Version May 2024
INTRODUCTION — The effect of angiotensin-converting enzyme (ACE) inhibitors on kidney function in the patient with hypertension is related both to the glomerular actions of angiotensin II and the mechanism of autoregulation of the glomerular filtration rate (GFR) [1]. Angiotensin II constricts both the afferent (preglomerular) and efferent (postglomerular) arterioles but preferentially increases efferent resistance [2]. At least three factors may contribute to this response:
●The efferent arteriole has a smaller diameter in the basal state; as a result, further constriction at this site will produce a greater increase in resistance than at the afferent arteriole [2].
●Angiotensin II stimulates the release of the vasodilator nitric oxide from the afferent arteriole, thereby minimizing constriction at this site [3].
●Angiotensin II minimizes vasoconstriction at the afferent arteriole via the stimulation of angiotensin II type 2 receptors, which results in vasodilation through a cytochrome P450-dependent pathway [4-6].
The net effect of the more prominent increase in efferent tone is that the intraglomerular pressure is stable or increased, thereby tending to maintain or even raise the GFR. In addition to these arteriolar actions, angiotensin II constricts the mesangial cells, an effect that tends to lower the GFR by decreasing the surface area available for filtration.
An overview of the kidney effects of ACE inhibitors will be reviewed here. The use of ACE inhibitors and angiotensin receptor blockers (ARBs) in patients with kidney disease is presented in detail elsewhere:
●(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
●(See "Treatment of hypertension in patients with diabetes mellitus".)
ANGIOTENSIN II AND AUTOREGULATION OF GFR — As the kidney perfusion pressure is diminished (due for example to antihypertensive therapy), the kidney is initially able to maintain both blood flow and glomerular filtration via the phenomenon of autoregulation (figure 1) [7]. The first part of the autoregulatory response is decreased afferent (precapillary) arteriolar tone, thereby allowing more of the systemic pressure to be transmitted to the glomerulus. Afferent dilatation is mediated both by tubuloglomerular feedback and by a direct myogenic response. With more marked reductions in kidney perfusion pressure, renin release is stimulated; the ensuing increase in angiotensin II production maintains both intraglomerular pressure and the glomerular filtration rate (GFR) via a preferential increase in resistance at the efferent arteriole [7]. The net effect is that the GFR and renal blood flow do not begin to fall until these autoregulatory changes in arteriolar resistance are maximized.
PRIMARY HYPERTENSION — In patients with primary hypertension, kidney perfusion pressure is elevated, and therefore maintenance of the glomerular filtration rate (GFR) is not as dependent upon angiotensin II. As a result, an angiotensin-converting enzyme (ACE) inhibitor generally induces little change in GFR in patients who have normal kidney function [8]. In comparison, some patients with a relatively recent onset of hypertension have increased angiotensin II activity, renal vasoconstriction, and a GFR below 80 mL/min. In this setting, an ACE inhibitor can raise the GFR by 10 to 30 mL/min, presumably due to reversal of angiotensin II-induced mesangial contraction [8,9].
The outcome may be different in patients who develop kidney disease due to benign nephrosclerosis. In this setting, an ACE inhibitor can lead to an acute decline in GFR due to intrarenal vascular disease via a mechanism similar to that in bilateral renal artery stenosis [10]. However, in one study of over 1000 Black patients with hypertensive kidney disease, the ACE inhibitor ramipril retarded the progression of kidney disease better than the calcium channel blocker amlodipine [11].
Angiotensin receptor blockers — The kidney effects of angiotensin receptor blockers (ARBs) in people with hypertension have not been studied to the same extent and detail as for ACE inhibitors. Some studies in experimental animals reported differences in kidney effects between ACE inhibitors and ARBs due to different effects on kinins and/or effects mediated by different angiotensin receptor subtypes. However, most of the evidence in humans suggests that the kidney effects of ARBs are broadly similar to those of ACE inhibitors. This notion is supported by large outcome trials with head-to-head comparisons between ACE inhibitors and ARBs. These issues are discussed elsewhere in detail:
●(See "Treatment of hypertension in patients with diabetes mellitus".)
Long-term effects — It remains uncertain whether ACE inhibitors offer preferential long-term protection of kidney function in patients with primary hypertension as they do in a variety of forms of chronic kidney disease [12] (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults"). One study of 257 patients with primary hypertension suggested that there may be a lower rate of loss of GFR in patients who are treated with an ACE inhibitor compared with a beta blocker despite equivalent degrees of blood pressure control [13]. (See "Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis", section on 'Treatment'.)
RENOVASCULAR HYPERTENSION — The hemodynamic response to angiotensin-converting enzyme (ACE) inhibition in renal artery stenosis may be different from that with uncomplicated primary hypertension. In this setting, lowering the systemic blood pressure will, because of the stenotic lesion, tend to reduce the intraglomerular pressure below normal. Although the glomerular filtration rate (GFR) can be maintained by autoregulation, blocking angiotensin II formation with an ACE inhibitor will blunt this response and tend to reduce the GFR (figure 1) [7]. This effect is more pronounced in the presence of diuretic-induced volume depletion since the increase in baseline angiotensin II levels makes maintenance of the GFR more angiotensin II dependent [7,14].
The net effect is that between one-third and one-half of patients with renal artery stenosis will have a usually mild decline in GFR after the administration of an ACE inhibitor [15]. For similar reasons, bilateral renovascular disease should be strongly suspected in patients with hypertension who are not hypovolemic and in whom the plasma creatinine concentration rises after starting an ACE inhibitor. Although many of these patients will have renal artery stenosis, a similar change can occur with hypovolemia (often induced by diuretics) and with intrarenal vascular disease due to hypertensive nephrosclerosis or systemic vasculitis (such as polyarteritis nodosa) [10,16]. It has been estimated, for example, that of all patients with hypertension in whom an ACE inhibitor raises the plasma creatinine concentration, more than one-half will have renal artery stenosis, while most of the remaining patients have nephrosclerosis [17].
The decline in GFR induced by an ACE inhibitor typically occurs within the first few days after the onset of therapy since angiotensin II levels are rapidly reduced. As a result, the plasma creatinine concentration should be remeasured three to five days after the institution of therapy in patients with known renal artery stenosis and in those at high risk for the disease (as with severe hypertension in the presence of atherosclerotic vascular disease). (See "Establishing the diagnosis of renovascular hypertension".)
When it occurs, the rise in the plasma creatinine concentration is usually mild and acceptable [17,18]. In one study, for example, 75 patients with known renovascular hypertension were randomly assigned to therapy with hydrochlorothiazide plus enalapril or hydrochlorothiazide plus timolol and hydralazine [18]. A 0.3 mg/dL or larger increase in creatinine occurred in 20 percent of patients treated with enalapril (the mean reduction in GFR in this group was 23 mL/min), one-half of whom had preexisting kidney function impairment and one-third of whom had bilateral renal artery stenosis. Blood pressure control was slightly better in patients treated with enalapril.
The decline in GFR that may occur with ACE inhibitors is indicative of a decrease in intraglomerular pressure, a probable mechanism for protection against progression of kidney disease [19]. Patients with renal artery stenosis who are able to tolerate ACE inhibitor therapy may derive a similar benefit [20-22]. In one study of 621 patients with renal artery stenosis followed at a single referral center, ACE inhibitors were prescribed in 378 patients, and nearly all such patients tolerated therapy (92 percent overall and 78 percent of those with bilateral renal artery stenosis) [20]. Compared with those prescribed other therapy, those taking ACE inhibitors had a significantly lower mortality after controlling for possible confounders (hazard ratio 0.61, 95% CI 0.40-0.81). (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
A large and persistent decline in kidney function resulting in a 30 percent or greater rise in serum creatinine (or 30 percent or greater fall in estimated GFR) occurs in less than 5 to 10 percent of cases. These patients generally require either institution of other antihypertensive agents that do not interfere with autoregulation (such as a calcium channel blocker) [23] or correction of the stenosis by angioplasty or surgery. Patients with severe bilateral disease may not tolerate any form of antihypertensive therapy, since an adequate intraglomerular pressure can be maintained only at very high systemic pressures (figure 2) [24]. In this setting, the GFR falls because the intraglomerular pressure is reduced below the level at which it can be maintained by autoregulation. (See "Treatment of bilateral atherosclerotic renal artery stenosis or stenosis to a solitary functioning kidney".)
The ACE inhibitor-induced reduction in GFR in renovascular disease almost always resolves after cessation of therapy. In addition, the plasma creatinine concentration can often be returned toward the baseline level by discontinuation of diuretic therapy [14]. It has been suggested, however, that irreversible kidney failure can rarely occur [25]. How this might happen is not clear. In most such patients, the decline in kidney function was noted weeks to months after the ACE inhibitor was started, thereby making a cause-and-effect relationship uncertain. One possible mechanism is the development of renal artery thrombosis [26]. This complication has been reported primarily in patients with marked (≥95 percent) stenotic lesions who have an excessive reduction in blood pressure. It is therefore unclear if there was any specific predisposing effect of the ACE inhibitor.
Unilateral renal artery stenosis — The effect in unilateral renal artery stenosis is more subtle. An ACE inhibitor may decrease the GFR in the stenotic kidney [27,28]. However, a substantial fall in the total GFR with a rise in the plasma creatinine concentration is usually not seen because of an equivalent increment in GFR in the contralateral kidney (due to removal of angiotensin II-induced renal vasoconstriction).
Risk of ischemic atrophy — Even when the total GFR is relatively well maintained, there is a concern that hypofiltration and the fall in perfusion pressure might eventually lead to ischemic atrophy [29]. The risk of this complication and whether it is more likely to occur with an ACE inhibitor are currently unresolved. (See "Treatment of unilateral atherosclerotic renal artery stenosis", section on 'Medical therapy'.)
Prolonged ACE inhibitor or angiotensin receptor blocker (ARB) use may result in significant worsening of kidney function in a few patients [30], and one small study has suggested that discontinuing these agents in patients with advanced chronic kidney disease may improve kidney function [31]. However, a trial that randomly assigned such patients to withdrawal or continuation of ACE inhibitor or ARB found no difference in GFR decline or kidney failure at three years; in addition, cardiovascular events tended to be fewer in the continuation group [32].
SUMMARY
●The effect of angiotensin-converting enzyme (ACE) inhibitors on the glomerular filtration rate (GFR) in patients with hypertension is related both to the glomerular actions of angiotensin II and to the mechanism of autoregulation of the GFR. Angiotensin II constricts both the afferent (preglomerular) and efferent (postglomerular) arterioles but preferentially increases efferent resistance. The net effect of the more prominent increase in efferent tone is that the intraglomerular pressure is stable or increased, thereby tending to maintain or even raise the GFR. (See 'Introduction' above.)
●As the kidney perfusion pressure is diminished, the kidney is initially able to maintain both blood flow and the GFR via the phenomenon of autoregulation (figure 1). The initial autoregulatory response to a decrease in systemic arterial pressure is decreased afferent arteriolar tone, thereby allowing more of the systemic pressure to be transmitted to the glomerulus. However, with more marked reductions in kidney perfusion pressure, renin-mediated increases in angiotensin II production maintain both intraglomerular pressure and the GFR via a preferential increase in resistance at the efferent arteriole. (See 'Angiotensin II and autoregulation of GFR' above.)
●These concepts are critical for understanding the effects of ACE inhibitors on GFR in various forms of hypertension:
•In patients with primary hypertension, kidney perfusion pressure is elevated, and therefore maintenance of the GFR is not as dependent upon angiotensin II. As a result, an ACE inhibitor generally induces little change in GFR in patients who have normal kidney function. (See 'Primary hypertension' above.)
•The outcome may be different in patients who develop kidney disease due to benign nephrosclerosis. In this setting, an ACE inhibitor can lead to an acute decline in GFR due to intrarenal vascular disease via a mechanism similar to that in bilateral renal artery stenosis, discussed above. (See 'Primary hypertension' above.)
•In patients with renovascular hypertension, lowering the systemic blood pressure with an ACE inhibitor will, because of the stenotic lesion, tend to reduce the intraglomerular pressure below normal. Although the GFR could be maintained by autoregulation, blocking angiotensin II formation with an ACE inhibitor will blunt this response and tend to reduce the GFR (figure 1). (See 'Renovascular hypertension' above.)
●Between one-third and one-half of patients with renal artery stenosis will have a usually mild decline in GFR, occurring within a few days after the administration of an ACE inhibitor. A large decline in kidney function occurs in less than 5 to 10 percent of cases. The ACE inhibitor-induced reduction in GFR in renovascular disease almost always resolves after cessation of therapy. (See 'Renovascular hypertension' above.)
●Bilateral renovascular disease should be strongly suspected in patients with hypertension in whom the plasma creatinine concentration rises by more than 30 percent within a week after starting an ACE inhibitor. Although many of these patients will have renal artery stenosis, a similar change can occur with intrarenal vascular disease due to hypertensive nephrosclerosis or systemic vasculitis (such as polyarteritis nodosa) and in hypovolemic patients. (See 'Renovascular hypertension' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
