Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

Abstract

Cardiorenal syndrome (CRS) is a multi‐organ disease, encompassing heart, kidney and vascular system dysfunction. CRS is a worldwide problem, with high morbidity, mortality, and inflicts a significant burden on the health care system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi‐organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi‐organ transplantation and innovative dialysis modalities have been considered but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrants further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uraemic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

Abbreviations

AKI

acute kidney injury

Ang II

angiotensin II

ANP

atrial natriuretic peptide

BNP

b‐type natriuretic peptide

Cer

ceramide

CKD

chronic kidney disease

CNP

C‐type natriuretic peptide

CRS

cardiorenal syndrome

CV

cardiovascular

CVD

cardiovascular disease

Des

dihydroceramide desaturase

dhCer

dihydroceramide

ESRD

end‐stage renal disease

HF

heart failure

HKTx

heart and kidney transplantation

HTx

heart transplantation

KTx

kidney transplantation

LVAD

left ventricular assist device

LVH

left ventricular hypertrophy

MARCE

major adverse cardiovascular renal event

MI

myocardial infarction

miRNA

microRNA

NPs

natriuretic peptides

PBUT

protein‐bound uraemic toxin

RAAS

renin, angiotensin, aldosterone system

S1P

sphingosine 1 phosphate

SPHK1

sphingosine kinase 1

SL

sphingolipid

SGLT2

sodium glucose transporter 2

SNS

sympathetic nervous system

sST2

soluble suppression of tumourigenicity 2

TIMPs

tissue inhibitors of MMPs

1. INTRODUCTION

The cardiovascular (CV), renal and vasculo‐endothelial systems work closely to maintain vascular tone, blood volume and haemodynamic stability and are therefore inevitably interrelated in diseased states. The bidirectional relationship of the heart and the kidney, whereby the failure of one organ escalates or causes pathological changes in the other, is now widely known as ‘cardiorenal syndrome’ (CRS). It is indubitable that cardiorenal syndrome must occur in the co‐presence of vascular dysfunction, most notably due to the hypertension caused by volume overload and venous congestion. Currently, no evidence‐based treatment guidelines exist for cardiorenal syndrome and thus treatment is largely pragmatic.

This review of cardiorenal syndrome will discuss its definition, classifications and pathophysiology. Challenges in current diagnostic and therapeutic management options, as well as novel developments in recent years will also be outlined. Finally, uraemic toxin accumulation and the role of the unconventional sphingolipids (SLs) in the cardiorenal setting will be highlighted.

2. OVERVIEW OF CARDIORENAL SYNDROME

2.1. Definition

The heart–kidney–vasculature crosstalk consists of complex biological processes, wherein these organs interact synergistically to maintain major physiological functions. Cardiorenal syndrome (also known as renocardiac syndrome) is the principal term involving either heart or kidney dysfunction that is detrimental to the other organ, ultimately leading to the failure of both. The deleterious impact of one organ on the other may be direct or indirect and comprises an intricate feedback system involving regulatory hormones, inflammatory molecules and oxidative stress responses (Figure 1).

FIGURE 1.

Organ crosstalk in cardiorenal syndrome pathophysiology. RAAS and SNS overactivation and natriuretic peptide system (NPS) derangement initiates phenotypic and other molecular changes in the heart, kidney and vasculature. These changes cause organ dysfunction, leading to systemic implications which in turn affect other organs due to bidirectionality

2.2. Classification

Cardiovascular co‐morbid illnesses are the predominant cause of death among people with chronic kidney disease (CKD) in a large part of the world, including Australia, Asia, Europe and North America (Shiba & Shimokawa, 2011). Nearly 75% of end‐stage renal disease (ESRD) patients have left ventricular hypertrophy (LVH), 40% of whom have coronary artery disease (Bongartz, Cramer, Doevendans, Joles, & Braam, 2005). Around 20% of heart failure (HF) patients have moderate to severe renal dysfunction and more than 60% at least have mild renal dysfunction (Liu, 2008). The incidence of chronic heart failure is also 15 times higher in chronic kidney disease patients than healthy individuals (Silverberg, Wexler, Blum, Schwartz, & Iaina, 2004). Furthermore, dialysis is associated with increased annual mortality rate of more than 20%, half of which is cardiovascular related (Liu et al., 2012).

Based on the Acute Dialysis Quality Initiative consensus, cardiorenal syndrome can be classified into five types based on, the primary organ which drives the disease crosstalk (cardiorenal or renocardiac), the disease onset and the presence of systemic disease (Table 1). Of note, this classification does not exclude a patient to a certain type of cardiorenal syndrome throughout the disease course. Thus, there is a possibility to transition between different cardiorenal syndrome types, which magnifies the complexity of the syndrome. It must also be highlighted that cardiorenal syndrome epidemiological figures (e.g., incidence and prevalence) often stand with large number variations attributed to the different definitions used. For example, while nephrologists use the term acute kidney injury (AKI), cardiologists refer to the condition as worsening renal failure (Ronco et al., 2010). The concept of major adverse cardiovascular renal event (MARCE) is useful to help researchers further understand the prevalence of cardiorenal syndrome and its utilization as an endpoint in contemporary trials is highly encouraged. The definition of MARCE varies from study to study but generally entails a combination of cardiovascular and renal parameters to assess cardiorenal endpoints.

TABLE 1.

Cardiorenal syndrome overview

CRS category	Disease onset and direction	Primary disease example	Secondary disease example	Epidemiology
Type 1	Acute, cardiorenal	Right ventricular failure, acute HF, acute coronary syndrome and cardiogenic shock	AKI and renal ischaemia	50% of alcases
Type 2	Chronic, cardiorenal	Chronic HF	CKD and ESRD	20% of all CRS cases
Type 3	Acute, renocardiac	AKI and renal ischaemia	Arrhythmia, acute HF and cardiac ischaemia	Poorly defined
Type 4	Chronic, renocardiac	CKD and ESRD	Chronic HF and diastolic dysfunction	Poorly defined
Type 5	Secondary CRS	Sepsis, cirrhosis and autoimmune diseases	CRS	Poorly defined

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; CRS, cardiorenal syndrome; ESRD, end‐stage renal disease; HF, heart failure.

2.3. Pathophysiology

The mechanisms involved in cardiorenal syndrome progression are multifaceted. Key contributors of cardiorenal syndrome progression encompass neurohormonal, haemodynamic, biochemical, immunological and inflammatory constituents, as well as non‐traditional exogenous causes (Figure 1).

2.3.1. Neurohormonal and sympathetic nervous system pathway interaction

Reduced cardiac output leads to renal hypoperfusion. This in turn induces sodium retention to preserve plasma volume via the activation of the renin–angiotensin–aldosterone system (RAAS). Increased sodium levels cause the narrowing of glomerular arterioles, reducing glomerular filtration rate (GFR). In turn, to maintain GFR vasoconstriction of the efferent arterioles is required to increase glomerular filtration pressure. However, vasoconstriction further decreases renal perfusion and, if prolonged, causes renal injury due to hypoxia. The production of aldosterone also instigates maladaptive sodium reabsorption in renal distal tubules, which leads to volume overload and expansion of extracellular fluid.

Angiotensin II (Ang II), a key neurohormone of RAAS, causes water and sodium retention by increasing the expression of sodium transporters in renal proximal tubule. Ang II also promotes aldosterone production, which acts on mineralocorticoid receptors in the renal distal tubules and collecting ducts to promote sodium retention. Additionally, both Ang II and aldosterone stimulate cardiac fibrosis by stimulating fibroblast growth and collagen synthesis (See, Kompa, Martin, Lewis, & Krum, 2005). Furthermore, cardiac myocytes undergo hypertrophy to compensate for haemodynamic impairment and elevated neurohormone levels (Buglioni & Burnett, 2015).

Sympathetic nervous system (SNS) hyperactivity is a major compensatory mechanism to maintain cardiac output and inotropic support. With progressing chronic kidney disease, SNS is overactivated in response to renal ischaemia, increased Ang II levels and decreased nitric oxide (NO) which results in hypertension, left ventricular hypertrophy (LVH) and left ventricular dilatation (Kumar, Bogle, & Banerjee, 2014). At the molecular level, cardiac myocyte hypertrophy, apoptosis and necrosis linked to ROS production are observed as a direct action of catecholamines (Bongartz et al., 2005). Persistent activation of the myocardial β₁‐adrenoceptors leads to impaired receptor‐signal transduction (Hatamizadeh et al., 2013). Increased SNS activity also induces vasoconstriction and reduces renal blood flow, which triggers the release of renin (Metra, Cotter, Gheorghiade, Dei Cas, & Voors, 2012). Furthermore, sodium transport at the proximal tubules increases due to up‐regulation of apical Na⁺/H⁺ exchanger via β‐adrenoceptor stimulation (Graziani et al., 2014). Antidiuretic hormone (or vasopressin), released via baroreceptor activation or indirectly through the SNS, is another vital hormone that leads to fluid retention (Ronco, Haapio, House, Anavekar, & Bellomo, 2008). Antidiuretic hormone activates the V_1A receptor on vascular smooth muscle cells to cause vasoconstriction and via the V₂ receptors in collecting distal tubules to promote water diffusion from tubular lumen into the interstitium (Graziani et al., 2014).

Increased salt/water retention due to RAAS/SNS activation also leads to increased intra‐abdominal pressure and venous congestion. Venous congestion in the form of increased central venous pressure decreases the pressure gradient across capillary network, reducing perfusion (Kumar, Wettersten, & Garimella, 2019). In the cardiorenal syndrome context, this results in congestion, glomerular dysfunction and compromised natriuresis (Kumar et al., 2019; Rangaswami et al., 2019). Elevated intra‐abdominal pressure also diminishes renal function by reducing GFR and plasma flow (Kumar et al., 2019).

Collectively with the RAAS and SNS, the natriuretic peptide system is also recognized an important neurohumoral system that maintains cardiorenal homeostasis. Specifically, the natriuretic peptide system is composed of four endogenous hormones: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C‐type natriuretic peptide (CNP) and urodilatin (Kuhn, 2016; Lee & Burnett, 2007; von Lueder et al., 2013). ANP and BNP are primarily produced in the heart with urodilatin synthesized in the kidney and these natriuretic peptides (NPs) activate the pGC‐A receptor, while CNP is primarily synthesized in the endothelium and kidney and activates the pGC‐B receptor. Following pGC activation, the second messenger cGMP is produced and elicits widespread beneficial cardiovascular and renal actions including vasodilation, natriuresis, diuresis and inhibition of fibrosis and cardiomyocyte hypertrophy. The natriuretic peptide system, RAAS and SNS are highly integrated systems of which considerable crosstalk exists between them and the natriuretic peptide system is counter‐regulatory to both the RAAS and SNS, which generally work in a cooperative manner. Indeed, the natriuretic peptide system has the ability to inhibit the RAAS and SNS and vice versa (Lee & Burnett, 2007). Thus, the pathophysiology of cardiorenal syndrome has classically been viewed as a consequence of an imbalance between the RAAS and/or SNS and the natriuretic peptide system.

2.3.2. Inflammation

In cardiorenal syndrome, volume overload and venous congestion are two major pathophysiological events leading to inflammation, wherein hyperactivation of RAAS and SNS (predominantly involving Ang II and aldosterone) are the leading instigators. Tissue injury is also known to recruit inflammatory cells, that is, monocytes, and increases cytokine production, most notably IL‐1, IL‐6 and TNF‐α to the damaged area. Physiologically, pro‐inflammatory molecules are needed for the stabilization of an injury site, such as the generation of scar tissues in myocardial infarction (MI), to prevent ventricular rupture. However, long‐term activation can result in pathological fibrosis (Liu et al., 2013) and endothelial impairment (Kumar et al., 2014), aggravating renal vasoconstriction and worsening of heart failure. Elevated IL‐1β levels post‐myocardial infarction were correlated with SNS hyperactivity (Bongartz et al., 2005). Increased renal TNF‐α and IL‐6 expression is linked to the activation of NF‐κB signalling pathway, a major regulator of cellular inflammation.

2.3.3. Oxidative stress

Oxidative stress is a condition of excess oxidant production relative to the stabilizing antioxidants (nitric oxide) (Virzi et al., 2015). It is noteworthy that a low amount of ROS is required for cellular growth, differentiation, adhesion, senescence and apoptotic activities, and this is only possible because of the ROS–‐nitric oxide homeostasis. During ischaemic events such as myocardial infarction, oxygen depletion impedes mitochondrial function causing generation of ROS during reperfusion, but increased ROS may induce cellular apoptosis resulting in compensatory ventricular hypertrophy and fibrosis (Rubattu et al., 2013). In the glomeruli, ROS is known to mediate cellular proliferation and cause glomerular hypertrophy and scarring, disrupting renal function (Gelasco & Raymond, 2006). ROS is also linked to up‐regulation of chemokines and cytokines via NF‐κB activation and thereby inflammation (Virzi et al., 2015). Following myocardial infarction, these mechanisms augment endothelial permeability, mediating kidney injury in the process. Indeed, Type 1 cardiorenal syndrome patients exhibit higher circulating levels of IL‐6 and ROS compared to acute heart failure patients alone (Virzi et al., 2015).

2.3.4. Fibrosis

Fibrosis, in form of extracellular matrix deposition, functions to maintain integrity of an organ after tissue injury (Liu et al., 2012; Rockey, Bell, & Hill, 2015). However, prolonged extracellular matrix accumulation can disturb the mechanical function and electrical conductivity of the heart. Extracellular matrix build‐up can also cause a progressive decline in renal function related to glomerular and tubular scarring. In addition, perivascular fibrosis is commonly observed in cardiac and renal fibrotic disease models and linked to vascular impairment. Therefore, fibrosis has been proposed to be a major contributor in the cardiorenal syndrome context.

Mechanisms underlying fibrosis are well highlighted in the literature, but treatments addressing this pathophysiology remain an unmet clinical need. In general, collagen synthesis and degradation (and thereby extracellular matrix) regulation and dysregulation is fundamental in facilitating physiological and pathological fibrosis. Collagen synthesis is promoted by pathophysiology and tissue injury, while its degradation is driven by matrix metallopeptidases (MMPs) and countered by tissue inhibitors of matrix metallopeptidases (TIMPs). An imbalance in the activity of matrix metallopeptidases and their tissue inhibitors results in pathological fibrosis. These events are also linked to vascular smooth muscle and endothelial cell trans‐differentiation into to a pro‐fibrotic phenotype (i.e. myofibroblasts), which is also well characterized in cardiac and renal fibroblasts (Fan, Takawale, Lee, & Kassiri, 2012; Hewitson, 2012; See et al., 2013). Fibrosis is also mediated by an array of intracellular and extracellular growth factors and cytokines (Liu et al., 2012; Yang et al., 2017). TGF‐β1 is one of the most prominent growth factors involved in extracellular matrix production, proliferation and differentiation, as well as immune modulation (Hundae & McCullough, 2014). Ang II exerts pro‐fibrotic effects through TGF‐β1 activation, and the Ang II–TGF‐β1 interplay is linked to chronic hypertension and myocardial fibrosis (See et al., 2013; Wang et al., 2015). Aldosterone is linked to cardiorenal matrix metallopeptidases and tissue inhibitor of metalloproteinases imbalance via NF‐κB activation and TGF‐β1 actions (Meng, Tang, Li, & Lan, 2015). Recently, more novel fibrosis mediators have been identified, chief among those is soluble suppression of tumourigenicity 2 (interleukin‐1 receptor‐like 1; sST2), a decoy of IL‐33. In chronic conditions, local or neighbouring cells release soluble suppression of tumourigenicity 2, which blocks the physiological binding of IL‐33 to ST2 receptor on the cell membrane and promotes pathological fibrosis and adverse cardiac remodelling (Bayes‐Genis, Gonzalez, & Lupon, 2018). In addition, uraemic toxins, chronic inflammation and metabolic disorders, such as dyslipidaemia are also associated with cardiac, renal and vascular fibrosis (Lekawanvijit, Kompa, Wang, Kelly, & Krum, 2012) with similar RAAS‐ and non‐RAAS‐related mechanisms, as well as deficiencies in natriuretic peptide systems (Sangaralingham et al., 2011), have been proposed to underlie the pathophysiology.

2.3.5. Vascular endothelial system dysfunction

Pressure overload in chronic kidney disease instigates hypertrophy of the arterial wall and increased wall‐to‐lumen ratio. This is signified by increased wall thickness and arterial diameter, specifically due to thickening of the arterial intima and deposition of extracellular matrix (Georgianos, Sarafidis, & Liakopoulos, 2015). These processes result in decreased arterial compliance, which compromises blood flow from the heart to various organ tissues. Diminished elasticity of the artery is the main contributing factor of natriuretic peptide system, myocardial hypoperfusion and eventually chronic heart failure (Georgianos et al., 2015). There is also increased expression of endothelial adhesion molecules, such as vascular and intracellular cell adhesion molecule‐1, which are involved in atherogenic proliferation of vascular smooth muscle cells, inflammation and plaque formation (Liu, Liu, Zhang, Cheng, & Jiang, 2014). Atherosclerosis, in turn, increases the risk of hypertension, left ventricular hypertrophy and decreased coronary perfusion (Sarnak et al., 2003). Decreased coronary perfusion also leads to narrowing of the arterial lumen, which further impairs the myocardium due to hypoxia (Sarnak et al., 2003).

Activation of RAAS also instigates the release of endothelin‐1 by endothelial cells, predominantly under the influence of Ang II. Endothelin‐1 promotes vascular remodelling by increasing inflammatory cell infiltration into the vasculature (Kohan, 2010). Pathological cardiac hypertrophy is also related to increased endothelin‐1 and decreased NO levels (Cohn, Ferrari, & Sharpe, 2000). These events incite cardiac fibroblast proliferation and collagen synthesis, resulting in maladaptive cardiac fibrosis (Cohn et al., 2000). In the kidney, endothelin‐1 is synthesized due to increased expression of cytokines, chemokines, growth factors and ROS leading to renal fibrosis and inflammation (Kohan, 2010).

2.3.6. Anaemia

Anaemia is an independent predictor for mortality in the cardiorenal syndrome setting, with the prevalence reported ranging from 5% to 55% (Rangaswami et al., 2019). Anaemia in the chronic kidney disease–heart failure setting is attributed to the defect in erythropoiesis and depletion of iron bioavailability due to reduced renal function. This leads to ischaemia and peripheral vasodilation and subsequently RAAS‐SNS hyperactivation, volume overload and venous congestion. Additionally, reduction of antioxidant‐containing red blood cells increases oxidative stress in organ tissues, further aggravating insults (Rangaswami et al., 2019). Pathologic outcomes include renal nephron loss and interstitial fibrosis, as well as natriuretic peptide system and ischaemic and necrotic myocardium (Otaki et al., 2014).

2.3.7. Systemic disease

Systemic disease is the underlying cause of secondary cardiorenal syndrome (Type 5). It is difficult to delineate a single pathway due to a plethora of mechanisms involved in the crosstalk of systemic disease and heart and kidney impairment. In general, any systemic or autoimmune disease will result in frequently observed cardiorenal syndrome pathophysiology such as RAAS activation, inflammation and oxidative stress. Sepsis is the most commonly reviewed condition in relation to Type 5 cardiorenal syndrome. Cardiorenal syndrome‐relevant biochemical and clinical profiles of septic patients include increased renal vascular resistance and under‐perfusion, early elevation of pro‐inflammatory molecules, infection‐induced cardiorenal toxicity and abnormal diastolic filling and arrhythmias due to dysfunction in autonomic nervous system (Kotecha, Vallabhajosyula, Coville, & Kashani, 2018; Kumar et al., 2019). Additionally, sepsis management such as intense fluid resuscitation efforts can exacerbate volume overload (McCullough & Ahmad, 2011), posing a clinical challenge.

3. DIAGNOSIS, PROGNOSIS AND TREATMENT OF CARDIORENAL SYNDROME

3.1. Diagnostic and prognostic measures

3.1.1. Cardiac, renal and vascular biomarkers—Which to trust?

Biomarkers are essential in the diagnostic and prognostic aspects of disease management, as well as to monitor patient response to therapy. Traditional cardiac markers such as leukocytosis and C‐reactive protein are non‐specific myocardial markers. In the renal context, serum creatinine and estimated GFR are central in acute kidney injury and chronic kidney disease diagnosis and staging. These markers are supported by clinical familiarity for interpretation and extensive availability but lack accuracy in regard to injury site or disease type. Blood urea nitrogen is associated with heart failure outcomes in healthy populations (Matsue et al., 2017) and is another common marker in renal disease. However, blood urea nitrogen is affected by factors such as protein intake, use of steroids and catabolism process (Sheerin et al., 2014). Early identification of organ damage, such as in the setting of acute kidney injury, can help preserve function and prevent disease progression. Other biomarkers should supplement traditional biomarkers to guide diagnosis and treatment in cardiorenal syndrome patients.

IL‐18, soluble suppression of tumourigenicity 2, kidney injury molecule, cystatin‐C, neutrophil gelatinase‐associated lipocalin and CNP are new, promising and highly specialized biomarkers that are renal site and/or time specific and responsive (Ronco & Di Lullo, 2014). Cystatin‐C also has prognostic value in heart failure mortality (Legrand, Mebazaa, Ronco, & Januzzi, 2014). Soluble suppression of tumourigenicity 2 is released by cardiac myocytes and endothelial cells in inflammation or cardiac dysfunction and is a good predictor of various cardiac function and sensitive to acute kidney injury prognosis in myocardial infarction patients (Fan, Chang, & Chen, 2018). Cardiac troponin is an excellent marker of myocardial injury and can predict cardiovascular and all‐cause mortality in chronic kidney disease and end‐stage renal disease (ESRD) patients (Fu, Zhao, Ye, & Luo, 2018). The cardiac stress peptide BNP is now a popular marker for ventricular impairment that predicts mortality in sepsis and renal replacement therapy (RRT) in acute kidney injury (Buglioni et al., 2015). More recently, urinary CNP has identified as potential biomarker of renal remodelling and injury in cardiorenal disease states such aging, heart failure and acute kidney injury (Chen et al., 2019; Sangaralingham et al., 2011; Zakeri et al., 2013) and has prognostic value with respect to all‐cause mortality and a combined endpoint of heart failure hospitalization and death in acute decompensated heart failure patients (Zakeri et al., 2013). Angiopoietin 2, which influences vascular permeability, is also increased in acute coronary syndrome patients and is a robust predictor of mortality in acute kidney injury patients requiring dialysis (Fan, Chang, & Chen, 2018). Soluble thrombomodulin, an endothelial injury marker, can reliably predict acute kidney injury in myocardial infarction patients together with angiopoietin 2 (Fan et al., 2018). MicroRNA (miRNA) is another potentially useful novel biomarker in the cardiorenal syndrome setting, with unique site‐ and function‐specific profiles in the heart, kidney and vasculature. However, clinical application of miRNA is hampered by a few factors, including the poorly defined use of single versus multiple miRNA markers (signature miRNAs), difficulty of reproducibility due to varying handling and processing methodologies, and complex analysis protocols and thus long turn‐around times (Backes, Meese, & Keller, 2016). Additionally, timing of miRNA dysregulation is poorly defined in cardiorenal and vascular diseases, with most studies (particularly cardiovascular disease [CVD] related) indicating late stage compensation (Huang, Li, Wu, Han, & Li, 2019). Therefore, breakthroughs of robust early‐phase miRNAs for diagnostic and prognostic use in these settings are much awaited.

Overall, given the complex pathophysiology of cardiorenal syndrome, a multi‐marker approach is likely needed to gain a better diagnostic/prognostic profile. New biomarkers are limited by their low availability in the clinic and a lack of universal guidelines for cut‐off values and proper use. Discovery and large clinical trial validations are needed to develop specific biomarkers for cardiorenal syndrome diagnosis and prognosis.

3.1.2. Imaging modalities

Imaging modalities play an important role in cardiorenal syndrome to assess organ structure and function for diagnostic purposes, as well as research. Ultrasonography is a safe, non‐invasive tool to help detect congestive signs, such as increased central venous and pulmonary artery pressure in both chronic kidney disease and cardiovascular disease populations (Ronco & Di Lullo, 2014). Echocardiography is particularly useful to detect left ventricular hypertrophy, ischaemic cardiomyopathy, valvular abnormalities and other cardiac structural pathologies. Renal ultrasound is useful to assess intrarenal haemodynamics, particularly the newly developed contrast‐enhanced ultrasonography (George & Kalantarinia, 2011). In an imaging study, Breidthardt et al. (2015) found that chronic renal parenchymal damage may be the underlying cause of renal impairment in heart failure, not renal hypoperfusion as widely postulated. This is supported by Iida et al. (2016) which showed that intrarenal venous flow, which depends highly on parenchymal integrity, was strongly correlated with right atrial pressure and clinical outcomes of heart failure patients. Altogether, these studies suggest that progressive renal pathophysiology in heart failure begin with increased renal venous congestion, followed by reduced intrarenal parenchymal compliance and eventually parenchymal damage. These studies also highlight the merit of ultrasonography to advance our understanding of cardiorenal syndrome.

MRI is useful to assess ventricular dimensions, function and fibrosis in the heart and GFR, renal blood flow and oxygenation in the kidney. MRI is a reliable alternative to echocardiography in suspected myocarditis or infiltrative disease (George & Kalantarinia, 2011). The new, gadolinium‐free BOLD MRI is advantageous to detect renal hypoxia and correlates well with renal biomarkers in the cardiovascular disease setting but currently lacks clinical application (Grande, Terlizzese, & Iacoviello, 2017). CT is rarely used to evaluate renal function due to contrast‐induced renal toxicity, though it is useful to detect cardio‐embolic sources (Grande et al., 2017; Hur & Choi, 2017). Similarly, coronary angiography is associated with contrast‐induced acute kidney injury (Meinel, De Cecco, Schoepf, & Katzberg, 2014). Although, both CT and MRI allow extensive visualization of vessel lumen and wall (Tuna & Tatli, 2014). Nuclear imaging, such as PET, provides additional structural information to CT and site‐specific localization of disease (George & Kalantarinia, 2011; Grande et al., 2017). Though its utilization is wide in cardiorenal research, PET is not often used in the clinic (Grande et al., 2017).

3.1.3. External and implanted devices

Bioelectrical devices can help assess fluid status. A number of studies have demonstrated a relationship between reduced impedance values (i.e. volume overload) and adverse events, including rehospitalization and mortality (Ronco & Di Lullo, 2014). Bioimpedance devices jointly with BNP have shown promise in guiding discharge timing and the prevention of diuretic‐induced acute kidney injury in heart failure patients and as hydration status indicator in haemodialysis patients (Yilmaz et al., 2014). Intra‐abdominal pressure is another important clinical parameter in cardiorenal syndrome, which is related to venous congestion. Intra‐abdominal pressure measurements can be obtained via a transducer‐equipped urinary bladder catheter (Ronco & Di Lullo, 2014).

Implantable devices to measure fluid status also exist, but such devices have yet to be evaluated in cardiorenal syndrome setting. One study showed the use of OptiVol (Medtronic), an intrathoracic impedance monitor, to improve heart failure prognosis, but had little effect on hospital admissions and outpatient visits despite utilization of visit alerts (Vamos et al., 2018). Pulmonary artery catheterization is no longer used clinically as it had demonstrated no benefit on mortality and rehospitalization in acute heart failure (Binanay et al., 2005), but it might be useful to detect and treat subclinical congestion (Rangaswami et al., 2019). Although cardiorenal haemodynamic measurements by invasive catheterization may be confounded by intra‐abdominal pressure or ascites (Rangaswami et al., 2019), thus, results must be interpreted with caution.

3.2. Management

3.2.1. Managing contradictory effect of multi‐organ drug interactions

Decongestive measures are essential to modulate volume overload and increased intra‐abdominal pressure as well as providing symptomatic relief. Diuretics remain the primary agent to correct volume overload, especially in cardiorenal syndrome of cardiac origin (Rubinstein & Sanford, 2019). Cardiorenal syndrome patients may require a much higher dose due to diuretic resistance (short‐term tolerance) (Koniari, Nikolaou, Paraskevaidis, & Parissis, 2010), which is common especially in those with Type 1 cardiorenal syndrome (Cohen, 2014). High‐dose diuretics certainly leads to a greater diuresis and decongestion effect but may cause transient renal impairment (Krishnamoorthy & Felker, 2014).

Inotropics are useful to treat hypotension and low cardiac output. For patients showing congestive signs without severe cardiac output reduction, inotropics are potentially pro‐arrhythmic and confer no survival benefit and should be avoided as per American College of Cardiology/American Heart Association heart failure guidelines (Cowger & Radjef, 2018). Dobutamine and milrinone improve cardiac index in proportion with renal blood flow, though their effect on mortality or clinical outcomes is unclear (Kim, 2013; Klein et al., 2008). Low‐dose dopamine–diuretic combination, as well as levosimendan (a PDE inhibitor), has shown conflicting results in various trials in terms of renal functional improvement (Giamouzis et al., 2010; Kim, 2013; Mebazaa et al., 2007). β‐adrenoceptor antagonists (blockers) may be useful to improve forward flow. Adjunct use of β‐antagonists (metoprolol, bisoprolol and nebivolol in heart failure and carvedilol in end‐stage renal disease patients) is renoprotective and associated with reduced hospitalization and mortality (Hart & Bakris, 2007; Rangaswami et al., 2019). Of note, β‐antagonists are contraindicated in decompensated heart failure due to potential side effects of hypotension and bradycardia. However, their withdrawal is associated with mortality (Prins, Neill, Tyler, Eckman, & Duval, 2015) and should be continued if deemed possible.

RAAS inhibition is one of the primary pharmacological therapies in heart failure and chronic kidney disease. Angiotensin II (AT₂) receptor antagonists and angiotensin converting enzyme inhibitors (ACE‐Is) are known to cause transient and reversible worsening of renal function; thus patient monitoring is necessary. The use of RAAS inhibitors is recommended after volume depletion has been addressed, starting at the lowest dose, while avoiding nonsteroidal anti‐inflammatory drugs (Takahama & Kitakaze, 2017). Of note, trials have shown reduced mortality rate by RAAS inhibition with higher dose only and whether the same outcome can be expected with lower dosage is uncertain (Rubinstein & Sanford, 2019). RAAS inhibitors may also be limited by hyperkalaemia, which can lead to detrimental arrhythmias (Clegg, Cody, & Palmer, 2017). Recently, a superior dual‐acting angiotensin receptor antagonists and neprilysin inhibitor, sacubitril–valsartan, was approved for use in heart failure with satisfactory renal tolerance (Damman et al., 2018). The addition of neprilysin inhibition provides modulatory effect on endogenous vasoactive peptides such as natriuretic peptides and bradykinin, resulting in beneficial remodelling and vasodilation (D'Elia et al., 2017). Given the therapeutic success of sacubitril–valsartan via natriuretic peptide augmentation, designer natriuretic peptide analogues such as MANP (also known as ZD100) (McKie et al., 2014), CRRL‐269 (Chen, Harty, et al., 2019), NPA7 (Meems et al., 2019), C53 (Chen et al., 2019) or cenderitide (also known as CD‐NP) (Kawakami et al., 2018) may offer an alternative, yet complementary, therapeutic strategy for cardiorenal syndrome and are currently under advanced preclinical and clinical development. Empagliflozin and canagliflozin, sodium‐glucose cotransporter 2 (SGLT2) inhibitors, demonstrated beneficial cardiovascular and all‐cause mortality and hospitalization in diabetic patients with high cardiovascular risk (Zinman et al., 2015). More recently, another SGLT2 inhibitor dapagliflozin was shown to reduce heart failure hospitalization and cardiovascular death when added to standard care in heart failure patients with normal to mild impairment in renal function, regardless of diabetic status (McMurray et al., 2019). The suitability of these novel classes of drugs in the cardiorenal syndrome setting is of high clinical interest.

3.2.2. Clinical devices to aid therapy

Volume expansion is a critical pathophysiology in cardiorenal syndrome that needs constant monitoring. There are a number of commercial blood volume devices available. Unfortunately, these devices have not been investigated in the context of cardiorenal syndrome. The CardioMEMS, an implantable haemodynamic sensor, demonstrated beneficial outcomes in heart failure patients with up to Stage 2 chronic kidney disease only (Givertz et al., 2017). Ultrafiltration, a mechanical fluid removal system, is linked with greater fluid removal and symptomatic relief (Marana, Marenzi, & Kazory, 2014). However, ultrafiltration is associated with reduced renal function with unknown effect on mortality and other hard endpoints (Marana et al., 2014). Furthermore, ultrafiltration systems for dialysis patients require highly trained staff to operate (Balter, Artemyev, & Zabetakis, 2015). Portable, user‐friendly ultrafiltration devices are constantly being developed and may be of use for suitable patients in the future.

Dialysis remains the most common option for renal replacement therapy (RRT) in end‐stage renal disease patients. A few small studies have been conducted in cardiorenal syndrome patients and are worth noting. Haemodialysis appears beneficial in terms of reducing hospital readmission, length of hospital stay and survival when combined with ultrafiltration for terminal Type 2 cardiorenal syndrome patients (Leskovar, Furlan, Poznic, Potisek, & Adamlje, 2017). Peritoneal dialysis appears to be safe and effective for fluid control in Type 1 (Ponce, Goes, Oliveira, & Balbi, 2017) and Type 2 cardiorenal syndrome patients (Shao et al., 2018); however, its benefit on survival is unclear. Whether continuous or intermittent dialysis or RRT altogether is suitable may depend on disease onset. For instance, continuous RRT as a rescue therapy for Type 1 cardiorenal syndrome was associated with poor prognosis and high in‐hospital mortality (Prins, Wille, Tallaj, & Tolwani, 2015), while intermittent RRT in chronic cardiorenal syndrome was shown to be beneficial in terms of reducing readmission and deaths (Repasos et al., 2015). These studies are largely limited by the small number of participants in the study, highlighting the need for larger studies to confirm these observations. Studies in cardiorenal syndrome of renal and systemic origin (Types 3–5) are also warranted.

A left ventricular assist device (LVAD) is an implantable mechanical pump to elevate cardiac output (Cowger & Radjef, 2018). Experts have suggested that LVAD may benefit those with Type 2 cardiorenal syndrome (Ross et al., 2018). LVAD use in patients not eligible for heart transplantation (HTx) improved 1‐year survival and quality of life (Cowger & Radjef, 2018). In terms of kidney function, LVAD's long‐term impact is concerning despite initial improvement in renal function, including in chronic kidney disease patients (Kazory, 2013; Roehm, Vest, & Weiner, 2018). Notably, acute kidney injury is observed in 15% to 45% of patients on left ventricular assist devices (Roehm et al., 2018; Ross et al., 2018). The Aortix (Procyrion), a percutaneous cardiac pumping device, has shown promising results in improving renal perfusion and cardiac output and is in process for the next clinical trial phase (Cowger & Radjef, 2018). Drawbacks of implantable devices include the need of constant anticoagulation therapy and risks of component dislodgement, acute kidney injury‐induced haemolysis and extracorporeal complications (Cowger & Radjef, 2018). Moreover, device use in general lacks widely accepted guidelines and is costly (Kazory, 2013). Perioperative complications are possible; however, this can be minimized with good clinical practice as well as extensive risk assessment prior to decision for implantation.

3.2.3. Transplantation: Heart, kidney or both?

Separate heart and kidney transplantations are options for end‐stage patients. Dual transplantation involving both organs is much less considered. Renal function is an important contributor to heart transplantation (HTx) post‐operative survival (Seoane‐Pillado et al., 2017). Likewise, cardiovascular risk factor in kidney transplantation (KTx) is well correlated with higher post‐transplantation mortality (Seoane‐Pillado et al., 2017). Multiple studies have shown combined heart and kidney transplantation (HKTx) to be a safe option in patients with concomitant heart and kidney failure (Reich et al., 2019; Wong et al., 2017). HKTx reduces rate of cardiac allograft vasculopathy and dysfunction than HTx alone (Karamlou et al., 2014; Sato et al., 2019). HKTx patients have the same rate of hospitalization lengths and long‐term survival, with better immune modulation benefits (lower cellular and antibody‐mediated rejection events) than HTx (Awad et al., 2017). Both dialysis‐dependent and patients with reduced preoperative GFR benefit from HKTx in terms of long‐term survival (Kilic et al., 2015). Furthermore, a recent analysis suggested similar safety and efficacy of HKTx in patients older and younger than 60 years, regardless of sensitization (panel‐reactive antibody) levels (Awad et al., 2019).

Presently, no formal guidelines exist for HKTx, including in the cardiorenal syndrome context. Limitations include lack of organ donors, especially a ‘single’ donor to source both heart and kidney. There are also concerns regarding the physiological aspect (differentiating patients needing the procedure) and ethical aspect (dissemination of a rare resource to a morbid population) of multi‐organ transplantation such as the HKTx (Stites & Wiseman, 2016). Not surprisingly, the procedure also comes with high costs. Another trade‐off is the high perioperative and post‐operative mortality, primarily due to KTx surgery complications (Lopez‐Sainz et al., 2015).

3.2.4. Other treatments

Unlike the other cardiorenal syndrome types, management of underlying disease is key for secondary cardiorenal syndrome. In sepsis, this includes early antibiotics and fluid resuscitation and vasopressor therapy for septic shock (Kotecha et al., 2018). Therapeutic adjuncts including source control, mechanical ventilation and blood product transfusions may be warranted in some clinical scenarios (Kotecha et al., 2018). Anaemic conditions in cardiorenal syndrome patients should also be addressed. Darbepoetin alfa, an erythropoiesis‐stimulating agent, did not improve cardiovascular outcomes in the chronic kidney disease cohort (Charytan, Fishbane, Malyszko, McCullough, & Goldsmith, 2015). In fact, general consensus points to negative effect of erythropoiesis‐stimulating agent use. However, iron supplementation is encouraged and was shown to improve symptoms and hospitalization in heart failure patients (Charytan et al., 2015).

Palliative care should also be directed throughout the disease course. The goal of palliative care is to improve quality of life and reduce suffering among patients and families. Clinicians must discuss clearly goals of care and make appropriate referrals and end‐of‐life treatment and hospice care planned accordingly in line with patient preference. With progressing heart failure, use of medical devices such as pacemakers is not as useful compared to symptomatic, emotional and spiritual care (Diop, Rudolph, Zimmerman, Richter, & Skarf, 2017). Dialytic and non‐dialytic options must be outlined openly to all kidney disease patients. Of note, renal replacement therapy may not benefit patients older than 75, especially those with multiple co‐morbidities (Combs & Davison, 2015). Additionally, chronic heart and kidney disease patients often have depleted psychosocial and spiritual drive due to significant fatigue, existential distress, depression and anxiety, among many others, which require integrated care (Figure 2).

FIGURE 2.

Principle of cardiorenal syndrome management. Management of cardiorenal syndrome (CRS) encompasses several important perspectives. Diagnostic measures should aid early and effective diagnosis to address underlying diseases, with special encouragement of multi‐marker use. Treatments may involve pharmacological or non‐pharmacological or a combination of both as warranted by disease progression. Special care should be exercised in patients with systemic disease or other clinical conditions such as anaemia, and the treatment should consider cardiorenal impacts. Palliative care is essential; physicians should not treat just the disease but psychosocial issues that come with having cardiorenal syndrome and seek to improve patient quality of life

4. SPECIAL CONSIDERATIONS FOR CARDIORENAL SYNDROME

4.1. Role of uraemic toxins

4.1.1. Gut dysbiosis

In the healthy human gut, the microbial community thrives symbiotically and aids in various metabolic functions, such as digestion and/or degradation of dietary nutrients and bile biotransformation. Gut dysbiosis refers to the quantitative and qualitative imbalance in intestinal microbial community, which negatively alters the overall composition and metabolic outcomes. Pathological changes seen in gut dysbiosis include inflammatory cell infiltration into the lamina propria, villous height reduction and crypt elongation (Nallu, Sharma, Ramezani, Muralidharan, & Raj, 2017). There is also reduction in tight junction proteins in the colonic mucosa (Nallu et al., 2017). This results in disrupted gut barrier function, allowing unfiltered translocation of uraemic toxins into the circulation.

Gut dysbiosis has been observed in both heart failure and chronic kidney disease patients. Pathophysiological processes in chronic kidney disease and cardiovascular disease may lead to hypoperfusion of intestinal villi, resulting in ischaemia and disturbance of intestinal permeability (Nallu et al., 2017). Reduced intestinal integrity has been linked to atherosclerotic plaque and vascular fibrosis, as well as alteration of vascular tone (Ahmadmehrabi & Tang, 2017; Lau et al., 2017). chronic kidney disease‐induced gut dysbiosis is thought to be the result of alteration of nutrient bioavailability and an increase in luminal pH due to the elevation in ammonia (Evenepoel, Poesen, & Meijers, 2017). Whether gut dysbiosis is a potential ‘cause’ or a downstream effect of cardiorenal syndrome is unclear. However, it is certain that the gut–heart–kidney axis exists and has a huge implication for cardiorenal syndrome therapeutics as discussed further below. It is also likely that the effect of gut dysbiosis can exacerbate cardiorenal syndrome pathophysiology and vice versa, although mechanisms remain largely unclear. One of the key contributors related to gut dysbiosis in the cardiorenal syndrome setting is uraemic toxin accumulation. Uraemic toxins are by‐products of microbial metabolism of dietary protein in the gut. Impaired renal excretory function leads to accumulation of these solutes, which has been shown to have cardiac, renal and vascular effects.

4.1.2. Protein‐bound uraemic toxins

Protein‐bound uraemic toxin (PBUT) is a subclass of uraemic toxin with high protein binding capacity. Its unbound free form has a relatively low (and hence dialyzable) molecular weight, however is non‐dialyzable in the large protein–toxin complex form (~500 kDa). Protein‐bound uraemic toxin equilibrium also cannot be restored during dialysis due to this extensive protein binding characteristic and therefore remains in circulation to enter organ tissues and cause deleterious effects. Jansen, Jankowski, Gajjala, Wetzels, and Masereeuw (2017) have meticulously reviewed protein‐bound uraemic toxin protein binding mechanisms. We have also comprehensively reviewed molecular mechanisms involved in protein‐bound uraemic toxins effect in the heart, kidney and vasculature based on preclinical findings (Savira et al., 2019).

Systemic accumulation of gut‐derived protein‐bound uraemic toxins has been recognized to be detrimental in both heart failure and chronic kidney disease, largely based on observational studies. Indoxyl sulfate (IS) and p‐cresol or its subjugate p‐cresol sulfate (PCS) are the most widely studied protein‐bound uraemic toxins to date. Indoxyl sulfate and p‐cresol sulfate are linked to increased progression and mortality in chronic kidney disease patients and p‐cresol sulfate to cardiovascular outcomes. In the chronic kidney disease cohort, increased indoxyl sulfate level is linked to elevated levels of adhesion molecules, plasma von Willebrand factor and thrombomodulin, signifying a pro‐thrombotic effect (Kaminski, Pawlak, Karbowska, Mysliwiec, & Pawlak, 2017). Indoxyl sulfate level is also negatively correlated with the number of circulating endothelial progenitor cells (Wu et al., 2013), highlighting a potential anti‐angiogenic characteristic. P‐cresol sulfate is associated with infection‐related hospitalization and septicaemia (Banerjee et al., 2017), while indoxyl sulfate is associated with the first heart failure event in the end‐stage renal disease cohort (Cao et al., 2015). ROS‐mediated cardiovascular and renal effects of protein‐bound uraemic toxins are widely demonstrated in preclinical settings (Savira et al., 2019). Most importantly, GFR is a poor predictor of protein‐bound uraemic toxin accumulation (Eloot et al., 2011). This suggests that GFR does not reflect protein‐bound uraemic toxinT accumulation and the deleterious effects it might have. In addition, protein‐bound uraemic toxin has potential applicability as diagnostic/prognostic marker in cardiac and renal disease. For instance, indoxyl sulfate was shown to be beneficial for the detection and prediction of atherosclerosis (Yamazaki et al., 2015) and the progression of cardiac and renal dysfunction (Shimazu et al., 2013; Taki & Niwa, 2007).

4.1.3. Addressing microbiome imbalance and uraemic toxin accumulation

There are several principles to manage circulating levels of uraemic toxins, particularly non‐dialyzable protein‐bound solutes: (1) mitigation of internal production, (2) inhibition of mechanistic pathways, and (3) improvement in dialysis modalities (Figure 3).

FIGURE 3.

Therapeutic strategies for protein‐bound uraemic toxin accumulation. Protein‐bound uraemic toxins (PBUTs) are generated in the gut and normally cleared by the kidney. Renal impairment results in PBUT accumulation in the circulation, leading to deleterious effects. Strategies to mitigate the effects of PBUTs can therefore be summarized into (1) inhibition of PBUT production in the gut; (2) inhibition of targeted pathways activated by PBUTs that have gained entry into cells; and (3) improvement of dialytic modalities for PBUT removal

To limit internal production of uraemic solutes, a low‐protein diet was shown to reduce indoxyl sulfate level in chronic kidney disease patients (Black et al., 2018). However, the Modification of Diet in Renal Disease study showed that low‐protein diet did not delay chronic kidney disease progression and instead increased the risk of death (Menon et al., 2009). There are also health concerns with long‐term low protein consumption. Use of symbiotic therapy (prebiotic and probiotic) showed positive modification of stool microbiome and reduced circulating indoxyl sulfate levels (Rossi et al., 2016); further evaluation in a larger trial is warranted. AST‐120, a carbon adsorbent of indole (indoxyl sulfate precursor), demonstrated a huge potential as a therapeutic strategy to counter protein‐bound uraemic toxins. Substantial evidence of cardiovascular and renal benefits in various preclinical and small to medium trials led to its approval in Japan, Taiwan, Korea and the Philippines. However, AST‐120 failed to achieve primary outcomes in two of its largest trials to date (EPPIC and CAP‐KD) (Cha et al., 2016; Schulman et al., 2015). Use of AST‐120 combined with a mild low‐protein diet has been suggested to be beneficial and warrants further investigation.

Theoretically, there will be circulating protein‐bound uraemic toxins that have already gained entry into cells and cause deleterious outcomes. The only approach to mitigate these effects is to inhibit signalling pathways activated by protein‐bound uraemic toxins at the molecular level. This has been tested mostly in preclinical scenarios and clinical studies in the cardiorenal syndrome context remain entirely non‐existent to date. Some noteworthy of protein‐bound uraemic toxin‐activated pathways include the pro‐inflammatory NF‐κB and the MAPK family: the apoptosis signal‐regulating kinase 1 and the downstream p38 MAPK, ERK1/2 and JNK. All these pathways are involved in protein‐bound uraemic toxin‐mediated heart, kidney and vascular dysfunction and are activated in cellular stress or inflammatory responses (Savira et al., 2019). Aryl hydrocarbon receptor is another important of protein‐bound uraemic toxin‐related intracellular target as it has been widely shown to mediate IS's deleterious effects (Koizumi et al., 2014). Further investigation may prove these and other potentially new pathways as therapeutic targets for cardiorenal syndrome. In terms of drug development, key challenges to overcome include toxicity issues, sufficient compound optimization and the need for exhaustive testing in both laboratory‐based setting and the clinic. Many inhibitors fail to progress further often due to toxicity issues in the early phase of trials.

Removal of protein‐bound uraemic toxin is limited by conventional dialysis. However, daily short haemodialysis compared to standard haemodialysis has been shown to improve protein‐bound uraemic toxin removal such as indoxyl sulfate and p‐cresol (precursor of P‐cresol sulfate), as well as uric acid, creatinine and urea (Fagugli, De Smet, Buoncristiani, Lameire, & Vanholder, 2002). Dialysis time extension also enhanced reduction ratio of protein‐bound uraemic toxins (Cornelis et al., 2015). Addition of nanoporous sorbents on the dialysis membrane was shown to increase protein‐bound uraemic toxin removal in a laboratory‐based study (Pavlenko et al., 2017). Reducing protein‐bound uraemic toxin protein binding by increasing blood ionic strength and pH in blood‐purification strategies may be viable options according to in vitro validations (Krieter et al., 2017; Shi et al., 2019). Similarly, competitive binding via chemical displacers is another feasible avenue (Madero et al., 2019; Tao et al., 2016). Newer dialysis machines equipped with a ‘medium cut‐off membranes’, such as the Theranova dialyser, are capable of removing middle‐sized molecules (García‐Prieto et al., 2018), but studies assessing protein‐bound uraemic toxin are limited. Importantly, most of these studies are preliminary in nature and remain to be validated in further preclinical models and larger human cohorts.

4.2. Lipid imbalance

4.2.1. Role of low‐ and high‐density lipids

Lipid metabolism is an integral part of cardiac function. LDL and HDL imbalance is an established process in mediating vascular dysfunction and atherosclerotic diseases. In both cardiovascular disease and renal disease, lipid metabolism is impaired. The clinical profile of dyslipidaemia in these settings comprises increased LDL and triglycerides and decreased LDL levels. LDL is critically involved in early atherosclerotic plaque formation due to its oxidization and structural modification. Oxidized LDL levels are markedly elevated in chronic kidney disease patients, likely due to increased oxidative stress events. Conversely, HDL is vasculoprotective, showcasing anti‐atherogenic, anti‐inflammatory and antioxidant effects.

The principal lipid‐lowering treatment is statin (HMG‐CoA reductase inhibitor) administration. Statins exhibit a cardiovascular‐protective effect, reducing and preventing cardiovascular disease, and potentially kidney disease (Bianchi, Grimaldi, & Bigazzi, 2011). However, statins are less efficacious in advanced renal impairment. Mortality benefit of statin has been challenged by large trials, though morbidity reduction is evident (Cleland, Hutchinson, Pellicori, & Clark, 2014). HDL agonists, such as niacins and fibrates, are a promising strategy in lipid‐lowering therapy. Fibrates are commonly prescribed for the triglyceride modulating effect, but clinical studies involving fibrates are far fewer than those of statins. Fibrates have beneficial cardiovascular‐reducing risk in mild–moderate chronic kidney disease, but the effect is unclear in advanced stages (Androulakis et al., 2017). Niacin is not cleared by the kidneys and may be safe in the chronic kidney disease setting but has poor tolerance (Androulakis et al., 2017). Statin and fibrate combinations are associated with increased PCSK9 level, an LDL receptor regulator, likely reducing lipid‐lowering effects (Dincer et al., 2019). PCSK9 inhibitors have been shown to be more efficacious than statins in reducing LDL and cardiovascular events (Dincer et al., 2019), and adjunct inhibition with statin and fibrate combination therapy may be beneficial.

4.2.2. Role of Sphingolipids

Sphingolipids are traditionally recognized as a part of the cell membrane structure. However, studies have shown sphingolipids involvement in various cellular function and dysfunction. The scope for sphingolipid discussion is vast, but notably, targeting enzymes and biomolecules involved in the de novo sphingolipid synthesis pathway for disease therapy has gained interest in recent years. This may be due to direct relevance with sphingolipid plasma level regulation (Magaye et al., 2018). The de novo pathway synthesis for sphingolipid production is best summarized into the non‐reversible conversion of dihydroceramide (dhCer) into ceramide (Cer). This is mediated by the gatekeeper enzyme dihydroceramide desaturase 1 and 2 (Des‐1 and ‐2) (Figure 4).

FIGURE 4.

Sphingolipid imbalance and potential impacts on cardiorenal and vascular systems. Sphingolipid imbalance has potential negative cardiac, renal and vascular implications. Of particular interest is the non‐reversible conversion of dihydroceramide (dhCer) into ceramide (Cer) within the de novo synthesis pathway mediated by Des‐1, conceivably making Des‐1 an attractive target to restore sphingolipid (SL) imbalance. RAAS, particularly angiotensin II, has been postulated to interact with sphingolipids, though mechanisms remain obscure. N.B. the de novo SL synthesis pathway has been simplified for illustration purposes

The implication of the dihydroceramide and ceramide imbalance remains largely unclear. However, higher ceramide levels have been linked to chronic oxidative stress, lipid raft formation, cardiac and ischaemic renal injury and mortality in heart failure patients (Reforgiato et al., 2016; Zager, Iwata, Conrad, Burkhart, & Igarashi, 1997). Ceramide increments, but not dihydroceramide, also cause smooth muscle cell apoptosis and instigate ROS‐related pathways in endothelial cells (Magaye et al., 2018). RAAS–sphingolipid interaction is poorly defined; however, aldosterone and Ang II‐mediated ceramide production is associated with cellular apoptosis, vascular contraction and oxidative stress (Ueda, 2017). On the other hand, reduced dhCer level is linked to increased insulin resistance (Magaye et al., 2018). Interestingly, suppression of the enzyme sphingosine kinase 1 (SPHK1) was demonstrated to exacerbate renal fibrosis in disease models (Ren et al., 2009), and conversely, its up‐regulation results in anti‐fibrotic outcomes (Bajwa et al., 2010). This is albeit SPHK1's role in converting ceramide‐derived sphingosine into sphingosine 1 phosphate (S1P) (Figure 4). S1P itself is linked to fibrotic lesions (Pyne, Dubois, & Pyne, 2013); however, such effects may arrive from its extracellular action, with intracellular S1P instigating anti‐fibrotic benefits (Schwalm, Pfeilschifter, & Huwiler, 2014). It is also puzzling that increased SPHK1 level in humans and disease models is associated with deleterious effects, while other studies confirmed the protective role of its overexpression as previously discussed (Huwiler & Pfeilschifter, 2018). Furthermore, increased dhCer level is realized in atherosclerotic plaques and hypercholesterolaemic rats (Magaye et al., 2018). Overall, current evidence suggests a more complicated physiological and pathophysiological implication to the dihydroceramide–ceramide balance than naming either one a straightforward ‘good’ or ‘bad’ sphingolipid, as such may be the case for LDL and HDL. There appears to be some factors influencing the effect of various sphingolipids, including bi‐functionality, site of action, type of sphingolipid (identified by structural variations) and potentially disease onset. With better understanding of their actions, sphingolipids could potentially become useful markers in cardiac, renal and vascular dysfunction.

Nevertheless, therapeutic implications of sphingolipid are evolving. sphingolipid‐based therapy is generally aimed to reduce synthesis of certain sphingolipid substrates. The current challenge is to avoid lethal implication of sphingolipid synthesis blockade, which largely depends on the magnitude (i.e. global and non‐global blockade), the target within the pathway and appropriate intracellular or extracellular inhibition as per the desired outcome (Schiffmann, 2015; Schwalm et al., 2014). Partial inhibition is generally benign, as demonstrated in preclinical models (Schiffmann, 2015). Targeting Des‐1 is largely contemplated to restore dihydroceramide and ceramide balance. However, the consequence of Des‐1 inhibition in the cardiorenal context is hardly known. SPHK1s and S1P receptors are also potential targets, with both inhibition and promotion of their expression being considered as therapeutic strategies. Further investigation detailing the behaviour of various forms of sphingolipids are necessary to understand the benefits for sphingolipid‐targeted therapy in diseases including cardiorenal syndrome.

5. CONCLUSION

Comprising a complex and multifactorial pathophysiology, cardiorenal syndrome is a clinical challenge. Diagnostic, prognostic and therapeutic measures in the cardiorenal syndrome setting are limited. Current pharmacological therapies are powerful, but insufficient to satisfactorily reverse or mitigate cardiorenal syndrome progression, thus is a high priority area for drug discovery and novel therapeutic strategies. Treatment for patients with cardiorenal syndrome needs to be integrative and continuous, addressing physical and psychosocial symptoms. Renewed initiatives and concerted efforts between nephrologists, cardiologists and scientists should be built to establish robust guidelines and promote translational research addressing this cohort of patients. Focus on potentially overlooked contributing factors, such as uraemic toxin accumulation and sphingolipid imbalance, is also warranted.

5.1. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander et al., 2019).

CONFLICT OF INTEREST

J.C.B. and S.J.S. are listed as co‐inventors on issued or filed patents related to the use of urinary CNP as a biomarker, and Mayo Clinic holds patent rights. J.C.B. is the co‐inventor on issued or filed patents related to cenderitide and NPA7, and Mayo Clinic holds patent rights. J.C.B. is also listed as a co‐inventor of MANP, and Mayo Clinic has licensed MANP to Zumbro Discovery of which J.C.B. is a co‐founder and holds equity. All other authors have no conflict of interest to declare.

Savira F, Magaye R, Liew D, et al. Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature. Br J Pharmacol. 2020;177:2906–2922. 10.1111/bph.15065