Cardiorenal syndrome (CRS) is a complex disorder observed in patients with kidney or heart diseases, wherein acute/chronic involvement of one organ induces disease in the other. The syndrome is important in the critical care context since co-involvement of the heart and kidney is commonly observed in many patients. As previously discussed in Chapter 16 (“Humoral Signaling in Cardiorenal Syndrome”), interorgan communication relies on intricate neurohormonal and inflammatory signaling networks. Building on this foundation, the present chapter expands the discussion beyond the cardiorenal axis to encompass the metabolic crosstalk among multiple organs affected in heart failure, including the liver, skeletal muscle, adipose tissue, and brain. Dysregulated humoral signaling by a multitude of mediators has an extremely detrimental effect by causing cardiac and renal injury, irrespective of the primary origin of the CRS. A deeper understanding of these integrated signaling mechanisms may lead to the identification of novel biomarkers and targeted therapies aimed at mitigating multi-organ dysfunction in advanced cardiovascular disease.