Cardiorenal syndrome (CRS) is an umbrella term used in the medical field that defines disorders of the heart and kidneys whereby “acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other”. The heart and the kidneys are involved in maintaining hemodynamic stability and organ perfusion through an intricate network. These two organs communicate with one another through a variety of pathways in an interdependent relationship. In a 2004 report from National Heart, Lung and Blood Institute, CRS was defined as a condition where treatment of congestive heart failure is limited by decline in kidney function. This definition has since been challenged repeatedly but there still remains little consensus over a universally accepted definition for CRS. At a consensus conference of the Acute Dialysis Quality Initiative (ADQI), the CRS was classified into five subtypes primarily based upon the organ that initiated the insult as well as the acuity of disease.
Ronco et al. first proposed a five-part classification system for CRS in 2008 which was also accepted at ADQI consensus conference in 2010. These include:
The distinction between CRS type 2 and CRS type 4 is based on the assumption that, also in advanced and chronic disease, two different pathophysiological mechanisms can be distinguished, whereas both CKD and HF often develop due to a common pathophysiological background, most notably hypertension and diabetes mellitus. Furthermore, the feasibility of the distinction between CRS type 2 and 4 in terms of diagnosis can be questioned.
Braam et al. argue that classifying the CRS based on the order in which the organs are affected and the timeframe (acute vs chronic) is too simplistic and without a mechanistic classification it is difficult to study CRS. They view the cardiorenal syndrome in a more holistic, integrative manner. They defined the cardiorenal syndrome as a pathophysiological condition in which combined heart and kidney dysfunction amplifies progression of failure of the individual organ, by inducing similar pathophysiological mechanisms. Therefore, regardless of which organ fails first, the same neurohormonal systems are activated causing accelerated cardiovascular disease, and progression of damage and failure of both organs. These systems are broken down into two broad categories of "hemodynamic factors" and non-hemodynamic factors or "cardiorenal connectors".
The following risk factors have been associated with increased incidence of CRS.
- Older age
- Comorbid conditions (diabetes mellitus, uncontrolled hypertension, anemia)
- Drugs (anti-inflammatory agents, diuretics, ACE inhibitors, ARBs)
- History of heart failure or impaired left ventricular ejection fraction
- Prior myocardial infarction
- New York Heart Association (NYHA) functional class
- Elevated cardiac troponins
- Chronic kidney disease (reduced eGFR, elevated BUN, creatinine, or cystatin)
The pathophysiology of CRS can be attributed to two broad categories of "hemodynamic factors" such as low cardiac output, elevation of both intra-abdominal and central venous pressures, and non-hemodynamic factors or "cardiorenal connectors" such as neurohormonal and inflammatory activation. It was previously believed that low cardiac output in heart failure patients result in decreased blood flow to the kidneys which can lead to progressive deterioration of kidney function. As a result, diuresis of these patients will result in hypovolemia and pre-renal azotemia. However, several studies did not find an association between kidney dysfunction and cardiac output or other hemodynamic parameters. In addition, CRS has been observed in patients with diastolic dysfunction who have normal left ventricular systolic function. Therefore, there must be additional mechanisms involved in the progression of CRS. Elevated intra-abdominal pressures resulting from ascites and abdominal wall edema may be associated with worsening kidney functions in heart failure patients. Several studies have shown that as a result of this increased intra-abdominal pressure there is increased central venous pressure and congestion of the kidneys' veins, which can lead to worsening kidney function. In addition, many neurohormonal and inflammatory agents are implicated in the progression of CRS. These include increased formation of reactive oxygen species, endothelin, arginine vasopressin, and excessive sympathetic activity which can result in myocardial hypertrophy and necrosis. Other cardiorenal connectors include renin-angiotensin-system activation, nitric oxide/reactive oxygen species imbalance, inflammatory factors and abnormal activation of the sympathetic nervous system, which can cause structural and functional abnormalities in both heart and/or the kidney. There is a close interaction within these cardiorenal connectors as well as between these factors and the hemodynamic factors which makes the study of CRS pathophysiology complicated.
It is critical to diagnose CRS at an early stage in order to achieve optimal therapeutic efficacy. However, unlike markers of heart damage or stress such as troponin, creatine kinase, natriuretic peptides, reliable markers for acute kidney injury are lacking. Recently, research has found several biomarkers that can be used for early detection of acute kidney injury before serious loss of organ function may occur. Several of these biomarkers include neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-B-D-glucosaminidase (NAG), Cystatin C, and kidney injury molecule-1 (KIM-1) which have been shown to be involved in tubular damage. Other biomarkers that have been shown to be useful include BNP, IL-18, and fatty acid binding protein (FABP). However, there is great variability in the measurement of these biomarkers and their use in diagnosing CRS must be assessed.
Medical management of patients with CRS is often challenging as focus on treatment of one organ may have worsening outcome on the other. It is known that many of the medications used to treat HF may worsen kidney function. In addition, many trials on HF excluded patients with advanced kidney dysfunction. Therefore, our understanding of CRS management is still limited to this date.
- Used in the treatment of heart failure and CRS patients, however must be carefully dosed to prevent kidney injury. Diuretic resistance is frequently a challenge for physicians to overcome which they may tackle by changing the dosage, frequency, or adding a second drug.
ACEI, ARB, renin inhibitors, aldosterone inhibitors
- The use of ACE inhibitors have long term protective effect on kidney and heart tissue. However, they should be used with caution in patients with CRS and kidney failure. Although patients with kidney failure may experience slight deterioration of kidney function in the short term, the use of ACE inhibitors is shown to have prognostic benefit over the long term. Two studies have suggested that the use of ACEI alongside statins might be an effective regimen to prevent a substantial number of CRS cases in high risk patients and improve survival and quality of life in these people. There are data suggesting combined use of statin and an ACEI improves clinical outcome more than a statin alone and considerably more than ACE inhibitor alone.
- Nesiritide which is an analogue of brain natriuretic peptide (BNP) was shown to result in poorer kidney outcome or have no effect.
- Tolvaptan showed to have no benefit. It is also a very costly drug.
- Adenosine is responsible for constriction of afferent arteriole and reduction in GFR. It was found that an adenosine A1-receptor antagonist called KW-3902 was able to improve kidney function in CRS patients.
- Many case reports have shown improved kidney function with ultrafiltration.
- Their roles remain unknown.
Kidney failure is very common in patients suffering from congestive heart failure. It was shown that kidney failure complicates one-third of all admissions for heart failure, which is the leading cause of hospitalization in the United States among adults over 65 years old. These complications led to longer hospital stay, higher mortality, and greater chance for readmission. Another study found that 39% of patients in NYHA class 4 and 31% of patients in NYHA class 3 had severely impaired kidney function. Similarly, kidney failure can have deleterious effects on cardiovascular function. It was estimated that about 44% of deaths in patients with end-stage kidney failure (ESKF) are due to cardiovascular disease.
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Maintenance of blood volume, vascular tone, and hemodynamic stability depends on a set of well-balanced interactions between the heart and kidneys. Both organs show endocrine functions with interdependent physiological actions, mostly related to natriuretic peptides and the renin-angiotensin-aldosterone system (RAAS). In addition, the sympathetic nervous system (SNS) plays a role in modulating the functional relationship between the two organs. Therefore, it is not surprising that dysfunction of either organ can severely compromise the function of the other.
The cardiorenal syndrome (CRS) is defined as a condition in which either cardiac or renal dysfunction amplifies the failure progression of the other organ, ultimately leading to increased cardiovascular morbidity and mortality.
The syndrome has been classified into five subtypes based on the organ primarily involved (heart or kidney) and on whether the failure is acute, chronic or secondary [1–3].
While hemodynamic derangements (elevated venous pressure, elevated intra-abdominal pressure, low cardiac output, hypotension) could explain the adverse relationship between heart and kidneys during an acute failure of either one, the interpretation of the complex physiological, biochemical, and hormonal derangements (RAAS, natriuretic peptides) encompassing the chronic CRS remains poorly understood.
The classical Guytonian model , which describes heart/kidney interaction by means of cardiac output, regulation of extracellular fluid volume, blood pressure, and renal sodium handling, appears unable to explain the profound organs derangements, the remodeling and the progression of the dysfunction observed in both organs in chronic CRS. Furthermore, chronic CRS, once established, leads to accelerated atherosclerosis [5,6], cardiac hypertrophy , microangiopathy , increased arterial stiffness  and coronary calcifications .
The present review article discusses evidence supporting the potential contribution of oxidative stress to CRS development and progression, mainly based on the key role of this mechanism in both heart and renal failure conditions when considered separately.
2. Oxidative Stress and Its Impact on Cellular Damage
Oxidative stress is defined as a result of an imbalance between oxidants and antioxidants in favour of the former that potentially leads to cell injury . Oxidative stress occurs when the formation of reactive oxygen species (ROS) exceeds the body’s ability to metabolize them, or when the antioxidant defense mechanisms are depleted. ROS are oxygen-derived small molecules, comprising oxygen radicals’ superoxide, hydroxyl, peroxyl, alkoxyl and non-radicals, such as hydrogen peroxide (H2O2). ROS generation occurs as by-product in several cellular processes. The mitochondrial respiratory chain activity is responsible for most of the ROS production in aerobiosis.
The multi-subunit transmembrane nicotinamide adenine dinucleotide phosphate (NADPH) oxidase proteins (NOXs) also play a relevant role in ROS production. They utilize NADPH as an electron donor to reduce oxygen and produce low levels of superoxide anion (O2−) and H2O2. Out of the seven oxidase family members (NOX 1-5 and dual oxidase 1-2), NOX1, NOX2, NOX4, and NOX5 are expressed in the cardiovascular system. NOX2 and NOX4 are the major isoforms present in cardiomyocytes. NOX2 activation requires the recruitment of several cytosolic subunits (p47phox, p67phox, p40phox and Rac1) which bind to flavocytochrome mainly to induce superoxide anion (O2−) production. NOX2, found predominantly in the sarcolemma and T-tubules, is activated by G-protein coupled receptors. NOX4 activation, primarily regulated by levels of its expression, mainly produces H2O2. It is localized in the endoplasmic reticulum and perinuclear regions of cardiomyocytes, although a mitochondrial location has also been suggested [12–14].
High levels of oxygen radicals inactivate mitochondrial enzymes, cause DNA damage and, by interacting with both DNA repair enzymes and transcription factors, lead to cell death.
Inactivation of the endothelium-derived relaxing factor nitric oxide (NO) is an important secondary ROS effect. Superoxide anion O2− reacts with NO and inactivates its beneficial effect by forming a very powerful oxidant and nitrosating agent, the peroxynitrite (ONOO−). The latter contributes to oxidative stress by oxidizing lipids, DNA, and proteins .
In addition, ROS production can lead to “ROS-induced ROS release”, a vicious circle in which ROS species activate the permeability of mitochondrial pores leading to mitochondrial dysfunction and to further ROS release .
Interestingly, ROS can damage mitochondrial macromolecules either at or near the site of their formation. Among them, the mitochondrial DNA (mtDNA) could be a major target for ROS-mediated damage for several reasons. First, mitochondria do not have the chromatin organization complex consisting in histone proteins which represent a protective barrier against ROS. Secondly, mtDNA has limited repair ability against DNA damage. Finally, since a large part of the superoxide anion O2− produced in mitochondria cannot pass through the membranes, ROS damage is largely contained within the mitochondria .
These mechanisms are associated with reduced mtDNA copy number and with a parallel decrease of mtDNA-encoded gene transcripts, which have been associated with reduced activity of mitochondrial complexes I, III, and IV (all containing subunits encoded by mtDNA). In contrast, complex II activity remains unchanged .
Oxidative damage may also affect critical steps of Krebs cycle and mtDNA polymerase γ, slowing mtDNA replication and eventually leading to inhibition of oxidative phosphorylation .
3. Role of Oxidative Stress in Heart Failure (HF)
Normal cardiac function requires high and continuous ATP supply. Being that mitochondria are the major source of ATP production, it is apparent that mitochondrial and cardiac functions are closely related to each other .
Strong evidence from both in vitro and animal studies shows that several pathways are dysregulated in HF, leading to increased oxidative stress production and to cardiac damage.
First of all, a metabolic shift from fatty acid (FA) oxidation to glycolysis has been reported in cardiomyocytes during HF. In a normal heart, most of the ATP is produced by FA oxidation whereas the remaining part is provided by oxidizing pyruvate, as an end product of glycolysis or derived from lactate . Both pyruvate and FA oxidation pathways are located within the mitochondrial matrix. During HF progression myocardial ATP content decreases, dropping to 60%–70% of normal levels [22–25]. This drop is due to a decrease in mitochondrial oxidative metabolism and it is balanced by a compensatory increase in glucose uptake and glycolysis [25,26].
The shift in the energy source within the cells may result in altered ATP yield, since glycolysis produces less ATP per substrate mole as compared to FA oxidation. Although the glycolitic rate is increased, it is insufficient to supply the energy demands of the failing heart.
The reduced oxidative metabolism leads to accumulation of free FA in cardiomyocytes, creating a self-perpetuating mechanism of ever-increasing oxidative stress and causing deleterious effects within the heart. Either lipotoxicity of circulating FA or the intracellular lipid accumulation contributes to mitochondrial oxidative stress through the activation of protein kinase C, and causes endoplasmic reticulum stress . The progressive decrease of ATP production is linked to both decrease of FA oxidation and reduction of mitochondrial respiration, due to electron transport chain (ETC) defects .
Several alterations in ETC components have been described in different stages of HF [29,30].
In particular, decreased activities of complexes III and IV , alterations in the components of the phosphorylation apparatus, decreases in the amount and activity of ATP synthase , were reported during HF. The altered mitochondrial ETC is a known source of ROS. The decrease in functional respirasomes in HF causes a further drop in oxidative phosphorylation, associated to an increased electron leakage and superoxide generation in complexes I and III. ROS production causes a vicious circle by amplifying the ETC dysfunctions .
Apart from the above described changes in the energy metabolism, RAAS and SNS activation also contributes to maintain and amplify the oxidative stress in HF. Angiotensin II activates NADPH oxidase as the primary source of ROS, causing mitochondrial dysfunction . Both NOX4 and NOX2 are upregulated by angiotensin II in a mitochondrial ROS-independent and -dependent manner, respectively , suggesting a close relationship between the two sources (Figure 1).
HF is accompanied by adaptive reactions, including the increase of orthosympathetic tone. In this regard, Rosca et al. proposed an elegant molecular model in which the increase in adrenergic drive caused a decrease in functional respirasomes and led to mitochondrial dysfunction and progressive decrease in cardiac performance .
Once produced, ROS become responsible for several negative effects in the failing heart. They are involved in cardiac remodelling, cardiomyocyte contractility, ion transport and calcium handling. In addition to their detrimental damaging effects, mitochondrial ROS play an important role in intracellular signalling by triggering multiple cellular pathways and the transcriptional activation of selected nuclear genes, finally eliciting transcriptional reprogramming [12,36].
The oxidative alterations causing the decreased activity of ETC complexes reported in severe HF potentially enhance the severity of the energy deficit with a further oxidative stress increase, finally leading to degradation of the oxidized complexes. Oxidative damage of myofibrillar proteins decreases calcium sensitivity, thus interfering with muscle contractile performance .
ROS have also been shown to activate matrix metalloproteinase (MMP) in cardiac fibroblasts . Myocardial MMP activity is increased in the failing heart . Prolonged MMP activation might influence the structural properties of the myocardium by providing an abnormal extracellular environment for myocytes. Importantly, it has been demonstrated that the ·OH scavenger dimethylthiourea inhibits the activation of MMP2 along with the development of left ventricular remodelling and failure .
Furthermore, the release of several mitochondria-specific proteins from the intermembrane space, including cytochrome c, endonuclease G (EndoG), apoptosis-inducing factor (AIF) and second mitochondria-derived activator of caspase (Smac), is crucial in the early triggering events of the apoptotic pathway leading to caspase activation, nuclear DNA fragmentation, and cell death . The release of EndoG and AIF, and their translocation to the nucleus promote nuclear DNA degradation, even in the absence of caspase activation . As previously noted, higher ROS concentrations activate stress kinases like c-Jun N-terminal kinase (JNK) and p38-mitogen activated protein kinase (MAPK) . JNK activation may link the hypertrophy to the mitochondrial dysfunction observed in HF. In fact, JNK activation not only promotes cardiomyocyte hypertrophy but also activates autophagy, through Bcl-2 and 19-KDa interacting protein-3 (BNIP3), which ultimately leads to apoptosis and mitochondrial selective autophagy (mitophagy) [43,44].
In this regard, Vacek et al. showed that an increased level of mitophagy may in turn lead to MMP activation .
4. Role of Oxidative Stress in Kidney Damage and Failure
Within the kidneys, ROS generation increases in response to specific stimuli, including Angiotensin II [46–49] and aldosterone [50,51], and it influences a number of physiologic processes.
Angiotensin II appears to act preferentially in tubular epitelial cells, whereas recent studies suggested a role of aldosterone in podocyte injury .
NOX enzymes are the primary source of ROS in vascular smooth cells in both kidney cortex and medulla [53,54]. Upon stimulation by angiotensin II and aldosterone, cytosolic subunits of NAD(P)H oxidase can translocate into the mitochondrial membrane and increase ROS production.
At least three different NOX isoforms are expressed in the kidney cortex: NOX4, NOX2 and NOX1 [55–58]. Although no strict comparisons have been performed, NOX4 appears to be the most abundantly expressed renal isoform. NOX4 is predominantly localized in renal tubular cell [55,56], but it can also be found at lower levels in other cell types, including glomerular mesangial cells [51,59].
The proposed function of NOX-derived ROS in the kidneys can be classified into three major categories: regulation of renal blood flow, alteration of cell fate and regulation of gene expression. The key mechanism by which ROS regulate renal blood flow is the reaction of superoxide anion O2− with NO, which limits its relaxing effect in afferent arterioles [49