Cardiorenal Syndrome and Inflammation: A Forgotten Frontier Resolved by Sorbents?

Cardiorenal syndrome (CRS) is a term that describes the maladaptive relationship between heart and kidney dysfunction. This relationship involves a bidirectional interconnection of pathophysiology, and several pathways remain incompletely understood since the term’s formal definition in 2008 [1]. Some of the most representative pathways include venous congestion, arterial underfilling, neurohormonal activation, endothelial dysfunction, oxidative stress, and inflammation. These pathways cause complications that perpetuate the pathophysiology [1, 2].

The prevalence of chronic kidney diseases in patients admitted for acute decompensated heart failure is 60% [3]. In addition, the prevalence of acute deterioration in renal function in patients admitted for acute decompensated heart failure is approximately 20–30%. If a decrease in GFR is not accompanied by appropriate decongestion, it may lead to adverse events, including an approximately 50% mortality rate if acute kidney injury is associated with cardiogenic shock [2, 4, 5]. Our understanding and treatment of this complex disease, with poor outcomes, is constantly improving; nevertheless, more consensus is needed.

One direction in this multifactorial syndrome is the treatment of the inflammatory axis. Inflammation and immune dysfunction contribute to the final nonhemodynamic pathways of organ dysfunction in the heart-kidney cross-talk and may be mediators and amplifiers of this pathological communication. Numerous studies are investigating novel agents, including monoclonal antibodies that target inflammatory cytokines and augment the innate and humoral immune system to combat inflammation and endothelial dysfunction [2, 6]. A study with the CANVAS database showed that a higher baseline IL-6 was independently associated with a higher risk of cardiovascular and kidney outcomes [7]. Valuable clinical data for the potential cardiovascular benefit of the treatment of inflammation in patients with chronic kidney diseases with a history of myocardial infarction and system inflammation were derived with canakinumab, a monoclonal antibody targeting IL-1β [8]. Nevertheless, with the use of monoclonal antibodies, along with the observed benefits, an increase in serious and fatal infections is also observed, increasing with higher doses [9, 10]. We must optimize all the pathophysiological pathways to treat the root issue rather than solely focusing on decongestion with diuretics and/or extracorporeal techniques and their new technologies [11]. However, the inflammatory pathway has been neglected.

Inflammation plays a vital role in both acute and chronic cardiorenal dysfunction. Various pathways of cytokine activation have been identified, including local production by myocardial cells due to injurious factors such as ischemia-reperfusion or viral injury; myocardial tissue injury leading to mononuclear cell infiltration, activation, and cytokine production; hemodynamic overload; oxidative stress; neurohormonal activation; and/or bacterial/endotoxin translocation across the gut wall [12].

Studies have found that proinflammatory cytokines, such as IL-6 and IL-18, were 5 times higher in CRS type 1 patients than in patients with acute heart failure, including a more prevalent monocytic activation, regardless of the volume state [13, 14]. Furthermore, higher levels of myeloperoxidase were also reported, suggesting a link between inflammation and oxidative stress [13, 14]. Studies conducted on CRS have shown that higher levels of IL-6 and IL-1β are associated with mortality and kidney injury. These cytokines have also been identified as crucial in the cardiorenal interaction due to a decrease in the expression of SOCS3 and increased neutrophil recruitment [15‒17]. In addition, elevated serum levels of IL-10 correlate with adverse outcomes in acute coronary syndromes and the development of AKI after cardiac surgery [18, 19]. Besides that, IL-6 is an upstream signal for myocardial Grb2 activation, which is a primary factor involved in myocardial damage following AKI, promoting cardiac hypertrophy and chronic myocardial remodeling following myocardial infarction through collagen synthesis and also modifying cellular bioenergetics and mitochondrial function, altering cardiomyocyte relaxation and compromising diastolic function [20]. The consequences of inflammation in CRS involve an aggravation in congestion. IL-6 stimulated epithelial sodium channels in the distal tubules, impairing natriuresis and contributing to volume expansion [21]. Moreover, when studying the immune system imbalance in type 1 CRS, researchers found that monocytes in vitro respond differently to plasma from these patients. Monocytes with higher levels of caspase-3 and -8 show a significantly higher level of apoptosis, indicating a link between immune system imbalance and the development of type 1 CRS [22]. In addition, IL-33 contributes to overactivation of immune cells with subsequent production of profibrotic and proinflammatory cytokines, and furthermore, IL-33 has been implicated in the development and progression of AKI and CKD. Blocking IL-33 in a mice model improved endothelial inflammation and attenuated kidney disease progression [23].

Current therapeutic strategies are not satisfactory in mitigating the inflammatory pathway in CRS. Hemoadsorption overcomes this limitation, and the soluble mediators of inflammation are potentially amenable to removal by sorbents in an acute or chronic setting from blood or plasma as a method of mass separation using a solid agent [24]. Extracorporeal hemoadsorption is an additional option for blood purification, either alone or in combination with other renal replacement therapies due to the limitations presented by current dialysis techniques based on diffusion and convection regarding membrane permeability characteristics. The solute’s final binding (adsorption) onto the porous surface is governed by the density and diameter of the pores of the sorbent structure (pore diameter ranges generally 20–500 Å) and the solute concentration. Hydrophobic binding is the main mechanism of solute removal from the extracorporeal circulation. Although other forces are involved, such as van der Waals and ionic bonds, the hydrophobic affinity of the sorbent with the target solutes represents the main mechanism of currently available sorbent cartridges [25].

CRS patients consequently have a risk of immune dysregulation with impaired outcomes. Mitigating the overexpression and increased plasmatic levels of pro- and anti-inflammatory mediators by blood purification techniques such as hemoadsorption could be associated with improved outcomes (Fig. 1). Information from specific studies on CRS and hemoadsorption has not yet been carried out. However, information on animal models and other patients’ profiles can give us a direction to follow. High-mobility group box 1 protein (HMGB1), a DAMP released secondary to cardiac cell necrosis, accentuating the inflammatory response, is also toxic to cardiomyocytes itself; nonetheless, the feasibility of removal by HA was demonstrated [26]. Studies in sepsis with JAFRON^® cartridges have shown an improvement in hemodynamic parameters such as cardiac index, improving cardiac function secondary to the elimination of myocardial-depressant mediators [27]. In addition, left ventricular hypertrophy is a common cardiovascular event in maintenance hemodialysis patients, increasing cardiovascular mortality. In this scenario, HA demonstrated a reduction in left ventricular mass index and a reduction in the levels of myocardial enzymes [28]. A pilot study in Vietnam with a 3-year follow-up showed a reduction in cardiovascular-related mortality in maintenance hemodialysis patients in which hemoadsorption was used [29]. In conclusion, the data from current pilot studies may provide a rationale to further investigate additional therapeutic targets in CRS (acute and chronic), evaluating the response in surrogate outcomes such as reduction in systemic inflammation, volume control, and improvement in hemodynamic parameters.

The authors confirm that the manuscript complies with all instructions to the authors. The authorship requirements have been met and the final manuscript was approved by all authors. The authors confirm that this manuscript has not been published elsewhere and is not under consideration by another journal.

We thank Anita Zurita Poza for her technical assistance in the design of this article.

C.R. has received funding for lectures and been a consultant or advisory board member for Asahi, Astute, B. Braun, Baxter, bioMérieux, Bioporto, CytoSorbents, Estor, Fresenius Medical Care, General Electric (GE), Jafron, Medtronic, and Toray. T.R. has received funding for lectures and been consultant or advisory board member for AstraZeneca, B. Braun, Baxter, bioMérieux, Boehringer Ingelheim, Contatti Medical (CytoSorbents), Eurofarma, Fresenius Medical Care, Jafron, Lifepharma, and Nova Biomedical. G.R. declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. The authors alone are responsible for the content and writing of this article.

There was no funding for the study.

G.R.G., T.R., and C.R. designed the work; G.R.G. and C.R. collected and analyzed the data; G.R.G., T.R., and C.R. drafted the work or substantively revised it; and all authors read and approved the final manuscript.