different chronic heart and kidney diseases [102]. Now we hypothesise that a vicious circle could arise, in which cachexia associated with either HF or CKD may contribute to further damage of the other organ (Fig. 1). Activation of the immune and neuroendocrine systems contribute to the genesis of cachexia, which in turn can negatively affect the heart and kidney function, worsening CRS types 2 and 4. In patients with cardiac cachexia, the same endogenous factors can affect different target organs other than the heart, particu- larly the kidney. Sustained activation of the immune and neuroendocrine systems and oxidative stress can increase renal vascular resistance and therefore impair renal perfu- sion, leading to worsening kidney function, i.e. a CRS type 2, or chronic cardio-renal syndrome. Similarly, in renal cachexia, increased levels of pro-inflammatory cytokines can cause progressive left ventricular systolic dysfunction, myocardial cell death, endothelial dysfunction and increased myocardial fibrosis [103], with consequent impairment of the haemodynamic conditions corresponding to the chronic reno-cardiac syndrome, or CRS type 4. Furthermore, we speculate that the occurrence of different types of CRS could also represent a fundamental CARDIO-RENAL CACHEXIA SYNDROMES Non-oedematous weight loss of >6% of total body weight over a period of 6 or more months CRS TYPE 2 Low Cardiac output Na and fluid overload Chronic hypoperfusion Embolism Venous Congestion Chronic inflammation Cardiac Remodeling Endothelial Dysfunction Acceler. Atherosclerosis Fig. 1 Cardio-renal cachexia syndromes CRS TYPE 4 Na and fluid overload Chronic inflammation Uremic Toxins Malnutrition Anemia EPO resistance pH abnormalities Ca-P abmormalities Lack of VDR activation Soft Tissue calcifications Malnutrition, loss of >10% of lean tissue or percent of ideal weight <90% . CKD Progression, Apoptosis Necrosis, Fibrosis, Sclerosis Heart Failure, Systolic/diastolic dysfunction, Myoc.Remodelling