Cardiorenal syndrome (CRS) type 1, consisting of acute cardiac events leading to acute kidney injury (AKI), is characterized by multiple factors and its pathophysiology is very complex. Given the circulating nature of many inflammatory mediators, it is tempting to examine the immune-mediated mechanism as a mediator of organ crosstalk. In this pilot study, we examined the possible role of immune-mediated mechanisms in the pathogenesis of this syndrome. We enrolled 12 patients with acute heart failure (AHF), 7 patients with type 1 CRS, and 5 healthy volunteers. EDTA plasma samples from the 3 groups were incubated with a monocyte cell line (U937) and cell apoptosis was subsequently evaluated by different methods. In addition, quantitative determination of TNF-alpha, IL-6 and IL-18 production in the supernatants was performed by ELISA. In U937 cells treated with type 1 CRS plasma, the results showed DNA ladder formation with different molecular weight fractions, suggesting the presence of apoptotic events. In fact, quantitative analysis of apoptosis and caspase-3 levels showed significantly higher apoptosis rates in cells incubated with plasma from patients with type 1 CRS (p<0.05). TNF-alpha levels in the supernatants were significantly elevated in both the AHF and type 1 CRS groups compared with control subjects (p<0.05). Furthermore, in patients with type 1 CRS the levels of the proinflammatory cytokines IL-6 and IL-18 were significantly higher than in AHF patients and the control group (p<0.05). This pilot study explores the premise of an immune-mediated process in the pathophysiology of type 1 CRS. These preliminary findings suggest the presence of defective regulation of apoptosis in patients with this syndrome and the involvement of an immune-mediated mechanism in its pathogenesis. Furthermore, inflammatory pathways seem to play a central role in organ crosstalk and may be fundamental to distant organ damage.