Heart failure treatment and renal function
Article Outline
Surprisingly, in the absence of pre-existing renal insufficiency, renal function often remains normal or near normal until the late stage of life in patients with advanced heart failure. Selective distribution of depressed cardiac output to essential organs, including the kidney, successfully protects this organ from functional deterioration. Also, inaccurate reflection of renal function measured with serum creatinine may contribute to the apparent preservation of renal function as the syndrome of chronic heart failure (CHF) progresses. However, in contrast to patients without pre-existing renal insufficiency, patients with renal insufficiency frequently experience a worsening of renal function when they are hospitalized for decompensated CHF.
Unfortunately, the coexistence of chronic renal insufficiency (CRI) and CHF is common, because these 2 syndromes share common predisposing conditions. Hypertension, coronary artery disease, and diabetes mellitus are the leading predisposing conditions for CHF. Additionally, hypertension and diabetes mellitus are overwhelmingly the predisposing conditions for CRI (Figure 1). It is no surprise that patients with CHF and CRI have a worse prognosis and more frequent complications during hospitalization than patients with CHF and preserved renal function. The worse clinical prognosis of patients with CRI is not specific to the syndrome of CHF. Patients with a history of cerebral vascular accident, with a history of myocardial infarction, and after open-heart surgery experience a worse clinical course when CRI is present.1
Figure 1.
The major predisposing conditions to CHF and CRI involve the peripheral circulartion, coronary circulation, or both (large circle). Hypertension, coronary artery disease, and diabetes mellitus are the predisposing conditions for CHF (medium circle). Hypertension and diabetes mellitus are the predisposing conditions for CRI (small circle). The area shared by the intersection of the 2 small circles contains the patients with CHF and CRI. They have a worse clinical outcome than patients with only CHF or CRI.
Analogous to the hepatorenal syndrome, further deterioration of renal function during hospitalization for CHF is increasingly referred to as the cardiorenal syndrome. The mechanisms that lead to worsening of renal function when patients with pre-existing renal insufficiency are hospitalized for decompensated CHF are incompletely understood. Loss of selective redistribution of cardiac output, cyclooxygenase inhibition, decreased effective arterial blood volume despite increased plasma volume as a result of vasodilator therapy, overzealous use of diuretics, and anemia are all likely precipitants of the cardiorenal syndrome.
Activation of the renin-angiotensin system (RAS) increases efferent glomerular arteriolar vasoconstriction and thereby contributes to preserve glomerular filtration rate despite a reduction in renal blood flow in patients with CHF. However, partial deactivation of the RAS with angiotensin-converting enzyme (ACE) inhibitors consistently exerts clinical benefits, including prolonged life expectancy in patients with CHF. However, at a very late stage of the syndrome of CHF, patients often become unable to tolerate ACE inhibitors because of worsening of renal function.2 Patients unable to tolerate ACE inhibitors have a poor prognosis, as evidenced by a mortality rate of 57% at 8.5 months. These patients often require high doses of loop diuretics to control their symptoms. In addition to the use of ACE inhibitors, age, baseline renal dysfunction, and atrial fibrillation increase the risk of worsening of renal function in patients who are hospitalized with CHF.3
In the observational study reported by Butler et al in this issue of the Journal, patients who experienced a worsening of renal function during their hospitalization received higher doses of loop diuretics than patients who did not experience a worsening of renal function.4 The use of calcium channel antagonists was also more prevalent in patients who experienced worsening renal function during their hospitalization. In contrast to the most recent report from their colleagues,2 Butler et al failed to observe an association between the use of ACE inhibitors and worsening renal function.
The association of poor clinical outcome and high doses of loop diuretics noted by the Prospective Randomized Amlodlpine Survival Evaluation (PRAISE) investigators indirectly supports the observation of Butler et al.5 Worsening renal function may partially explain the detrimental effects of high doses of loop diuretics on clinical outcome. However, whether high doses of loop diuretics are responsible for worsening of renal function in patients hospitalized for CHF or only reflect the severity of symptoms and a precarious hemodynamic state cannot be ascertained from the data presented by Butler et al. The dismal clinical outcome observed in patients receiving high-dose loop diuretics who are unable to tolerate ACE inhibitors argues in favor of the latter possibility. Overzealous use of loop diuretics may also have been responsible for intravascular volume depletion that resulted in worsening of renal function in some patients reported by Butler et al. Records of oral intake and urinary output are notoriously unreliable in patients hospitalized with CHF, and subsequent fluid replacement may prevent recognition of intravascular depletion by measured body weight.
The potential detrimental effects of loop diuretics on renal function may be caused acutely by decreased glomerular perfusion or more chronically by direct toxic action resulting in interstitial nephritis. Intravenous administration of a loop diuretic acutely decreases glomerular function by mechanisms that are still incompletely understood.6 Additionally, oral administration of a loop diuretic for 1 month has been demonstrated to increase plasma renin and aldosterone activity in therapeutically naive patients with CHF.7 Consequently, the detrimental effects of loop diuretics on renal function may partially be attributed to increased neurohormonal activation that decreases renal flow and alters its distribution within the renal parenchyma.
Recent availability of novel means of fluid extraction will allow us to conduct randomized trials aimed at differentiating the direct effects of loop diuretics on the kidneys from the effects resulting from rapid removal of intravascular fluid. BG9719 is an A1 adenosine receptor antagonist that promotes diuresis without worsening renal function.6 Alternatively, the Simple Access Fluid Extraction (SAFE) ultrafiltration device (UFC 100, CHF Solutions, Minneapolis, Minn) is a peripherally inserted filtration device that may allow for safe and rapid removal of extracellular and intravascular fluid volume excess without the need for central venous catheter placement.8 Confirmation that patients who are hospitalized with CHF and receive high doses of loop diuretics are independently at increased risk of worsening renal function will await the results of these randomized trials involving the removal of fluid by safe pharmacological means or by devices allowing ultrafiltration at moderate cost and risk to the patient.
References
- Correlates and impact on outcomes of worsening renal function in patients ≥65 years of age with heart failure. Am J Cardiol. 2000;85:1110–1113
- Development of circulatory-renal limitations to angiotensin-converting enzyme inhibitors identifies patients with severe heart failure and early mortality. J Am Coll Cardiol. 2003;41:2029–2035
- . Aggravated renal dysfunction during intensive therapy for advanced chronic heart failure. Am Heart J. 1999;138:285–290
- Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004;147:331–8
- Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J. 2002;144:31–38
- BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation. 2002;105:1348–1353
- Untreated heart failure (clinical and neuroendocrine effects of introducing diuretics). Br Heart J. 1987;57:17–22
- Peripherally inserted veno-venous ultrafiltration for rapid treatment of volume overloaded patients. J Card Fail. 2003;9:227–231
PII: S0002-8703(03)00709-9
doi:10.1016/j.ahj.2003.10.003
© 2004 Mosby, Inc. All rights reserved.
