Renal effects of ACE inhibitors in heart failure

INTRODUCTION — Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of heart failure. These agents decrease the formation of angiotensin II, thereby decreasing both arteriolar and venous resistance. This vasodilator effect causes immediate improvement in the symptoms of heart failure by decreasing left ventricular afterload, thereby increasing cardiac output and decreasing left and right heart filling pressures, which ameliorates pulmonary and systemic venous congestion. Due to their pleiotropic effects on various target organs including the heart, vasculature, and kidneys, ACE inhibitors slow the rate of progressive cardiac dysfunction and produce an approximately 25 percent reduction in cardiovascular mortality at one to three years [1-4]. In addition, the administration of an ACE inhibitor after an acute myocardial infarction can preserve cardiac function (as evidenced by an increased ejection fraction and slowed ventricular enlargement) and improve long-term survival [5].

●(See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".)

●(See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.)

An ACE inhibitor given with a loop diuretic may have the additional advantage of raising the plasma sodium concentration in patients with heart failure and hyponatremia [6]. This synergism may reflect factors that result in an increase in free water excretion. (See "Hyponatremia in patients with heart failure".)

In addition to a possible elevation in free water excretion, ACE inhibitors have other renal actions in heart failure, including changes in the glomerular filtration rate (GFR), reduced potassium excretion that can lead to hyperkalemia, and variable effects on the natriuretic response to diuretics.

EFFECT ON GLOMERULAR FILTRATION RATE — In view of the improvement in cardiac output and in renal blood flow, it might be assumed that ACE inhibitors would also increase the glomerular filtration rate (GFR). However, this expected response occurs in only 10 to 25 percent of patients, while an increase in the plasma creatinine concentration is a more common finding [7-9]. As an example, the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial of patients with severe heart failure noted a mean elevation in the plasma creatinine concentration of 0.1 to 0.2 mg/dL (10 to 20 micromol/L); furthermore, 11 percent of patients had more than a 100 percent rise in the plasma creatinine concentration [8]. This usually modest decline in GFR occurs within the first week; kidney function then tends to be stable unless a complicating factor, such as worsening of cardiac function, is superimposed [8].

A reduction in GFR in heart failure is most likely to occur in those settings in which maintenance of the GFR is dependent upon high ambient angiotensin II levels [6-10]:

●Patients on high-dose diuretic therapy in whom there is relative hypovolemia due to excessive diuresis

●Patients with relative hypotension (mean arterial pressure below 75 mmHg) after therapy, which is usually reflective of a low cardiac output and associated low renal blood flow

●Patients with a pretreatment plasma sodium concentration below 137 mEq/L, which is a marker for marked neurohumoral activation

●Patients with significant renovascular disease, a common finding among older adults with heart failure [10]

In theory, the plasma renin activity should also identify patients at risk. However, measurement of the plasma renin activity is not a useful clinical test because circulating renin may not reflect the activity of tissue renin-angiotensin systems (see "Renin-angiotensin system inhibition in the treatment of hypertension"). As an example, patients with stable heart failure may have a normal plasma renin activity [11]. However, studies in animals with heart failure have shown that the intrarenal renin-angiotensin system may still be activated in this setting, an appropriate response to the fall in kidney perfusion [12]. Thus, even in patients with a normal plasma renin activity, an ACE inhibitor may lower the GFR by decreasing intrarenal angiotensin II.

The ACE inhibitor-induced fall in GFR in heart failure is due, at least in part, to a preferential reduction in efferent arteriolar resistance in the glomerulus, which leads to a reduction in intraglomerular pressure, which is the primary driving force for glomerular filtration. The baseline level of glomerular filtration can often be restored by lowering the diuretic dose, thereby decreasing the angiotensin II dependence of glomerular filtration. In addition, use of nonsteroidal antiinflammatory drugs should be avoided, if possible. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Worsening renal function'.)

It has also been suggested that a decline in GFR may be less likely to occur with a short-acting ACE inhibitor such as captopril [13]. This observation was based upon a study in which relatively high doses of enalapril were used [13]. Initiating therapy with a low dose of enalapril or lisinopril (as with 2.5 mg of enalapril) is probably as safe as captopril in most patients [1,6,14].

Studies in experimental animals suggest that there may be differences in the degree to which individual ACE inhibitors inhibit tissue-converting enzymes in the presence of heart failure. As an example, enalapril may be a more potent inhibitor of renin ACE than captopril; rather than leading to a reduction in GFR, this change may lead to a moderate increase in sodium excretion, a possible reflection of diminished proximal sodium reabsorption due to removal of the normal stimulatory effect of angiotensin II [15]. The relevance of these findings to humans remains to be proven.

Patients who also have chronic kidney disease — Due to the potential that ACE inhibitors may lower GFR, they tend to be underused in patients with heart failure who also have chronic kidney disease. However, several studies suggest that the beneficial effects of ACE inhibitors and angiotensin receptor blockers (ARBs) on mortality and heart failure hospitalization extend to patients with chronic kidney disease and impaired kidney function [16].

Approach to changes in glomerular filtration rate — The decline in GFR induced by an ACE inhibitor in heart failure can be minimized or prevented by the combination of low initial doses plus a transient decrease in diuretic dosage [7]. The plasma creatinine and potassium concentrations should be measured within the first week since a deleterious change in renal hemodynamics or potassium excretion should occur in this time period [8].

Our approach to deleterious changes in kidney function after initiation of ACE inhibitor therapy are as follows:

●The ACE inhibitor should be stopped, and specialist advice should be sought, if any of the following occur:

•The serum creatinine increases by more than 100 percent above baseline

•The serum creatinine rises to above 3.5 mg/dL (310 micromol/L)

•The estimated GFR falls to below 20 mL/min/1.73 m²

●The dose of the ACE inhibitor should be decreased by one-half, and the creatinine should be repeated in approximately one week, if any of the following occur:

•The serum creatinine increases to a level that is 50 to 100 percent above baseline

•The serum creatinine increases to a level between 3 and 3.5 mg/dL (266 to 310 micromol/L)

•The estimated GFR fall to a level between 20 and 25 mL/min/1.73 m²

If the response to decreasing the dose is not satisfactory, specialist advice should be sought.

●By contrast, the following changes in kidney function are generally considered acceptable:

•An increase in serum creatinine of up to 50 percent above baseline

•An increase in serum creatinine up to 3 mg/dL (266 micromol/L)

•An estimated GFR that falls as low as 25 mL/min/1.73 m²

HYPERKALEMIA — Patients with underlying kidney function impairment are also at higher risk for the development of hyperkalemia following the administration of an ACE inhibitor [6,17]. Advanced heart failure is associated with decreased sodium and water delivery to the potassium secretory site in the collecting tubules. Maintenance of adequate potassium secretion in these patients is dependent upon increased secretion of aldosterone, a response that may be partially impaired if there is diminished production of angiotensin II (since angiotensin II is the primary mediator of the hypoperfusion-induced increase in aldosterone release). The risk of hyperkalemia is increased with the concomitant administration and/or uptitration of an aldosterone antagonist such as spironolactone.

NATRIURETIC RESPONSE TO DIURETICS — Although ACE inhibitors commonly decrease the glomerular filtration rate (GFR) due to their differential effects on proximal and distal glomerular arterioles, ACE inhibitors can increase the natriuretic response to diuretics under certain circumstances. As an example, when acutely given in very low doses (eg, 1 mg of captopril), the response to a loop diuretic is enhanced. This may be mediated by a decline in proximal sodium reabsorption induced by the reduction in intrarenal angiotensin II [18]. The GFR is stable in this setting, presumably because sufficient angiotensin II is available to sustain efferent arteriolar tone. At higher doses, however, both a fall in systemic blood pressure and, as described above, a decrease in GFR can occur that may attenuate the diuretic response by as much as 50 percent [18,19].

This interplay between ACE inhibitors and diuretics may be clinically important. One study that evaluated patients chronically treated with captopril (given at 12.5 mg three times daily) found that ACE inhibition moderately increased the diuretic response to furosemide by approximately 20 percent, despite reductions in blood pressure and GFR [20]. In another study, captopril administration to patients who had been diuretic resistant on therapy with hydralazine or nitroprusside improved diuretic responsiveness and also improved GFR and renal blood flow [21]. Because ACE inhibitors are relatively selective for renal arteries, the increase in renal blood flow with ACE inhibitors for any given increase in cardiac output is greater than with nonselective vasodilators such as hydralazine or inotropes such as dobutamine [22].

SUMMARY AND RECOMMENDATIONS

●Effects on kidney function – Approximately 10 to 25 percent of patients with heart failure have improvement in kidney function after initiation of angiotensin-converting enzyme (ACE) inhibitors, presumably due sequentially to an improvement in cardiac output and increase in renal blood flow. However, a worsening of glomerular filtration rate (GFR) is more common. Worsening of GFR is due, at least in part, to reduction of efferent arteriolar resistance superimposed on relatively low kidney perfusion. A reduction in GFR in heart failure is most likely to occur in the following settings (see 'Effect on glomerular filtration rate' above):

•Patients on diuretic therapy in whom there is relative hypovolemia

•Patients with relative hypotension (mean arterial pressure below 75 mmHg) after therapy

•Patients with a pretreatment plasma sodium concentration below 137 mEq/L

•Patients with significant renovascular disease

●Monitoring – This usually modest decline in GFR occurs within the first week; kidney function then tends to be stable unless a complicating factor, such as worsening of cardiac function, is superimposed. Thus, the plasma creatinine and potassium concentrations should be measured within the first week since a deleterious change in renal hemodynamics or potassium excretion should occur in this time period. (See 'Approach to changes in glomerular filtration rate' above.)

Patients with underlying kidney function impairment and those taking aldosterone antagonists are at higher risk for the development of hyperkalemia following the administration of an ACE inhibitor. (See 'Hyperkalemia' above.)