Panoramic Dominance of the Immune System in Cardiorenal Syndrome Type I

Physiological organ cross-talk is necessary to maintain equilibrium and homeostasis. Heart and kidney are the essences of this equilibrium. Organ failure in either of these organs can perturb the bidirectional communication between them, impinging this unpleasant vascular and cellular milieu on other distant organs. Cardiorenal syndrome (CRS) type I occurs due to acute deterioration of cardiac function, ultimately causing acute kidney injury (AKI). This syndrome is an intricate condition with neurohormonal and inflammatory aspects. Inflammation creates a vicious circle filled with the innate and adaptive immune systems, pro-inflammatory cytokines, chemokines to actuate hemodynamic compromise in CRS type I patients. Pro-inflammatory cytokines not only aggravate fluid retention and venous congestion but also initiate apoptosis and oxidative stress. The immune response's primary motive is to elicit the heart and kidney to produce cytokines, intensifying the inflammatory process. Despite the possible standard of care, patient mortality, treatment cost, readmissions are extreme in CRS type I, and inflammation certainly has critical inferences warranting future research in humans.


Introduction And Background
"Physiological interaction between organs is necessary for the optimal equilibrium and functioning of the organism" [1]. The human body continuously strives to achieve one critical goal: homeostasis. The human body has an intricate communication system, collectively termed as "organ cross-talk." Irrespective of their distance, the synergy between each organ, tissue, and cell is vital to attain equilibrium and a stable internal environment. This communication is in the form of hormones, proteins, mechanical stimuli, and electrical signals. Altering this cross-talk produces some drastic consequences, adaptive or maladaptive.
Cardiorenal syndromes are such instances where specific maladaptive changes alter the bidirectional link between heart and kidneys. The term cardiorenal syndromes constitute of five subtypes: in type I (acute cardiorenal syndrome), rapid cardiac dysfunction causes acute kidney injury (AKI) while in type II (chronic cardiorenal syndrome), chronic cardiac disorders invoke chronic kidney disease. On the same spectrum, in type III (acute nephrocardiac syndrome) and type IV (chronic nephrocardiac syndrome), AKI and chronic kidney disease surmount to acute heart failure. In type V, nonetheless, a systemic illness elicits simultaneous damage of heart and kidneys [2]. This article focuses on cardiorenal syndrome type I (CRS type I). Etiology of CRS type 1 stems from sudden and abrupt pump failure due to conditions such as cardiogenic shock, acute decompensated heart failure (ADHF), acute coronary syndrome, and cardiac surgery [2][3][4]. In patients with acute decompensated heart failure and acute heart failure, CRS type 1 represents an astonishing 25% to 33% of patients and 27% to 45% of patients in the hospital, respectively [5][6][7][8][9].
Most patients first manifest laboratory evidence of AKI -an increase in serum creatinine greater than 0.3 mg/dL -and gradually reveal symptoms of kidney dysfunction three to five days after admission [10][11][12]. Although AKI is an independent predictor of mortality, it also has significant implications for prognosis, treatment cost, hospitalization duration, readmissions, cardiovascular events, and rapid progression to chronic kidney disease in CRS type I patients [12][13][14].
As the disease evolves, underlying pathology holds the key to unravel promising therapeutic and diagnostic benefits. Like its counterparts, the pathophysiology of CRS type I is multifactorial. There are hemodynamic mechanisms -arterial underfilling, decreased cardiac output, increased venous congestion, hyponatremia, and non-hemodynamic mechanismsactivation of the sympathetic nervous system and renin-angiotensin-aldosterone-system (RAAS) including the uncontrolled formation of reactive oxygen species (ROS) and nitric oxide [15][16][17]. One of the most speculated non-hemodynamic mechanisms of CRS type I is the immune system.
The immune response is a powerful defense system adapted by the human body that has drastic repercussions if gone rogue. A savior and savage, immune system orchestrates organ healing and damage mediated by many components [18]. The normal immune response occurs with antigen recognition/presentation, activation of the complement and innate/ adaptive immune systems, and finally, resolution of the response.
Interestingly, studies have shown that the function of the immune system is skewed in CRS type I partly because of improper inflammatory stimulation and inhibition [4]. Recent evidence shows that patients with severe heart failure and AKI demonstrate high pro-inflammatory cytokines, chemokine up-regulation, neutrophil migration and extravasation, toll-like receptor expression, and unregulated apoptosis leading to oxidative stress [4,19]. In CRS type I, the immune response induces a high-pressure system, fabricates mechanical stress in the vasculature, and promotes additional inflammation [20]. Numerous researches are underway to elaborate on the influence of the immune system in CRS type I, but the disease's complex nature poses a significant limitation.
Recent studies analyzed the overzealous immune system in CRS type I, and how it evokes multiple organ damage. Nevertheless, a few crucial aspects remain in question: Does the immune system govern other etiologic factors in CRS type I? What triggers the immune system in CRS type I? Is immune response the culprit for patient deterioration and high mortality? Will there be any therapeutic benefit from immunomodulation? This review primarily centers on immune system dominance over CRS type I pathogenesis.

Review Discussion
CRS type I is characterized by a multifactorial etiology; however, there is a causal relationship between the factors that promote functional deterioration of the heart and kidney. Changes at the cellular level are fundamental for detrimental tissue remodeling and aberrant organ crosstalk. As shown in Figure 1, inflammation instigates an environment to advance these microscopic changes through its integral units-cells, cytokines, and toll-like receptors (TLRs) [4]. These components mediate the hemodynamic abnormalities of CRS type I. Fluid reabsorption is a strictly controlled process in the pulmonary interstitium, and immune activation interferes with the reabsorption process causing fluid overload in the lungs [21,22]. Inflammation creates a framework for third spacing that contributes to many of the hemodynamic abnormalities in the kidney. A few of the underlying mechanisms are insufficient renal perfusion with a subsequent decrease in glomerular filtration rate (GFR), ischemic damage to the tubular epithelium, and peritubular edema [4].

FIGURE 1: Various inflammatory components instrumental in
the hemodynamic pathophysiology of cardiorenal syndrome (CRS) type I Inflammation superimposes itself on CRS type I and plays a pivotal role in the pathophysiology of the disease. There are four forms of CRS: in type I and II, recent cardiac injury incites AKI and chronic kidney disease. However, in types III and IV, acute exacerbation of chronic cardiac disease promotes AKI and the sudden worsening of chronic kidney disease [4]. Excluding the first subtype, the remaining three subtypes are acute on chronic decompensation of heart or kidney disease. A noteworthy characteristic of chronic diseases is a subtle yet concealed and active immune response. Hence, when CRS type I manifests symptomatically, a formerly well established inflammatory activation gets magnified and sets in stone a series of events, including hemodynamic consequences that increase mortality in these patients.

Innate Immune System
The first line of defense from foreign antigens is the innate immune system. Cells of the innate immune system are perpetually circulating in the blood monitoring for any signs of insults in the organ systems. Nevertheless, during chronic illnesses, tissue injury releases ROS and reactive nitrogen species (RNS) along with mitochondrial products provoking the inflammatory response [5]. In terms of CRS type I and as Figure 2 illustrates, neutrophils, dendritic cells (DCs), monocytes/macrophages are integral to the dysfunctional immune response. Notably, after an ischemia-reperfusion injury, neutrophils infiltrate tissues, produce harmful proteases, ROS, and myeloperoxidase (MPO) enzyme debilitating organ function [23,24]. Table 1

Pro-inflammatory and Proapoptotic Factors
Inflammatory cytokines in the plasma of CRS patients induce the production of more cytokines leading to unregulated apoptosis. ACE-angiotensin-converting enzyme, AKI-acute kidney injury, IL-interleukin, TLR-toll-like receptors, TNF-tumor necrosis factor, GM-CSF-granulocyte/monocyte-colony stimulating factor, G-CSF-granulocyte-colony stimulating factor.
TLRs induce activation of the innate immune response. They are transmembrane proteins located on the plasma membrane of leukocytes and lymphocytes cardinal for mounting an immune response. Ten subtypes of TLRs dimerize with each other to recognize pathogenassociated molecular patterns (PAMPs) traversing through our bodies, depicted in Figure 2. These receptors create a functional change in the immune cells activating them to secrete cytokines (IL-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha) and chemokines (keratinocyte chemoattractant-1 and monocyte chemoattractant protein-1) [25]. During CRS type I and especially AKI, TLRs play a critical role in influencing inflammatory activation and poor bidirectional communication. Studies have shown that TLRs are involved in various cardiac pathologies, such as acute myocardial infarction, cardiac failure, ischemic myocardial injury, and myocardial dysfunction [26][27][28].

FIGURE 2: Mechanisms that activate toll-like receptors (TLRs)
and their impact in cardiorenal syndrome (CRS) type I pathophysiology.
1. Tissue trauma releases products called endogenous ligands that stimulate TLRs. This pathologic trigger is the earliest immune response in AKI injury that sets a cascade of events in motion, which eventually causes massive tissue damage, 2. Amplification of pro-inflammatory cytokines occurs through translocation of transcription factor nuclear factor-kappa B to the nucleus, 3. Sustained TLR activation and inflammatory response leads to apoptosis of renal tubular epithelium, 4. TLRs fuel further cytokine release from neutrophils, monocyte/macrophages, neutrophils, and natural killer cells, resulting in the adaptive immune system activation.
Virzì et al. discuss the aftermath in AKI after inducing the TLR pathway; Figure 2 reveals the critical events related to TLRs activation [18]. Similarly, Clementi and colleagues mentioned that TLRs incite innate and adaptive immune systems, coordinating the deleterious cardiorenal cross-talk [1]. Allam et al. defined another perspective for TLR signaling where histones released from dying tubular epithelium initiate cytokine production and exacerbate kidney injury [29]. These studies suggest that TLRs are essential components of immunity and serve as bridges between innate and adaptive immune systems. Furthermore, inflammation is one of the earliest responses to tissue injury that damages the bidirectional communication in CRS type I and sets the platform for ensuing pathogenesis.
DCs are antigen-presenting cells (APC) of the innate immune system that provoke adaptive immune cells. As noted in Figure 2, they depend on TLRs for maturation and always scrutinize for antigens in many tissues. These cells interact with other subtypes using CD40-CD40 ligand and produce many pro-inflammatory substances, including interleukin (IL)-12, IL-6, TNFalpha, and monocyte chemoattractant protein-1 [30,31]. Clementi et al. elucidated the vital role of renal dendritic cells in the inflammatory response and, after maturation, increase MHC II expression levels and costimulatory molecules [1]. Additionally, Virzì et al. emphasized that DCs maturation and antigen presentation regulates CD4+ and CD8+ T lymphocyte function and proliferation [5]. In other articles, however, Virzì and colleagues also shed light on the unclear contribution of DCs in AKI, including their part in the pathophysiology of CRS type I [18,32]. The majority of the data regarding DCs in heart and kidney illnesses arises from murine models where research-induced ischemic-reperfusion injury mimics in vivo effects [33,34].
Virzì and Clementi extrapolated their ideas about the role of dendritic cells in CRS type I from mouse models. Since these researchers chronicled this emerging evidence of DCs in CRS type I, there has been no further research or clinical trials to document the effects of DCs in CRS dysfunction. Although animal studies cannot be applied to humans precisely, these studies prove that inflammatory cells are principal for the dysfunction associated with cardiorenal syndromes, warranting future research in patients.
The monocyte/macrophage system is another potent immune regulator. They produce cytokines that enhance the immune response and function as APCs to the B and T lymphocytes.
Notably, in heart failure, monocytes are the primary cells for cytokine generation and are also responsible for most of the inflammatory process in heart diseases [35][36][37]. Concerning CRS type I, there are dual points of observation for monocytes. Virzì et al., in their review, acknowledged the presence of monocytes/macrophages in myocardial pathologies; however, they also asserted the uncertain contribution of these cells in repair or damage of the myocardium [5].
Additionally, while the in vitro study led by Pastori et al. supported the pro-inflammatory effect of monocytes, they also endorsed the theory of monocyte apoptosis from cytokine laced plasma of CRS type I patients [38]. Specifically, Clementi et al. also stressed the significance of high inflammatory levels associated with acute heart failure caused monocytes' death and oxidative stress [1]. Even though in vitro studies are the weakest evidence, they laid the groundwork to enunciate the vicious milieu created by the immune system's components.

Provocation of Humoral Signaling and Its Repercussions
This moiety of the immune system includes water-soluble mediators that principally strive to reinforce initial immune response. Standard humoral signaling components include cytokines, chemokines, interferons, and growth factors. Cytokines such as interleukins establish powerful communication strategies between white blood cells while chemokines facilitate chemotaxis, especially for neutrophils, and interferons have antiviral properties [5]. The continuous presence of these mediators magnifies immune response, precipitates inter/intracellular changes, deteriorates organ function, and impairs organ cross-talk [5].

IL-interleukin
Various pathological aspects in CRS type I govern cytokine production, as depicted in Figure 3.
Virzì et al. stressed that the release of humoral factors from damaged cells supervises TLRs activation and increases cytokine generation-TNF-alpha, IL-1, IL-4, IL-6, IL-13, and IL-17, which are fatal in cardiac critical care units and instigate organ damage in CRS type I [18]. At the same time, Clementi et al. discussed that venous congestion in CRS type I fosters cytokine release, crippling renal function [1]. Furthermore, Colombo et al. hinted at the prospect of sodium and water retention, which aggravates fluid overload, congestion, and inflammatory cytokine production [20].  [20]. Ronco et al. elaborated on this idea and ascertained that low intestinal perfusion in CRS type I and heart failure liberates LPS promoting IL-1, IL-6, and TNF-alpha generation [4]. These reviews validate the ideology where multiple pathways exist for inflammation to debilitate organ function and impair the physiological equilibrium. Therefore, targeting one mechanism or organ system does not compensate for the systemic imbalance.
Humoral mediation proves that inflammation not only disturbs communication between organs but also influences metabolism in CRS type I. Figure 4 demonstrates cytokine impact on multiple cells and on homeostasis. Clementi and colleagues described the inverse relation between IL-6 and hemoglobin; pro-inflammatory cytokines cause anemia by bone marrow suppression, erythropoietin receptor down-regulation, red blood cell precursors destruction, and iron sequestration [1]. Additionally, they noted the interrelation between clotting and inflammation; immune response damages renal vessels and activates platelets, resulting in additional cytokine and chemokine production [1]. In another study, Colombo et al. explained the cardio depressant actions of TNF-alpha through increased nitric oxide [20]. Ronco and colleagues emphasized this concept of cytokine and TLRs' role in diminishing myocardial excitability, altering resting membrane potential, modulating substrate metabolism, and responding to the sympathetic nervous system [4]. Moreover, Colombo et al. delineated the vascular abnormalities of inflammation, such as immune system induced arterial stiffness and endothelial permeability [20]. All these reviews remark on various neurohormonal effects of inflammation, and therefore, it is the principal element mediating the pathogenesis of CRS type I. Apoptosis is a highly regulated, essential physiologic process. Cell death is dependent on timing, and just like inflammation, it can create havoc if stimulated inappropriately. Two apoptosis pathways are intrinsic pathways that result from disturbance to intracellular homeostasis, and the extrinsic pathway results from the coupling of death receptors on the plasma membrane [18]. Virzì et al. deciphered that TLR stimulation instigates caspases to initiate pathological apoptosis of renal tubular epithelial cells [18]. In another article, Virzì and colleagues affirmed that low perfusion and hypoxia evoked cellular metabolism changes, ultimately causing cell death [39].
Pro-inflammatory cytokines have a dual purpose where they provoke other immune cells to produce additional inflammatory markers, creating an environment for cell death and altering organ fate. Virzì et al. incubated monocytes with CRS type I plasma and identified a two-fold increase in caspase-8 levels, a three-fold surge in IL-6, and a ten-fold hike in TNF-alpha levels [40]. Likewise, Pastori et al. analyzed this theory in their in vitro study, where they incubated monocytes and renal tubular epithelial cells in CRS type I plasma. They found high IL-6, IL-18, and TNF-alpha levels that increased humoral mediators and caspase 8 and 3 levels in monocytes, and also discerned that CRS type I plasma initiated dual apoptotic pathways [38,41].
In vitro studies justify the notion that inflammation alters organ destiny compared to other compensatory mechanisms. These studies also create a compelling foundation for future observational studies or clinical trials targeting the immune system as a treatment strategy.

Oxidative Stress
Oxidative stress and inflammation are intertwined, and their clinical ramifications are a subject of interest in the medical literature. A delicate equilibrium exists between essential and excessive amounts of an element. Notably, every tissue needs a certain amount of oxidative species to protect itself, while excessive amounts can cause dysfunction, injury, and organ failure [5,42]. An ongoing inflammatory process in CRS type I renders the heart and kidney incapable of controlling oxidative stress [5]. Similar to multiple humoral signaling pathways, there are different mechanisms to bring about oxidative stress in CRS type I.  RAS-renin-angiotensin system, SNS-sympathetic nervous system, ESRD-end stage renal disease, MPO-myeloperoxidase Lullo and companions drew attention to significant elevations in ROS, RNS, IL-6 levels, and MPO, which generates ROS through hydrogen peroxide and nitrogen dioxide [2,42,43]. This hypothesis was endorsed by Virzì et al. when they observed higher MPO levels, an enzyme present in neutrophil granules, in CRS type I plasma [39]. Their findings also confirmed a strong correlation between oxidative stress, immune response, IL-6, and IL-18 [39].
Virzì et al. [42], organized another in vitro study and presented five fundamental points on oxidative stress: 1. There was a dramatic rise in ROS and RNS species in CRS type I plasma compared to acute heart failure patients, 2. Hydrogen peroxide and nitric oxide augment IL-6 levels in CRS type I patients, 3. In CRS type I, inflammation reduces the metabolism of free fatty acids decreasing myocardial ATP levels, increasing glycolysis, and enhancing ROS, 4. ROS disturbs cardiomyocyte contractility, calcium processing, and ion transport affecting cardiac and renal function, 5. Diabetes was a strong risk factor for oxidative stress as hyperglycemia substitutes other pathways for glucose metabolism.
Furthermore, Bongartz stressed that oxidative stress provokes IL-6, IL-1, and TNF-alpha, and hinders renal compensatory mechanisms [16]. Another take on ROS generation is iron, and McCullough put forward this initiative in his review. He rationalized that unstable iron converts into hydroxyl radicals, which result in cellular dysfunction and apoptosis [13]. All these studies on oxidative stress corroborate the theory inflammation has a spectrum of molecular manifestations that depress heart and kidney function in CRS type I. These disturbances clinically deteriorate patients making them refractory to treatment.

Biomarkers
In chronic diseases, biomarkers are crucial elements. Their rising levels indicate occult pathologies before apparent evidence of symptoms. In CRS, these markers indicate heart and renal dysfunction and anticipate renal injury in cardiac disease [44]. Additionally, they predict prognosis, assess treatment efficacy, and aid in treatment strategy [44]. Inflammatory biomarkers are the earliest markers to spike; however, clinicians do not prefer to utilize them.  Fu et al. [44], enlightened biomarkers function in their review. They focused on inflammatory and non-inflammatory markers, but for this review, we shall solely enumerate on inflammatory markers in CRS, as seen in Figure 5. Cardiac inflammatory markers include: 1. MPO-released by neutrophils and monocytes, predicts disease severity in acute heart failure and kidney disease, 2. Suppression of tumorigenicity 2 (ST2)-a member of the IL-1 family, is specific for the prognosis of heart failure with kidney malfunction, 3. Procalcitonin-usually elevated after bacterial infection, but also assess for readmissions in heart failure. Renal inflammatory biomarkers include: 1. Neutrophil gelatinase-associated lipocalin (NGAL)-increases in ischemic AKI and anticipates worsening renal failure, 2. IL-18-a marker of blood vessel stiffness that exacerbates kidney injury and foresees mortality in systolic dysfunction. Figure 5 represents an overview of cardiac and renal inflammatory markers.

FIGURE 5: Inflammatory cardiac and renal biomarkers during acute heart failure and acute kidney injury (AKI).
MPO-myeloperoxidase, NGAL-neutrophil gelatinase-associated lipocalin, IL-interleukin, ST2suppression of tumorigenicity 2 Moreover, McCullough elaborated on NGAL, IL-18, and catalytic iron in CRS [13]. As Figure 5 also demonstrates, catalytic iron is the root of the lethal hydroxyl radical and rises before serum troponin in acute coronary syndromes. NGAL or siderocalin, the first renal marker to be detected in blood and urine after AKI, is a scavenger of catalytic iron limiting oxidative stress. IL-18 increases 48 hours before creatinine and has an area under the operating curve of >90% for sensitivity and specificity in ischemic AKI. Virzì and assistants in their in vitro study emphasized the importance of high NGAL levels in CRS type I patients on the third day of admission [39]. Similarly, Ronco et al. prioritized NGAL because one urinary NGAL measurement in AKI patients renders a sensitivity of 90% and specificity of 99% [6].
In the medical literature, most inflammatory markers like C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) are non-specific markers of inflammation in chronic diseases. Nonetheless, these studies stress on inflammatory biomarkers that specifically pertain to cardiac or renal damage. Compared to non-inflammatory markers, NGAL and IL-18's statistics validate their accuracy in CRS.

Non-Immune Cells With Inflammatory Profile
In CRS type I, two cell lines succumb to immune attack and gradually change their course: endothelial cells (EC) and renal tubular epithelium. Endothelial cells are the medium between blood and tissues controlling vascular, inflammatory, and coagulation stability [32]. Vascular dysfunction emanates with endothelial remodeling that affects their function and the organs they serve. On the other hand, renal tubular epithelium, delicate tissue of the kidney, has different coping mechanisms that feed-forward into the inflammatory response and subsequently loses its structure and function [45]. CD40 serves a dual purpose, promoting inflammatory ROS and anti-inflammatory heme oxygenase-1. Finding the balance between these two effects has a therapeutic purpose in inflammatory renal disease. Clementi and colleagues, postulated endothelial transformation effects on the heart and kidney. In AKI, endothelial injury boosts inflammation, thrombosis, and vasoconstriction while in heart failure, it influences afterload and preload [1]. Virzì et al., in their review, analyzed the cytokine-induced accumulation of MHC class I and adhesion molecules-ICAM-1, ICAM-2, VCAM-1, E-selectin, P-selectin on ECs that function as unconventional APCs [32]. Colombo and companions further clarified TNF-alpha and IL-1 beta as the primary cytokines that actuate cell adhesion molecules on endothelium and also diminish nitric oxide-mediated vasodilation [20]. Vasoconstriction compromises hemodynamics of the heart and kidneys, worsening venous congestion that stimulates endothelium to produce additional cytokines [20].
On the contrary, tubular epithelium alters cell surface molecules and stimulatory pathways to withstand inflammatory stress. As noted by Virzì et al., endothelial permeability opens the gate for immune cell invasion into the renal interstitium, causing epigenetic and DNA changes [18]. As manifested by Laxmanan et al. in their in vitro study, epigenetic alterations encourage the cells to express more inflammatory receptors like CD40/CD40-ligand [46]. Inflammation recruits other cells into the immune response, thereby creating a vicious circle. These recent studies prop up the feed-forward mechanism, magnifying the anomalous type I cardiorenal cross-talk.
We were not able to find any randomized controlled trials and observational studies relevant to this topic. Therefore, we could not establish causal relationships delineating risk factors and inflammation-related incidence and prevalence. General questions that could guide future research include: 1. Could the combination testing of inflammatory biomarkers confirm the dominance of inflammation? 2. Can these markers also be used to categorize the severity profile of CRS type I patients? 3. Does the inflammatory remodeling of cardiac and renal parenchyma guide future research to define diagnostic and therapeutic protocols? 4. Should patients with cardiac abnormalities have a regular checkup of inflammatory markers? 5. What is the specific treatment for CRS type I? 6. What are the treatment options to control the inflammatory process in CRS type I patients?

Limitations
Unfortunately, most of the evidence in this paper comes from other reviews, animal studies, and in vitro studies from patients in Italy. There were few reviews from the United States, but the data for in vitro studies came from CRS type I patients in Italy. Pertinent data from in vitro studies is inapplicable to clinical practice due to limited patients and high bias. We formulated only mere associations about inflammatory control on CRS type I pathology. Another limitation of this paper is the lack of human studies to establish certain prognostic factors like NGAL, ST2, and IL-18 as risk factors in CRS type I patients.

Conclusions
CRS type I challenges clinicians and complicates patient recovery. Neurohormonal mechanisms have been the interest of diagnosis and treatment in clinical care, but the disease's mortality and morbidity are sorely high, indicating a hidden medium playing along. Inflammation governs the hemodynamics, end-organ dysfunction, and severity of CRS type I. AKI is a dreadful aspect of this disease extending hospitalization periods, cost of care, and risk of adverse events. A hyperactive immune system sabotages cardiorenal cross-talk and sets the ground for injurious cellular remodeling. In CRS type I, inflammation facilitates this damage through its components, altering homeostasis and metabolism, breaking barriers, and disintegrating communication. Since inflammation can modulate heart and kidneys' identity, a swift change in the diagnostic and therapeutic approach of CRS type I is necessary. In summary, the high prevalence of this syndrome entails future human clinical trials not only to catch the disease at an appropriate time but also to discover new treatment options to curb inflammation.