Drug Safety 1996Sep; 15 (3): 200-211

RISK-BENEFIT ASSESSMENT o 114-5916/96/CXXl9-D2oo/S06.oo/0

© Adis Internotio nalUmited. All rights reserved.

ACE Inhibitors and the Kidney

A Risk-Benefit Assessment
Gerjan Navis, Harald J. Faber, Dick de Zeeuw and Paul E. de Jong
Groningen Institute for Drug Studies (GIDS), Division of Nephrology, Department of Internal
Medicine, University Hospital Groningen, Groningen, The Netherlands

Contents
Summary ........ . 200
1. Mechanism of Action of ACE Inhibitors 201
2. Renal Effects of ACE Inhibitors . 202
2.1 Essential Hypertension 202
2.2 Renovascular Hypertension . . 203
2.3 Proteinuria and Nondiabetic Chronic Renal Failure 203
2.4 Diabetic Nephropathy . . . . . . . . 205
2.5 Heart Failure . . . . . . . . . . . . . . 205
2.6 Idiosyncratic Renal Adverse Effects 206
3. Drug Interactions ... . . . . . . . . . . . 206
4. Directions for Use . . . . . . . . . . . . . . 206
5. Comparison with Angiotensin II Receptor Blockers 207
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . 208

Summary ACE inhibitors effectively reduce systemic vascular resistance in patients with
hypertension, heart failure or chronic renal disease. This antihypertensive effi-
cacy probably accounts for an important part of their long term renoprotective
effects in patients with diabetic and non-diabetic renal disease.
The renal mechanisms underlying the renal adverse effects of ACE inhibitors
- intrarenal efferent vasodilation with a consequent fall in filtration pressure -
are held to be involved in their renoprotective effects as well. The fall in filtration
pressure presumably contributes to the antiproteinuric effect as well as to long
term renoprotection. The former is suggested by the positive correlation between
the fall in filtration fraction and the reduction in proteinuria found during ACE
inhibition. The latter is suggested by the correlation between the (slight) reduction
in glomerular filtration rate at onset of therapy and a more favourable course of
renal function in the long term . Such a fall in filtration rate at the onset of ACE
inhibitor treatment is reversible after withdrawal, and can be considered the trade-
offfor long term renal protection in patients with diabetic and nondiabetic chronic
renal disease.
In conditions in which glomerular filtration is critically dependent on angio-
tensin II-mediated efferent vascular tone (such as a post-stenotic kidney, or patients
with heart failure and severe depletion of circulating volume), ACE inhibition
can induce acute renal failure, which is reversible after withdrawal of the drug.
Systemic and renal haemodynamic effects of ACE inhibition, both beneficial
ACE Inhibitors and the Kidney 201

and adverse, are potentiated by sodium depletion. Consequently, sodium repletion

contributes to the restoration of renal function in patients with ACE inhibitor-induced
acute renal failure. On the other hand, co-treatment with diuretics and sodium
restriction can improve therapeutic efficacy in patients in whom the therapeutic
response of blood pressure or proteinuria is insufficient.
Patients at the greatest risk for renal adverse effects (those with heart failure,
diabetes mellitus and/or chronic renal failure) also can expect the greatest benefit.
Therefore, ACE inhibitors should not be withheld in these patients, but dosages
should be carefully titrated, with monitoring of renal function and serum potas-
sium levels.

Since their introduction as antihypertensives in
the early 1980s, the use of ACE inhibitors has ex-
panded greatly. This expansion is not only attrib-
utable to their antihypertensive efficacy, but also to
the discovery of their beneficial effects in other con-
ditions such as heart failure and proteinuria.
Hypertension and heart failure are common con-
ditions in general practice. A recent survey in The
Netherlands, for instance, showed that 1.25% of in-
dividuals over 55 years of age were receiving long
term ACE inhibitor therapy)l] The increase in prev-
alence of long term use of ACE inhibitors, 285%
over the last 5 years, has been more rapid than for
any other class of drugs.
This widespread use prompts a thorough risk-
benefit assessment, with particular reference to
populations at risk. In this article, we present a risk-
benefit assessment of the renal effects of ACE in-
hibitors, both for patients with renal disease and for
patients treated with ACE inhibitors for other con-
ditions.
The renal risk: benefit ratio is of particular in-
terest. Shortly after the introduction of ACE inhib-
itors as antihypertensive agents, severe renal ad-
verse effects (acute renal failure and proteinuria)
were reported, which may have led to a certain ret-
icence over the use of these drugs in patients with
renal disease over those early yearsP] Of note,
however, ACE inhibitors appear to have reno-
protective properties, to the extent that today they
are used to provide renoprotection in patients with
conditions such as diabetic nephropathy[3] and
nondiabetic proteinuria.l 4 ]
It is an apparent paradox that the mechanisms
underlying ACE inhibitor-induced acute renal fail-
ure most likely account for the reno protective ef-
fects as well. Understanding these mechanisms
will help to tailor therapy, and thus allow the clini-
cian to achieve the most favourable risk: benefit
ratio in individual patients.
1. Mechanism of Action of
ACE Inhibitors
ACE inhibitors interact with the renin-angio-
tensin-aldosterone system (RAAS) by competitively
blocking angiotensin-converting enzyme (ACE),
which forms the effector hormone of the RAAS,
the octapeptide angiotensin II, from the inactive
decapeptide angiotensin I. Reduced formation of
angiotensin II is considered to account for many, if
not all, of the known effects of ACE inhibitors.
Angiotensin II is a potent vasoconstrictor of the
systemic and the renal vascular bed. Consequently,
ACE inhibitors produce systemic and renal vaso-
dilation, resulting in a fall in blood pressure and an
increase in renal blood flow. As renal vasodilation
is mainly located at the efferent arteriole, filtration
pressure is reduced by ACE inhibition. In addition,
angiotensin II induces mesangial cell contraction,
thus reducing the glomerular filtration area;[5,6]
thus, ACE inhibitors increase the surface area
available for filtration. As a consequence of these
actions, the lower filtration pressure does not auto-
matically lead to a reduction in glomerular filtration
rate (GFR), as it is counterbalanced by the simul-
taneous increases in renal blood flow and filtration
area. Accordingly, GFR may increase, remain stable

© Adis International Limited. All rights reserved. Drug Safety 1996 Sep: 15 (3)
202
or decrease, depending on the prevailing condi-
tions in the renal microcirculation and the effects
on blood pressure.
The decrease in filtration pressure is believed to
be involved in the initial antiproteinuric effect of
ACE inhibition, as well as in the occurrence of ACE
inhibitor-induced renal failure in some pathologi-
cal conditions. In situations with a low renal perfu-
sion pressure, such as hypovolaemia, heart failure
or renal artery stenosis, GFR is often critically
dependent on angiotensin II-mediated efferent
arteriolar tone. In such conditions, reduction of ef-
ferent vascular tone by ACE inhibitors can dramat-
ically lower GFR, more so when systemic blood
pressure decreases as well. These effects are poten-
tiated by prior sodium depletionP] Thus, a func-
tional, haemodynamically mediated renal insuffi-
ciency can occur, that is reversible after withdrawal
of the ACE inhibitor.
As angiotensin II induces renal sodium reten-
tion by stimulation of aldosterone and by direct
tubular effects,L8] ACE inhibitors induce natriuresis
and mild potassium retention. L9,IO) The latter is cor-
related with the fall in circulating aldosterone
leveIJ II ] Finally, angiotensin II modulates growth
and proliferation of cell types such as vascular
smooth muscle cells Ll2 ] and mesangial cells.£13]
Therefore, angiotensin II probably contributes to
mesangial cell proliferation and matrix accumula-
tion,LI4] processes that are involved in the develop-
ment of focal segmental glomerulosclerosis, LIS] the
alleged final common pathway of progressive renal
failure . In experimental renal disease, the develop-
ment of glomerulosclerosis is prevented or amelio-
rated by ACE inhibitors. LI6 ,17] The clinical counter-
part of this renoprotection is the favourable effect
on the long term course of renal function loss in
patients with diabetic nephropathy and nondiabetic
proteinuria. Whether, in man, anti proliferative ef-
fects contribute to the renoprotective effects of
ACE inhibitors is as yet unknown.
The enzymatic action of ACE is not limited to
the cleavage of angiotensin I; in addition, ACE
(also denoted kininase II) cleaves a number of en-
dogenous peptides, of which bradykinin is proba-
© Adis International Umited. All rights reserved.
Navis et al.
bly the most important. Thus, ACE inhibitors re-
duce bradykinin degradation. Whether this contrib-
utes to their therapeutic effects on the kidney is still
a matter of debate. LI8 ]
To optimise the risk: benefit ratio of ACE in-
hibitors by tailoring therapy, 2 concepts are impor-
tant. First, the mechanism underlying the class-
related adverse effects of ACE inhibitors on renal
function (efferent vasodilation with a fall in filtra-
tion pressure) is also thought to be involved in the
renoprotective effects of ACE inhibitors. Second,
as the systemic and renal haemodynamic effects of
ACE inhibitors (beneficial and adverse) depend on
RAAS blockade, the prevailing state of activation
of the RAAS is an important determinant of these
effects of ACE inhibitors. Thus, the desired thera-
peutic effects of ACE inhibitors can be potentiated
by inducing sodium depletion, by co-treatment with
diuretics and/or by dietary sodium restriction. LI9 ,20]
This will, however, increase the vulnerability of the
kidney to the abovementioned adverse effects.
Tailoring ACE inhibitor therapy, therefore, not
only entails dosage adjustment, but also control of
sodium status.
2. Renal Effects of ACE Inhibitors
2.1 Essential Hypertension
In patients with essential hypertension, ACE in-
hibitors reduce blood pressure and increase renal
blood flow; GFR usually rises or remains stable. In
the subgroup of patients with essential hypertension
who also have an elevated pretreatment renal vas-
cular tone (either resulting from a state of vasocon-
striction inherent to the hypertension L21 ] or from
moderate dietary sodium restriction[22) both renal
blood flow and GFR increase. In essential hyper-
tension ACE inhibitors induce natriuresis during
both low and liberal sodium intake.£19) As these pa-
tients have normal renal function, the fall in aldo-
sterone level does not elicit hyperkalaemia, except
when ACE inhibitors are combined with other
potassium-sparing drugs. (23 )
ACE inhibitors reduce microalbuminuria in pa-
tients with essential hypertension. L24 ] The prognostic
Drug Safety 1996 Sep; 15 (3)
ACE Inhibitors and the Kidney
significance of microalbuminuria with regard to
long term renal outcome in this population remains
to be established, but the association between micro-
albuminuria and rises in serum creatinine levels[25]
suggests that microalbuminuria may be a marker
of long term renal function loss in this population.
Whether this implies that, in essential hyperten-
sion, ACE inhibitors offer advantages over other
classes of antihypertensives with respect to the
long term course of renal function,[26.27] and overall
morbidity and mortality, is still under investigation.
2.2 Renovascular Hypertension
ACE inhibitors were originally designed to treat
high-renin hypertension, of which renovascular
hypertension is the classical example. Not surpris-
ingly, therefore, ACE inhibitors effectively lower
blood pressure in many patients with renovascular
hypertensionPS] Yet, in some patients ACE inhib-
itors fail to lower blood pressure, probably as a
result of the sequential mechanisms that account
for the high blood pressure in patients with renal
artery stenosis. Renin release initiates the hyper-
tension, but when volume expansion subsequently
becomes an additional perpetuating factor for the
hypertension, blood pressure may respond less
well to ACE inhibitors. Thus, a poor blood pressure
response to ACE inhibitors does not exclude the
presence of renal artery stenosis.l 29 )
The presence of (unrecognised) renal artery ste-
nosis in patients treated with ACE inhibitors is a
matter of concern, considering the renal effects of
ACE inhibitors in renovascular hypertension. In a
post-stenotic kidney, glomerular filtration is often
critically dependent on angiotensin II-mediated
efferent vasoconstriction. Thus, ACE inhibitors
can induce a substantial decrease in GFR in a post-
stenotic kidney,[3o.31] which does not occur with other
antihypertensive agents despite similar effects on
blood pressure.[32] In patients with renal artery ste-
nosis of a solitary kidney (a native kidney[33) or a
renal transplant[34]) or in those with bilateral renal
artery stenosis, this can induce acute renal fail-
ure.[35] However, in the presence of a functionally
normal contralateral kidney, even dramatic reduc-
© Adis International Limited. All rights reserved.
203
tions in GFR in the stenotic kidney can go un-
noticed.
In view of its functional nature, the fall in GFR is
reversible after withdrawal of the ACE inhibitor,
even after prolonged use according to some case re-
ports.[36.37] Nevertheless, irreversible loss of stenotic
kidney function during long term ACE inhibition has
also been reported, attributed to accelerated progres-
sion of the stenosis as such. [3S] Therefore, renal artery
stenosis is considered a contraindication for the use
of ACE inhibitors. In selected patients, however,
when anatomical correction of the stenosis is impos-
sible and when blood pressure fails to respond to
other antihypertensives, a trial with a low dosage of
an ACE inhibitor, preferably conducted with the pa-
tient hospitalised, with daily control of blood pres-
sure and creatinine clearance at the onset of therapy,
can sometimes be justified. .
The renal haemodynamic effects of ACE inhib-
itors in patients with renal artery stenosis provide
the physiological basis for the use of acute ACE
inhibitors to increase the sensitivity of renography
in the detection of renal artery stenosis)39,40] Of
note, experimental evidence indicates that long
term ACE inhibition may not increase the sensitiv-
ity of renography as effectively as acute ACE inhi-
bition.[41) In humans, this issue has not been ade-
quately addressed as yet.
2.3 Proteinuria and Nondiabetic Chronic
Renal Failure
ACE inhibitors effectively reduce proteinuria
by approximately 50%.[4] Sodium balance is an im-
portant determinant of the antiproteinuric efficacy;
the latter is virtually abolished when there is a lib-
eral sodium intake,[20) but is restored by dietary
sodium restriction and/or concomitant use of a di-
uretic.l42 ] Dietary protein restriction also increases
the antiproteinuric effect.l43 ]
2.3. , Antiproteinuric Effect
The antiproteinuric effect of ACE inhibitors ex-
ceeds that of other antihypertensives that have sim-
ilar effects on blood pressure;[4,44,45] therefore, it
cannot be explained solely by the decrease in blood
pressure. The reduction in proteinuria is associated
Drug Sofety 1996 Sep; 15 (3)
204
with an improved lipid profile,[46) which may
favourably affect both cardiovascular and renal
outcomeJ47,48)
The antiproteinuric response at the onset of
treatment is correlated with the magnitude of the
early renal haemodynamic response: a larger de-
crease in GFR is associated with a better anti-
protein uric response. Interestingly, an effective
anti protein uric response at the onset of treatment
predicts a more favourable long term course of re-
nal function.[49,50) This supports the assumption
that proteinuria per se is involved in progressive
loss of renal function[51 J and emphasises the impor-
tance of reducing proteinuria as a therapeutic strat-
egy in preventing progressive renal function loss
in patients with proteinuriaJ52,53) This also implies
that a larger fall in GFR at the onset of treatment is
associated with a more favourable long term course
of renal function. [54) Thus, a haemodynamically
mediated decrease in GFR is the price to be paid
for a reduction in proteinuria and for long term
renoprotection.
Unfortunately, this association can limit the use
of ACE inhibitors as antiproteinuric treatment in
patients with severe renal insufficiency; thus, in
patients with advanced renal failure, institution of
ACE inhibitors requires close monitoring of renal
function.
All in all, ACE inhibitors have become drugs of
choice for the symptomatic treatment of proteinuria.
Antiproteinuric efficacy is augmented by concur-
rent treatment with nonsteroidal anti-inflammatory
drugs (NSAIDs),[55) provided that volume over-
load has been adequately corrected by sodium re-
striction and diuretics. However, as this combina-
tion can considerably depress GFR, renal function
and serum potassium levels should be closely mon-
itored, especially in patients with pre-existing im-
pairment of renal function.
2.3.2 Long Term Renal Protection
Whether ACE inhibitors offer better protection
against long term renal function loss in patients
with nondiabetic renal disease than other, equally
effective, antihypertensives is a much-debated is-
sue. Experimental evidence,[16) as well as a number
© Adis International Limited. All rights reserved.
Navis et al.
of retrospective[56) and randomised prospective
studies[57,58) of ACE inhibitor-based treatment re-
gimens, support this assumption. Other studies,
however, have failed to show an advantage of ACE
inhibitors over other antihypertensivesJ59)
The disparities between the studies may result
from differences in study design, degree of blood
pressure control or patient populations. The pro-
portion of patients with proteinuria, for instance,
may be relevant in achieving a protective effect on
long term renal function in a particular study. In
this respect, our recent observation might be rele-
vant: the long term renal function loss in patients
with renal disease and hypertension treated with
either an ACE inhibitor or a ~-blocker, was more
rapid in patients with a DD-polymorphism for the
ACE gene.[60) This genetic polymorphism was re-
cently found to be associated with increased cardio-
vascular riskJ61) The DD-genotype is associated
with elevated serum and tissue ACE levelsJ62)
Whether this phenotypic abnormality affects the
systemic or the renal response to ACE inhibition,
however, is still unclear.[63,64)
2.3.3 Renal Adverse Effects
A number of renal adverse effects of ACE inhib-
itors has been reported in patients with renal fail-
ure. In most cases, these effects result from the
pharmacological actions of ACE inhibitors, namely,
the decreases in filtration pressure and in aldoste-
rone level. Reversible acute renal failure during
ACE inhibition was reported in patients with poly-
cystic kidney disease[65) as well as in patients with
hypertensive nephrosclerosis,[66) in the absence of
renal artery stenosis.
The impairment of renal function is often re-
lated to symptomatic hypotension, and is revers-
ible after discontinuation of ACE inhibitor therapy
and after sodium repletion. Re-institution of the
ACE inhibitor at a lower dosage is often well tol-
eratedJ66) In this respect, it is relevant that many
ACE inhibitors are excreted by the renal route, and
dosage should be reduced accordingly in patients
with renal failure . In renal transplant recipients,
ACE inhibitors can also induce reversible renal
failure in the absence of renal artery stenosis; it has
Drug Safety 1996 Sep; 15 (3)
ACE Inhibitors and the Kidney
been suggested that impaired glomerular perfusion
pressure, caused by changes in the renal micro-
vasculature by chronic vascular rejection (or cyclo-
sporin therapy), predisposes to GFR impairment
during ACE inhibition in these patients,f67]
In patients with renal failure, an elevated aldo-
sterone level helps to maintain potassium bal-
ance;[6S] ACE inhibitors can elicit hyperkalaemia
in these patients because of the decrease in aldo-
sterone level,[69] particularly in patients with ad-
vanced renal failure or those receiving concurrent
treatment with other potassium-sparing drugs.
2.4 Diabetic Nephropathy
Diabetic nephropathy is a major cause of end-
stage renal failure. The natural history of the dis-
ease is characterised by early microalbuminuria and
hyperfiltration, with overt proteinuria and ongoing
renal function loss as the disease progresses. ACE
inhibitors reduce proteinuria in patients with insulin-
dependent diabetes mellitus (IDDM)[3] and non-
insulin-dependent diabetes mellitus (NIDDM),[70]
and retard the rate of renal function loss,f71 .72] The
reduction in proteinuria is associated with an im-
provement in the lipid profile,[73) a risk factor for
both cardiovascular morbidity and long term renal
function loss,f74)
Blood pressure control is an important prereq-
uisite for renoprotection in patients with diabetic
nephropathy, [75] although whether ACE inhibitors
provide long term renoprotection by their effects
on blood pressure or by specific renal effects,[76.77]
is still a matter of debate. Specific renal effects
could include the reduction in proteinuria, lower-
ing of glomerular pressure,[78] antiproliferative ef-
fects, or a combination of these.
Of note, ACE inhibitors also retard the progres-
sion of microalbuminuria to overt proteinuria[79]
and subsequent renal function loss in normotensive
patients with either IDDM[SO] or NIDDM,fsl] As a
consequence, ACE inhibitors are drugs of choice
for hypertensive as well as normotensive patients
with diabetic nephropathy or microalbuminuria. In
hypertensive patients with NIDDM, ACE inhibi-
tors retard the onset of microalbuminuria. [S2J It has
© Adis International Limited. All rights reserved.
205
been recommended,[S3] therefore, that ACE inhib-
itors should be instituted before microalbuminuria
develops.
Hyporeninaemic hypoaldosteronism, resulting
in an elevation of serum potassium levels, is a rel-
atively frequent condition in patients with diabetic
nephropathy;[S4,S5 J therefore, patients with diabetic
nephropathy are at particular risk of developing
hyperkalaemia during ACE inhibitor therapy,[S6]
especially when renal function is impaired.
2.5 Heart Failure
ACE inhibitors have been convincingly shown
to increase life expectancy in patients with heart
failure,ls7J and are now widely used in this common
condition. Their renal effects can vary greatly, de-
pending on the prior condition of the patient.
ACE inhibitors induce renal vasodilation, and
increase renal blood flow in heart failure patients.[SS]
For instance, it has been calculated that two-thirds
of the rise in cardiac output during ACE inhibitor
therapy is accounted for by the increase in renal
perfusion,fs9J However, ACE inhibitors have been
shown to induce acute renal failure, as a result of
functional renal insufficiency, in approximately
one-third of patients with severe heart failure.[90]
Patients prone to develop acute renal failure are
those taking diuretics, with depletion of the effective
circulating volume, and/or with hyponatraemia[9l J
indicating that prior sodium depletion predisposes
to the development of renal failure in these patients.
Indeed, sodium repletion restores renal function de-
spite continuation of ACE inhibitor therapy.[S9J
Diabetic patients with heart failure tend to be par-
ticularly vulnerable to ACE inhibitor-induced
functional impairment of renal function[S9J when
the abovementioned risk factors are present. This
has been suggested to be caused by potentiation of
diuretic-induced volume depletion secondary to
hypoaldosteronism in these patients.
Although patients with heart failure are at a par-
ticular risk of developing renal insufficiency during
ACE inhibition, the cardiac benefits of ACE inhib-
itors in terms of mortality are substantiaL There-
fore, in patients with an ACE inhibitor-induced
Drug Safety 1996 Sep: 15 (3)