Failing heart, failing kidney: Double trouble?

Barcelona, Spain, 30 August: Concomitant kidney dysfunction and/or worsening renal function in patients with heart failure is a frequent finding and is associated with a poor prognosis. Current treatment of heart failure has beneficial effects on cardiac function but does not favorably affect renal function. The possibility to improve renal function and/or obtain kidney protection with new drugs or devices is still uncertain.

Heart failure remains the most important cause of hospitalisation for patients aged more than 65 years and this proportion is going to increase because of aging of the general population and improvement in outcomes of most cardiac diseases. Current treatment has improved the clinical course and prognosis of chronic heart failure. However, hospitalisations for heart failure continue to be associated with a poor prognosis with in-hospital mortality rates of 4% to 9%, and post-discharge mortality and re-hospitalisation rates of 9-15% and 30-45%, respectively, in the following 6-12 months.

Comorbidities and, namely, kidney dysfunction play a major role in the poor prognosis of heart failure patients. The development, or coexistence, of kidney dysfunction in patients with heart failure is often defined as cardiorenal syndrome Current treatment has improved cardiac function but seems to have no effect on concomitant kidney dysfunction and this has become a major determinant of outcomes.

A mild to moderate impairment of kidney dysfunction is present in 40-50% of the patients admitted for acute heart failure and 30-40% of the patients develop worsening renal function, generally defined as an increase in serum creatinine >0.3 mg/dl, during their hospitalisations.

The causes of the frequent coexistence of kidney and cardiac dysfunction are multiple. First, these two conditions may share common causes, such as hypertension, diabetes, atherosclerosis, as well as common pathogenetic mechanisms, such neurohormonal and inflammatory activation and endothelial dysfunction. In addition, heart failure causes kidney dysfunction through its hemodynamic abnormalities, namely low cardiac output and increased central venous pressure. Lastly, treatment of heart failure may also favor kidney dysfunction.

Both kidney dysfunction and worsening renal function are associated with a poor prognosis in patients with heart failure. Multiple studies have consistently shown that the prognostic value of simple parameters used to assess renal function, such as BUN, serum creatinine, estimated glomerular filtration rate, is greater than that of parameters traditionally used to evaluate cardiac function, such as the left ventricular ejection fraction. Moreover, the predictive value of renal function is independent from that of other parameters related to the severity of heart failure. This suggests (but not proves!) that renal dysfunction may contribute to the poor outcome of the patients with heart failure.

There are many mechanisms by which kidney dysfunction may contribute to the poor prognosis of the patients with heart failure. First, patients with heart failure and concomitant kidney dysfunction (i.e. the cardio-renal syndrome) have a greater tendency to hydro-saline retention and are less sensitive to diuretics (namely furosemide). The administration of higher diuretic doses in patients with heart failure is also associated with a poor prognosis as it may cause greater kidney dysfunction (thus triggering a positive feedback), electrolyte abnormalities and neurohormonal activation (another deleterious mechanism). Second, patients with renal dysfunction are less likely to tolerate angiotensin converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists, drugs which have a favorable impact on prognosis in heart failure but which may further impair renal function in patients with heart failure. Kidney dysfunction is also associated with anemia, neurohormonal activation, inflammation, oxidative stress and endothelial dysfunction, all conditions that contribute to the progression of heart failure.

Based on the importance of the cardio-renal syndrome, many new agents or tools are currently studied with the aim of improving renal function or at least prevent its deterioration during hospitalisations for acute heart failure. New classes of agents are currently being tested. Vasopressin antagonists have been shown to increase water diuresis and decrease body weight in clinical trials. However, this has not been associated with an improvement in outcomes in a large trial with the vasopressin antagonist tolvaptan.

In the kidney, adenosine causes afferent glomerular arteriole constriction and its release may be triggered by an increase in the sodium load in the distal tubule as after furosemide administration. Therefore, adenosine may be a mediator of the deterioration of renal function occurring in patients with acute heart failure. In addition, it causes an increase in sodium reuptake in the proximal tubule. Adenosine antagonists are therefore currently studied with the aim of preserving renal function during treatment of acute heart failure and to enhance the diuretic and natriuretic effects of furosemide administration in patients with acute heart failure. To date, rolofylline is the first adenosine type 1A receptor antagonists studied in a large trial enrolling more than 2000 patients hospitalized for acute heart failure, the Placebo-controlled Randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute HF and volume Overload to assess Treatment Effect on Congestion and renal function Trial (PROTECT). Its results will be presented during this ESC meeting at the Hotline session III.

Other tools currently being tested to improve renal function and treat congestion in heart failure include the administration of lower doses of diuretics, the administration of vasodilators and/or inotropic agents to improve the hemodynamic abnormalities and hence renal function, and the use of new devices, such as ultrafiltration. Their efficacy will need further testing in large randomized trials.

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