NHLBI Working Group
Cardio-Renal Connections in Heart Failure and Cardiovascular Disease
August 20, 2004
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
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
- 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.
Last updated: February 18, 2005