1. Introduction

There is a close link between the heart and kidney: cardiovascular damage drives a worsening of kidney function; in turn kidney failure worsens cardiovascular injury^[1] [1]. Heart Failure (HF) affects 5.8 million people within the USA, and over 23 million worldwide^[2] [2]. Approximately 20–30% of patients admitted for acute decompensated HF will suffer a decline in kidney function while hospitalized, and 40–60% of patients with chronic HF have CKD. The coexistence of these two diseases worsens their prognoses^[3][4] [3,4].

Cardiorenal syndrome (CRS) is a multi-organ disease that includes a spectrum of disorders resulting from the close interaction between the heart and kidney during acute or chronic dysfunction of one of these organs.

It was described for the first time by Robert Bright, in 1836, who found cardiac structural changes in a patient with advanced renal failure^[5] [5]. Since then, several cases have been reported, and the knowledge of its pathophysiology has gradually led to a better clinical classification of the syndrome. In 2004, the Working Group of the National Heart, Lung, and Blood Institute defined, for the first time, CRS as “the result of interactions between the kidneys and other circulatory compartments that increase circulating volume, which exacerbates the symptoms of heart failure and disease progression”^[6] [6]. In this context, the heart is considered to be the main actor, and in which the decline of renal function worsens the congestive symptoms of HF.

In 2008, the Acute Dialysis Quality Initiative divided CRS patients into two groups based on the primary organ failure driving the disease process (cardiorenal or renocardiac)^[7] [7]. This classification was further elaborated and arranged into five groups according to clinical presentations to facilitate the early differential diagnosis and the most appropriate therapy ( Figure 1 ), and biomarkers may represent decisive prognostic factors in assessing risk prediction in patients with HF and impaired kidney function.

2. Pathophysiology of Cardiorenal Syndrome

In acute decompensated heart failure, the cardiac pump cannot maintain optimal blood flow, resulting in volume overload and increased central venous pressure (CVP). CVP is the thoracic vena cava’s pressure near the right atrium. It indicates the blood volume returning to the heart and its ability to pump the blood back into the arterial system. When this mechanism fails, consequent venous congestion results in renal dysfunction caused by reduced renal blood flow and glomerular filtration rate (GFR), and decreased urine output.

Classical biomarkers for the assessment of kidney function include serum creatinine (SCr), albuminuria, and cystatin C (CysC), as well as urine output and eGFR. Urine and serum biomarkers, including urinary angiotensinogen, urinary enzyme N-acetyl-β-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18) , high sensitivity troponin I (hs-cTnI), and kidney injury molecule 1 (KIM-1) measured at the time of CRS diagnosis show improved risk stratification in determining which patients will experience adverse outcomes ^[8][13]. Among these, NGAL is the most widely used, and its urinary determination has been found to be more sensitive and specific than even plasma NGAL^[9] [14]. The increase in NGAL levels has a predictive role for the onset of acute renal injury, considerably anticipating the increase of creatinine serum levels and thus allowing prompt preventive therapeutic strategies^[10] [15].

In CRS the increased oxidative stress is also related to ischemic injury and venous congestion, resulting in the reduction of fatty acid oxidation in favor of glycolysis in myocytes. These metabolism alterations lead to a reduction in ATP production, in turn leading to major susceptibility to hypoxemia, apoptosis, and cellular death. In addition, the reduced metabolism of fatty acid oxidation leads to an increase of free fatty acid and subsequent lipotoxicity.

Increased synthesis of pro-inflammatory mediators is known in CKD and HF to promote tissue damage, and lead to cell death and fibrosis. Cytokines, also induced through the extra-hemodynamic effects of angiotensin II, are fundamental in explaining the inflammatory mechanisms involved in CRS^[11] [38]. C-reactive protein (CRP), a non-specific inflammation protein, is frequently increased in CRS. It is associated with the activation of the complement system and tissue factor production. A study of acute decompensated heart failure syndromes prospectively assessed 4269 hospitalized AHF. In these patients, elevated CRP was independently associated with higher mortality (adjusted hazard ratio [HR], 1.68)^[12] [39].

3. Neurohormonal Dysregulation

Both HF and CKD are characterized by abnormal alteration of the sympathetic nervous system (SNS). Sympathetic hyperactivity is usually a compensatory system in the

acute phases of CVD that, continuing over time, has cardio and nephrotoxic effects^[13] [26].

In CKD, in addition to up-regulation of the renin-angiotensin-aldosterone system (RAAS),

sympathetic hyperactivation causes desensitization of cardiac beta-adrenergic receptors;

furthermore, catecholamine clearance is reduced, resulting in a self-deteriorating cycle

that worsens the GFR itself, and a progression of heart failure^[14][15] [27,28]. The direct effects of

sympathetic hyperactivation also include the alteration of cardiac calcium homeostasis,

increased hypertrophy, and apoptosis of myocytes. This results in the increased predisposition to the chronicization of cardiac remodeling^[16] [29]. Indirect effects are essentially

mediated by inflammatory molecules, such as cytokines^[17] [30].

RAAS activation has important effects in the pathogenesis of CRS. The hypoperfusion of peripheral tissue in HF determines the sympathetic nervous system’s overactivity,

with increased renin release from the juxtamedullary apparatus. Renin synthesis is also

stimulated by the reduction of hydrostatic pressure at glomerular afferent arterioles, and a

reduction of sodium delivered to the macula densa. The result of renin release is the increased production of angiotensin II, which causes renal efferent arteriolar vasoconstriction,

increasing the hydrostatic pressure inside the glomerulus to keep the GFR stable. Consequently, it decreases the peritubular hydrostatic pressure, and enhances the reabsorption of

sodium in the proximal tubules. Furthermore, angiotensin II stimulates the synthesis of

aldosterone, which in turn increases the reabsorption of sodium in the distal tubule and

increases the endothelin-1 in the kidney, a potent vasoconstrictor, proinflammatory, and

profibrotic peptide. Angiotensin II also plays a role in other tissues, especially in the heart,

where it promotes the process of remodeling and fibrosis.

Dysregulation of adenosine and arginine vasopressin (AVP) is also implicated in the

neurohormonal pathogenesis of CRS. Adenosine is generated by enzymatic degradation

of adenosine triphosphate. It is released when there is an increment of sodium levels

in the distal tubule. After binding to A1 receptors, it causes vasoconstriction of afferent

arterioles, reducing renal blood flow. Activation of A2 receptors stimulates renin secretion,

increasing sodium reabsorption in the proximal tubule and decreasing the glomerular

filtration. The use of drugs that block adenosine receptors can be useful in improving renal

function. Unfortunately, clinical trials have failed to demonstrate the beneficial support

of this therapy in reducing death and hospitalization, and improving heart and kidney

function^[18] [31].

AVP is a peptide synthesized in the supraoptic and paraventricular nuclei of the

hypothalamus that is stored in the posterior pituitary gland until released into the blood

based on the serum osmolality. It increases the solute-free water reabsorption in the distal

tubule of the kidney promoting aquaporin 2 (AQP2) movement from the intracellular

compartment to the apical membrane. AQP2 is a water channel that drives water into the

cell according to the osmotic gradient. In addition, AVP causes arteriole vasoconstriction,

which increases vascular resistance. This mechanism leads to an increase in venous return

to the heart, which worsens venous congestion. On the other hand, the vasoconstriction

reduces kidney perfusion, resulting in GFR reduction. Several studies have evaluated the

efficacy of tolvaptan, a selective, competitive AVP receptor antagonist, in CRS. The most

important trial (EVEREST) recruited 4133 patients with ADHF, and found that early use of

tolvaptan was linked to a lower mean body weight and ameliorated clinical symptomatology. Nevertheless, compared with placebo, tolvaptan effected no difference in longterm outcomes^[19] [32]. Based on the pathophysiology of the CRS, much attention was paid to

AVP as a biomarker. However, the measured values of AVP are not always reliable^[16] [29].

4. Endothelial Dysfunction and Atherosclerosis

The neurohormonal dysregulation and the accumulation of the uremic toxins in CRS

play an important role in the development of oxidative stress. The alteration of balance

between oxidant and antioxidant agents results in an increased concentration of reactive

oxygen species (ROS), leading to cellular damage and endothelial dysfunction.

Endothelial dysfunction is another important commonality between chronic kidney

disease (CKD) and HF. Endothelial cells are responsible for the functional vascular response

to hemodynamic and oxidative stress ^[20][34]. The anti-inflammatory, antioxidant action, and

vascular tone regulation of the endothelium-derived relaxing factor (EDRF) are dysregulated in both HF and CKD independent of each other^[21] [35]. Endothelial dysfunction, on the

other hand, is an early marker of atherosclerosis. Arteriosclerotic vascular disease (ASVD)

plays a primary role in the pathogenesis of CRS. As is well known, ASVD (and consequent

ischemic coronary artery disease) is both the main cause of HF and one of the main causes

of ischemic renal failure^[22] [36]. The increased cardiovascular (CV) risk related to CKD is

partly linked to a more intense and faster development of atherosclerosis, independent of

the other risk factors^[23] [37].

5. Oxidative Stress and Inflammation

In CRS the increased oxidative stress is also related to ischemic injury and venous

congestion, resulting in the reduction of fatty acid oxidation in favor of glycolysis in

myocytes. These metabolism alterations lead to a reduction in ATP production, in tur n

leading to major susceptibility to hypoxemia, apoptosis, and cellular death. In addition,

the reduced metabolism of fatty acid oxidation leads to an increase of free fatty acid and

subsequent lipotoxicity.

Increased synthesis of pro-inflammatory mediators is known in CKD and HF to

promote tissue damage, and lead to cell death and fibrosis. Cytokines, also induced

through the extra-hemodynamic effects of angiotensin II, are fundamental in explaining the

inflammatory mechanisms involved in CRS^[11] [38]. C-reactive protein (CRP), a non-specific

inflammation protein, is frequently increased in CRS. It is associated with the activation

of the complement system and tissue factor production. A study of acute decompensated

heart failure syndromes prospectively assessed 4269 hospitalized AHF. In these patients,

elevated CRP was independently associated with higher mortality (adjusted hazard ratio

[HR], 1.68) ^[12][39].

As is well known, prolonged inflammation is often capable of inducing anemia in

predisposed individuals. Anemia is a common characteristic of CKD and HF patients,

with a prevalence between 5% and 55%^[24] [40], and represents an independent risk factor

for mortality^[25] [41]. It contributes to CRS development in several ways: reduced oxygen

delivery, reduced antioxidants synthesized from red blood cells, activation of sympathetic

nervous system (SNS), RAAS, AVP because of tissue ischemia that leads to vasoconstriction,

salt-water retention, and venous congestion. The role of erythropoiesis-stimulation agents

(ESAs) in the treatment of CRS is controversial. A randomized double-blind controlled

study demonstrated that improvement in hemoglobin levels with ESAs and oral iron over

one year led to an increase in cardiac function compared with oral iron therapy alone^[26] [42].

On the contrary, a trial with a higher hemoglobin level (>13.5 gr/dl) as target found an

association with a higher rate of adverse events and no improvement in the quality of

life^[27] [43].

Finally, there is burgeoning interest in the adoption of parenteral iron to improve

anemia in patients with congestive HF. Several studies^[28] [44] have reported that patients

treated with intravenous iron develop symptomatic improvement and increased exercise

capacity independent of hemoglobin level effects. These findings indicate that intravenous

iron therapy can be a promising option for the treatment of CRS.