Cardiorenal Syndrome: A Physician Perspective

Cardiac diseases are associated independently with decrease in kidney function and progression of existing kidney diseases. Conversely, chronic kidney disease (CKD) represents an independent risk factor for cardiovascular events and outcomes. Renal dysfunction frequently accompanies cardiac failure and that cardiac dysfunction frequently accompanies renal failure. This interdependent relationship has come to be known as the “cardiorenal syndrome”. Direct and indirect effects of each organ that is dysfunctional can initiate and perpetuate the combined disorder of the two organs through a complex combination of neurohormonal feedback mechanisms. In this review pathophysiology and management of fi ve different subtypes of cardiorenal syndrome is discussed. Case Report Cardiorenal Syndrome: A Physician Perspective Deepak Jain1*, HK Aggarwal2, Promil Jain3 and Pulkit Chhabra4 1Associate Professor, Department of Medicine, India 2Senior Professor and Head, Department of Medicine III, India 3Assistant Professor, Department of Pathology, India 4Resident, Department of Medicine, India Dates: Received: 25 January, 2017; Accepted: 03 March, 2017; Published: 06 March, 2017 *Corresponding author: Deepak Jain, Doctor, Department of Medicine, PGIMS, Rohtak-124001 (Haryana), India, Tel: +91-9416147887; E-mail:


Introduction
Cardiac diseases are associated independently with decrease in kidney function and progression of existing kidney diseases. Conversely, chronic kidney disease (CKD) represents an independent risk factor for cardiovascular events and outcomes. Acute decompensated heart failure, cardiac ischemia, and arrhythmia may lead to acute impairment of kidney function through renal arterial under fi lling and a drop in renal blood fl ow secondary to low cardiac output.
Investigative and therapeutic procedures such as percutaneous coronary intervention, coronary artery bypass surgery, or fi brinolytic therapy can also lead to impaired kidney function Data from the Acute decompensated Heart Failure National Registry (ADHERE) of over 100,000 patients admitted with acute decompensated heart failure(ADHF) revealed that almost one third of patients have a history of renal dysfunction [1].
An acute increase in serum creatinine level accompanies 21%-45% of hospitalizations for ADHF, depending on the time frame and magnitude of creatinine level increase. In patients with ADHF, an acute increase in serum creatinine level > 0.3 mg/dl is associated with increased mortality, longer hospital stay and more frequent readmissions. 39% patients in New York Heart Association (NYHA) class 4 and 31% of patients in NYHA class 3 had severely impaired renal function (creatinine clearance <30 ml/minute) [2]. Decreased kidney function also present as a signifi cant comorbid condition in approximately 50% of patients with chronic heart failure. Renal failure is clearly linked with increased adverse cardiovascular outcomes.
Almost 44% of deaths in patients with end-stage renal disease (ESRD) are due to cardiovascular diseases [3]. Meta-analysis indicated that patients with ESRD are more likely to die from cardiovascular causes than from renal failure itself. Death from cardiovascular causes is 10-20 times more common in patients with chronic renal failure than in matched segments of the general population [4]. It should therefore come as little surprise that renal dysfunction frequently accompanies cardiac failure and that cardiac dysfunction frequently accompanies renal failure. This interdependent relationship has come to be known as the "cardiorenal syndrome". Cardiorenal syndrome (CRS) is thus defi ned as "disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other". The mechanism underlying the interplay of cardiac failure and kidney dysfunction is still not completely understood.

Cardiorenal Connection
Both heart and the kidneys are richly vascular (the kidneys are more vascular than the heart) and both organs are supplied by sympathetic and parasympathetic innervations. These two organs act in tandem to regulate blood pressure, vascular tone, diuresis, natriuresis, intravascular volume homeostasis, peripheral tissue perfusion and oxygenation. They have endocrine functions with interdependent physiological hormonal actions regulated by arterial natriuretic peptide, a vasodilator secreted from the heart and renin-angiotensinaldosterone system (RAAS). Dysfunction of either of the two organs can cause dysfunction of the other. Changes in the RAAS, the imbalance between nitric oxide (NO) and reactive oxygen species (ROS), the sympathetic nervous system (SNS) and infl ammation are the cardiorenal connectors to develop CRS [2].
Previous terminology did not allow physicians to identify and fully characterize the chronology of the pathophysiological interactions that characterize a specifi c type of combined heart/kidney disorder. A diseased heart has numerous negative effects on kidney function but, at the same time, renal insuffi ciency can signifi cantly impair cardiac function. Thus, direct and indirect effects of each organ that is dysfunctional can initiate and perpetuate the combined disorder of the 2 organs through a complex combination of neurohormonal feedback mechanisms. For this reason, a subdivision of CRS into 5 different subtypes seems to provide a more concise and logically correct approach [5]. The various subtypes of cardio renal syndrome are depicted in Table 1 Pathophysiology Recent advances in basal and clinical sciences have

The low-Flow-State hypothesis
Progressive decline in GFR observed in HF primarily refl ects inadequate renal perfusion secondary to reduced cardiac output. Inadequate renal blood fl ow or perfusion pressure prompts renin release by the juxtaglomerular cells of the afferent arterioles through low-fl ow states in the ascending limb of the loop of Henle and pressure-sensing baroreceptors.
Renin release and RAAS activation confer extreme sodium avidity, volume retention, decreased glomerular perfusion (i.e. afferent arteriolar constriction), and profi brotic neurohormone increases, leading to ventricular remodeling and thus worsening pump failure [6]. However recent work especially ESCAPE trial founding no correlation between improvement of cardiac index with renal functions lead to conclusion that there is much more than simply reduced blood fl ow to explain the pathophysiology of CRS [7].

Renin-Angiotensin-Aldosterone axis and oxidative injury
The extreme sodium and water retention along with ventricular remodeling conferred by RAAS elaboration in HF are a maladaptive response to altered hemodynamics, sympathetic signaling, and progressive renal dysfunction. System in heart failure patients, increasing both preload and afterload and thus myocardial oxygen demands. Ang II activates the enzyme NADPH oxidase in endothelial cells, vascular smooth muscle cells, renal tubular cells, and cardiomyocytes [9][10][11]. This leads to the formation of ROS, mostly superoxide. A growing body of evidence suggests that ROS are responsible for the processes of aging, infl ammation, and progressive organ dysfunction. Nitric oxide (NO) is responsible for vasodilation and natriuresis and assists in renal control of ECFV. Superoxide antagonises these effects but also reduces bioavailability of NO. 8 Oxidative stress damages DNA, proteins, carbohydrates, and lipids and also shifts cytokine production towards pro infl ammatory mediators such as interleukin-1, interleukin-6, and tumour necrosis factor alpha. Interleukin-6 also stimulates fi broblasts leading to increased cardiac and renal fi brosis [12]. These cytokines hormones. This problem is compounded in patients with HF with advanced renal insuffi ciency because there is reduced clearance of catecholamines by the kidneys [13]. SNS activation also increase the release of neuropeptide Y which is a vascular growth promoter.it causes neointimal proliferation, leading to atherosclerosis,vasoconstriction and interfere with normal immune system function [14].

Endothelin effects
The release of endothelin has some adverse effects because it causes vasoconstriction and induces hypertrophy of cardiac myocytes. Moreover, it stimulates and potentiates noradrenaline, angiotensin II and aldosterone [15].

Arginine vasopressin effects
Arginine vasopressin (AVP), too, has adverse effects on CRS progression by fl uid retention and potentiation of angiotensin II and noradrenaline actions. It also stimulates myocardial hypertrophy [16].

Drugs and Toxins
Some drugs may have harmful effects in the progression of CRS. Inotropic drugs augment neurohormonal activation.
High-dose diuretics produce hypovolemia, and intravenous vasodilators cause hypotension. Contrast agents also found to have same effects and enhance progression of CRS.

Biomarkers of cardiorenal syndromes
For decades, the rise in serum creatinine has been the only detectable sign of a reduction in glomerular fi ltration. Creatinine has had the disadvantages of being linked to creatine and the overall body muscle mass, hence, differing according to body size in addition to the rate of renal elimination. Furthermore, the kidney both fi lters and secretes creatinine. Hence, there is a clear need for better laboratory markers of renal fi ltration unlike cardiac biomarkers indicating myocardial injury and overload (troponin, creatine kinase myocardial band, and natriuretic peptides), the fi eld of nephrology has been devoid of approved blood or urine markers of AKI. Thus, the current paradigm is that when renal injury occurs, clinicians must wait to observe a reduction in GFR before AKI is inferred. The concept of measuring makers of the acute injury process is crucial to the early upstream identifi cation of AKI before there is serious loss of organ function. Some emerging novel biomarkers are useful in the setting of both cardiac and renal dysfunction are depicted in Table 2 [17].

Prevention and Management
Acute cardiorenal syndrome: type 1 Avoidance of volume depletion, removal of superimposed renal toxic agents, minimization of the toxic exposure (iodinated contrast, time on cardiopulmonary bypass) and the use of antioxidant agents such as N-acetylcysteine and BNP in the perioperative period after cardiac surgery can act as a preventive measure. Use of continuous renal replacement therapy (CRRT) can also be useful as it ensures euvolemia and avoids hypo-or hypervolemia and provides sodium and solute (nitrogenous waste products) removal.
In case of acute decompensated heart failure or cardiogenic shock, diuretics should be used to deplete the extracellular fl uid

Secondary cardiorenal syndromes: type V
There are no proven methods to prevent or ameliorate this form of CRS at this time. Supportive care with a judicious intravenous fl uid approach and the use of pressor agents as needed to avoid hypotension are reasonable but cannot be expected to avoid AKI or cardiac damage [22].
It is diffi cult to formulate a common treatment strategy, as type V CRS includes a heterogeneous group of disorders such as sepsis, SLE, amyloidosis and diabetes mellitus. Therapies directed to the improvement in function of one organ need to consider the interaction with, and role of the other ,as injury to one organ is likely to infl uence or injure the other organ and vice versa.

Future directions in treatment of cardiorenal syndrome
Potentially promising pharmacological approaches include selective adenosine A1 receptor blockers as adenosine lowers cortical blood fl ow, resulting in anti-natriuretic responses. A1 receptor antagonists have been shown to cause diuresis and natriuresis while minimally affecting potassium excretion or glomerular fi ltration [23]. Vasopressin antagonists (V2 receptor antagonists "vaptans", e.g. conivaptan and tolvaptan) have also been proved useful [24]. Other interventions include the earlier use of dialysis and ultrafi ltration, and ultimately, left ventricular assist devices to manage these patients effectively, at least in the short-term.

Conclusion
The various subtypes of CRS present unique challenges because therapies directed at one organ may have benefi cial or detrimental effect on the other. Better understanding of the bidirectional pathways by which the heart and kidneys infl uence each other's function is necessary to tailor therapy appropriate to the situation. A multi-disciplinary approach that includes the nephrologist, cardiologist, and intensive care specialist is preferred.