J R Soc Med 2002;95:391-397
doi:10.1258/jrsm.95.8.391
© 2002 Royal Society of Medicine
Targeting the renin-angiotensin system in patients with renal disease
Mark A J Devonald BSc MRCP
Fiona E Karet PhD FRCP
Departments of Medical Genetics and Nephrology, University of Cambridge,
Cambridge, UK
Correspondence to: Dr M A J Devonald, Cambridge Institute for Medical
Research, Box 139 Addenbrooke's Hospital, Cambridge CB2 2XY, UK E-mail:
majd2{at}medschl.cam.ac.uk
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INTRODUCTION
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The rationale for use of angiotensin-converting enzyme (ACE)
inhibitors in
patients with proteinuria or established renal
impairment is in general
twofold—first, to slow the progression
of renal disease, by reducing
blood pressure (BP) and proteinuria
or by other renoprotective mechanisms;
second, to lessen the
risk of cardiovascular morbidity and mortality
associated with
chronic renal disease and with one of its leading causes,
diabetes.
This review highlights the evidence for and against targeting
the
renin-angiotensin system in the treatment of patients with
different types of
nephropathy. Findings from the major studies
are summarized in
Table 1.
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HYPERTENSION AND PROTEINURIA AS MODIFIABLE RISK FACTORS
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Hypertension and the degree of proteinuria are the two most
important
factors influencing the rate of decline in renal function
in most forms of
chronic renal disease. There is evidence for
renoprotective benefit from
pharmacological intervention in
types 1 and 2 diabetes as well as in
non-diabetic nephropathy.
Almost 20 years ago, Parving
et al.
reported that, in a small
group of patients with type 1 diabetes and
nephropathy, lowering
of BP with combinations of beta-blockers, diuretics and
vasodilators
reduced albuminuria and slowed the decline in glomerular
filtration
rate
(GFR)
1. More
recently his group published data from a prospective
observational cohort
study suggesting that aggressive BP control
in some patients with type 1
diabetes may even improve the GFR
as well as reduce proteinuria, thus
challenging the widely held
belief that diabetic nephropathy progresses
relentlessly
2.
The United Kingdom Prospective Diabetes Study
(UKPDS)3 and the
Modification of Diet in Renal Disease (MDRD)
study4 provided
evidence for the renoprotective effect of BP lowering in type 2 diabetes and
in non-diabetic nephropathy respectively, as have numerous smaller studies.
There is also evidence that the baseline level of proteinuria correlates with
rate of progression of renal impairment in both type 1 and type 2 diabetes and
in non-diabetic
nephropathy4,5.
Furthermore, the extent of reduction of proteinuria on initiation of
antihypertensive therapy correlates with the degree of subsequent
renoprotection6,7.
Proteinuria is thus regarded as an independent risk factor for progression of
nephropathy, rather than simply as a marker. There is at present much research
interest in the mechanisms by which the protein filtered by the glomerulus
damages renal function. Reabsorption in the proximal tubule may activate
inflammatory pathways, leading to interstitial
fibrosis8; thus,
reduction of proteinuria to a minimum seems an important target in the
management of nephropathy of any aetiology.
The issue of whether ACE inhibitors are more renoprotective than other
modes of antihypertensive therapy has been clarified for some subgroups with
renal disease but not others; the question of cardioprotection adds complexity
to the debate.
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ACE INHIBITORS IN TYPE 1 DIABETES
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Tertiary prevention
In a landmark study published in 1993, Lewis
et al. provided
evidence
for a renoprotective effect of captopril independent of BP lowering
in
type 1 diabetes
9.
Thereafter, ACE inhibitors were regarded as
first-line antihypertensive agents
in patients of the same kind—namely,
those with type 1 diabetes,
clinical grade proteinuria (>
500 mg/24 h) and mild to moderate renal
impairment (creatinine
< 221 µmol/L). Despite the possible confounding
factors
of slightly lower average BP and baseline proteinuria in the
captopril
group, the results are widely seen as robust. The
use of ACE inhibitors in
normotensive patients with type 1 diabetes
has been proposed on the argument
that hypertension was not
an entry criterion for Lewis's study, although in
practice over
75% of the patients were hypertensive and the target BP at <
140/
< 90 mmHg was higher than most current guidelines.
Meta-analyses incorporating studies of both types 1 and 2 diabetes
supported these
conclusions10,11
and generated further interest in ACE inhibition for such
‘normotensive’ patients. Bohlen and colleagues calculated that ACE
inhibitors caused a 28% reduction in proteinuria when the benefit of
blood-pressure reduction was allowed for, whereas the antiproteinuric effect
of other classes of antihypertensive was thought to be blood-pressure
related11. More
recently Parving et al. suggested that ACE inhibition in normotensive
type 1 diabetes provides long-term benefit through keeping BP within normal
limits and preventing an increase in
albuminuria12.
However, this small non-blinded follow-up study could not show whether ACE
inhibitors are superior in this respect to other antihypertensives.
Secondary prevention
Similarly, numerous studies have suggested a role for ACE inhibition in
reducing the rate of progression of microalbuminuria (30-300 mg/24 h) to overt
nephropathy (> 300
mg)13,14,15,16.
A meta-analysis of individual patient data has pointed to an ACE-inhibitor
effect beyond that of blood-pressure
lowering17.
Primary prevention
In view of the evidence that proteinuria is nephrotoxic and that
microalbuminuria predicts progression to overt nephropathy in a substantial
proportion of patients with type 1 diabetes, an obvious strategy is to delay
the onset of microalbuminuria. This in turn may delay the development of
hypertension—which in this group tends to correlate with the progression
of proteinuria, creating a vicious circle. The Diabetes Control and
Complications Trial
(DCCT)18 suggested
that tight glycaemic control has a role in primary prevention, but to date
there is no convincing clinical evidence in favour of ACE inhibition or
antihypertensives in general. The EUCLID study group concluded that lisinopril
slowed the progression of renal disease in normotensive patients with little
or no albuminuria, but the small benefit in the normoalbuminuric subgroup was
not statistically significant, even before correction for BP
lowering16. Data
from streptozotocin-diabetic rats suggest a role for ACE inhibition in primary
prevention19, and
this important area is likely to receive further attention in clinical
trials.
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ANGIOTENSIN II RECEPTOR BLOCKERS IN TYPE 1 DIABETES
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Various small studies have suggested equivalence of angiotensin
II receptor
blockers (ARBs) to ACE inhibitors in both overt
nephropathy and
microalbuminuria
20,
21. However, in the
absence
of outcome data from large prospective randomized trials, ARBs
(which
selectively antagonize the type 1 receptor) have not
as yet challenged ACE
inhibitors as first-line antihypertensive
or anti-proteinuric agents in these
groups.
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ACE INHIBITORS AND ARBs IN TYPE 2 DIABETES
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It is the increase in prevalence of type 2 diabetes that is
largely
responsible for the dramatic rise in end-stage renal
failure in Europe and the
USA. Yet convincing evidence for renoprotection
from interruption of the
renin-angiotensin system has only recently
been acquired, far behind that for
type 1 diabetes and non-diabetic
nephropathy.
Comparisons of ACE inhibitors with other antihypertensives have yielded
conflicting results with respect to progression of renal disease. In the
UKPDS, BP reduction led to a clear reduction in the rate of progression of
microalbuminuria, in addition to macrovascular benefits, over 9 years'
follow-up3. No
significant difference in microvascular or macrovascular outcomes was detected
between the ACE-inhibitor and beta-blocker groups, suggesting that BP
reduction was
paramount22.
However, this study was not powered to detect a large difference between these
groups.
In the MICRO-HOPE study, ramipril reduced the risk of progression from
microalbuminuria to overt nephropathy in diabetic patients (98% type 2) with
high cardiovascular risk, the comparison being with
placebo23. This
result was consistent with data previously published by Ravid et al.,
but again there was the possible confounding influence of a small BP
difference between
groups24,
25. Italian workers
suggested that the absence of clear benefit from ACE inhibition in type 2
diabetes could reflect the more heterogeneous nephropathy than that of type 1
diabetes, relating to the later onset of the disease and greater probability
of coexistent renal injury from hypertension, dyslipidaemia and
smoking26. This may
be true, but we think that a more important reason for the lack of clarity is
the dearth of large prospective studies with a primary renal outcome.
Some of the answers have now emerged from three studies investigating the
benefits of ARBs rather than ACE inhibitors. In the Irbesartan
Microalbuminuria Study 2 (IRMA-2), Parving et al. demonstrated a
significant renoprotective effect, independent of blood-pressure lowering, of
irbesartan in hypertensive type 2 diabetic patients with
microalbuminuria27.
Lewis et al., in the Irbesartan Diabetic Nephropathy Trial (IDNT),
showed a similar renoprotective benefit of irbesartan, this time in
hypertensive diabetic patients with established nephropathy, the primary
outcome being a doubling of serum
creatinine28. 300mg
irbesartan per day was more renoprotective than either amlodipine or placebo,
with no difference between the latter two groups. Cardiovascular morbidity and
mortality did not differ between any of the groups, but these were secondary
endpoints and the study was not necessarily powered to detect such
differences.
Brenner et al. conducted a similar study, RENAAL, with the same
endpoints but comparing losartan (50 mg or 100 mg per day) with placebo, other
antihypertensives being used in each
group29. In this
study hypertension was not an entry criterion, although over 90% of patients
were hypertensive. Again, a significant renoprotective effect was seen with
the ARB, independent of BP, with no difference in the cardiovascular secondary
endpoints between the groups.
A greater evidence base has therefore been established for ARBs than for
the older and cheaper ACE inhibitors for renoprotection in the potentially
huge population of patients with type 2 diabetes and proteinuria. Important
though these studies are, they have not proved that ARBs are superior to ACE
inhibitors, since there are no similar ACE-inhibitor studies and no large
studies have directly compared the two. With several ACE inhibitors
approaching end of patent, there may be little commercial interest in funding
comparative studies of this kind.
Furthermore, the relative importance of renal and cardiovascular endpoints
is not clear. The lack of significant cardiovascular protection in the IDTN
and RENAAL studies may reflect inadequate statistical power and the exclusion
of high-cardiovascular-risk patients, since the prime purpose was to
investigate renoprotection rather than cardioprotection. Recently, the LIFE
(losartan intervention for endpoint reduction in hypertension) study has
provided useful information on cardioprotection in hypertensive patients with
left ventricular hypertrophy (LVH), comparing atenolol and
losartan30. In a
substudy involving 1195 hypertensive diabetic patients (>80% type 2) with
LVH, about 11% of whom had clinical albuminuria at baseline, losartan was
significantly more effective than atenolol in reducing cardiovascular and
all-cause
mortality31.
Notably, the intended mean follow-up time of RENAAL was shortened by about one
year because of the publication of a subgroup analysis from the HOPE study
suggesting cardiovascular benefit from ACE inhibition in patients with renal
impairment and other cardiovascular risk factors, a proportion of whom were
diabetic32. Indeed
from MICROHOPE (the diabetic subgroup of HOPE) it is argued that any patient
with type 2 diabetes aged over 55 with microalbuminuria or hypertension
should, in the absence of contraindications, be given an ACE inhibitor. These
criteria include a large proportion of the type 2 diabetic population, and it
might be reasonable also to include those with overt nephropathy, since
cardiovascular risk increases with advancing renal impairment.
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TYPE 2 DIABETES AND RENAL ARTERY STENOSIS
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Functionally significant bilateral renal artery stenosis (RAS)
is
recognized as a contraindication to the use of ACE inhibitors
and ARBs. This
is because reduction of pressure in the afferent
arteriole caused by the
stenosis renders maintenance of adequate
intraglomerular filtration pressure
dependent on constriction
of the efferent arteriole by angiotensin II. In view
of the
high prevalence of atherosclerosis in type 2 diabetes, the possible
presence
of RAS is of concern when ACE-inhibitor or ARB therapy is
contemplated.
Using magnetic resonance angiography Valabhji
et al.
detected
a prevalence of 17% in 117 hypertensive patients with type 2
diabetes
33.
The
functional significance of the stenoses in this and other
studies was not
clear, but 1% of patients in the captopril group
in the UKPDS were withdrawn
from the study because of a rise
in creatinine (degree
unspecified)
22.
Valabhji
et al. suggested
from their study that a femoral bruit was
predictive of RAS,
and markers suggested by others include advanced age,
hypertension,
and history of peripheral vascular or coronary artery disease.
High-risk
‘vasculopaths’ should have their renal function
monitored
with great care if an ACE inhibitor or ARB is prescribed.
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ACE INHIBITORS IN NON-DIABETIC PROTEINURIC NEPHROPATHY
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The MDRD study demonstrated that BP-lowering reduces proteinuria
in
non-diabetic nephropathy, with greater benefit the higher
the proteinuria at
baseline. This baseline level was also a
prognostic indicator for the rate of
decline in renal
function
4.
A meta-analysis of eleven randomized controlled trials (two of which had
not been published) suggested that antihypertensive regimens containing ACE
inhibitors are more efficacious than regimens without ACE inhibitors in
reducing progression of renal impairment, as well as in limiting proteinuria,
in patients with baseline proteinuria of 0.5 g per day or
more34. Yet again,
BP was a possible confounding factor, with the mean fall in systolic BP 4.5
mmHg greater in the ACE inhibitor group. After correction for the predicted
benefits of reduction in BP and level of proteinuria, the ACE inhibitor
remained more effective. However, in a separate analysis of the same eleven
trials, it was concluded that the greater benefit of ACE inhibition on decline
in renal function in patients with high baseline proteinuria was due to the
greater reduction in
proteinuria35. It
was suggested that the degree of proteinuria at any given time after treatment
has begun is a better prognostic indicator than baseline level.
In a post-hoc analysis of the Ramipril Efficacy in Nephropathy
(REIN) trial, the original part of which was included in the above
meta-analyses, ACE inhibition was shown to be renoprotective for all levels of
renal function, down to a GFR of 10 mL/min, although the maximum benefit
occurred when treatment started with a GFR of >50
mL/min36. This
result may be of considerable interest to clinicians managing patients with
advanced renal failure. There is often a dilemma as to whether or not to start
an ACE inhibitor in the patient who presents late with low GFR, or whether to
continue the drug in an individual approaching end-stage renal failure, given
that ACE inhibition initially causes a small fall in GFR (resulting from a
decrease in intraglomerular capillary pressure). As with most ACE inhibitor
studies designed to investigate renal endpoints, no cardiovascular benefit was
seen in REIN.
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ARBs IN NON-DIABETIC NEPHROPATHY
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Several experimental studies and small clinical trials have
suggested that,
in this group of patients, ARBs have similar
effects to ACE inhibitors in
reduction of proteinuria and
renoprotection
37.
There
is some weak evidence that ARBs cause less hyperkalaemia than
ACE
inhibitors in patients with chronic renal disease; this
advantage, if it
exists, might be due to less suppression of
plasma
aldosterone
38.
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COMBINATION THERAPY IN RENOPROTECTION
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Since angiotensin II can be produced by pathways other than
ACE—for
example, by
chymase
39—addition
of an ARB
to an ACE inhibitor should give more complete blockade of the
renin-angiotensin
system than ACE inhibition alone. It is less obvious why
this
combination should be more efficacious than an ARB alone, if
the latter
causes complete blockade of the angiotensin II type
1 receptor
(AT
1,
Figure 1).
Reduction in circulating angiotensin
II by ACE inhibition might provide some
synergy, as might the
increased levels of the vasoactive peptide bradykinin,
which
is also broken down by
ACE
40.
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Figure 1. Schematic representation of renin-angiotensin-aldosterone. Agents
providing pharmacological blockade are shown in italics. ACEI-angiotensin
converting-enzyme inhibitor; ARB=angiotensin II receptor blocker;
NSAID=non-steroidal anti-inflammatory drug; AI=angiotensin I; AII=angiotensin
II; AT1 and AT2=type 1 and type 2 angiotensin II
receptors respectively
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So, is combination therapy likely to yield further improvement in renal
(and cardiovascular) outcomes? From the small studies published to date, there
does seem some promise. The combination of enalapril with losartan reduced
proteinuria more than either drug alone in a group of 10 normotensive patients
with normal GFR and biopsyproven IgA
nephropathy41.
Similarly, Ruilope et al. demonstrated a synergistic antiproteinuric
effect between benazepril and valsartan in non-diabetic renal
disease42. Whilst
they did not report any serious adverse effects, the possibility of
hyperkalaemia, particularly in patients with severe renal impairment, requires
further investigation. In the CALM study, involving 199 hypertensive patients
with type 2 diabetes and microalbuminuria, the combination of lisinopril and
candesartan was more effective than either agent alone in reducing
BP43. A reduction
in albuminuria was also seen, but may have been attributable to the BP effect
rather than to the combination.
Moving one step further down the renin-angiotensin system, the addition of
spironolactone to enalapril in a small study of 8 patients with mild renal
impairment of various aetiologies and persistent proteinuria (> 1g/day)
resulted in a 54% decrease in proteinuria with no effect on
BP44. This raises
the question of the relative importance of aldosterone and angiotensin II in
glomerular haemodynamics.
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CONCLUSIONS
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Should all hypertensive renal patients be treated with an ACE
inhibitor?
From current evidence, patients with type 1 diabetes
who have microalbuminuria
or overt proteinuria should be so
treated—as should non-diabetic
nephropaths with > 0.5g/day
proteinuria. Patients with type 2 diabetes and
microalbuminuria
or worse should be treated with an ACE inhibitor or an ARB,
and
‘normotensive’ diabetic patients of both types will
probably
benefit, the evidence being less comprehensive. Less
clear still is the
optimal therapy for non-diabetic nephropaths
with < 0.5g/day protein urea.
The most important confounding
factor in most of the studies comparing ACE
inhibitors or ARBs
with other antihypertensives is the BP difference between
groups.
Without this difficulty, blockade of the renin-angiotensin system
might
have become more widely accepted as first-line renoprotective
therapy in
most forms of nephropathy.
A possible treatment algorithm is shown in
Figure 2. There is no clear
consensus at present on blood-pressure targets for these groups of patients.
The Joint British recommendations on prevention of coronary heart disease in
clinical practice45
suggest a target of < 130/80 mmHg for type 1 diabetic patients, and we feel
that on current evidence it is reasonable to use this as a target in type 2
diabetes and non-diabetic nephropathy, with respect to both renoprotection and
cardioprotection. Where proteinuria is > 1g/day, the suggested target of
< 125/75 mmHg is based on the MDRD study.
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Figure 2. Possible treatment algorithm for patients with proteinuria. See text
for explanation of target BPs. Broken arrows indicate points of particular
caution. ACEI=angiotensin converting-enzyme inhibitor; ARB=angiotensin II
receptor blocker; RAS=renal artery stenosis
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Footnotes
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Note This review follows a meeting of the Nephrology section
of
the RSM in Cambridge, which included a debate entitled ‘This
house
believes that all renal patients with hypertension should
receive an ACE
Inhibitor’. MAJD and FEK are funded by
the Children's Kidney Care Fund
and the Wellcome Trust, respectively.
The meeting was supported by an
unrestricted educational grant
from AstraZeneca UK Ltd.
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INTRODUCTION
HYPERTENSION AND PROTEINURIA AS...
