136 shown that worsening renal function is associated with dismal prognosis [4–6]. These conditions are generally grouped under the umbrella term cardio-renal syndromes (CRS). Cachexia is a frequent and serious complication of chronic diseases, including HF, chronic kidney disease (CKD), cancer and acquired immunodeficiency syn- drome [7, 8]. It has been calculated that in 2006, approximately 5 million people in the USA were cachectic because of cancer or other chronic diseases [9]. Uremic cachexia increases the risk of death of patients with CKD up to 100- to 200-fold that of the general population [10]; similarly, cardiac cachexia is a negative prognostic factor in patients with CHF independently of left ventricular systolic function and exercise capacity: cachectic patients have a poor outcome [11, 12], with survival rates at 18 months <50%. Interestingly, cardio-renal syndromes and cachexia share common pathophysiological mechanisms, and we hypothe- sise that the presence of one of these conditions may favour the occurrence or worsening of the other. A better understanding of the complex interplay between the heart and kidney could help improve the management of these patients. The same may be true for cachexia. In the present article, we will focus on the relationship between cachexia and cardio-renal syndromes, exploring the potential mech- anisms contributing to the vicious circle leading to a combined cardio-renal cachexia syndrome (CRCS) and its progressive worsening. 2 Cardio-renal syndromes CRS, defined as ‘disorders of the heart and kidney whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other’ [13], have been recently classified into five categories [14]. CRS type 1, or acute CRS, is determined by any of the acute HF syndromes [2] causing AKI. This type of CRS is frequent, with acute HF syndromes being the most common and the most expensive diagnosis-related group for Medi- care patients [15] and worsening renal function occurring in 30–45% of patients during hospitalisation [16, 17]. The mechanisms contributing to worsening renal function after an episode of acute HF are multiple and complex. Whilst some haemodynamic factors, like heart rate, systolic arterial blood pressure and pulmonary wedge pressure, do not seem to play a major role, an incremental risk of developing AKI has been described with increased central venous pressure [18]. Other factors may contribute to worsening renal function in acute HF, like drug and contrast media use, or systemic activation of neurohormonal systems and pro- inflammatory cytokines [19–21]. J Cachexia Sarcopenia Muscle (2011) 2:135–142 CRS type 2, or chronic CRS, is defined as progressive CKD caused by chronic cardiac dysfunction. The preva- lence of this subtype is approximately 25% [22], and the associated risk of cardiovascular mortality and hospital- isation for worsening HF for chronic HF patients is more than three times higher when the glomerular filtration rate (GFR) falls below 45 ml min−1/1.73 m2 as compared with a normal GFR. The pathophysiological basis for the inter- actions between heart and kidney in CRS type 2 has not been fully understood yet. It is likely that a chronic hypoperfusion of the kidney may progressively lead to alterations in renal vasculature; increased renal vascular resistance, continuous activation of hormonal systems and drug-induced damage all contribute to further impairment of renal function moving from an initial insult to a progressive fibrosis and sclerosis of the renal parenchyma. CRS type 3, or acute reno-cardiac syndrome, is charac- terised by an AKI which leads to acute HF, ischaemia or arrhythmias. AKI can affect the heart through multiple mechanisms. First, volume overload can lead to pulmonary congestion, particularly in the presence of left ventricular dysfunction; second, acidosis and uraemia itself can depress cardiac systolic function [23, 24], and acidosis and hyper- kalemia carry a pro-arrhythmic risk. Another important factor is the activation of inflammation at the cardiac level, which can be triggered by renal ischaemia [19, 25, 26]. CRS type 4, or chronic reno-cardiac syndrome, is defined as a condition in which primary CKD contributes to cardiac abnormalities of various types and degrees, like hypertro- phy, diastolic and systolic dysfunction, and increased risk of cardiovascular morbidity and mortality [27, 28]. Many pathways are implicated as pathogenetic mechanisms of cardiac damage in chronic renal disease: Activation of the renin–angiotensin–aldosterone system, volume overload, endothelial dysfunction, inflammation and anaemia all can contribute to functional and structural changes in the heart and vessels [29]. Less than 20% of patients with end-stage renal disease have a normal heart at echocardiography, whilst the majority have left ventricular hypertrophy or dilation [30]. A baseline GFR <60 ml min−1/1.73 m2 is independently associated with increased incidence of peripheral artery disease [31] and CHF [32], and almost half of the mortality affecting patients with CKD is due to cardiovascular events [33, 34]. CRS type 5, or secondary CRS, occurs when an acute or chronic systemic disorder causes both renal and cardiac dysfunction. Examples of this type of CRS include sepsis, haemorrhagic shock, diabetes, sarcoidosis and amyloidosis. The model of sepsis is paradigmatic in this context: Up to 60% of patients with systemic infection develop AKI, which contributes to higher morbidity and mortality [35, 36]; at the same time, cardiac damage is common. Septic patients have increased markers of cardiac-specific damage