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- ↵⁎Reprint requests and correspondence:
Dr. Larry A. Weinrauch, Harvard Medical School, 521 Mt. Auburn Street, Suite 204, Watertown, Massachusetts 02472.
Markedly depressed cardiac function may be associated with decreased glomerular filtration rate (GFR) as renal perfusion diminishes; conversely, lower GFR has been associated with increased risk for cardiovascular events in population studies (1) and in studies of patients with systolic dysfunction (2,3), coronary artery disease (4), or heart failure (5). Moreover, worsening of renal function has been associated with adverse prognosis in heart failure (HF) patients (6,7). The exact mechanisms by which renal dysfunction contributes to increased cardiovascular risk remain to be elucidated.
Current management of symptomatic HF exacerbations is focused on reduction of both pre-load and afterload, the former accomplished primarily through pharmacologic fluid removal and venodilator drugs, with volume removal through ultrafiltration an option in the most critically ill patients, and the latter accomplished through the use of vasodilator agents, primarily inhibitors of the renin-angiotensin-aldosterone system (RAAS). All of these approaches have the potential to increase serum creatinine (SCr) and lead to worsening renal function. Nevertheless, inhibition of the RAAS, an approach that can reliably increase SCr, has been shown to retard the progression of renal disease and improve cardiovascular outcomes in patients with reduced renal function (8,9).
It is not uncommon for clinicians to respond to progressive SCr elevation with reduction or cessation of diuretics or inhibitors of the RAAS in HF patients. However, whether alterations in pharmacologic management—particularly diuretics—are warranted in the setting of creatinine elevation remains unclear. The data from the ESCAPE (Evaluation Study of Congestive heart failure And Pulmonary artery catheterization Effectiveness) trial published in this issue of the Journal (10) adds further insight into problems faced by clinicians when a patient with systolic dysfunction (ejection fraction ≤30%) presents with HF and renal dysfunction. The ESCAPE trial was designed to assess whether the use of pulmonary artery hemodynamic measurements in the treatment of HF patients would improve overall morbidity and mortality over 6 months. In this study of 433 hospitalized patients, mean SCr on admission was 1.5 mg/dl (maximum SCr ≤3.5 mg/dl and admission systolic blood pressure ≤125 mm Hg), and estimated baseline GFR was <60 ml/min in 117 (27%) patients. This secondary analysis focused on the relationship between baseline and in-hospital changes in SCr and estimated GFR and death and rehospitalization at 6 months. Predictors of interest for patient outcomes at 6 months included SCr and estimated GFR at admission, changes in renal function during hospitalization, use of diuretics and vasodilators during the hospitalization, and treatment assignment.
While the findings suggest that baseline GFR was predictive of outcome, as has been shown in prior studies, elevation of SCr ≥0.03 mg/dl, the standard definition of worsening renal function (6,7), during hospitalization had less impact on prognosis than did baseline renal function. There are a number of potential explanations for these results. First, a change in SCr from 1.5 to 1.8 mg/dl represents a greater absolute loss of renal function than a change from 3.0 to 3.3 mg/dl. Therefore, the impact of a ≥0.3 mg/dl rise in SCr may differ based on baseline renal function. Second, elevations in SCr may have different prognostic implications depending on the patient population and therapies utilized. In patients with HF, aggressive use of diuretics and inhibitors of the RAAS, which may improve both symptoms and possibly outcomes, are likely to result in increases in SCr. Indeed, in a randomized trial comparing the angiotensin-converting enzyme inhibitor captopril to placebo in patients with systolic dysfunction after myocardial infarction, worsening renal function—defined in the same way as in ESCAPE—was associated with adverse outcomes in patients randomized to the placebo group, but not in patients receiving captopril (11).
The authors suggest that “risk factors for renal disease probably make the kidney more susceptible to cardiac compromise” (10). We can also speculate that normal compensatory mechanisms that maintain GFR are overwhelmed by the circulatory changes that occur in HF when intrinsic renal disease is present, as it almost certainly is in most of these patients since hemodynamic parameters of poor forward flow correlated poorly with baseline renal dysfunction. History of hypertension or diabetes (both conditions that promote progressive renal scarring) and thiazide use (whose addition to loop diuretics is often needed to promote adequate diuresis in patients with chronic kidney disease) was also significantly associated with worsening of renal function, and provides further evidence that many in this study cohort had covert intrinsic kidney disease.
If elevations in SCr are less important than initial renal function in HF patients, should we continue to withdraw beneficial medications in the setting of moderate increases in SCr levels in the absence of uremic symptoms, or would our patients benefit to a greater extent from a strategy of optimizing hemodynamics? Further diuresis in the HF patients whose creatinine has increased might still lead to reduced atrial stretch, lower brain natriuretic peptide, and reduced tendency to atrial arrhythmias. The cardiology community has been skittish in general about utilizing proven medication, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, in the setting of renal dysfunction, despite encouragement and evidence from the renal community. Still, creatinine elevations may increase the risk of adverse events such as hypotension or hyperkalemia (12), and heightened surveillance is warranted in this setting.
Nohria et al. (10) underscore the extremely high morbidity and mortality in those with cardiorenal disease. These data reinforce the need for further basic research to clarify the mechanisms that underlie the increased risk associated with renal dysfunction along with well-designed clinical studies to further explore the implications of medical interventions in patients with both heart and kidney disease.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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