Cardiorenal Syndrome
Immunomediated Mechanisms of Organ Damage in Cardiorenal Syndrome Type 1
Grazia Maria Virzì,1,2 Dinna N Cruz,1,2 Annalisa Angelini,4 Chiara Bolin,3 Manish Kaushik,2 Massimo de Cal,1 Wang Daihong,2 Elisa Scalzotto,1,2 Giorgio Vescovo3 Chiara Castellani,4 and Claudio Ronco1,2
1. Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza; 2. International Renal Research Institute Vicenza; 3. Department of Internal Medicine, San Bortolo Hospital, Vicenza; 4. Department of Cardiac, Thoracic and Vascular Sciences, Cardiovascular Pathology, University of Padua Medical School
Abstract
Cardiorenal syndrome (CRS) type 1 is characterised by a rapid worsening of cardiac function leading to acute kidney injury (AKI). The pathophysiology of CRS type 1 is very complex. Immune-mediated damage and alterations in immune response have been postulated to be potential mechanisms involved in the syndrome. In a pilot study, we examined the possible role of immune-mediated mechanisms in the pathogenesis of CRS type 1. The main objective of the study was to analyse in vitro whether the plasma of patients with CRS type 1 was able to trigger a response in monocytes, resulting in apoptosis and in cytokine release and inflammation. We enrolled seven patients with CRS type 1 (CRS type 1 group), 12 patients with acute heart failure (AHF) (AHF group) and five healthy volunteers (control group). Heparinised plasma from different groups was incubated with monocytes and cell apoptosis was subsequently evaluated by fluorescence microscopy, DNA ladder kit and caspase-3 detection. In addition, quantitative determination of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the supernatants was performed using an enzyme-linked immunosorbent assay (ELISA) kit. In U937 cells treated with CRS type 1 plasma, the results showed DNA ladder formation with different molecular weight fractions, suggesting the presence of an apoptotic event. In fact, a quantitative analysis of apoptosis showed significantly higher apoptosis rates (p<0.005). Moreover, caspase-3 levels in cells incubated with the plasma from these patients demonstrated a significantly higher concentration. When compared with healthy subjects, TNF-α levels in the supernatant were significantly elevated in both the AHF and CRS type 1 groups (p<0.05). Furthermore, in CRS type 1 patients, the pro-inflammatory cytokine IL-6 was significantly higher compared with AHF patients and the control group (p<0.05). This pilot study suggests the presence of defective regulation of monocyte apoptosis in CRS type 1 patients. An immune-mediated mechanism may play a role in the pathophysiology of this syndrome. Furthermore, these preliminary results suggest that inflammatory pathways play a central role in the pathogenesis of CRS type 1.
Keywords Cardiorenal syndrome type 1, acute heart failure, apoptosis, immune-mediated mechanism, monocytes, inflammation
Disclosure: The authors have no conflicts of interest to declare. Received: 9 February 2012 Accepted: 2 March 2012 Citation: European Nephrology, 2012;6(1):25–9 Correspondence: Claudio Ronco, Professor, Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, International Renal Research Institute Vicenza, Via Rodolfi 37, 36100 Vicenza, Italy. E:
cronco@goldnet.it
Heart performance and kidney function are closely interconnected and a synergistic relationship exists between these two organs. Dysfunction of one often leads to deterioration in the function of the other.1
This clinical entity has been defined as cardiorenal syndrome (CRS). A recent definition and classification system has been generated to include a vast array of acute or chronic conditions in these two important organs, where the primary failing organ can be either the heart or the kidneys.1
The classification has been endorsed
and further developed by the Acute Dialysis Quality Initiative (ADQI) consensus group, leading to a comprehensive characterisation of the complex heart–kidney crosstalk.2
This new classification represents a
step towards a better understanding of the pathophysiology and management strategies of the bidirectional heart–kidney interactions.
CRS type 1 is characterised by an acute worsening of cardiac function leading to acute kidney injury (AKI) and/or dysfunction. Pre-morbid renal
© TOUCH BRIEFINGS 2012
dysfunction is common in heart failure patients (de novo acute heart failure [AHF] or acute decompensated heart failure) and predisposes them to AKI, which has been associated with higher risks of both prolonged hospitalisation and/or re-hospitalisation, and cardiovascular and all-cause mortality – as well as with faster progression to chronic kidney disease.3–5
hospital with AHF every year.6
develop AKI (defined as an increase in serum creatinine of ≥0.3 mg/dl).7 Furthermore, patients who develop AKI after an acute cardiac event have a significantly high mortality risk.8
A number of pathological processes
contribute to AKI, including endothelial and epithelial cell death as well as immunological and inflammatory processes.9
evidence supports a pathogenic role for apoptosis in AKI.9
The pathophysiology of CRS type 1 is complex and poorly understood, as it involves several factors that are interrelated.4
In addition, experimental
In the US, more than 1 million patients present to Approximately one-third of AHF patients
It has been 25
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