Role of adenosine antagonism in the cardio-renal syndrome: Pathophysiology and therapeutic potential

Abstract

The adversarial relationship between the heart and the kidney in heart failure results from normal homeostatic mechanisms which become inappropriate in the setting of heart failure. The cardio-renal syndrome represents the sum total of this adversarial relation and is clinically manifest as worsening renal function limiting diuresis in spite of volume overload. Tubuloglomerular feedback is a major pathophysiologic component of this syndrome. Adenosine, acting via A1 receptors, plays a major role in tubuloglomerular feedback in the normal state and in cardio-renal syndrome. Preclinical studies and initial human studies suggest that adenosine antagonism increases diuresis and preserves glomerular filtration in the setting of decompensated heart failure. Considering the ubiquitous distribution of adenosine receptors in the body, it is crucial to tailor this therapeutic agent to avoid side effects, especially neurotoxicity. Larger studies are presently underway to understand the therapeutic potential of this novel class of agents.

Pathophysiological model of chronic heart failure complicated with renal failure caused by three-quarter nephrectomy and subcutaneous injection of isoprenaline

“…Inflammation and activation of the RAAS promotes the occurrence and development of cardiorenal failure. Hemodynamic changes cause an increase in Ang II release, vasoconstriction, contraction of the efferent glomerular arteriole, cardiac remodeling and an increase in aldosterone release, as well as water and sodium retention, which promote myocardial fibrosis (20). …”

Cardiorenal Syndromes – Recommendations from Clinical Practice Guidelines: The Cardiologist's View

“…Additionally, adenosine increases sodium uptake at the level of the proximal and distal tubule and collecting duct. Thus, adenosine A1 receptor blockers may become an interesting tool in the treatment of acute HF with impaired renal function, and trials with these agents are currently ongoing [8]. Hyponatremia is common in patients with acute HF, being associated with more severe clinical status, renal dysfunction, and high morbidity and mortality.…”

Organ Cross Talk in the Critically Ill: The Heart and Kidney

“…Additionally, adenosine release from the macula densa in response to increased sodium delivery results in afferent arteriolar vasoconstriction, which decreases GFR and renal blood flow and likely increases renal sodium avidity further. Increased proximal tubular sodium reabsorption is likely a luminal effect of adenosine [25,26] .…”

“…In the setting of heart failure and attempted diuresis, however, this mechanism becomes maladaptive, resulting in diuretic resistance and contributing to decreased GFR. Adenosine appears to mediate these effects by causing afferent arteriolar vasoconstriction and increased proximal tubular sodium reabsorption [26,62] . There are multiple adenosine receptor subtypes throughout the body's various tissues.…”