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)