Cardiorenal Syndrome Type 1 May Be Immunologically Mediated: A Pilot Evaluation of Monocyte Apoptosis

Abstract

Background: Cardiorenal syndrome (CRS) type 1 is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). An immune-mediated damage and alteration of immune response have been postulated as potential mechanisms involved in CRS type 1. In this pilot study, we examined the possible role of the immune-mediated mechanisms in the pathogenesis of this syndrome. The main objective was to analyze in vitro that plasma of CRS type 1 patients was able to trigger a response in monocytes resulting in apoptosis. The secondary aim was to evaluate TNF-α and IL-6 plasma levels of CRS type 1 patients. Methods: Fifteen patients with acute heart failure (AHF) and CRS type 1 were enrolled and 20 healthy volunteers without AHF or AKI were recruited as control group. Plasma from these two groups was incubated with monocytes and, subsequently, cell apoptosis was evaluated. In addition, the activity of caspase-8 was assessed after 24 h incubation. Quantitative determination of TNF-α and IL-6 levels was performed. Results: Plasma-induced apoptosis was significantly higher in CRS type 1 patients compared with healthy controls at 72 h (78 vs. 11%) and 96 h (81 vs. 11%). At 24 h, the activity of caspase-8 was significantly higher in monocytes incubated with plasma from the CRS type 1 group. TNF-α (2.39 vs. 28.49 pg/ml) and IL-6 (4.8 vs. 16.5 pg/ml) levels were significantly elevated in the CRS type 1 group (p < 0.01). Conclusions: In conclusion, there is a defective regulation of monocyte apoptosis in CRS type 1 patients, and inflammatory pathways may have a central role in the pathogenesis of CRS type 1 and may be fundamental in damage to distant organs.

Cardiorenal Syndrome Type 1: A Defective Regulation of Monocyte Apoptosis Induced by Proinflammatory and Proapoptotic Factors

“…In particular, in a recent study [25], they observed that the plasma of CRS type 1 patients induces apoptosis in U937 cells. However, this study had a strong limitation: all 15 patients included with CRS type 1 had CKD prior to their enrollment in the study.…”

“…Indeed, in previous studies, de Cal and colleagues [27,28] had shown that the plasma of patients with CKD by itself induces apoptosis in these cells. In fact, Virzì et al [25] reported that apoptosis appeared to increase across CKD stages 1-4 and that this was associated with increased proinflammatory activity.…”

The Hemodynamic and Nonhemodynamic Crosstalk in Cardiorenal Syndrome Type 1

“…Recently, Virzì et al [41] explored the premise of an immune-mediated process in the pathophysiology of this syndrome and showed marked apoptotis in monocytes incubated with CRS type 1 plasma. The specific immune responses during AKI facilitate and enhance distant heart-kidney crosstalk; in particular, inflammation of renal tissue stimulates the expression of adhesion molecules in endothelial cells, which leads to the deposition of immune complexes and vascular stiffening in kidney disease [30].…”

“…In addition, apoptotic pathways and caspases seem to have direct effects on cardiomyocyte contractility and remodeling, cleaving myocardiac contractile proteins and promoting systolic dysfunction [67,68]. Recent evidence has suggested that immune-mediated mechanisms are implicated in the pathogenesis of CRS type 1 [41,69]. It has been recently shown that plasma from CRS type 1 patients induced apoptosis in monocytes with an activation of caspase cascade; furthermore, IL-6 levels were significantly higher in these patients when compared with healthy controls and heart failure patients without kidney impairment [41,69].…”

“…Recent evidence has suggested that immune-mediated mechanisms are implicated in the pathogenesis of CRS type 1 [41,69]. It has been recently shown that plasma from CRS type 1 patients induced apoptosis in monocytes with an activation of caspase cascade; furthermore, IL-6 levels were significantly higher in these patients when compared with healthy controls and heart failure patients without kidney impairment [41,69]. In a different study, Virzì et al [69] demonstrated that TNF-α levels, detected in monocyte cell supernatants, were significantly elevated in cells treated by plasma from heart failure and CRS type 1 patients compared with supernatants from cells treated by plasma from healthy subjects; in the cell supernatants obtained from monocytes of patients with CRS type 1, the levels of the proinflammatory cytokines IL-6 and IL-18 were significantly higher than in monocyte supernatants of heart failure patients and controls.…”