The National Heart, Lung, and Blood Institute convened a Working Group of investigators on August 20, 2004, in McLean, Virginia to evaluate the current state of knowledge regarding interactions between the cardiovascular system and the kidney, to identify critical gaps in our knowledge, understanding, and application of research tools, and to develop specific recommendations for NHLBI in cardio-renal interactions related to heart failure and other cardiovascular diseases congenital heart disease.
The Working Group focused on cardio-renal connections in which abnormalities of cardiac function were not preceded by a known diagnosis of chronic kidney disease, such that acute and chronic renal responses are due to primary impairment of cardiac function. Among patients hospitalized for decompensated heart failure, worsening renal function predicts adverse cardiovascular outcomes. Since these patients are routinely excluded, clinical heart failure trials provide little evidence or information on which to base therapy for heart failure patients experiencing worsening renal function. As a result, treatment for these patients is largely empirical. The lack of formal interaction across clinical disciplines, with insight into the diverse factors that affect both cardiac and renal function, has also limited our recognition, understanding, and potential therapies for cardio-renal dysregulation in heart failure. New and effective therapies need to be identified for the treatment and prevention of this challenging syndrome. The deliberations and considerations of this Working Group should broaden the perspective and enhance understanding across traditional specialty boundaries.
A working definition of cardio-renal dysregulation was introduced and served as the basis of subsequent discussion and recommendations. In heart failure, it is the result of interactions between the kidneys and other circulatory compartments that increase circulating volume and symptoms of heart failure and disease progression are exacerbated. At its extreme, cardio-renal dysregulation leads to what is termed "cardio-renal syndrome" in which therapy to relieve congestive symptoms of heart failure is limited by further decline in renal function. It is clear that our current understanding of cardio-renal connections is inadequate to explain many of the clinical observations in heart failure or to direct its therapy. Further investigation is required to elucidate the pathways by which integration of the cardiovascular and renal systems effectively maintains volume regulation in order to develop effective therapies.
The following recommendations are proposed. They focus primarily on clinical studies in subsets of patients with heart failure:
- Asymptomatic patients with left ventricular dysfunction measured by reduced EF. Studying the physiologic response to volume challenge, prior to the onset of clinical volume overload, will help determine the mechanisms and time course by which volume retention develops during heart failure progression. Clinical studies should be supported by studies in suitable animal models.
- Patients with preserved EF but a risk profile (hypertension, diabetes, advanced age) for heart failure. Studying the physiologic response to volume challenge in these patients, both with and without history of prior clinical fluid retention, will provide the opportunity to compare and contrast mechanisms of primary fluid retention.
- Patients with compensated symptomatic heart failure. A particular priority for these patients is studying of the effects of exercise training on the components of volume regulation. Studying these patients will also improve our understanding of the dynamics of the response to volume challenge during stabilization with diuretic, ACE inhibitor, and beta blocker therapy.
- Patients with advanced or severe heart failure at high risk to develop cardio-renal syndrome. This study should include a three-prong comparison of standard therapy without restriction, newer neurohormonal modulation, and techniques of direct fluid removal. Even though these patients are complex physiologically and inter-individual variations make it difficult to elucidate isolated mechanisms, treatment is an urgent issue because of the size of this population.
- An additional recommendation was to formalize collaboration between nephrologists, cardiologists, and experts in hypertension and diabetes to study cardio-renal connections. The overwhelming sentiment of the Working Group participants is that the integrative nature of the physiologic principles and the vast numbers of affected patients mandate transcendence of traditional specialty boundaries. An ongoing working group should be established with specific formalized links to the relevant branches of the National Institutes of Health and sub-specialty organizations. An initial responsibility of this ongoing working group would be to review progress to understand primary fluid retention and the interventions to improve renal function in cardiac disease.
The report will be posted on the NHLBI public web site with a link to the journal or journals where the report is published.
Frank Evans, Ph.D., NHLBI, NIH
John Fakunding, Ph.D.