12/7/2021 Efectos renales de los inhibidores de la ECA en la hipertensión - UpToDate

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Autores: Johannes FE Mann, MD, Karl F. Hilgers, MD

Editores de sección: Dr. George L Bakris, William J Elliott, MD, PhD
Editor adjunto: John P Forman, MD, MSc

Divulgaciones del colaborador

Todos los temas se actualizan a medida que hay nueva evidencia disponible y nuestro proceso de revisión por
pares se completa.

Revisión de la literatura vigente hasta:  junio de 2021. | Última actualización de este tema:  28 de mayo de
2019.

INTRODUCCIÓN

El efecto de los inhibidores de la enzima convertidora de angiotensina (ECA) sobre la función

renal en el paciente hipertenso está relacionado tanto con las acciones glomerulares de la
angiotensina II como con el mecanismo de autorregulación de la tasa de filtración glomerular
(TFG) [ 1 ]. La angiotensina II contrae las arteriolas aferentes y eferentes, pero aumenta
preferentemente la resistencia eferente [ 2 ]. Al menos tres factores pueden contribuir a esta
respuesta:

● La arteriola eferente tiene un diámetro más pequeño en el estado basal; como resultado,
una mayor constricción en este sitio producirá un mayor aumento de la resistencia que en
la arteriola aferente [ 2 ].

● La angiotensina II estimula la liberación del óxido nítrico vasodilatador de la arteriola

aferente, minimizando así la constricción en este sitio [ 3 ].

● La angiotensina II minimiza la vasoconstricción en la arteriola aferente mediante la

estimulación de los receptores de angiotensina II tipo 2, lo que da lugar a vasodilatación a
través de una vía dependiente del citocromo P450 [ 4-6 ].

El efecto neto del aumento más prominente del tono eferente es que la presión intraglomerular
es estable o aumenta, por lo que tiende a mantener o incluso aumentar la TFG. Además de

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estas acciones arteriolares, la angiotensina II contrae las células mesangiales, un efecto que
tiende a disminuir la TFG al disminuir el área de superficie disponible para la filtración.

Aquí se revisará una descripción general de los efectos renales de los inhibidores de la ECA. El
uso de inhibidores de la ECA y bloqueadores de los receptores de angiotensina (ARA) en
pacientes con enfermedad renal se presenta en detalle en otra parte:

● (Consulte "Terapia antihipertensiva y progresión de la enfermedad renal crónica no

diabética en adultos" ).

● (Ver "Tratamiento de la hipertensión en pacientes con diabetes mellitus" ).

ANGIOTENSINA II Y AUTOREGULACIÓN DE FG

A medida que disminuye la presión de perfusión renal (debido, por ejemplo, a la terapia
antihipertensiva), el riñón puede inicialmente mantener tanto el flujo sanguíneo como la filtración
glomerular a través del fenómeno de autorregulación ( Figura 1) [ 7 ]. La primera parte de la
respuesta autorreguladora es la disminución del tono arteriolar aferente (precapilar), lo que
permite que una mayor parte de la presión sistémica se transmita al glomérulo. La dilatación
aferente está mediada tanto por retroalimentación tubuloglomerular como por una respuesta
miogénica directa. Con reducciones más marcadas en la presión de perfusión renal, se estimula
la liberación de renina; el consiguiente aumento de la producción de angiotensina II mantiene
tanto la presión intraglomerular como la tasa de filtración glomerular (TFG) a través de un
aumento preferencial de la resistencia en la arteriola eferente [ 7 ]. El efecto neto es que la TFG
y el flujo sanguíneo renal no comienzan a caer hasta que se maximizan estos cambios
autorreguladores en la resistencia arteriolar.

HIPERTENSIÓN PRIMARIA

En pacientes con hipertensión primaria, la presión de perfusión renal está elevada y, por lo
tanto, el mantenimiento de la tasa de filtración glomerular (TFG) no depende tanto de la
angiotensina II. Como resultado, un inhibidor de la enzima convertidora de angiotensina (ECA)
generalmente induce pocos cambios en la TFG en pacientes con función renal normal [ 8 ]. En
comparación, algunos pacientes con hipertensión de inicio relativamente reciente tienen mayor
actividad de angiotensina II, vasoconstricción renal y una TFG por debajo de 80 ml / min. En
este contexto, un inhibidor de la ECA puede elevar la TFG de 10 a 30 ml / min,
presumiblemente debido a la reversión de la contracción mesangial inducida por angiotensina II
[ 8,9 ].

The outcome may be different in patients who develop renal disease due to benign
nephrosclerosis. In this setting, an ACE inhibitor can lead to an acute decline in GFR due to
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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 renal disease, the ACE
inhibitor ramipril retarded the progression of renal disease better than the calcium channel
blocker, amlodipine [11].

Angiotensin receptor blockers — The renal 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 renal 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
renal 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 "Renin-angiotensin system inhibition in the treatment of hypertension", section on

'Angiotensin II receptor blockers'.)

● (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in

adults", section on 'Angiotensin II receptor blockers'.)

● (See "Treatment of hypertension in patients with diabetes mellitus".)

Long-term effects — It remains uncertain whether ACE inhibitors offer preferential long-term
protection of renal function in patients with primary hypertension as they do in a variety of forms
of chronic renal 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 to 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].

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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 hypertensive patients
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 hypertensive patients 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), half
of whom had preexisting renal 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 renal
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 renal 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

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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 renal failure can occur [25]. How this might happen is not clear. In most
such patients, the decline in renal 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 CKD may improve renal function [31]. The
possible detrimental effects of ACE inhibitors and ARBs in people with stage 4 nephropathy
should be considered until long-term outcome studies are performed.

SUMMARY

● The effect of angiotensin-converting enzyme (ACE) inhibitors on the glomerular filtration rate
(GFR) in hypertensive patients 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
(pre-glomerular) and efferent (post-glomerular) arterioles, but preferentially increases

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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 renal 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 renal 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, renal 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
renal function. (See 'Primary hypertension' above.)

• The outcome may be different in patients who develop renal 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 below. (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 renal 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 hypertensive patients 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

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nephrosclerosis or systemic vasculitis (such as polyarteritis nodosa). (See 'Renovascular

hypertension' above.)

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