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ORIGINAL INVESTIGATION
Angiotensin-Converting Enzyme
Inhibitor–Associated Elevations in Serum Creatinine
Is This a Cause for Concern?
George L. Bakris, MD; Matthew R. Weir, MD
Background: Reducing the actions of the reninangiotensin-aldosterone system with angiotensinconverting enzyme inhibitors (ACEIs) slows nephropathy progression in patients with or without diabetes. Post
hoc analyses of many ACEI-based clinical trials demonstrate the greatest slowing of renal disease progression
in patients with the greatest degree of renal insufficiency at study initiation. However, many physicians fail
to use ACEIs or angiotensin receptor blockers in patients with renal insufficiency for fear that either serum
creatinine or potassium levels will rise.
Objective: To determine if limited initial reduction in
either glomerular filtration rate (GFR) or elevation in serum creatinine levels, associated with ACEI or angiotensin receptor blocker use, results in long-term protection
against decline in renal function in patients with renal
insufficiency.
Methods: We reviewed 12 randomized clinical trials that
evaluated renal disease progression among patients with
preexisting renal insufficiency. Six of these studies were
multicenter, double-blinded, and placebo controlled, with
the remainder being smaller randomized studies with a
minimum 2-year follow-up on renal function. These investigations evaluated patients with and without diabetes or systolic heart failure. Average duration of follow-up for all studies was 3 years. Trials were examined
in the context of changes in either serum creatinine levels or GFR in the group randomized to an ACEI
From the Rush University
Hypertension/Clinical Research
Center, Department of
Preventive Medicine, Rush
Presbyterian–St Luke’s Medical
Center, Chicago, Ill
(Dr Bakris), and Division of
Nephrology, Department
of Medicine, University of
Maryland Medical Center,
Baltimore (Dr Weir).
T
(N = 1102). Sixty-four percent of these individuals (705/
1102) had renal function data at both less than 6 months
and at the end of the study.
Results: Most trials demonstrated that patients with pre-
existing renal insufficiency manifested an acute fall in
GFR, a rise in serum creatinine, or both. Those randomized to an ACEI with a serum creatinine level of 124
µmol/L or greater ($1.4 mg/dL) demonstrated a 55% to
75% risk reduction in renal disease progression compared with those with normal renal function randomized to an ACEI. An inverse correlation was observed between the amount of renal function loss at baseline and
the subsequent rate of annual decline in renal function
following randomization to an antihypertensive regimen that contained an ACEI.
Conclusions: A strong association exists between
acute increases in serum creatinine of up to 30% that
stabilize within the first 2 months of ACEI therapy
and long-term preservation of renal function. This
relationship holds for persons with creatinine values
of greater than 124 µmol/L (.1.4 mg/dL). Thus, withdrawal of an ACEI in such patients should occur only
when the rise in creatinine exceeds 30% above baseline within the first 2 months of ACEI initiation, or
hyperkalemia develops, ie, serum potassium level of
5.6 mmol/L or greater.
Arch Intern Med. 2000;160:685-693
HE SIXTH REPORT of the Joint
National Committee
(JNC VI) states that there
are specific indications for
angiotensin-converting enzyme inhibitor (ACEI) use as part of a regimen to lower blood pressure to levels less
than 130/85 mm Hg in patients with diabetes mellitus.1 Moreover, ACEIs should
also be part of the “antihypertensive cocktail” used to achieve this same lower level
of blood pressure reduction in individuals with renal insufficiency.1 However, data
from the Third National Health and NuARCH INTERN MED/ VOL 160, MAR 13, 2000
685
trition Examination Survey III (NHANES
III) demonstrate that only half of the 53%
of hypertensive patients treated actually
achieve the blood pressure goal of less than
140/90 mm Hg.1 From these data, it is estimated that about 3% to 5% of patients
achieve a blood pressure goal of less than
130/85 mm Hg, as recommended by the
JNC VI report for persons with renal insufficiency or diabetes. The failure to
achieve these blood pressure goals may be
due, in part, to physician indifference, fear
or ignorance, or patient noncompliance
with medication therapy.2 Moreover, this
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MATERIALS AND METHODS
We reviewed randomized clinical trials that focused
on renal disease progression and had ACEI therapy
as one of its arms. Studies included in the evaluation met the following criteria: (1) were randomized to either ACEI-based therapy or blood pressure
control using an ACEI as part of the therapeutic armamentarium; (2) had a minimum follow-up period of 2 years; (3) had the majority of participants
with greater than 25% loss of their renal function at
baseline, regardless of cause; and (4) had blood pressure goals of less than 140/90 mm Hg.
Twelve randomized clinical trials met these
criteria. Six of these studies were multicenter, doubleblinded, and placebo controlled, with the remainder
being smaller randomized studies with a minimum
follow-up on renal disease progression of 2 years. All
studies evaluated renal disease progression among patients with and without diabetes or systolic heart failure. Mean ± SD duration of follow-up for all studies
was 3.2 ± 0.3 years. Trials were examined in the context of changes in either serum creatinine level or GFR
in the group randomized to or receiving an ACEI
(N = 1102). Sixty-four percent of these individuals
(705/1102) had renal function data at both less than
6 months and at the end of the study.
Data were assessed using the achieved blood
pressures and changes in renal function of a given
trial. Serum creatinine values, collected at time periods of less than 6 months and at trial end, were used.
If serum creatinine values were not available, then
GFR data are reported. Trends in the changes of serum creatinine values or GFR are reported. In addition, changes in serum potassium values were assessed at baseline and study end. These are reviewed
in the context of changes in renal function.
failure to achieve adequate blood pressure control halted
the previously observed trend in reduction of cardiovascular mortality and subsequently increased morbidity from myocardial infarction, heart failure, stroke, and
renal disease.1
Another group that may require reductions in arterial pressure to less than 130/85 mm Hg to slow the
rate of renal disease progression are African Americans.3,4 Many such patients experience a transient rise in
serum creatinine levels after treatment with an ACEI or
angiotensin receptor blocker (ARB) is started or after blood
pressure is adequately reduced. A rise in the serum creatinine level consequently leads to physician reticence
to stay the course with a given therapy. This action subsequently results in failure to maintain adequate blood
pressure goals. Thus, some patients are deprived of known
strategies that delay progression of renal disease.
It is noteworthy that clinical trials in both heart failure and progression of renal disease support the concept
that ACEIs reduce cardiovascular mortality and renal disease progression.5-19 However, the dose of ACEIs used in
these trials was, on average, 2 to 3 times higher than those
used by the average practicing physician treating similar
ARCH INTERN MED/ VOL 160, MAR 13, 2000
686
types of patients. Despite these trial outcomes, lower doses
of ACEIs are used in everyday practice, a trend not explainable by data from clinical trials. It likely reflects, however, concern about safety and tolerability of higher ACEI
doses. Physicians should be aware that at these lower doses,
ACEIs might not provide the same positive outcomes in
preservation of renal function as noted in clinical trials. This
reduced benefit from lower doses of ACEIs may relate to
either a failure of blood pressure control or the relative degree of ACE inhibition itself.
Some of the main reasons for the failure to achieve
adequate drug dosing relate to “emotion-based” rather than
evidence-based” medicine. Physicians recall that there are
increased side effects as doses increase. While this is true
for older antihypertensive agents, it is not true for ACEIs
or ARBs. Specifically, cough and angioedema are not dose
related and not observed with use of ARBs.15,20 Doserelated changes in serum creatinine and potassium levels
do occur with ACEIs, however, and are predictable in many
cases. These ACEI-associated changes may serve to be diagnostic as well as therapeutic. However, many physicians, including nephrologists, view a rise in serum creatinine level as a contraindication for ACEI use.
The most common cause of an acute rise in serum
creatinine level, following inhibition of the renin angiotensin system (RAS), results from a decreased effective
arterial blood volume. This is due to hypoperfusion secondary to volume depletion from overaggressive diuresis, low cardiac output seen in heart failure, or both.21
In these clinical settings, the reduced pressure head from
the afferent arteriole further lessens the already reduced
intraglomerular pressure imposed by ACEIs. Thus, the
compensatory elevation of single-nephron glomerular
filtration rate (GFR) seen in renal insufficiency and
diabetes is reduced in an almost additive fashion when
hypoperfusion and ACE inhibition coexist.21,22
One of the major reasons for this renal hemodynamic effect is a loss of the kidney’s ability to autoregulate pressure through the nephron.22-24 Consequently,
there is a direct relationship between blood pressure and
GFR, whereas under normal circumstances there is a sigmoidal relationship. This is discussed later in this article. In addition, achievement of recommended lower
blood pressure goals, ie, less than 125/75 mm Hg may
also raise serum creatinine levels, regardless of the type
of antihypertensive agent used.1 This is especially prominent in persons with a long history of markedly elevated blood pressure and renal insufficiency.25
Last, bilateral renal artery stenosis might also be a
cause of elevated serum creatinine levels following initiation of ACEI therapy. It occurs, however, with a much
lower frequency and should be considered in patients with
extensive atherosclerotic cardiovascular disease or who
smoke. It should also be considered in individuals in
whom rehydration has not stabilized or serum creatinine reduced toward normality within a few weeks. Factors to consider when an acute rise in serum creatinine
level is observed are
• decreased effective circulating volume (most common);
• advanced age (.65 years) with and without preexisting lipid abnormalities; and
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Inhibition of the RAS blunts the maximal capacitance of organs such as the heart and kidney to respond
to increased metabolic and physical demands. Clinical
trial data support the observation that a small reduction
in GFR or rise in serum creatinine level markedly slows
renal disease progression. An analogous example in the
cardiovascular system is the relationship between heart
rate and cardiovascular events. Data support the concept that a reduction in heart rate, by b-blockers,
reduces the incidence of cardiovascular events. Thus,
we argue that an initial, limited, rise in serum creatinine level is beneficial within the context of preserving
renal function.
RESULTS
GENERAL TRENDS
The clinical studies reviewed indicate that a limited elevation in serum creatinine, ie, 30% or less above baseline, following initiation of therapy with an ACEI or ARB
was seen in patients with renal insufficiency who achieved
their blood pressure goal.1,8-19,25,26 Moreover, an increase
in serum creatinine level, if it occurs, will happen within
the first 2 weeks of therapy initiation (Figure 1). Assuming normal volume and sodium intake, a rise in serum creatinine that follows ACEI or ARB therapy should stabilize within 2 to 4 weeks (Figure 1). Moreover, if a significant
change in serum creatinine level has not been observed
within the first month of therapy and blood pressure has
been adequately controlled, the probability of an acute rise
in serum creatinine level following this period is unlikely. There are 3 exceptions to this statement: (1) initiation of or increasing the dose of currently prescribed
diuretics; (2) initiation by either the patient or physician
of a nonsteroidal anti-inflammatory drug; or (3) development of volume depletion from nondiuretic-induced causes
such as gastroenteritis.
ACEI-ASSOCIATED IMPACT ON NATURAL
HISTORY OF RENAL DISEASE
Blood pressure reduction to levels less than 140/90
mm Hg clearly slows renal disease progression regardless of the class of antihypertensive agent used.1 Many
clinical trials, however, demonstrate additional slowing
of renal disease progression when ACEIs are used as part
of the “antihypertensive cocktail.”1,8-19,25 This is especially true for diabetic nephropathy. The effects of ACEIs
on serum creatinine values and renal function from clinical trials in patients with renal insufficiency are summarized in the Table.
Two representative, long-term studies in patients with
diabetic nephropathy illustrate that the initial reduction
in GFR, following initiation of ACE inhibition, reverted
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687
Creatinine, µmol/L (mg/dL)
• baseline serum creatinine level of 124 µmol/L or greater
($1.4 mg/dL), either alone or in association with (1)
diabetes, (2) heart failure, or (3) achievement of low
blood pressure goal, ie, less than 125/75 mm Hg when
previously elevated to levels greater than 180/110
mm Hg for long periods of time.
256 (2.9)
239 (2.7)
221 (2.5)
203 (2.3)
186 (2.1)
168 (1.9)
150 (1.7)
133 (1.5)
115 (1.3)
97 (1.1)
80 (0.9)
62 (0.7)
A
ACEI or ARB
Started
B
C
Baseline
1
2
3
4
Weeks
Figure 1. Possible changes in serum creatinine levels in individuals with
normal renal function with volume depletion, heart failure, or bilateral renal
artery stenosis started on therapy with an angiotensin-converting enzyme
inhibitor (ACEI) or angiotensin receptor blocker (ARB) (A); individuals with
abnormal renal function started on therapy with an ACEI or ARB, without
conditions noted in case A (B); and individuals with normal renal function
started on therapy with an ACEI or ARB (C).
to rates not significantly different from baseline 1 month
after ACE inhibition was withdrawn.26,30 In a follow-up
study by Hansen et al,26 42 hypertensive diabetic subjects
received ACEIs for an average period of 6 years. In the ACEI
group there was a clear initial reduction in GFR by 3% to
9% below baseline at this time. Overall, mean arterial pressure ranged from 105 to 109 mm Hg. However, at the end
of 6 years when therapy with ACEIs was stopped, GFR
increased by an average of 6.1% over a period of 1 month.
This supports the concept that initial or persistent GFR
declines are reversible despite prolonged ACEI use. We
also noted that patients with diabetic nephropathy given
the ACEI lisinopril had from a 1% to 9% fall in GFR at 1
month following treatment initiation (Figure 2).30 The
range of mean arterial pressure achieved in this study was
99 to 105 mm Hg. After an average of 5 years of ACEI
therapy, patients were withdrawn from the ACEI treatment and clonidine was substituted to maintain blood pressure control. The GFR returned to levels not different from
baseline within 1 month of ACEI termination, despite similar blood pressure control (Figure 2). This study further
supports the concept that while GFR may be reduced
acutely, one can markedly blunt the rate of progression
of renal disease with ACEIs. Moreover, these initial ACEIassociated declines in GFR are reversible and partially independent of systemic arterial pressure.
Proteinuria has been recently implicated as not only
a risk factor associated with renal disease progression but
also a culprit in its genesis.8,31 Two recent meta-analyses
clearly support the concept that ACEIs should be part
of the antihypertensive regimen to lower blood pressure. This is because ACEIs lower proteinuria and markedly slow nephropathy progression, a relationship that
is most pronounced in patients with renal insufficiency
(Figure 3).32,33 Results of these studies, together with
the results of other clinical trials that used ACEI therapy,
support the concept that achievement of lower blood
pressure goals preserves renal function.9-11,25 Moreover, these studies support the notion that patients
with the greatest degree of proteinuria also garner the
greatest benefit from blood pressure reduction when
ACEIs are used (Figure 3).
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Long-term Outcome of Renal Function in Clinical Trials in Persons With Renal Disease: Impact of ACEI Therapy*
Study
Diabetic subjects
Captopril Trial27
Bakris et al8
Lebovitz et al13
Nielsen et al28
Bjorck et al16
Nondiabetic subjects
AIPRI Trial29
REIN Trial10
Zucchelli et al17
Hannedouche et al14
MDRD Trial25
Ihle et al19
Kamper et al18
D Renal Function‡
N†
Duration of
Follow-up, y
Achieved
MAP, mm Hg
,6 mo
Trial End
207
18
28
21
40
3
5
3
3
2.2
105
98
104
112
102
?
−9.47 (GFR)§
?
−3.97 (GFR)§
−3.8 (GFR)
−0.15 (Cr clear)
−0.02 (Cr clear)
−6.3 (GFR)
−7.1 (GFR)
−2.0 (GFR)
300
78
32
52
255
3
3.5
3
3
3
36
35
2
2.2
100
106
100
105
105
94
101
99
+26 (Cr)
?
?
?
−5.7 (GFR)
−14.4 (GFR)
−0.42 (GFR)
−3 (GFR)
+31 (Cr)
−6.3 (GFR)
−0.04 (Cr Clear)
−4.8 (GFR)
−3.8 (GFR)
−2.9 (GFR)
−0.7 (GFR)
−2.4 (GFR)
*ACEI indicates angiotensin-converting enzyme inhibitor; MAP, mean arterial pressure; AIPRI, Angiotensin-Converting Enzyme Inhibition in Progressive Renal
Insufficiency; REIN, Ramipril Efficacy in Nephropathy; and MDRD, Modification of Dietary Protein in Renal Disease.
†Number of patients randomized to an ACEI in a given trial. Note that for the last 3 trials listed in the table, although many of these patients with a glomerular
filtration rate (GFR) of 13 to 24 mL/min received an ACEI, they were not randomized to this class. They were randomized to a MAP level of either 102 to 107
mm Hg or less than 92 mm Hg.
‡GFR is expressed as milliliters per minute; creatinine clearance (Cr Clear), milliliters per second; and serum creatinine (Cr), micromoles per liter. To convert
creatinine clearance values to milliliters per minute, divide by 0.01667; to convert serum creatinine to milligrams per deciliter, divide by 88.4.
§These values were converted to the annual decline rates by converting the GFRs obtained at or before 4 months. Note also that with the exception of 1 study all
rates of GFR decline are slower at study end, especially in those with average blood pressures below 130/85 mm Hg.
90
125
85
80
∗
BP, mm Hg
GFR, mL/min
115
∗
∗
∗
105
75
∗
70
65
60
95
Baseline
1 mo
6y
1 mo Off ACEI
+ Clonidine
Baseline
1 mo
6y
1 mo Off ACEI
+ Clonidine
Figure 2. Effects of an angiotensin-converting enzyme inhibitor (ACEI) on creatinine clearance in 23 patients with type 2 diabetes mellitus who received therapy
for an average of 5.6 years. Glomerular filtration rate (GFR) returns toward baseline with good blood pressure (BP) control maintained by treatment with clonidine.
Asterisk indicates P,.05 compared with baseline. Bars indicate SD.
THERAPEUTIC INDEX OF RAS BLOCKADE
What is the level of renal insufficiency above which an
ACEI or ARB loses its therapeutic index (risk-benefit
ratio)? The available data from the randomized clinical
trials reviewed demonstrate that ACEIs slow progression
of renal disease in both diabetic and nondiabetic subjects. This is likely due to important blood pressure–
dependent and –independent effects. Moreover, this
effect is most pronounced among those with preexisting
renal insufficiency. The data, however, are limited to
ARCH INTERN MED/ VOL 160, MAR 13, 2000
688
persons with serum creatinine values up to 265 µmol/L
(3.0 mg/dL). This includes studies of patients who have
lost more than 75% of their renal function. Thus, no
definitive statement can be made about renal outcomes
or the therapeutic index of ACEIs in patients with profound renal insufficiency, ie, GFR less than 30 mL/min.
It should also be appreciated that, regardless of serum
creatinine value, manifestations of renal failure, as
assessed by standard laboratory tests, are not apparent
until the GFR is well below 30 mL /min (Figure 4).
This lower level of GFR may be apparent when the
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ACEI Benefit
0
(Based on Serum
Creatinine Level)
–2
∗
∗
120
∗
–8
–10
–12
80
Age >65 y or Weight <49.5 kg
60
Lab Abnormalities of Renal Failure Start
40
ACEI Benefit
GFR, mL/min
–6
–14
General Population
100
(Based on GFR)
∆ GFR, mL/min
–4
20
Initial GFR (<92 mm Hg MAP)
Final GFR (<92 mm Hg MAP)
Dialysis
–16
0-250
250-1000
†
1000-3000
Proteinuria, mg/d
Figure 3. Changes in glomerular filtration rate (GFR) among patients with
GFR between 13 and 24 mL/min from the Modification of Dietary Protein in
Renal Disease trial as a function of the different levels of proteinuria. Asterisk
indicates P,.05 compared with initial fall in GFR; dagger, P,.05 compared
with initial GFR from less proteinuric groups. MAP indicates mean arterial
pressure. Bars indicate SD.
serum creatinine level is as low as 141 µmol/L (1.6
mg/dL) (Figure 4). It should also be noted, that even in
this GFR range, ACEIs have been shown to preserve
renal function.10,17-19,25
It appears from the collective data that the patients
with the greatest degree of renal insufficiency garner
the greatest protection from renal disease progression in
whatever trial is examined. This is further evidenced by
data from the Captopril Trial, 11,12 in which patients
whose serum creatinine values were greater than 177
µmol/L (2.0 mg/dL) derived the greatest benefit from
ACE inhibition. In this trial, ACEI or placebo were
added to a standard antihypertensive regimen to lower
blood pressure to less than 140/90 mm Hg. The ACEI
group had a 74% risk reduction in doubling of serum
creatinine and a 75% risk reduction in the incidence of
death, dialysis, or transplantation, compared with the
placebo group.11,12 Conversely, patients with a serum
creatinine value of less than 88.4 µmol/L (1.0 mg/dL),
and similar degrees of blood pressure reduction with
the ACEI, experienced only a 4% risk reduction in doubling of serum creatinine or incidence of death, dialysis,
or transplantation.
Seven separate trials have examined the natural
history of renal disease among patients with nondiabetic renal insufficiency, with a range of serum creatinine values between 133 and 265 µmol/L (1.5-3.0
mg/dL) (GFR range, 17-55 mL/min) (Table). Patients
in these trials were randomized to receive antihypertensive therapy that contained either placebo or an
ACEI to achieve blood pressure control. In the
Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) trial,29 patients
with a serum creatinine level greater than 177 µmol/L
(.2.0 mg/dL) had a 66% risk reduction in renal disease progression. This in contrast to those with a
serum creatinine level less than 177 µmol/L (,2
mg/dL) who had a 38% risk reduction.9,29 Likewise in
the Ramipril Efficacy in Nephropathy (REIN) trial,
patients who had serum creatinine values greater than
ARCH INTERN MED/ VOL 160, MAR 13, 2000
689
0
88
(1)
177
(2)
265
(3)
354
(4)
442
(5)
530
(6)
619
(7)
707
(8)
796
(9)
Serum Creatinine, µmol/L (mg/dL)
Figure 4. Relationship of glomerular filtration rate (GFR) decline to change
and serum creatinine level. Persons older than 65 years and adults weighing
less than 49.5 kg have much lower GFRs for a given level of serum creatinine
compared with the usual reference population. Laboratory (lab)
manifestations of renal failure start to occur when the GFR is about 30
mL/min. This may occur at serum creatinine values as low as 177 µmol/L
(2 mg/dL). These changes include mild anemia and elevations in serum
phosphorus levels. As GFR falls below 20 mL/min, additional problems
occur, such as acidosis and a tendency toward hyperkalemia. The lighter
shaded area indicates the area of shown protection from clinical trials and
the darker shaded area indicates the range of where dialysis is usually
required. ACEI indicates agiotensin-converting enzyme inhibitor.
177 µmol/L (.2.0 mg/dL) and more than 3.0 g/d of
proteinuria had a 62% risk reduction in renal disease
progression.10,34 Post hoc analyses of data from the
Modification of Dietary Protein in Renal Disease Trial
(MDRD)25 also suggest that those with the lowest GFR
had the largest reduction in GFR in the presence of an
ACEI.
These data, together with data from previous trials,
support the concept of a bell-shaped curve with regard
to the acute effects of ACE inhibition on serum creatinine levels. That is, at normal levels of serum creatinine
there is little to no effect on the change in serum creatinine value although GFR is reduced 5% to 20%. With
relatively greater degrees of renal dysfunction, there is a
loss of renal reserve as well as autoregulatory ability of
the kidney. This results in a greater acute fall in GFR
following ACE inhibition that becomes more clinically
evident.
HYPERKALEMIA
Several factors contribute to the development of hyperkalemia in the presence of ACEI use. Some of the more
common factors include a diet high in fruit, especially
dried fruit, and vegetable intake or use of salt substitute.
A reduction in aldosterone production as well as concomitant use of nonsteriodal anti-inflammatory agents
and/or reduced potassium clearance secondary to reduced GFR, ie, less than 20 mL/min are also common
contributory factors.
Data from the clinical studies reviewed as well as
others suggest that elevations in serum potassium levels that follow ACEI initiation limit the use of ACEI in
most patients with concomitant renal or cardiac disease. A case-controlled study of outpatients followed
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Serum Creatinine
>133 µmol/L
(>1.5 mg/dL)
Long-Acting ACEIs
Heart Failure
Serum Creatinine
<133 µmol/L
Concomitant Use of Diuretics
0
1
2
3
4
5
6
7
Relative Risk
Figure 5. Risk factors with relative risk (and 95% confidence interval) for
developing hyperkalemia from use of angiotensin-converting enzyme
inhibitors (ACEI). Adapted from Reardon and Macpherson.35
up in a general medicine clinic with baseline serum
potassium levels of greater than 5.1 mmol/L while
receiving ACEI therapy illustrates this point. 35 The
ACEIs evaluated in this trial included some with dual
modes of excretion (fosinopril), and some with a long
half-life (lisinopril). Only 194 (11%) of 1818 patients
reviewed developed further increases in serum potassium levels. Thirty-seven of the 194 patients had
potassium levels of 5.6 mmol/L or greater. Moreover,
only 3 (1.5%) of the 194 had potassium levels of 6
mmol/L or greater. The most relevant factor for predicting hyperkalemia was a baseline serum creatinine
level of 144 µmol/L (1.6 mg/dL) or greater. Other factors that predicted development of hyperkalemia are
shown in Figure 5. Note that only 15 (0.8%) of 1818
patients required termination of the ACEI due to
hyperkalemia.
Other clinical trials that used ACEIs for blood
pressure control in patients with diabetic or nondiabetic renal disease (serum creatinine levels, 133-265
µmol/L [1.5-3.0 mg/dL]) further support the notion
that serum potassium levels increase by 0.4 to 0.6
mmol/L; such elevations in serum potassium levels are
self-limited. 9,10,12-15 In the AIPRI trial, the average
increase in serum potassium was 0.5 mmol/L.9 Only
5 (1.7%) of the 300 patients in the benazepril hydrochloride group and 3 (1.0%) of the 283 patients in
the placebo group developed serum potassium levels
of 6 mmol/L or greater. In the REIN trial, there were
only 2 (1.2%) of 166 stop points due to hyperkalemia;
one patient was taking an ACEI, the other was taking
placebo.10 In the Captopril Trial, hyperkalemia defined
as serum potassium level of 6 mmol/L or greater was
only observed in 3 (1.4%) of the 207 patients in the
group randomized to captopril. No hyperkalemia was
observed in the 202 patients receiving placebo.12,36
Taken together these studies demonstrate a very
low risk (,2%) of hyperkalemia with drugs that block
the RAS when used in patients with moderate to severe
renal impairment. This low incidence of hyperkalemia
is further exemplified by the results of clinical trials in
patients with heart failure. A recent trial of elderly
patients with heart failure evaluated the risk for development of either functional renal insufficiency or
ARCH INTERN MED/ VOL 160, MAR 13, 2000
690
hyperkalemia between an ACEI, captopril, or an ARB,
losartan potassium.15 The incidence of persisting functional renal insufficiency was approximately 10.5% in
each group. Fewer than 2% of the more than 700
patients required drug discontinuation. The risk for
hyperkalemia (potassium .6 mmol/L) was low in the
captopril group (5/370 [1.4%]), and even lower in the
losartan group (2/352 [0.57%]).
Other smaller randomized studies have also observed this lower incidence of hyperkalemia with use of
angiotensin receptor antagonists.37,38 These studies evaluated the effects of ACEIs and ARBs on potassium balance and the RAS among patients with renal insufficiency; this includes one crossover study that compared
each drug class in the same group of patients.38 In these
studies, the average increase in serum potassium, at the
highest dose of an ARB, ranged from 0.05 to 0.3 mmol/L;
the average increase when given an ACEI was approximately double this value.
COMMENT
The available clinical evidence suggests that the use of
drugs that block the RAS are appropriate for patients
with renal insufficiency. Moreover, ACEIs are specifically indicated for use in patients with renal insufficiency by the JNC VI.1 They have proven therapeutic
benefits, particularly in patients with renal insufficiency
(ie, serum creatinine level 133-265 µmol/L [1.5-3.0
mg/dL]). This class of drugs may also provide renoprotective effects that are non–blood pressure dependent
when used as part of combination antihypertensive
therapy in patients with more advanced renal disease.
Drugs that block the RAS might have diagnostic benefits as well. This is exemplified by increases in serum
creatinine of more than 25% as indicative of diminished
effective arterial blood volume from volume contraction
and/or anatomical renal artery disease. An increase in
serum potassium may be reflective of increased intake
or concomitant use of nonsteroidal anti-inflammatory
drugs or salt substitutes. These clinical situations can
and should be remedied.
Once marked elevations in serum creatinine are
present and renal reserve is lost (serum creatinine
level 265-309 µmol/L [3.0-3.5 mg/dL] in persons aged
.50 years and with normal body habitus), the unique
benefits of ACEIs may not exceed that of achieving the
recommended level of blood pressure reduction alone
(Figure 4). Thus, in a person with preexisting renal
insufficiency, aggressive blood pressure control itself,
in the absence of ACE inhibition, may lead to a rise in
serum creatinine level. This is secondary to a loss of
renal reserve and autoregulatory ability when blood
pressure falls. Consequently, the nephron fails to
maintain the required perfusion pressure to sustain
GFR in the remnant “functional” nephrons.39,40
The mechanisms that portend increases in serum
creatinine following ACEI therapy are discussed. Inhibition of the RAS by either an ARB or ACEI leads to a
reversible reduction in intraglomerular pressure in most
nephrons.22,41 In the case of preexisting renal insufficiency, however, fewer functional nephrons, “remnant
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691
150
140
GFR (mL/min) or HR (beats/min)
nephrons,” are present and thus function at a relatively
higher baseline pressure to maintain stable renal function.39,40 Under these circumstances, if RAS activity is
reduced, the resultant reduction in intraglomerular
pressure is proportionally greater in these remnant
nephrons. Thus, the fewer the functional nephrons
(higher serum creatinine level) the greater the likelihood that GFR will decrease when RAS activity is
reduced. This reduction in renal function may not be
reflected as a fall in GFR, however, unless blood pressure falls substantially, ie, at least to levels well below
140/90 mm Hg.34,42,43 The change in GFR under these
circumstances depends on the amount of autoregulatory ability preserved by the kidney. If autoregulation
is not present, then the GFR will change in direct relation to the level of blood pressure.43,44 The degree of
blood pressure reduction necessary to see this effect is
variable and depends on preexistent level of renal
function.
Another reflection of how ACEIs may protect
against declines in renal function may be their effect on
“renal reserve.” Angiotensin-converting enzyme inhibitors blunt the rise in renal blood flow and GFR that follow a protein load.45 This may be another harbinger of
how this class of antihypertensive agents protects
against the chronic decline in renal function. The nephron responds to factors such as increased protein intake
with an elevation in GFR. This is referred to as “renal
reserve” since it reflects the ability of the kidney to
increase its clearance rate in the presence of higher urea
genesis. This increase in GFR is due to afferent glomerular arteriole dilation in response to various amino
acids.45 Many investigators have described a blunted rise
in GFR in the presence of an ACEI in both animal models of renal insufficiency and in people with renal dysfunction following protein loading.45-48 The blunted
rise in GFR, in part, secondary to persistent efferent
arteriolar dilation that results from decreased angiotensin II effects, thus inhibits one mechanism by
which the nephron compensates to heightened urea
loads. This is analogous to the b-blocker effect on the
heart’s ability to increase its rate in response to
increased metabolic demands. From these data, it
becomes axiomatic that the protective effect of a given
antihypertensive agent relates to its ability to blunt a
given organ’s response to a heightened work demand.
This assertion is based on the observation that these
classes of agents have been shown to reduce cardiovascular mortality.5-7
A simple way to conceptualize the benefits of
ACEIs to the kidney is through an analogy with cardiac function. We propose that ACEIs reduce the
maximal response of a given nephron to excrete metabolic waste products by reducing its baseline GFR.
This is analogous to the effects of b-blockers that
reduce baseline heart rate and thus blunt the maximal
increase in heart rate and blood pressure during
excerise (Figure 6). Thus, by decreasing the maximal
effort of the myocardium and improving coronary
flow, it is not surprising that these drugs are associated with a reduction in cardiac mortality in secondary
prevention trials.49 When b-blocker therapy is stopped,
HR Response to
Exercise–Normal
130 GFR Response to
Protein Load–Normal
120
110
100
90
Reduced
Baseline
HR Response to
Exercise–b-Blockers
GFR Response to
Protein Load–ACEI
80
70
60
Reduced
Baseline
50
0
100
% Effect
Figure 6. Representative changes in heart rate (HR) or glomerular filtration
rate (GFR) in response to exercise or protein loading in the presence and
absence of a given angiotensin-converting enzyme inhibitor (ACEI).
heart rate and myocardial work increase. One could
argue that ACEIs in much the same way reduce the
level of baseline function of individual “functional
nephrons,” and thus preserve nephron function. The
aforementioned data from various clinical trials clearly
support this concept9,10 (Table).
Angiotensin-converting enzyme inhibitors also
affect the morphology of the heart, kidney, and vasculature over time. They are known to have antifibrogenic effects on various organs including the vasculature and thereby help to preserve organ function.50-52
Their effects are secondary to inhibition of various
cytokines including transforming growth factor b,
collagen IV, and others. 51 Thus, these agents may
provide additional protection against renal and
cardiovascular disease progression by mechanisms
independent of their blood pressure–lowering effects.
This is exemplified by restoration of endothelial function by ACEIs in the Trial on Reversing ENdothelial
Dysfunction (TREND).52
Angiotensin-converting enzyme inhibitors have a
proven benefit in delaying progression of diabetic renal
disease and are recommended by the JNC VI for use in
patients with diabetes and renal insufficiency. Moreover, data from clinical trials in both diabetic and nondiabetic renal disease demonstrate that if an elevation in
serum creatinine occurs, it stabilizes quickly and does
not progressively worsen. Moreover, this reduction in
GFR is reversible. Thus, no patient should be denied a
long-term trial of an ACEI because of a preexisting
elevation in serum creatinine level or one that increases
up to 30% above baseline and stabilizes within 2 to 3
weeks. A suggested paradigm for ACEI use in patients
with renal insufficiency is outlined in Figure 7. Note
that if chronic increases in serum creatinine level of
more than 30% following 4 or more weeks of ACEI
therapy occurs, the patient should be evaluated as suggested in Figure 7. This is especially true in patients
with more advanced renal disease. This magnitude of
reduction in renal function may interfere with other
metabolic functions of the kidney, such as vitamin D
metabolism, erythropoietin synthesis, and maintenance
of acid-base balance (Figure 4). Thus, elevations in
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ACEI Started
Check Electrolytes and
Serum Creatinine
(1-2 wk)
B Serum Creatinine Increased
<30%
No Electrolyte Issues
A Serum Creatinine
Unchanged
BP in Goal
Continue to Titrate Agent Until
BP in Goal∗
C Serum Creatinine +
Increased ≥50%
BP Not in Goal
Recheck Serum Creatinine in
2-3 wk
Continue ACEI; Add Other Agents
to Achieve BP Goal
>30% Increase in Creatinine
Level
Recheck Creatinine + Electrolytes
in 2-3 wk
Recheck Electrolytes and
Serum Creatinine (3-4 wk)
Reduce Dose of ACEI by 50%
Add Other Agents to BP Goal
If Stable, Recheck Annually;
If NSAID Started or
Hypoperfusion State Develops,
Recheck More Frequently
Recheck in 4 wk; If Stable, as
per A; If Still >30% Rise, Stop
ACEI and Achieve BP Control
With Other Agents
<30% Increase in Creatinine +
BP in Goal
Proceed as per A
<30% Increase in Creatinine +
BP∗∗
If Not in Goal–Add Other
Agents to Achieve BP Goal
Exclude Hypoperfusion States
(Volume Depletion and NSAID
Use)
Captopril Renal Scan or
Angiogram to Rule Out
Bilateral Renal Artery Stenosis
Check Serum Creatinine in
3-4 wk
If BP in Goal, Proceed as
per A, If >30% Rise See ∗∗
Figure 7. A schematic approach to a patient with renal insufficiency started on therapy with an angiotensin-converting enzyme inhibitor (ACEI). Asterisk indicates blood
pressure (BP) less than 130/85 mm Hg for those with renal insufficiency or diabetes; double asterisks, if serum creatinine level increases more than 30%, reduce ACEI
dose by 50% and add other BP-lowering agents; plus sign, if serum creatinine rise is greater than 30% and less than 50% within the first month of therapy, causes for
hypoperfusion are eliminated, and nonsteroidal anti-inflammatory drugs (NSAIDs) are not given, treat as if bilateral renal arterial disease is present.
serum phosphorus or in potassium levels above 5.6
mmol/L should prompt a reduction in ACEI dose, a
change to one with dual mode of excretion (eg, trandolapril or fosinopril), or its discontinuance. This is particularly true for patients with New York Heart Association class IV heart failure.20,53
Accepted for publication May 27, 1999.
Reprints: George Bakris, MD, Rush Presbyterian–St
Luke’s Medical Center, Department of Preventive Medicine, 1700 Van Buren St, Suite 470, Chicago, IL 60612
(e-mail: [email protected]).
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