Heart–kidney crosstalk and role of humoral signaling in critical illness

Review Open Access Heart–kidney crosstalk and role of humoral signaling in critical illness Grazia Maria Virzì1, 2, 3Email author, Sonya Day1, 2, Massimo de Cal1, 2, Giorgio Vescovo4 and Claudio Ronco1, 2 Critical Care201418:201 https://doi.org/10.1186/cc13177 ©  BioMed Central Ltd. 2014 Published: 6 January 2014 Abstract Organ failure in the heart or kidney can initiate various complex metabolic, cell-mediated and humoral pathways affecting distant organs, contributing to the high therapeutic costs and significantly higher morbidity and mortality. The universal outreach of cells in an injured state has myriad consequences to distant organ cells and their milieu. Heart performance and kidney function are closely interconnected and communication between these organs occurs through a variety of bidirectional pathways. The term cardiorenal syndrome (CRS) is often used to describe this condition and represents an important model for exploring the pathophysiology of cardiac and renal dysfunction. Clinical evidence suggests that tissue injury in both acute kidney injury and heart failure has immune-mediated inflammatory consequences that can initiate remote organ dysfunction. Acute cardiorenal syndrome (CRS type 1) and acute renocardiac syndrome (CRS type 3) are particularly relevant in high-acuity medical units. This review briefly summarizes relevant research and focuses on the role of signaling in heart–kidney crosstalk in the critical care setting. Keywords Renal Replacement TherapyAcute Kidney InjuryTubular Epithelial CellProximal Tubular Epithelial CellMyocyte Apoptosis Introduction Heart performance and kidney function are closely interconnected, and communication between these organs occurs through a variety of bidirectional pathways. The severity of the failing organ can initiate various complex metabolic, cell-mediated and humoral pathways affecting distant organs, contributing to the high therapeutic costs and significantly higher morbidity and mortality. Both acute and chronic cardiac disease can directly contribute to concurrent acute/chronic worsening kidney function and the converse [1, 2]. The term cardiorenal syndrome (CRS) is often used to describe this condition, representing an important model for exploring the pathophysiology of cardiac and renal dysfunction [1, 3]. The CRS classification system includes 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. The current definition has been expanded into five subtypes whose etymology reflects the primary and secondary pathology, the time frame, as well as cardiac and renal co-dysfunction secondary to systemic disease [1] (Table 1). Epidemiological studies of CRS indicate that patients transition between different CRS subtypes [4]. There are a number of potential contributing factors for CRS that may predispose a patient to the development of this syndrome and which are relevant for the susceptibility, etiology, severity and duration of the disease state. The intersection of cardiac and renal disorders has important therapeutic and prognostic implications; this new classification represents a step towards a better understanding of the pathophysiology and management strategies of this bidirectional crosstalk. Table 1 Cardiorenal syndrome classification system Classification Abbreviation Characteristic Acute cardiorenal syndrome CRS type 1 Abrupt worsening of cardiac function leading to acute kidney injury; for example, acute coronary syndrome causing acute heart failure and then renal dysfunction Chronic cardiorenal syndrome CRS type 2 Chronic abnormalities in cardiac function causing progressive chronic kidney disease; for example, congestive cardiac failure Acute renocardiac syndrome CRS type 3 Sudden worsening of renal function causing acute cardiac dysfunction; for example, uremic cardiomyopathy secondary to acute renal failure Chronic renocardiac syndrome CRS type 4 Condition of primary chronic kidney disease leading to an impairment of the cardiac function and/or increased risk of adverse cardiovascular events; for example, left ventricular hypertrophy and diastolic heart failure secondary to renal failure Secondary cardiorenal syndrome CRS type 5 Systemic disorders causing both cardiac and renal dysfunction; for example, septic shock, vasculitis CRS, cardiorenal syndrome. Clinical evidence suggests that tissue injury such as acute kidney injury (AKI) is not an isolated event and it has become apparent that much of the increased risk of death is derived from distant complications [5, 6]. A recent multicenter, multinational study reported that 5 to 6% of these at-risk patients suffer from AKI and subsequently are treated with renal replacement therapy (RRT) [7]. Twenty-five percent of patients in the ICU develop AKI [8, 9]. RRT is the only US Food and Drug Administration-approved treatment for AKI [10, 11]. For more than 40 years, despite the advent of RRT, there has been limited improvement in the mortality rate associated with AKI [12]. In the critical care setting, AKI remains an important predictor of outcome, and frequently results in remote organ dysfunction involving the heart, lung, liver, intestines, and brain through immune-mediated inflammatory mechanisms [13–15]. In the organ crosstalk, the combination of AKI with acute lung injury remains a formidable challenge for clinicians treating critically ill patients. New experimental data have emerged in recent years focusing on the interactive effects of kidney and lung dysfunction, and providing evidence that kidney–lung crosstalk occurs and can be bidirectionally deleterious. These studies have highlighted the pathophysiological importance of proinflammatory and proapoptotic pathways in the kidney–lung crosstalk [16, 17]. Inflammatory dysregulation resulting from each organ failure results in rising levels of circulating chemokines, cytokines and activated lymphocytes [17]. Cellular (for example, neutrophils) as well as soluble mediators (cytokines) contribute to the inflammatory dysregulation under these circumstances [18]. The liver and kidney are important regulators of body homeostasis and are involved in excreting the toxic byproducts of metabolism and exogenous drugs [19]. Liver injury often correlates with severity of kidney injury. AKI induces oxidative stress and promotes inflammation (production of TNFα, IL-1, IL-6), apoptosis and tissue damage in hepatocytes [20–23]. Another important mechanism of end-organ dysfunction in kidney–liver crosstalk is the development of hepatorenal syndrome, a functional renal failure that often occurs in patients with cirrhosis and ascites. Two different types of hepatorenal syndrome have been described. Hepatorenal syndrome type 1 develops as a consequence of a severe reduction of effective circulating volume due to both an extreme splanchnic arterial va (...truncated)